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Alzheimer’s in Focus Evidence, Answers and Perspectives Across an Evolving Alzheimer’s Landscape

CLINICAL INSIGHTS SEPTEMBER 2026

Q&A edition

CONTRIBUTORS Maryam Tabatabai, PharmD Associate Vice President, Clinical Information Olivia Pane, PharmD, CDCES Pharmacist, Drug Information Amy Pappas, DO Physician Clinical Reviewer, Medical Affairs Andrea Henry, PharmD, MBA, BCPS Pharmacist Principal, Drug Information Stacy Berndt Graphic Designer Jessica Byerly Senior Copy Editor

Contents 1

Introduction and current state

44 Resources for caregivers

Risk factors

45 Prime’s perspective

Diagnostic considerations

46 Summary

20 Lifestyle influences

47 References

27 Treatment approaches

57 Appendices Appendix A: Commonly used herbal supplements for AD

36 The future of Alzheimer’s treatment

Appendix B: Phase 2 pipeline drugs for AD

Dedicated to the people living with Alzheimer’s disease and their loved ones

All brand names are property of their respective owners. The information contained in this publication is intended for educational purposes only and is not intended to define a standard of care, course of treatment or substitute for treatment. Prime Therapeutics LLC and/or its affiliates (collectively, “Prime”) expressly disclaim any and all liability relating to the use of, or reliance on, the information contained herein. © 2026 Prime Therapeutics LLC

Introduction and current state AD versus dementia¹,³,⁴,⁷

What is Alzheimer’s disease? The most common form of dementia, Alzheimer’s disease (AD) is a complex condition involving gradual damage to and destruction of neurons in the brain, leading to issues with memory, thinking, reasoning and language.¹-⁵ This progressive and irreversible disease is characterized by the accumulation of beta-amyloid plaques outside of neurons — which affects communication between brain cells — and abnormal tau tangles inside of neurons — which disrupts nutrient transport and causes damage to the cells. These changes can begin decades before the onset of symptoms; the damage ultimately leads to atrophy, or shrinkage, of the brain. AD symptoms typically worsen over time, with many cases progressing to dementia, or a loss of cognitive functioning to the extent that it interferes with activities of daily living (ADLs).¹-⁵ While there are several types of dementia (e.g., cerebrovascular disease, Lewy body, Parkinson’s disease), and many patients with dementia have brain changes associated with more than one type, this evidence-based paper will focus primarily on AD.²

Brain changes in AD

Did you know? Degenerative brain disease

M ost common cause of dementia (accounts for 60%–80% of cases)

Caused by cell damage that leads to complex brain changes

Healthy brain size

Shrunken brain with AD

May progress to an inability to carry out simple tasks Dementia

Dying neuron with tangles

Umbrella term describing a group of symptoms associated with a decline in memory, reasoning or other thinking skills

Dr. Alois Alzheimer AD is named after Dr. Alois Alzheimer, who encountered a 51-year-old female patient with an unusual mental illness in Frankfurt in 1901.³,⁹ For years, Dr. Alzheimer studied the patient’s symptoms, which included memory loss, language issues and unpredictable behavior. After the patient died in 1906, Dr. Alzheimer performed a brain biopsy that revealed a thinned cerebral cortex, abnormal clumps (now recognized as amyloid plaques) and tangled fibers (now coined tau tangles).

S evere enough to interfere with ADLs

Many types (e.g., AD, Lewy body, frontotemporal degeneration, vascular disease)

Healthy neuron

Plaque

AD is a costly and debilitating disease. In 2024, it was the sixth leading cause of death overall and the fifth leading cause of death in patients ≥65 years of age in the United States.1 Some studies suggest that patients ≥65 years of age survive an average of only 4–8 years after diagnosis. Further, it is projected that between $409 billion and $818 billion will be spent on AD and other dementias in the United States in 2026.¹,⁸

It is projected that between

$409 billion and $818 billion will be spent on AD and other dementias in the United States in 2026.¹,⁸

How many people are affected by Alzheimer’s disease? In 2026, it is estimated that a total of 7.4 million Americans ≥65 years of age have AD.¹ This translates to about 1 in 9 (11%) people in the United States ≥65 years of age. Given the forecasted population growth, the number of adults ≥65 years of age with AD is expected to reach 13.8 million by 2060. Although people younger than 65 years of age can also develop AD, prevalence studies are limited, with estimates suggesting that 200,000 total Americans between the ages of 30 and 64 years had youngonset dementia in 2021.¹,¹0 In the United States, the risk of AD and other dementias is highest in Hispanic and non-Hispanic Black older adults, with certain studies reporting that Black older adults are about twice as likely to have AD or other dementias as White older adults.¹ States and counties in the eastern and southeastern regions of the United States have the highest prevalence of AD, aligning with a higher population of older adults and Black and Hispanic residents in those regions.

Number of people ≥65 years of age with AD, 20261

25.7%

65–74 years of age 1.9 million (25.7%) 75–84 years of age 2.9 million (39.3%)

Total:

7.4M

85+ years of age 2.6 million (34.9%)

34.9%

*Percentages do not total 100 due to rounding. The denominator for each percentage is 7.4 million, the total number of people with AD in the United States in 2026.

Projected number of people ≥65 years of age (total and by age) in the United States (U.S.) population with AD, 2020–20601 Millions of people

65–74 years of age

75–84 years of age

11.2

12 10 8 6

12.7

85+ years of age 13.8

8.5 6.1

4 2 0 Year

39.3%

Globally, AD is the leading cause of dementia, with a rising prevalence. According to the World Health Organization (WHO), the number of people worldwide living with dementia is expected to grow from 57 million in 2021 to 152 million by 2050.¹¹,¹2 Each year, there are approximately 10 million new cases.

2020

2030

2040

2050

The AD Atlas developed by Alzheimer’s Disease International has mapped the global AD landscape and is helping to shine a light on how different countries are responding to AD by highlighting the healthcare and policy constructs shaping care for people living with dementia.¹3

Prevalence of AD in the United States and the 10 counties with the highest prevalence, 2020¹

8.8%–9.9%

10%–10.9%

11%–11.9%

12%–12.9%

3 2 4

Would you like to know how your country is responding to AD?

8 5

Learn more by visiting the interactive AD Atlas.

1. Miami-Dade County, FL (16.6%)

6. Orleans Parish, LA (15.4%)

2. Baltimore City, MD (16.6%)

7. Dougherty County, GA (15.3%)

3. Bronx County, NY (16.6%)

8. Orangeburg County, SC (15.2%)

4. Prince George’s County, MD (16.1%)

9. Imperial County, CA (15%)

5. Hinds County, MS (15.5%)

10. El Paso County, TX (15%)

2060

What are the signs and symptoms of Alzheimer’s disease?

Typical age-related changes versus signs of AD¹ Typical age-related changes

Signs of AD

Typical age-related changes

Signs of AD

While the initial symptoms of AD vary from person to person, memory loss is a key early indicator.³,⁵ Those with early AD may have trouble remembering new information, in particular, because the part of the brain associated with learning, the hippocampus, is often the first to be impacted.⁷,¹⁴ Patients experiencing memory loss may repeat statements or questions; forget appointments, events or conversations; misplace items; get lost in familiar places; or forget the names of family members and everyday objects. For some, decline in nonmemory aspects of cognition like word finding, judgment/ reasoning or visual/spatial awareness indicates early-stage AD.³

Occasionally forgetting names or appointments but remembering them later

Memory loss that disrupts daily life

Occasionally having trouble finding the right word

New problems with words in speaking and writing • Having trouble following or joining a conversation • Stopping in the middle of a conversation and being unable to continue • Struggling with vocabulary • Having trouble naming familiar objects or using the wrong name

Misplacing items from time to time and retracing steps to find them

Misplacing items and losing the ability to retrace steps • Placing items in unusual places • Losing items and being unable to retrace steps to find them • Accusing others of stealing

Making poor decisions or mistakes occasionally

Decreased or poor judgment • Demonstrating changes in judgment or decision-making • Showing poor judgment when dealing with money • Paying less attention to grooming and personal hygiene

Occasionally becoming disinterested in family and social obligations

Withdrawal from work or social activities • Withdrawing from hobbies, social activities or other engagements • Having trouble keeping up with favorite sports teams or activities

Developing specific routines and becoming irritable when routines are disrupted

Changes in mood, personality and behavior • Becoming confused, suspicious, depressed, fearful or anxious • Becoming easily upset at home, at work, with friends or when outside of typical comfort zones

Despite the devastating memory loss associated with AD, many patients can maintain certain skills even as symptoms worsen.⁵ These “preserved” skills may include reading, storytelling, sharing memories, singing, listening to music, dancing, drawing and crafting. It is thought that patients retain these skills because the areas of the brain that manage them are not affected until the latest stages of AD.

• Forgetting recently learned information (one of the most common signs of early AD) • Repeatedly asking the same questions • Increasingly relying on memory aids (e.g., reminder notes, electronic devices) or family members

Occasionally making errors when managing finances or bills

Problems planning or problem-solving • Experiencing changes in ability to develop and follow a plan or work with numbers • Having trouble following familiar recipes or keeping track of monthly bills • Having difficulty concentrating

Intermittently needing help to use microwave settings or to record a television show

Trouble completing familiar tasks

Getting confused about the days of the week but figuring it out later

Confusion with time or place

• Having trouble driving to a familiar location, organizing a grocery list or remembering the rules of a favorite game

• Losing track of dates, seasons and the passage of time • Having trouble understanding things that are not happening immediately • Forgetting one’s current location

Experiencing vision changes related to cataracts

Difficulty understanding visual images and spatial relationsh ips • Experiencing vision problems • Having problems judging distance and determining color and contrast (leading to issues with driving)

Risk factors for dementia, 2024 update²0

Risk factors

What causes Alzheimer's disease, and who is at risk? There is no single cause of AD; rather, a variety of nonmodifiable and modifiable risk factors may contribute to its development.1 Nonmodifiable risk factors Age: The most well-recognized, nonmodifiable risk factor for AD is older age, with risk doubling every five years after age 65 and reaching nearly one-third after age 85.¹,⁴,¹⁵ Notably, although age increases risk, it is not a direct cause of the disease. Genes: Results from family studies show that genetic factors may have an impact on at least 80% of AD cases, with one of the most prominent being variants in the apolipoprotein E gene APOE ε4.² However, while about 25% of the population carries a copy of APOE ε4, inheriting this gene does not automatically cause a person to develop AD.¹⁶ Other genes that have been linked to higher AD risk include amyloid beta precursor protein (APP), presenilin-1 (PSEN1) and presenilin-2 (PSEN2).³ Notably, patients

Early life

with Down syndrome are at higher risk of developing AD because they have an extra chromosome 21 that carries the APP gene. Gender also plays a role, with about two-thirds of AD cases in the United States being female.² While the exact mechanism behind sex differences is unknown, certain evidence suggests that sex hormones and chromosomes may interact with disease mechanisms during aging, resulting in differences in disease progression between women and men.¹⁷ Family history: Those who have a parent or sibling with AD are also at higher risk, suggesting that family history is a risk factor of significance.¹ Risk increases even further if multiple family members have AD. Modifiable risk factors Numerous modifiable risk factors may contribute to the development of AD, such as poor diet (including increased consumption of ultra-processed foods), physical inactivity, alcohol use, low education, inadequate cognitive/ social engagement, hypertension, poor cardiovascular health, inadequate sleep,

sensory loss, diabetes, smoking, unfavorable social environments, air pollution and traumatic brain injury.¹,²,⁵,¹⁸ The WHO released the second edition of its guideline on risk reduction of cognitive decline and dementia in July 2026, which expands on evidence and recommendations from the prior 2019 edition and emphasizes the importance of addressing modifiable risk factors.¹⁸ Consistent with WHO recommendations, the 2024 update from The Lancet Standing Commission on Dementia Prevention, Intervention, and Care identifies 14 modifiable risk factors that may collectively account for approximately 45% of dementia cases worldwide.²0 As the following figure illustrates, these risk factors span all stages of life and highlight the broad range of opportunities for dementia risk reduction through behavioral, social, environmental and health-related interventions. While each identified factor may contribute independently to dementia risk, many are interrelated and may act through overlapping biological and social mechanisms. Understanding these factors and their relationships to one another may help inform individual and public health strategies aimed at reducing risk.

Less education

Percentage reduction in cases of dementia if this risk factor is eliminated

Midlife

Hearing loss

High LDL cholesterol

Depression

Traumatic brain injury

Social isolation

Physical inactivity

Air pollution

Diabetes

Visual loss

Smoking

Hypertension

Obesity

Excessive alcohol

(New for 2024)

Late life

(New for 2024)

45%

Potentially modifiable

Risk factor spotlight The list of modifiable risk factors for AD is extensive and continues to evolve. While a deep dive into each factor is outside of the scope of this paper, the following section examines hearing loss, sleep and air pollution in greater detail because of their fascinating potential links to AD. Hearing loss: Interestingly, data from both clinical and epidemiological studies have shown that hearing loss is a risk factor for the development of dementia.²¹ In fact, findings from a recent cross-sectional analysis showed that the prevalence of clinically significant hearing loss was 79.4% in patients with dementia and increased to 94.2% in those with dementia who were ≥85 years of age.²² An exact mechanism to explain the relationship between hearing loss and AD is not yet known, but animal studies have found that hearing loss may promote AD via the growth differentiation factor 1 (GDF1) pathway.²¹ The 2026 WHO guidelines recommend hearing aids be offered to adults with hearing loss to reduce the risk of cognitive decline and/ or dementia (strength of recommendation, conditional; certainty of evidence, low).¹⁹ Sleep: Although sleep is not included in the list of modifiable risk factors for dementia published in The Lancet, it is recognized by the

Alzheimer’s Association as a modifiable risk factor for AD.¹ On one hand, changes in sleeping habits may be one of the symptoms of patients with AD, as brain pathology changes occur and increased levels of beta-amyloid and tau may interrupt the sleep-wake cycle.¹,²³,²⁴ On the other hand, research has shown that poor sleep patterns, such as trouble falling asleep or staying asleep, are linked to an increased risk of AD. During sleep, the body removes toxic beta-amyloid and other substances.²⁵ Inadequate or poor sleep may compromise the brain’s ability to remove beta-amyloid and other toxins, enabling levels of toxins to remain elevated. Obstructive sleep apnea may also increase the risk of dementia, potentially by interfering with blood flow to the brain and the normal patterns of brain activity that support memory and attention. This dynamic has led some researchers to view the relationship between sleep and AD as bidirectional.²⁶,²⁷ The 2026 WHO guidelines recognize that sleep disturbances are associated with cognitive decline; however, they note that current evidence is “insufficient” to recommend interventions to treat certain sleep-wake disorders or to improve sleep quality/duration with the aim of reducing the risk of cognitive decline/dementia.¹⁹ Moreover, studies have primarily focused on cognitive outcomes, not dementia or the incidence of mild cognitive impairment (MCI).

The age-adjusted prevalence of adults experiencing insufficient sleep is

36.8% The rate ranges by state, with Vermont at 33.4% and Hawaii at 45.9% .²⁸,²⁹

Rigorous long-term studies are needed to better understand the relationship between sleep and AD.

Did you know?

Blood sugar The relationship between poorly controlled blood sugar and an increased risk of AD is so compelling that some refer to AD as “diabetes of the brain” or “type 3 diabetes.”30 While these terms are not widely accepted by medical professionals and organizations, it is well-established that patients who have type 2 diabetes mellitus (T2DM) are at higher risk for AD, and concomitant diabetes seems to accelerate AD disease progression. 31 Given that T2DM is a modifiable risk factor, this provides an opportunity for practitioners to collaborate with their patients to ensure adequate glycemic control and to screen for early stages of AD.

Air pollution: The 2026 WHO guidelines recommend reducing exposure to household and ambient air pollution (especially fine particulate matter 2.5, or PM2.5) because it may lower the risk or incidence of cognitive decline and/or dementia (strength of recommendation, conditional; certainty of evidence, very low).¹⁹ The studies have been observational in nature; therefore, causality cannot be established. A nationwide cohort study from Emory University examined approximately 27.8 million U.S. Medicare beneficiaries ≥65 years of age from 2000 to 2018.32 It found that a five-year higher exposure to air pollution at PM2.5 prior to AD onset was associated with an increased risk of AD in the overall population (hazard ratio [HR] per interquartile range [IQR, 3.8 mcg/m3] increase: 1.085 [95% confidence interval (CI), 1.078–1.091]), largely independent of comorbid conditions such as hypertension and depression; although, this association was slightly higher (4.2%) in individuals with stroke. While the mechanism of increased risk of AD is unknown, neuroinflammation and oxidative stress have been theorized.33,34 While the nationwide cohort study finding cannot show cause and effect, it adds to the emerging body of research from prior studies suggesting air pollution as a risk factor for AD.

RESEARCH SPOTLIGHT In a cross-sectional study published in JAMA Neurology in 2022, investigators assessed the estimated proportion of AD and related dementia (ADRD) cases in the United States that were associated with modifiable risk factors.³⁵ Using U.S. Behavioral Risk Factor Surveillance Survey data from January 2018 to December 2018, the study analyzed 378,615 noninstitutionalized adults, 48.7% of whom were male and 21.1% of whom were ≥65 years of age. Findings showed that more than 1 in 3 ADRD cases (36.9%) was associated with eight modifiable risk factors, including physical inactivity, depression, smoking, low education, diabetes, hearing loss, midlife obesity and midlife hypertension. The authors found that midlife obesity (17.7%), physical inactivity (11.8%) and low education (11.7%) were associated with the largest proportion of ADRD cases.

Are certain medications linked to the development of Alzheimer’s disease? Opioids, gabapentin, antidepressants, proton pump inhibitors (PPIs), benzodiazepines, sleep medications and anticholinergic drugs have all been associated with AD, but causality remains unclear. The Beers list is a set of criteria developed to assist clinicians with appropriate prescribing for adults >65 years of age. The American Geriatrics Society (AGS) updates these guidelines every few years, providing the rationale for use.³⁶ The goal of this list is to assess the risk of prescribing certain types of medications in this age group, not just regarding dementia. According to the Beers list, among drugs with anticholinergic properties, dementia risk is pronounced with the usage of anti-Parkinson’s, urological and antidepressant medications. Other examples of anticholinergic medications include diphenhydramine, some PPIs, antihistamines, and medications used for gastrointestinal (GI) symptoms (e.g., prochlorperazine, promethazine) and vertigo (e.g., meclizine). Anticholinergic drugs can impair cognitive function by reducing acetylcholine neurotransmission and by speeding up neurodegeneration

via inhibition of an acetylcholinedependent, anti-inflammatory system.³⁷ While long-term use of anticholinergic medication is approached cautiously in clinical practice, no study results have supported the connection between an anticholinergic mechanism and increased risk of dementia, and the risk versus the benefit of therapy should always be considered. Antidepressants with strong anticholinergic activity, including tricyclic antidepressants (e.g., amitriptyline, amoxapine) and the selective serotonin reuptake inhibitor (SSRI) paroxetine, generally should be avoided in adults >65 years of age due to risk of confusion and other anticholinergic effects.³⁶,³⁷ Antihistamines with high anticholinergic burden (e.g., chlorpheniramine, diphenhydramine, doxylamine, hydroxyzine) are often metabolized slowly with increasing age and accumulate in the body, leading to intensified side effects. Across all ethnicities, long-term use of anticholinergic medications poses an increased risk of AD. In general, all benzodiazepines increase the risk of cognitive impairment in older adults.³⁶,³⁷ Some studies suggest that older adults using benzodiazepines for an extended period may have a 50% increased risk of AD.

use and dementia across dosage levels, age groups or sex categories.³⁹ A metaanalysis of five observational studies found modestly higher estimated odds of AD with gabapentin use; however, because of bias risk and between-study heterogeneity, causality could not be inferred, and the findings did not establish that gabapentin causes dementia.⁴0

Nonbenzodiazepine benzodiazepine receptor agonists, commonly known as “Z-drugs,” are often used for sleep and can cause adverse effects like those seen with benzodiazepines in older adults.³⁶ Common examples like zolpidem, zaleplon and eszopiclone may cause confusion and should not be used regularly. They bind to gamma-aminobutyric acid (GABA)-A receptors in the brain and, with regular use, can contribute to cognitive and/or motor impairment. Limited studies have evaluated whether gabapentin contributes to dementia or AD. A retrospective study suggested that patients using gabapentin long-term were more likely to develop AD, though polypharmacy may have contributed to this association.³⁸ In contrast, another retrospective analysis of more than 200,000 patients ≥50 years of age found no association between long-term gabapentin

Chronic opioid use has been associated with dementia risk over time.³⁷ Opioids may alter neurotransmitter levels and reduce neurogenesis, which could contribute to cognitive effects over time. Populationbased studies of chronic opioid use in adults ≥65 years of age have shown mixed results, with some suggesting a trend toward increased AD risk. PPIs are commonly used to treat GI issues, such as gastroesophageal reflux disease (GERD). Data from studies regarding the development of AD from long-term PPI use are mixed and do not clearly substantiate a link between the two.³⁷ Long-term PPI use can cause vitamin B12 deficiency, a reversible cause of dementia, but there is no clear link to the development of AD from PPI usage. Prolonged use of PPIs may cause dysfunction to the cholinergic system, leading to cholinergic burden in the brain, but this has not been definitively determined.⁴¹ One study showed that use of PPIs for longer than 4.4 years by individuals ≥45 years of age was associated

with a 38% risk of developing dementia later in life; however, at a 5.5-year follow-up, there was no significant association.⁴² One meta-analysis of observational studies showed that long-term statin use decreases the risk of dementia.³⁷ While there was some initial concern that statins cause AD, statins actually decrease neuroinflammation and exert a “neuroprotective” effect on the brain. Some studies have even shown that statins may lower the risk of AD development. One cohort study of more than 15,000 patients showed a doseresponse effect regarding statin use to objective improvement in memory. Use of statins for three years (on average) showed an approximate one-point increase on Mini-Mental Status Examination (MMSE) testing in patients treated with statins compared with untreated patients.⁴³ The largest meta-analysis of statins and dementia risk was published in 2025 and included 55 observational studies, comprising data from more than 7 million patients.⁴⁴ The main finding was that statin use reduced the risk of AD, and the increased neuroprotective effect correlated to longer duration of use. In this analysis, rosuvastatin showed the greatest risk reduction for AD development. A 2023 American Heart Association scientific statement concluded that there is no strong evidence that statins adversely affect cognition.⁴⁵

Did you know?

Statins and PPIs Statins and PPIs are not clearly linked to dementia.³⁷ For a drug to exert effects on the brain, it needs to cross the blood-brain barrier. Due to the level of permeability, variable effects are seen on the brain in long-term treatment with statins and PPIs (both positive and negative).

Myth or fact: Are these commonly debated Alzheimer’s disease potential risk factors supported by evidence-based research? Aluminum: Concern for aluminum exposure as a risk factor for AD began in the 1960s, when a study was published that found neurofibrillary tangles in the brains of animals exposed to very high levels of aluminum.¹⁵,⁴⁶ Subsequently, the safety of everyday items like cookware, foil, antacids, antiperspirants and beverage cans fell into question. Aluminum may cause neurotoxicity due to its ability to penetrate the blood-brain barrier, leading to accumulation in the frontal cortex and hippocampus and causing inflammation and damage in these areas, which are primarily responsible for executive functioning, mood, and memory development and storage.⁴⁷ Although aluminum has been linked to other

neurological disorders, study results in humans are mixed, and researchers have not found a definitive link between aluminum exposure and AD. For example, a meta-analysis and systematic review published in 2018 found that patients with AD had higher levels of aluminum than controls, while a 2021 cohort study found no association between exposure to aluminum in drinking water and risk of AD.⁴⁸,⁴⁹ A 2025 metaanalysis suggested a strong association between aluminum exposure and development of AD; however, out of the 54 studies included in the analysis, only four met inclusion criteria, and evidence was insufficient to explain aluminum’s role in AD development.⁴⁷ Further research is needed to determine whether aluminum exposure increases AD risk and at what level of exposure. Estrogen: Given that women have a higher prevalence of AD than men, the relationship between estrogen — particularly hormone replacement therapy (HRT) — and AD has been called into question.⁵0 Results from a 2025 metaanalysis found that women who received estrogen therapy at ≥65 years of age were at higher risk of dementia, while women who received early initiation of

estrogen therapy (near menopause) were at lower risk, suggesting that timing of estrogen therapy may affect risk of AD.⁵¹ Additional studies support the notion that midlife (generally defined as within five years of menopause) estrogen-only therapy may be protective and has been associated with a 30%–44% lower risk of developing AD, while combination therapy with estrogen and progesterone could increase risk.52,53 An updated metaanalysis published in The Lancet in 2025 found no evidence that hormone use later in life is linked to AD, with either positive or negative effects.54 The WHO recommends against use of HRT for the purpose of reducing risk of cognitive decline and/or dementia in postmenopausal women ≥65 years of age, and states that evidence is insufficient to recommend for or against HRT to reduce dementia in women <65 years of age.19 The jury is still out on the potential risks and benefits of HRT when it comes to AD risk.

Gut microbiome: The gut microbiome has gained recent attention for its role in maintaining overall health and reducing inflammation.55 Since AD may be a result of brain inflammation, the connection between AD and the gut microbiome is under exploration. Current research does, in fact, show that dysbiosis in the gut microbiome is linked to pathophysiologic changes of AD, which may be mediated by the “microbiota-gut-brain” axis.56 Abnormalities in the gut microbiome have been observed throughout the entire clinical spectrum of AD, which suggests that the gut microbiome may even eventually serve as a useful biomarker of AD. One systematic meta-analysis of 11 studies and 805 individuals with AD showed an increased amount of Proteobacteria, Bifidobacterium and Phascolarctobacterium and a decreased amount of Firmicutes, Clostridiaceae, Lachnospiraceae and Rikenellaceae compared to controls.57 Individuals with MCI or normal cognition showed no difference in gut concentrations of these bacteria.

For several microbiota (e.g., Proteobacteria, Phascolarctobacterium, Clostridiaceae), altered microbial abundance was found to scale in unison with progression from normal cognition to MCI to AD. Further, cerebrospinal fluid (CSF) levels of the gut metabolite trimethylamine N-oxide (TMAO) have been found to be elevated in individuals with AD and correlate with CSF markers of amyloid pathology, tau pathology and neurodegeneration. The potential connection between the gut microbiome and AD may open the door for future dietary interventions and novel therapeutic approaches to target the gut microbiome.58

Diagnostic flow

Diagnostic considerations

How is Alzheimer’s disease currently diagnosed? AD has seven clinical stages, with decline reflected in memory and ADLs.1

Memory concerns

Clinical/Neurologic evaluation and ruling out other causes

Cognitive screening

Imaging and/or biomarker testing, when appropriate

Clinical interpretation

Clinical stages of AD1 Stage

Description

Stage 0

Presymptomatic; deterministic gene carrier, normal biomarkers

Stage 1

Asymptomatic; biomarkers show beta-amyloid and tau changes

Stage 2

Transitional decline; cognitive testing may detect subtle changes within normal limits, may be accompanied by subjective memory concerns, independence is preserved

Stage 3

MCI; testing shows decline, basic ADLs intact but complex activities pose difficulty

Stage 4

Dementia; mild impairment in instrumental ADLs, basic ADLs remain intact

Stage 5

Moderate dementia; progressive cognitive decline with moderate functional impairment, help with ADLs required

Stage 6

Severe dementia; progressive cognitive and functional impairment, complete dependence on help with basic ADLs

AD cannot be diagnosed based on a single symptom or test.1 Patients with memory impairment should be evaluated by a primary care physician and a neurologist, when appropriate, to assess reversible causes. Vitamin B12 or folate deficiency, thyroid dysfunction, depression, chronic pain, poor sleep or untreated sleep apnea; medication effects or polypharmacy; and hearing loss can all mimic AD, and memory loss may improve by treating these underlying conditions.1,59 A standard memory evaluation often includes brain imaging, with magnetic resonance imaging (MRI) preferred over computed tomography (CT) because it provides greater detail and can help rule out other treatable causes of cognitive decline. 2,5 A detailed medical and behavioral history should also be obtained. The neurologic examination assesses strength, speech,

memory, balance, coordination, sensation, reflexes and cranial nerve function, including vision, hearing and facial movement or sensation. Cognitive screening may also be performed. Abnormal results can document baseline impairment but do not identify the underlying cause. Common tools include the Mini-Mental State Examination (MMSE) and Montreal Cognitive Assessment (MoCA), which provide objective measures for tracking change over time.60 These tests can detect deficits in memory and judgment but cannot determine the specific cause. Other tools, such as the Clinical Dementia Rating Sum of Boxes (CDR-SB), provide subjective patient or caregiver assessment across functional domains, including memory, orientation, judgment

and problem-solving; community affairs, home and hobbies; and personal care. Although these tools are not used alone to stage dementia, they can help monitor functional change over time. Additional cognitive testing may include a comprehensive neuropsychological evaluation, performed by a neuropsychologist, to identify patterns consistent with the suspected clinical diagnosis.1,60,61 This testing is typically used for mild or unclear cases, atypical presentations or early-onset disease. If cognitive testing confirms mild memory impairment and the evaluation excludes other causes, next steps may include additional testing, such as positron emission tomography (PET) imaging, CSF assessment and/or serum biomarkers for AD-specific pathology.

In appropriate clinical circumstances, PET imaging can support an AD diagnosis.62 PET scans are not routinely performed; therefore, the frequency of positive amyloid PET findings in individuals without memory impairment is unknown. Amyloid PET may show elevated amyloid deposition years before cognitive changes develop. Amyloid burden can be quantified using centiloid values, although how these values predict progression and the rate of decline remains unclear.63 One retrospective longitudinal study performed by the Mayo Clinic showed that lifetime and 10-year absolute risk of MCI and dementia increased continuously with increasing centiloid values for all sex-apolipoprotein E (APOE) combinations.64 Of all predictors evaluated, the amyloid PET centiloid value was the strongest predictor for lifetime risk of both MCI and dementia, providing a direct correlation with PET scan results and disease severity. While not currently utilized in clinical practice as a predictor of dementia, this study supports the use of screening cognitively normal patients with PET scans prior to development of AD symptoms to quantify risk. Three types of PET scans may be used in the dementia work-up.1,65,66 An amyloid PET evaluates the amount and distribution of amyloid deposition in the brain. A fluorodeoxyglucose (FDG)-PET assesses cerebral glucose metabolism. While an

FDG-PET can help clarify other dementia types, an amyloid PET is now considered one of the most accurate diagnostic tools for AD. A tau PET is less commonly utilized due to the development of the amyloid PET, as the amyloid PET can detect disease states earlier than the tau PET. Brain glucose metabolism may begin declining up to 18 years before expected symptom onset, and brain atrophy may begin up to 13 years before symptom onset.1 Glucose metabolism and brain atrophy are not routinely used to establish an AD diagnosis, but they may provide supportive evidence in the appropriate clinical context. Brain atrophy can be assessed with structural MRI, although this is not routinely used in clinical practice.1,65,66 Amyloid PET is a more sensitive measure for AD because it quantifies amyloid deposition in the brain. Appropriateuse criteria recommend amyloid PET when the diagnosis remains uncertain after comprehensive evaluation by a dementia specialist, when AD is a diagnostic consideration, and when candidacy for amyloid-lowering therapy is being assessed.

Did you know?

Genetic testing Genetic testing is not routinely indicated or recommended for patients with AD and should be performed only with genetic counseling.1 APOE ε4 testing is primarily used to assess treatmentrelated risks with monoclonal antibody therapies, as individuals with this allele have a higher risk of treatment-related adverse effects.67 Testing for early-onset AD genes should be considered carefully because of the implications of a positive result.1 Risk assessment and familypedigree review can help determine whether family history is consistent with early-onset disease and whether testing for an autosomal-dominant mutation is appropriate. Genetic specialists can help estimate risk and provide counseling. Although genetic testing is accurate, interpreting results can be complex. Because approximately 20 genes are involved in AD development, there is no single definitive genetic diagnosis. The Huntington Disease Society of America’s Guidelines for Genetic Testing for Huntington Disease are widely regarded as a gold standard for adultonset genetic testing and may serve as a framework for determining when testing is appropriate for AD and how results should be interpreted.68

What is the role of bloodbased biomarker testing in the diagnosis of Alzheimer’s disease? Biomarkers are biological changes that can be measured to indicate the presence or absence of a disease or the risk of developing symptoms from a disease.1 Biomarkers for AD can be found in serum (blood) or CSF, and while they are not currently used to predict clinical disease, they may assume this role in the future. Studies suggest that beta-amyloid, serum neurofilament light chain (NfL) and CSF tau may begin increasing approximately 20 years before clinical dementia symptoms develop. Levels of beta-amyloid and tau in the blood and spinal fluid can be used to measure whether a patient is at risk of developing AD.1 CSF testing is the most invasive biomarker assessment because it requires a lumbar puncture. The test measures tau and beta-amyloid levels, and the resulting pattern of abnormalities can be used to quantify disease.69 Over the last year, NfL in both serum and CSF commercial testing has been made available; notably, this test can be elevated in many different neurological diseases and is not specific to AD.

In 2025, serum biomarkers became commercially available for use in identifying AD.70,71 Serum biomarkers are less invasive than CSF analysis and have shown promising diagnostic performance. These markers are cleared by the Food and Drug Administration (FDA) and include the Lumipulse G pTau217/β-Amyloid 1-42 Plasma Ratio and the Elecsys pTau181 Plasma Test. As of August 2026, the Elecsys pTau217 has also been approved for use.72 The Lumipulse pTau217 measures the phosphorylated tau (p-tau)217 to beta-amyloid 1:42 ratio and is used for early detection of amyloid plaques in individuals ≥50 years of age with signs and symptoms of the disease. The Elecsys pTau181 test measures the amount of p-tau protein in the blood and can be used for individuals ≥55 years of age with signs and symptoms to determine the brain changes associated with AD. While the intended use of the pTau181 test is to rule out the disease, the newly approved Elecsys pTau217 demonstrates a high agreement with amyloid PET imaging and may provide a minimally invasive option for ruling in AD. One head-to-head comparison of Lumipulse pTau217 and Elecsys pTau217 found that the Elecsys plasma pTau217 showed high discriminative performance for AD versus non-AD (area under the curve [AUC], 0.93), comparable to

Lumipulse pTau217 (AUC, 0.95; P=0.485).73 Elecsys pTau181 performed lower than Elecsys pTau217. Elecsys pTau217 had high diagnostic accuracy for AD, with higher levels correlated with lower baseline MoCA, and a trend toward faster MoCA decline. Head-to-head studies have shown that p-tau217 is the most accurate assessment of tau and amyloid status.74 Major laboratory companies are starting to offer consumer-based screening tests, including the AD-Detect, which is a serum test that screens for levels of amyloid beta (Aβ)42 and Aβ40.75 It is noted, however, in updated appropriate-use criteria for diagnostic testing published by the Alzheimer’s Association in 2025 that the robustness of plasma Aβ42/Aβ40 at the individual patient level may be suboptimal for clinical use.66 Updated diagnostic criteria published by the Alzheimer’s Association in 2024 proposed that the following can be diagnostic of AD: amyloid PET, CSF Aβ42/40, CSF p-tau181/Aβ42 and CSF t-tau/Aβ42.65 Phosphorylated mid-region tau variants (p-tau217, p-tau181 and p-tau231) become abnormal around the same time as amyloid PET and well before tau PET. CSF or plasma p-tau217 are more robust for diagnosis than Aβ42/40 assays. In addition, there are studies currently attempting to validate the use

• Marker of neurodegenerative disease, not specific to AD

p-tau217

• Serum or CSF • Most sensitive serum test for AD • Used for early detection in patients >50 years of age • Can be used for diagnosis and to assess disease progression over time

Current recommendations from the Alzheimer’s Association state that blood biomarker tests with

>90% sensitivity

CED

ST R ES

S A N D I N FL A M

MAT

Dyslipidemia

ION

Poor sleep ER

D EC

Hypertension

TI A

U RO PATH O LO GY

AG E

Potential to reduce dementia risk

Traumatic brain injury

Vision impairment

• In combination with p-tau217, improves sensitivity for low amyloid levels

• Cannot be used alone to diagnose

Harmful alcohol use

AM RD

• More convenient; now available for direct consumer use

Diabetes

• Serum

Air pollution

HIV

Aβ42/40 ratio

How treating modifiable risk factors may prevent or delay dementia19

can be used as triaging tests, and markers with >90% sensitivity and specificity can substitute for amyloid PET or CSF markers in the appropriate clinical context.74

• Used for detection in patients >55 years of age

Lifestyle modifications are an important component of AD management and should be considered a first-line approach for managing the behavioral and psychological symptoms of dementia.1 While these interventions cannot target the underlying biology of AD nor cure the disease, they play a key role in maintaining or improving cognitive and functional health, overall quality of life and the ability to perform ADLs.

S VA

>75% specificity

• Plasma

Lifestyle influences

p-tau181

• Serum or CSF

NfL

Since the validation and availability of less-invasive serum biomarker testing, CSF evaluation may be reserved for individuals with borderline markers that need improved diagnostic clarification of disease.

Notes

Biomarker

TI V

Blood-based biomarker tests

CO G N I

of microtubule binding region (MTBR)-tau 243 and p-tau217 as staging tools for disease, when compared against a PET-based staging system.76

Hearing loss

Early/Premature menopause

• CSF • Can be used to diagnose AD Social isolation

Obesity

Physical inactivity

Cognitive inactivity Depression

Unhealthy diet Stroke

Smoking

What is the role of diet and nutrition in the prevention and treatment of cognitive decline? Numerous studies have found an association between following a healthy diet during mid- and/or late life and a lower risk of dementia.1 While the mechanism by which nutrition affects the brain is still under investigation, it is thought that certain eating patterns may increase nutrients that offer brain protection through anti-inflammatory and antioxidant properties.77

A healthy diet may also play a more indirect role by affecting major risk factors for AD — such as diabetes, obesity and heart disease — and contributing to the makeup of the gut microbiome.77,78 Two dietary patterns with substantial, though mixed, evidence for cognitive health benefits are the Mediterranean diet and a hybrid of the Mediterranean diet and the Dietary Approaches to Stop Hypertension (DASH) diet, coined the Mediterranean-DASH Intervention for Neurodegenerative Delay (MIND) diet.77 Data suggest that adherence to these diets may result in slower rates of cognitive decline with age and better

Features of the Mediterranean and MIND diets77,81 Mediterranean diet

MIND diet

• Vegetables

• Vegetables (particularly leafy greens)

• Fruits

• Fruits (particularly berries)

• Whole grains

• Legumes

• Beans

• Fish and other seafood (≥3 servings per week)

• Nuts

• Unsaturated fats (e.g., olive oil) • Limits red meat, eggs and sweets

cognitive function. 2,5,79 For instance, in a study published in Neurology in 2023, participants who donated their brains to be autopsied after death were asked to score their adherence to the Mediterranean or MIND diet, and those who had higher diet scores showed less postmortem AD pathology, including lower levels of amyloid plaques. 80,81 It is important to note that, while much of the evidence points to beneficial

• Fish (≥1 serving per week) • Olive oil • Limits red meat, sweets, cheese, butter/ margarine and fast/fried food

effects of these diets in AD, not all studies have had positive results, and more research is warranted.77,82 Other notable dietary patterns with promising evidence of benefit in AD include modified Mediterranean ketogenic diets and plantbased diets. 2,83 While preference for certain dietary patterns is highly patient-specific, preliminary guidance published in

Neurobiology of Aging offers more general dietary recommendations for prevention of AD.84 The guidance suggests minimizing intake of saturated fats and trans fats; incorporating vegetables, legumes, fruits and whole grains as primary staples in the diet; obtaining adequate dietary vitamin E through sources such as seeds, nuts, leafy greens and whole grains; and achieving the recommended daily allowance of vitamin B12 through fortified foods or supplements.

What other lifestyle modifications can be beneficial for the prevention and treatment of Alzheimer’s disease? Perhaps one of the most impactful lifestyle modifications when it comes to the prevention and treatment of AD is physical activity.85–88 It is postulated that exercise may improve neuroplasticity and neurotrophic factor production while offering indirect benefits to the brain by improving cardiovascular health and immune function.19 There is even evidence to suggest that those who perform frequent, moderate-to-vigorous-intensity exercise have larger brain volumes than those who exercise less often.89 A review published in 2023 found strong evidence of a protective effect against AD when participants met general WHO recommendations for physical activity

(150–300 minutes of moderate-intensity or 75–150 minutes of vigorous-intensity aerobic activity per week and musclestrengthening activities ≥2 days per week), though the dose-response association requires further evaluation.85 A systematic review and meta-analysis published in 2022 found that physical activity was associated with a 20% decreased risk of all-cause dementia and a 14% decreased risk of AD, and the lower risk was observed regardless of baseline age or length of follow-up.86 Combining physical activity with a healthy diet and other lifestyle modifications may lead to a markedly lower risk of developing AD.90,91 In an observational study published in Neurology in 2020, data from more than 2,700 participants found that those who implemented 4–5 specified healthy behaviors had a 60% lower risk of AD compared with those who followed 0–1, while those that followed 2–3 healthy behaviors had a 37% lower risk. The healthy behaviors in the study were: 1) participating in at least 150 minutes per week of moderate-to-vigorous-intensity physical activity, 2) eating according to the MIND diet, 3) refraining from smoking, 4) limiting use of alcohol and 5) engaging in late-life cognitive activities. These results highlight just how impactful lifestyle modifications can be for brain health, particularly when combined.

Several additional lifestyle tools can be incorporated into the care plan of a person living with AD. Intentional reminiscence through photos, keepsakes, music, and familiar scents and places can bring back pleasant memories while sparking joy and connection.92 For a more structured approach, a trained professional can conduct reminiscence therapy sessions, which typically involve guided conversations about the past and include music, art, storytelling or familiar objects. Patients with AD may also benefit from recreationally listening to music, as it may reduce agitation and improve common behavioral issues while providing a means of expression when verbal communication becomes difficult.93 Other helpful interventions that can be considered include pet companion and light therapies.94,95 The table on the following page summarizes key lifestyle recommendations from the 2026 WHO guidelines. Of note, the Alzheimer’s Association is also planning to release guidelines on the prevention of AD and other dementias, with a publication date yet to be determined.96

WHO 2026 guideline recommendations for reducing the risk of cognitive decline and dementia19 Intervention Physical activity

Description

WHO recommendation

Strength of evidence

Aerobic movement and muscle strengthening activities; reduction of sedentary behavior

To specifically reduce the risk of cognitive decline, physical activity should be recommended to adults with normal cognition.

Strength of recommendation: strong

Description

WHO recommendation

Strength of evidence

Social activity

Participation in activities to promote social connection

To specifically reduce the risk of cognitive decline and dementia, engagement in social activity may be recommended to adults with normal cognition or MCI.

Strength of recommendation: conditional

Sleep

Sufficient hours of uninterrupted, deep and restorative sleep

To specifically reduce the risk of cognitive decline and dementia, there is currently insufficient evidence to recommend interventions to improve sleep (quality or duration).

Insufficient evidence

Certainty of evidence: moderate

To specifically reduce the risk of cognitive decline, physical activity may be recommended to adults with MCI.

Strength of recommendation: conditional Certainty of evidence: low

Tobacco use cessation

Evidence-based behavioral and pharmacological cessation interventions; protection from tobacco smoke

To specifically reduce the risk of cognitive decline and dementia, tobacco cessation support should be offered to adults who use tobacco.

Strength of recommendation: strong

Alcohol use reduction

Reduction or cessation of harmful consumption of alcohol

To specifically reduce the risk of cognitive decline and dementia, interventions aimed at reducing or eliminating hazardous and harmful alcohol use (including alcohol dependence) may be offered to adults with normal cognition or MCI.

Strength of recommendation: conditional

Diet providing sufficient essential nutrients to prevent deficiencies and promote health; balanced intake from diverse sources; minimal intake of foods associated with detrimental health effects

To specifically reduce the risk of cognitive decline and dementia, a healthy, balanced dietary pattern may be recommended to adults with normal cognition or MCI.

Strength of recommendation: conditional

Cognitive training involving targeted and repetitive cognitive exercises or tasks that stimulate specific cognitive domains

To specifically reduce the risk of cognitive decline and dementia, cognitive training may be offered to older adults with normal cognition or MCI.

Strength of recommendation: conditional

interventions focused on physical activity, healthy diet, cognitive activity,

Certainty of evidence: low

social engagement and heart-health monitoring. Those in the structured

Cognitive stimulation involving structured activities or programs in a group or social setting, within a set amount of time; everyday activities that enhance general cognitive function (e.g., reading, storytelling, playing games)

To specifically reduce the risk of cognitive decline and dementia, engagement in cognitive stimulation may be encouraged.

Strength of recommendation: conditional

Healthy, balanced diet and nutrition

Cognitive activity

Intervention

U.S. POINTER brain health recipe1

Certainty of evidence: low

RESEARCH SPOTLIGHT Certainty of evidence: moderate

In 2025, results from the Alzheimer’s Association’s U.S. Study to Protect Brain Health Through Lifestyle Intervention to Reduce Risk (U.S.

Certainty of evidence: moderate

POINTER) were published in JAMA.1,97 This was a two-year, randomized controlled trial (RCT) that aimed to determine whether lifestyle interventions are effective in protecting cognitive function in older adults at risk for cognitive decline and dementia. A total of 2,111 participants were assigned to either a structured or self-guided intervention, with both

intervention group were prescribed goals shown in the U.S. POINTER brain

Certainty of evidence: very low

health recipe. The study found that both intervention groups experienced improved cognitive functioning, but the structured intervention group outperformed the self-guided group, with a mean composite z-score increase of 0.243 standard deviation (SD) per year versus 0.213 SD per year.

Physical exercise Engage in 30–35 minutes of moderateto-intense aerobic activity four times per week and strength and mobility training twice per week. Health monitoring Regularly check blood pressure, weight and lab results with HCP. Nutrition Adhere to the MIND diet, which emphasizes berries, nuts, whole grains, olive oil, fish, and dark, leafy greens while limiting sugar and unhealthy fats. Cognitive exercise Complete 30 minutes of computerbased, brain-training program activities three times per week and regularly participate in other intellectually challenging and socially engaging activities.

Lifestyle in focus Coffee and tea: A few studies have investigated the effects of caffeine consumption on cognitive decline, dementia and AD, with compelling but inconclusive results.98 Results from the Cardiovascular Risk Factors, Aging and Dementia (CAIDE) trial suggested that drinking 3–5 cups of coffee per day at midlife was associated with a roughly 65% decreased risk of AD and dementia later in life. Additionally, a prospective cohort study that included over 130,000 individuals, with up to 43 years of follow-up, found that higher caffeinated coffee intake was associated with an 18% reduction in dementia risk and a modestly lower prevalence of subjective cognitive decline, with the most pronounced differences seen with 2–3 cups of coffee or 1–2 cups of tea per day. 99 Healthcare providers (HCPs) should ensure that patients do not have contraindications to caffeine intake before recommending this intervention. Eggs: Eggs provide several key nutrients that support brain health. They are rich in choline, which is essential for memory and neurotransmitter activity, and contain lutein and zeaxanthin, antioxidants associated with cognitive performance and reduced oxidative stress.100,101 Egg yolks also provide phospholipids and omega-3 fatty acids,

both of which play important roles in neuronal function and cell signaling. Building on this nutritional foundation, a study published in The Journal of Nutrition evaluated the association between egg consumption and the incidence of AD using data drawn from U.S. Seventh-day Adventists.102 In this observational study, any egg intake was associated with a 17%– 27% relative reduction in AD risk compared with no egg consumption. These findings from a health-conscious population suggest a potential neuroprotective role for eggs when included as part of a balanced diet; however, additional research is needed to determine whether this association applies more broadly. It should be noted that although cholesterol concerns have historically limited egg intake, recent reviews suggest moderate consumption is not associated with adverse cardiovascular or metabolic outcomes for most individuals when included as part of a balanced diet.103,104 Brain training: Cognitive training, or brain training, involves speeded, dual-attention, adaptive tasks delivered during regularly scheduled, structured sessions. There is much debate about whether brain training interventions can help slow cognitive decline in AD. The Advanced Cognitive Training for Independent and Vital Elderly (ACTIVE) study aimed to evaluate the long-term

Did you know?

Eggs The United States is the world’s fourth largest egg producer, and Iowa leads the pack with more than 44.4 million laying hens.105 In 2026, Americans are projected to eat about 274 eggs per person.106

effects of cognitive training on the risk of AD and related dementias (ADRD).107 This trial randomized over 2,000 communitydwelling adults ≥65 years of age to one of three intervention arms, or to a nocontact control arm. The intervention arms consisted of speed, memory and reasoning training groups. Each received up to 10 small group training sessions lasting 60–75 minutes each over 5–6 weeks. Additional booster training sessions were offered at 11 and 35 months after baseline. Results found that participants in the speed-training group who completed one or more booster sessions had a 25% lower risk of ADRD diagnosis over a 20-year follow-up period. Those in the speed-training group with no booster training did not achieve a lower risk of ADRD, nor did participants in the memory- or reasoning-training groups. The speed training intervention offered

in the ACTIVE trial involved identifying objects on a screen and forming quick decisions about them. Though it may represent an impactful tool for the nonpharmacological prevention and treatment of AD, more research is needed. Puzzles: While research is limited and insufficient to support puzzles as a proven treatment or preventive measure for AD, they may serve as an enjoyable and useful tool.108 An observational study that followed 488 cognitively intact patients found that completion of crossword puzzles delayed the onset of memory decline by about 2.5 years in those who developed dementia.109 Another observational study that included data from over 19,000 healthy adults found a close relationship between frequency of use of both number puzzles (e.g., Sudoku) and word puzzles and quality of cognitive function.110,111 An additional observational study that included 100 cognitively healthy adults found that completing jigsaw puzzles strongly engaged multiple cognitive abilities and may lead to longterm cognitive benefits.112 Because these studies are all observational in nature, it is important to emphasize that more research is needed to determine the exact impact of puzzles on AD.

Tai chi: Tai chi is a mind-body practice originating in China that combines slow, gentle movements and physical postures with meditation and deep breathing.113,114 Evidence is modest when it comes to the potential cognitive benefits of tai chi. For instance, a scoping review including eight systematic reviews with meta-analyses and six additional RCTs found that tai chi may improve memory and cognition; however, only studies in healthy adults were identified in the review.114 A separate systematic review that included nine studies found that tai chi can potentially improve short-term cognitive function in elderly patients at the onset of dementia.115 Interestingly, results from a 2023 randomized superiority trial including over 300 older adults with MCI suggest that cognitively enriched tai chi is superior to standard tai chi when it comes to improving global cognition.116 This cognitively enriched form of tai chi combines mental puzzles and challenges with traditional tai chi movements; for example, the instructors have participants spell words forward and backward while performing the physical movements.

Can Alzheimer’s disease be reversed? There is currently no evidence to suggest that AD can be reversed. While recent headlines have claimed that supplementation with nicotinamide adenine dinucleotide (NAD+) may reverse AD, this molecule has only been studied in mice and has no data to support its use in humans, warranting additional research.117–119 Because AD is considered to be irreversible, it is fundamental to emphasize the importance of prevention. Following a comprehensive lifestyle program that incorporates healthy diet, physical activity and cognitive exercise, such as the U.S. POINTER brain health recipe, can have a robust impact.1,19,120 HCPs should also work with patients to manage chronic diseases that are risk factors for AD — such as T2DM, hypertension and dyslipidemia — while counseling patients on smoking cessation and alcohol reduction, as applicable.1,19,20 Further, patients should be encouraged to prioritize social connection and high-quality sleep as part of their AD prevention plan.19

Negligible side effects compared with placebo were seen in clinical trials.

Treatment approaches

What medications can be used for the treatment of Alzheimer’s disease?

or suboptimal dosing are GI-related (e.g., nausea, vomiting, anorexia, diarrhea). Syncope is a rare side effect.

No oral medication is currently available that cures AD; however, several medications are commonly used in clinical practice to help slow cognitive and functional decline.

Rivastigmine was the second AChEI approved for use in mild or moderate AD. While its mechanism of action is not entirely clear, it does work to increase acetylcholine in the brain.122,123 Rivastigmine has additional approval for treatment of Parkinson’s disease dementia. It is available for use in pill or patch formulations. Similar to donepezil, GI side effects are common.

Acetylcholinesterase inhibitors (AChEIs) are typically started first and titrated to the maximum tolerated dose. There are three medications in this class: donepezil, rivastigmine and galantamine. In 1996, donepezil was approved as the first medication for use in mild, moderate and severe AD.121 Donepezil works in the brain to enhance cholinergic function by decreasing the breakdown of acetylcholine via inhibition of the enzyme that breaks it down (acetylcholinesterase). It is available in pill and oral dissolvable forms, with once- and twice-daily dosing formulations. The most common side effects that often lead to discontinuation

Typically, treatment is initiated with an AChEI and increased over time to a maximum dose (or maximum tolerated dose based on side effects). Once the AChEI is maximized, memantine may be added to enhance cognitive functioning. Namzaric, a combination drug containing memantine and donepezil approved in patients with moderate-to-severe dementia, delivers a lower strength of each medication, but its utility in practice is limited.128

Galantamine, the third AChEI, was approved for use in 2001, also for mildto-moderate AD. It is available in pill formulation, in both extended-release and twice-daily dosing options.124 Benzgalantamine is a prodrug of galantamine, allowing for a delayedrelease effect.125 In clinical practice, donepezil and rivastigmine are used more commonly than galantamine or benzgalantamine.126

Once AChEIs are titrated to the maximum dose, memantine (Namenda) may be added.127 In fact, memantine is the only FDA-approved add-on treatment for AD. Initial approval was granted for use in moderate-to-severe dementia. Memantine is an N-methyl-D-aspartate (NMDA) receptor antagonist that is used to treat AD symptomatically. Persistent activation of the NMDA receptors by the excitatory amino acid glutamate has been hypothesized as a contributor to the clinical symptoms seen in AD. Memantine works by blocking these receptors, preventing the excitation of these channels by glutamate. Its package insert does state that there is no evidence that memantine prevents or slows neurodegeneration in patients with AD.

Other medications can also play a role in the treatment of AD symptoms. Suvorexant (Belsomra) can be used for the treatment of insomnia.129 Brexpiprazole (Rexulti) is an FDA-approved treatment for agitation in AD.130 An atypical antipsychotic, it needs to be used on a regular maintenance dosing schedule for efficacy. Due to its mechanism of action, it can be used to treat major depressive disorders, but it is only indicated for the treatment of agitation in AD and not psychosis. In April 2026, dextromethorphan/ bupropion (Auvelity) was approved as the first non-antipsychotic treatment for agitation associated with AD dementia. It is taken orally twice daily on a scheduled basis following initial titration and also carries an indication for the treatment of major depression.

What is the place in therapy for the monoclonal antibodies Leqembi and Kisunla? Over the last five years, there have been three new drugs approved for the treatment of AD. Of the three drugs developed, two are utilized in clinical practice. Both lecanemab-irmb (Leqembi) and donanemab-azbt (Kisunla) are FDAapproved for use in individuals with MCI or mild dementia (clinical stages 3 and 4).131,132 Leqembi originally received Accelerated Approval as an intravenously (IV)-infused Aβ-directed antibody for use in MCI or mild dementia.131,133 It now has full FDA approval and works by reducing amyloid plaque formation in the brain, with the goal of slowing disease progression and cognitive decline. A positive biomarker — such as a serum/CSF biomarker or PET scan — is required to qualify for treatment. In clinical studies, Leqembi caused a reduction in plasma p-tau181 and an increase in plasma Aβ42/40 ratio. There was a dose-responsive relationship between use and serum findings, with tau and beta-amyloid consistent with a decrease in amyloid-PET centiloid values. There are still uncertainties regarding treatment duration, redosing strategies and long-term effects.134 Currently, IV Leqembi is administered every two weeks, with recommendations to stop treatment

once a patient has progressed to a moderate stage of dementia. Progression is monitored by objective cognitive testing over time; a comparison PET scan may be of benefit when deciding whether to continue treatment. The goal of treatment is to preserve independence and maintain cognitive functioning; no objective improvements in functioning have been substantiated with ongoing use. Appropriate-use recommendations considering treatment goals and the risks versus the benefits of therapy can help determine candidacy. There are strict initiation and monitoring criteria with use of Leqembi, as one of its main side effects is an infusion reaction in the brain called amyloid-related imaging abnormalities (ARIA).131,134 Since these brain changes can be asymptomatic, routine MRI monitoring is required. Patients who are APOE ε4/ε4 homozygotes have an increased risk of ARIA, and genetic testing is used to quantify risk (not development or severity of disease). Leqembi does not permanently remove amyloid and tau protein from the brain, and use of this treatment requires enrollment in a study to better understand its long-term use. In September 2025, Leqembi was also approved as a weekly, at-home, subcutaneous (SC) autoinjector (Leqembi Iqlik). Initially, Leqembi Iqlik was approved for use after completion of 18 months of

IV treatment; however, it was approved in July 2026 for initial at-home treatment.135 Data from the Phase 3 Clarity AD open-label extension trials show that transitioning to the SC formulation after 18 months maintains clinical and biomarker benefits comparable to IV dosing.136 The main benefits can be seen in convenience of infusion, as it is administered at home and takes less than 15 minutes to receive the full dose.135,136 Systemic reactions were less common with SC dosing, and ARIA rates were similar to patients receiving ongoing IV therapy. MRI monitoring at baseline and at various points during treatment is required. Kisunla, an immunoglobulin G1 (IgG1) monoclonal antibody that targets the N-terminal form of Aβ, was approved for use in early symptomatic AD one year after full approval of Leqembi.132 Qualifications for treatment and the risk of ARIA are the same as for Leqembi. However, ARIA risk may be reduced with a new recommended dosing schedule, which involves titrating the infusion upward from treatment initiation.137 The goal of Kisunla treatment is to remove Aβ pathology from the brain.132,138 Approval studies showed that there was a dose reduction of amyloid plaques in a time-dependent manner, and there was a recurrence of accumulation after therapy was discontinued for a period. Recommendations regarding

when to restart therapy are limited by lack of Stage 2 and Stage 3 data, and long-term dose effects are limited to the 76-week duration of the Phase 3 TRAILBLAZERALZ 2 trial.139 Currently, clinicians may consider discontinuing treatment if amyloid PET shows clearance on repeat scan; typically, this is assessed around 12–18 months of use.138 It is unknown whether redosing after this time is necessary and what the long-term effects might be. Kisunla is administered in monthly IV infusions, and MRI monitoring for ARIA at various points in therapy is required for continued treatment.132 Current data show that both Leqembi and Kisunla continue to have clinical benefit after three and four years of use, with individuals remaining in earlier stages of AD comparatively longer.132,136,138,139

Leqembi and Kisunla at a glance lecanemab-irmb (Leqembi)

donanemab-azbt (Kisunla)

Manufacturer

Eisai/Biogen

Eli Lilly

Approval

Accelerated Approval designation: January 2023

July 2024

Full approval: July 2023 Mechanism of action

Aβ-directed antibody; reduces amyloid plaque formation in the brain

Aβ-directed antibody; targets the N-terminal form of Aβ

Indication

AD (patients with MCI or mild dementia stage of disease)

Dosage forms and strengths

IV infusion: 200 mg/2 mL and 500 mg/5 mL singledose vial

IV infusion: 350 mg/20 mL single-dose vial

Leqembi Iqlik SC injection: 250 mg/1.25 mL and 360 mg/1.8 mL single-dose prefilled autoinjector Dosing

Starting dose:

IV infusion every 4 weeks over 30 minutes:

IV: 10 mg/kg once every 2 weeks over 1 hour

Infusion 1: 350 mg

SC: 500 mg once weekly

Infusion 2: 700 mg

Maintenance dose (after 18 months):

Infusion 3: 1,050 mg

IV: 10 mg/kg IV every 4 weeks over 1 hour

Infusion 4 and beyond: 1,400 mg

SC: 360 mg once weekly

Label recommends considering stopping therapy based on reduction of amyloid plaques to minimal levels on amyloid PET

Contraindications

Serious hypersensitivity to lecanemab-irmb or excipients

Serious hypersensitivity to donanemab-azbt or excipients

Warnings/Precautions

ARIA (boxed warning), infusion-related reactions

MRI monitoring

Baseline and after 1, 2, 3 and 6 months of treatment

Baseline and before 2nd, 3rd, 4th and 7th infusions

Common adverse reactions (≥10%)

Infusion-related reactions (IV), injection-related reactions (SC), ARIA-microhemorrhage, ARIA-edema (ARIA-E), ARIA-effusion, headache

ARIA-E, ARIA-microhemorrhage, ARIA-superficial siderosis, headache

What is Aduhelm and why was it discontinued? In June 2021, the FDA granted Accelerated Approval to Biogen’s aducanumab (Aduhelm), a monoclonal antibody targeting beta-amyloid, for AD.140 Approval was based on the surrogate endpoint of reduction of betaamyloid plaque in the brain, as measured by PET brain imaging. The manufacturer was given nine years to complete a required confirmatory trial to verify aducanumab’s anticipated clinical effect. The pivotal Phase 3 randomized trials EMERGE and ENGAGE investigated aducanumab in early symptomatic AD.141,142 The 18-month trials were terminated early based on an interim futility analysis. In a surprising reversal, Biogen announced a few months later that the interim futility analysis was wrong and that post hoc analysis data from EMERGE (high-dose group) had met its primary endpoint (a clinical dementia rating [CDR]). In EMERGE, the CDR-SB increased by 1.74 in the placebo arm and by 1.35 in the drug arm (high-dose group), a difference of 0.39 equating to a 22% relative slowing of decline (P=0.01). Results from ENGAGE were negative. ARIA-E was the most common adverse event in both studies.141,142 ARIA-E occurred in 35% of the high-dose group and was

more common in APOE ε4 carriers. In the high-dose group, approximately onefourth of ARIA-E was symptomatic, with a median symptom duration of five weeks. There was substantial controversy within the medical and scientific community after the FDA approval of aducanumab.143–145 The decision went against the FDA’s own Peripheral and Central Nervous Systems Drugs Advisory Committee’s external experts, who had overwhelmingly voted against its approval due to insufficient evidence for clinical benefit. Biogen initially set a list price of $56,000 per year, and the drug was broadly approved for AD despite having been studied only in patients with early-stage, mild dementia. As the story unfolded, several members of the advisory committee resigned, the label was revised to narrow its use to MCI and earlier stages of dementia with AD, and the manufacturer lowered the price. However, aducanumab was met with poor uptake, Medicare coverage was limited to patients participating in qualifying studies, and the product encountered strict payor coverage restrictions due to efficacy and safety concerns. Biogen discontinued aducanumab in January 2024. The story of aducanumab is a cautionary tale, underscoring the need for a transparent regulatory process grounded in clinical evidence.

Are there any vaccinations that can prevent or treat Alzheimer’s disease? Currently, there are no approved vaccines for the prevention or treatment of AD. Several investigational vaccines are being developed that target Aβ or tau pathology. Notable candidates include ACI-24.060 (AC Immune), an Aβ agent in a Phase 1b/2 trial; ALZ-101 (Alzinova), a toxic Aβ oligomer in a Phase 2 study initiated in early AD; and ACI-35.030 (AC Immune/Janssen), a tau protein in a Phase 2b trial in preclinical AD.146 These are therapeutic vaccines designed to stimulate the immune system to generate antibodies against amyloid or tau and potentially slow disease progression rather than prevent infection. The strongest vaccine-related evidence currently exists for repurposed vaccines, specifically the shingles vaccines Shingrix (recombinant zoster vaccine) and Zostavax (older live-attenuated vaccine), that are being evaluated for their potential to reduce the risk of dementia.147 Several observational studies have found that people who received shingles vaccines had a lower risk of developing dementia later in life. No clinical guidelines currently recommend the shingles vaccine specifically to prevent or treat dementia. While recent observational studies suggest a lower risk of cognitive

decline in vaccinated older adults, health organizations like the Centers for Disease Control and Prevention (CDC) recommend vaccination strictly for shingles prevention. In a large, observational, comparator 1:2-matched cohort design, researchers used a random sample of Centers for Medicare & Medicaid Services (CMS) claims data to evaluate whether completing the two-dose recombinant zoster vaccine (RZV) series was associated with lower risk of newonset dementia.148 The study included participants ≥65 years of age who were continuously enrolled in Medicare for most of the year before the index date and had no prior dementia diagnosis, AD, vascular dementia, MCI or age-related cognitive decline. The RZV-exposed group (n=502,845) included beneficiaries who received two doses of RZV between 2018 and 2020. The index date was the date of the second RZV dose. Unvaccinated comparators (n=1,005,690) were Medicare beneficiaries who had a preventive care visit during the same period but had not received RZV by that visit. Followup began the day after the index date and continued until dementia diagnosis, death, Medicare disenrollment, the end of the study period or receipt of zoster vaccination in the comparator group.

The primary outcome was new-onset dementia of any type, as identified using International Classification of Diseases (ICD)-10 claims data. Two-dose RZV vaccination was associated with a significantly lower risk of new-onset dementia compared with no RZV vaccination, with adjusted HRs of 0.67 (95% CI, 0.65–0.68) within three years and 0.74 (95% CI, 0.7–0.79) after more than three years of follow-up, corresponding to a 33% and 26% lower risk, respectively. Because the findings were based on an observational study, the results show association rather than causation. There are now prospective clinical trials evaluating this question, including NCT07485283, DAN-ZOSTER, a Phase 4 randomized trial evaluating whether Shingrix reduces incident dementia in adults ≥65 years of age; and NCT07502560, a Phase 4 interventional trial evaluating the effect of recombinant zoster vaccine on new diagnosis of dementia in older adults in Finland.149,150

Are GLP-1 receptor agonists effective for treatment of Alzheimer’s disease? The EVOKE and EVOKE+ trials were two large, Phase 3, randomized, double-blind, placebo-controlled studies that evaluated whether up to 14 mg once daily of oral semaglutide, a glucagon-like peptide-1 (GLP-1) receptor agonist, could slow clinical progression in individuals with early-stage, symptomatic AD.151 A total of 3,808 participants with amyloid-confirmed AD were randomized across 566 sites in 40 countries. Participants had either MCI or mild dementia due to AD; EVOKE+ also included a small subgroup with significant small vessel pathology. In a pooled analysis of EVOKE and EVOKE+ trials, obesity was the most common comorbidity (defined as body mass index [BMI] ≥30 kg/m²), affecting 15.5%, followed by diabetes (13.6%). Across both trials, participants receiving oral semaglutide had a mean body weight reduction of 5.8% (4.3 kg) from baseline at Week 104 compared with a slight increase of 0.6% (0.2 kg) in the placebo group. The primary endpoint was the change from baseline in the CDR-SB score, which was assessed at Week 104, but additional safety and efficacy data were collected in the extension phase, up to Week 156, for some participants.151 Across both trials, semaglutide did not significantly slow cognitive or functional decline compared 33

with placebo. The mean change in CDRSB score from baseline to Week 104 was 2.3 for semaglutide and 2.3 for placebo in EVOKE and 2.2 for semaglutide and 2.1 for placebo in EVOKE+, demonstrating very similar progression between the treatment groups. No meaningful differences were observed in secondary clinical outcomes, including functional measures, cognition scales, disease progression, quality of life or composite clinical scores.

While oral semaglutide significantly reduced high-sensitivity C-reactive protein (hsCRP), suggesting an antiinflammatory effect, this did not translate into clinical benefit.151 Plasma AD biomarkers such as p-tau181 and p-tau217 showed no significant differences between groups. In a CSF substudy, semaglutide was associated with reductions in several AD-related neuroinflammatory, neurodegenerative and synaptic biomarkers; however, these biomarker changes were not accompanied by measurable clinical improvement. Although oral semaglutide produced statistically significant reductions in CSF AD biomarkers, including p-tau181, the changes were modest and did not translate into clinical benefit in the EVOKE trials.151 The EVOKE trials found that oral semaglutide reduced certain CSF biomarkers of AD pathology by about

10%, but this effect was considered too small to meaningfully improve cognitive or functional outcomes. Despite favorable changes in CSF biomarkers, oral semaglutide failed to demonstrate clinical efficacy, suggesting that these biomarker shifts may not be sufficient to predict benefit for non-amyloid and non-tau therapies. Experts noted that the modest biomarker reductions observed with oral semaglutide highlight the need for further research into how amyloid- and tau-based biomarkers should be interpreted for therapies with alternative mechanisms of action.151,152 Overall, the EVOKE findings suggest that, while oral semaglutide may influence AD-related biomarkers, the magnitude of change is not enough to produce meaningful clinical improvement. Oral semaglutide is no longer advancing in Novo Nordisk’s late-stage AD program after the Phase 3 EVOKE and EVOKE+ trials failed to show a statistically significant slowing of clinical disease progression versus placebo, despite improvements in AD-related biomarkers.153 Based on these negative efficacy results, Novo Nordisk discontinued the one-year extension periods for both trials, leaving the future role of semaglutide or other GLP-1 receptor agonists in AD treatment and prevention uncertain.

Are there any medications that can be used off-label to treat Alzheimer’s disease? Sildenafil, a phosphodiesterase inhibitor used to treat pulmonary hypertension and erectile dysfunction, has shown promise in preclinical studies. In vivo data suggest that sildenafil may reduce amyloid beta– induced oxidative stress and cell death while increasing cerebral oxygenation.154 However, sildenafil is not currently used to treat AD, and further trials are needed to clarify its potential role. T2DM is a recognized risk factor for AD, prompting investigation of insulin for treatment of AD. Some trials of intranasal insulin in patients with AD found improved memory associated with increased CSF Aβ42 levels and lower tau/Aβ42 ratios, while other trials found no significant benefit with insulin administered by infusion or intranasally.155,156 Modafinil has been reported to enhance cognitive performance in AD. Based on its mechanism of action, preclinical data suggest that modafinil may promote neurogenesis and normalize brain-derived neurotrophic factor (BDNF) expression, which is deficient in AD; however, this is not currently being studied in clinical trials.157 Lithium has been shown in mouse models to reduce tau phosphorylation and Aβ

production, and long-term exposure may prevent or lessen AD severity.158 Increased CSF Aβ in lithium-treated individuals may suggest disease-modifying effects. Acyclovir has also been proposed as a possible AD treatment. Herpes simplex type 1 (HSV-1) infection may contribute to AD development in APOE ε4 carriers by triggering autophagy, and acyclovir could potentially disrupt this process; however, more evidence is needed before it can be recommended for prevention.159 The VALAD trial is currently evaluating valacyclovir for AD treatment, using PET imaging to assess efficacy and CSF testing to assess central nervous system (CNS) penetration.160 Minocycline crosses the blood-brain barrier and has anti-inflammatory effects. In vivo studies showed reduced amyloid beta accumulation and behavioral improvement with minocycline, but these findings did not translate into clinical practice, and the high doses (>400 mg) required to achieve the intended effect were not recommended.161,162 Rifamycin may have neuroprotective effects by reducing Aβ; however, clinical evidence in AD is limited, and studies of rifamycin with or without doxycycline have shown conflicting cognitive results.163,164

Studies suggest it may improve memory retention in older adults and reduce sundowning symptoms.166,167 Most nonsteroidal anti-inflammatory drugs (NSAIDs) have been associated with lower AD prevalence, but no effect on cognitive decline has been observed.168 Diclofenac was significantly associated with both reduced incidence and slower cognitive decline and may warrant further study as a potential therapeutic option. Allopurinol and carvedilol showed a clear inverse association with AD, with use of either drug associated with lower risk of the disease.169 Medications that block xanthine dehydrogenase/oxidase (allopurinol) or inhibit the enzyme’s effect (carvedilol) were inversely associated with the development of not only AD but also Parkinson’s disease and amyotrophic lateral sclerosis. Allopurinol had the highest association and showed a 13%–34% lower risk for all three disease states.

Melatonin is an antioxidant that may prevent amyloid fibril formation and protect cells from oxidative injury.165

Are any herbal supplements beneficial in the treatment of Alzheimer’s disease? With an overwhelming number of herbal and dietary supplements on the market claiming to enhance memory and delay AD, it is understandable that patients and caregivers may want to utilize alternative therapies. Although there are studies showing modest benefit with certain herbal products, no single vitamin or herbal supplement has been proven to prevent, treat or cure AD or improve cognitive function, and many product labels include false or unproven claims.170–172 In fact, herbal supplements should be approached with caution given that they are not regulated or monitored by the FDA, which means their exact effectiveness, safety and purity are unknown, and they could have major interactions with prescription medications.

The Global Council on Brain Health (GCBH) does not endorse any ingredient, product or supplement specifically for brain health, unless a deficiency has been identified by an HCP, and recommends against taking supplements for brain health without first consulting an HCP.173 Guidance from the GCBH states that vitamin B12 and folate supplementation may be beneficial for brain health in those who are deficient; there is a paucity of evidence for other vitamins and supplements. Ultimately, the GCBH recommends lifestyle and dietary interventions over the use of dietary supplements to promote brain health. Similarly, the American Academy of Neurology does not endorse supplements for the prevention or treatment of AD. A list of commonly used herbal supplements for AD, and the corresponding research studies that have examined these products, is included in Appendix A. It is important to note that most of the studies investigating supplements for AD measured improvement by nonstandardized methods.174–176 Some used objective scoring tests (e.g., MMSE, MoCA), some used subjective improvements and some used a combination of both to substantiate recommendation for use. One recent review showed that, of all supplements measured, none produced any significant

Did you know?

Herbal products Although there are studies showing modest benefit with certain herbal products, no single vitamin or herbal supplement has been proven to prevent, treat or cure AD or improve cognitive function, and many product labels include false or unproven claims.170–172

improvement in the Alzheimer’s Disease Assessment Scale–Cognitive Subscale (ADAS-Cog), which is a more sensitive measure of overall cognitive functioning and memory impairment.176 With all herbal supplements, further research is warranted to determine potential benefit in the prevention and treatment of AD.

The future of Alzheimer’s treatment

What types of medications are in the pipeline for Alzheimer’s treatment? Phase 3 pipeline

The Phase 3 AD pipeline is evolving beyond amyloid-focused therapies toward disease-modifying potential with a more diverse mix of taudirected agents, neuroinflammation modulators, metabolic therapies, neuroprotective agents, synapticfunction enhancers and precisionmedicine approaches targeting genetically defined populations.

A few unique agents are in Phase 3, with potential first-in-class mechanisms and disease-targeted therapy options. Some drugs in the pipeline are being studied to delay or prevent the clinical onset/ progression of AD, although none has proven preventive at this time. Amyloid-targeting therapies — including buntanetap, nivegacetor, remternetug, simufilam, trontinemab and valiltramiprosate — account for approximately 21% of the pipeline representation in Phase 3 clinical trials. Trontinemab, an IV Aβ/TfR1 bispecific antibody that uses Roche’s Brainshuttle technology to improve antibody delivery across the blood-brain barrier, represents a next-generation, anti-amyloid approach. It is designed to improve CNS delivery

Phase 3 AD pipeline by therapeutic approach • Amyloid: 21%

• Metabolic/Lipid/Vascular biology: 21%

• Cannabinoid: 11%

• Neuroinflammation/Immune modulation: 14%

• Tau: 7%

• Infection-linked: 4%

• Synaptic/Neurotransmission/Cognition: 14%

• Miscellaneous: 7%

These are approximate percentages.

through transferrin receptor-mediated transport.177 Remternetug, an IV/SC anti-amyloid monoclonal antibody, may join donanemab by allowing treatment discontinuation once plaque burden is adequately reduced. Both target pyroglutamate Aβ in plaques.178 Valiltramiprosate (ALZ-801), an oral amyloid-targeting agent, is focused on APOE ε4/ε4 homozygotes, a population with the highest risk of serious ARIA. ALZ-801 is notable because it acts upstream by preventing formation of neurotoxic soluble amyloid oligomers, potentially slowing brain atrophy, with no increased risk of ARIA.179 Nivegacetor, an oral gamma-secretase modulator, uses a potentially cleaner, secondgeneration approach to slow down or prevent amyloid accumulation. It is used either as monotherapy or in combination with amyloid targeting monoclonal antibodies.180 Buntanetap reduces production of multiple neurotoxic proteins and is one of the novel programs in development; rather than targeting a single pathogenic protein, it is a translational inhibitor of neurotoxic

aggregating proteins (TINAPs).181 This broader upstream approach may differentiate it from therapies focused solely on amyloid or tau. Tau-targeting therapies account for approximately 7% of the pipeline. Etalanetug, an anti-tau antibody, is among the most advanced anti-tau antibodies and is being evaluated as adjunctive therapy alongside amyloid removal.182 Early biomarker data demonstrated substantial reductions in CSF MTBR of tau protein, tau243 and p-tau217, supporting tau pathology engagement. Hydromethylthionine mesylate, a tau protein aggregation inhibitor, may provide an oral alternative to injectable monoclonal antibody therapies.183 Neuroinflammation and immune modulation therapies account for approximately 14% of the pipeline. Growing evidence supports neuroinflammation as a major contributor to disease progression. Masitinib has demonstrated potential to regulate mast cells and is among the most advanced neuroinflammation programs that could become an important add-on therapy.184 Atuzaginstat remains unique because it targets Porphyromonas gingivalis gingipains, representing the infectious hypothesis of AD.185 Bezisterim combines anti-inflammatory effects with insulin-sensitizing activity; however, its Phase 3 failures may significantly impact its prospects.186 37

Metabolic, lipid and vascular biology therapies represent about 21% of the pipeline. Novel standouts include T3D959, the first peroxisome proliferatoractivated receptor (PPAR)-delta activating compound specifically developed for AD, and obicetrapib, which explores the relationship between cholesterol metabolism, APOE ε4 biology and amyloid clearance.187,188 Synaptic and neurotransmitter function modulators represent about 14% of the pipeline. Several highly novel approaches aim to improve neuronal resilience rather than directly target protein aggregates. Mirodenafil (AR1001) is a potential firstin-class phosphodiesterase 5 (PDE5) inhibitor being developed specifically as a disease-modifying AD therapy.189 Phase 3 POLARIS-AD topline results are expected in late 2026. Blarcamesine oral formulation may offer practical advantages over antiamyloid antibodies; it will not require PET confirmation, MRI monitoring or lumbar puncture and may have a broader potential treatment population.190 Tannquilynne, a novel D-amino acid oxidase inhibitor, could enhance NMDA receptor signaling and improve cognition.191

of the endocannabinoid system, particularly the cannabinoid-1 (CB1) and cannabinoid-2 (CB2) receptors, may influence multiple pathways implicated in neurodegeneration, including neuroinflammation, oxidative stress, synaptic dysfunction, cerebral blood flow and neuronal survival. Unlike amyloid- or tau-directed therapies, cannabinoidbased approaches are generally being investigated as multifactorial neuroprotective therapies that may improve cognition, behavioral symptoms or overall brain health rather than directly targeting protein aggregates. Although cannabinoid-based therapies currently represent a relatively small segment of the AD pipeline (about 11%), they are noteworthy because they introduce a novel endocannabinoidsystem approach to dementia treatment. Research for cannabinoid options includes DehydraTECH-CBD, CogniCann and MIRA-55, which are dementiafocused agents using cannabidiol (CBD)/tetrahydrocannabidiol (THC) or cannabinoid-receptor pathways to target cognition, behavioral symptoms and neuroinflammation.

Phase 3 pipeline AD drugs Generic name/API

Manufacturer

Clinical use

Route of administration

Target

Amyloid buntanetap (previously known as ANVS401 or Posiphen)

Annovis Bio

TINAPs

nivegacetor (RG6289)

Roche

Gamma-secretase modulator

remternetug

Eli Lilly and Company

IV, SC

Anti-Aβ monoclonal antibody

simufilam

Filana Therapeutics

Filamin A (FLNA)

trontinemab (RG6102)

Roche/Genentech

Aβ/TfR1 bispecific antibody

valiltramiprosate (ALZ-801)

Alzheon

Aβ protein inhibitor

Cannabinoid cannabidiol

Lexaria Bioscience

Dementia

CB1 & CB2 receptor

CogniCann

Argent BioPharma

Dementia

CB1 & CB2 receptor

MIRA-55

MIRA

Dementia

CB1 & CB2 receptor

(DehydraTECH-CBD)

Cannabinoid-based therapies represent an emerging and highly exploratory area of AD and dementia research.192 Current development efforts are based on the hypothesis that modulation

Phase 3 pipeline AD drugs (continued) Generic name/API

Manufacturer

Clinical use

Route of administration

Target

Generic name/API

Manufacturer

Tau

Clinical use

Route of administration

Target

Neuroinflammation/Immune modulation

etalanetug (E2814)

Eisai

Anti-tau antibody

BBT-209 (also known as HY-209)

Shaperon

Dementia

IV, PO, Topical

TGR5 (GPBAR1) agonist; TSLP

hydromethylthionine mesylate (LMTX)

TauRx

MTBR tau; tau aggregation inhibitor (TAI)

masitinib mesylate (Masican)

AB Science

FGFR3; KIT/c-KIT; Lyn kinase; mast cell; plateletderived growth factor receptor; Src kinase family; receptor TKI

tertomotide (GV1001)

GemVax/KAEL

Intradermal, SC

Immune system; reverse transcriptase; telomerase; immunomodulator

THN-391

Therini Bio

Dementia

IV, Intravitreal

Fibrinogen (coagulation factor I)

Kgp inhibitor

Synaptic/Neurotransmission/Cognition blarcamesine (ANAVEX2-73)

Anavex Life Sciences

Sigma-1 receptor agonist

mirodenafil dihydrochloride (AR1001)

AriBio

PDE5 inhibitor

tannquilynne (SND51)

SyneuRx

Dementia

N/A

DAAO inhibitor

S-898270

Shionogi

Dementia

Type 4 cyclic nucleotide phosphodiesterase inhibitor

Infection-linked atuzaginstat (COR388)

Cortexyme/Quince

Miscellaneous

Metabolic/Lipid/Vascular biology bezisterim (NE3107)

NeurMedix/BioVie

MAPK1/ERK2; MAPK3/ ERK1; NF-κB; TNF-alpha; anti-inflammatory agent; insulin sensitizer

nilvadipine (ARC029)

Archer

Dihydropyridine CCB

obicetrapib (TA-8995)

NewAmsterdam

CETP inhibitor

piromelatine (Neu-P11)

Neurim

AD/Dementia

Melatonin receptor agonist

tricaprilin (AC-SD-03)

Cerecin/Accera

Omega-3 fatty acids and derivatives

T3D-959

T3D

PPAR agonist

HOB-075

Hyundai

Dementia

N/A

Beta-secretase (BACE); serotonin receptors

PST-900

Pharmasum

Dementia

N/A

DYRK1A

active pharmaceutical ingredient (API); Alzheimer’s disease (AD); by mouth (PO); translational inhibitor of neurotoxic aggregating proteins (TINAPs); amyloid beta (Aβ); cannabidiol (CBD); cannabinoid 1 (CB1); cannabinoid 2 (CB2); intravenous (IV); microtubule binding region (MTBR); subcutaneous (SC); phosphodiesterase 5 (PDE5); d-amino-acid oxidase (DAAO); mitogen-activated protein kinase (MAPK); extracellular signal-regulated kinase (ERK); nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB); tumor necrosis factor (TNF); calcium channel blocker (CCB); cholesteryl ester transfer protein (CETP); Takeda G protein-coupled receptor 5 (TGR5); G protein-coupled bile acid receptor 1 (GPBAR1); fibroblast growth factor receptor 3 (FGFR3); tyrosine kinase inhibitor (TKI); thymic stromal lymphopoietin (TSLP); lysine-specific gingipain (Kgp); beta-site amyloid precursor protein cleaving enzyme (BACE); dual-specificity tyrosine-phosphorylation-regulated kinase 1A (DYRK1A); peroxisome proliferator-activated receptor (PPAR); transferrin receptor 1 (TfR1) *This table is not all-inclusive.

Phase 2 pipeline

Overall, the Phase 2 AD pipeline is broad and increasingly differentiated, with diseasemodifying potential and unique features, including vaccines, cell/ gene therapies, immune modulation, metabolic rescue and non-amyloid/ tau mechanisms. For the full list, see Appendix B. Phase 2 AD pipeline by therapeutic approach • Neuroinflammation/ Neuroimmune: 15% • Synaptic/Cognition enhancers: 14% • Metabolic/Lipid: 12% • Cell/Gene therapy: 12% • Vaccine: 10% • Tau: 8% • Kinase regulation: 7% • Amyloid: 7% • Neuroprotection/Growth-factor signaling: 8% • Infection-linked: 2% • Cannabinoid: 2% • Miscellaneous: 3% These are approximate percentages.

The cell-therapy programs in Phase 2 mainly used autologous adipose- or bonemarrow-derived mesenchymal stem cells (MSCs), while lomecel-B uses allogeneic donor bone-marrow MSCs and LX1001 is a separate adeno-associated virus (AAV)-based APOE ε2 gene therapy.193 Administration ranges from IV or SC infusions to direct CNS delivery, with AstroStem, HB-adMSC and lomecel-B given IV; NurOwn given intrathecally; RB-ADSC delivered intraventricularly via Ommaya reservoir every two months for six doses; and LX1001 given as an intrathecal one-time gene therapy. These cell and gene therapies mostly target symptomatic AD, especially mild to mild-to-moderate AD. AstroStem and Lomecel-B focus on mild AD, HB-adMSC/RB-ADSC/NurOwn are aimed at AD patients with symptomatic disease, and LX1001 targets APOE ε4homozygous AD with biomarker evidence rather than preclinical prevention. There are six vaccine candidates in Phase 2 proposed for AD, including taudirected vaccines (AADvac1, JNJ-2056) and amyloid-directed vaccines (ACI-24, ALZN002, UB-311, ALZ-101). These vaccines are mainly being studied in early AD, including mild AD, MCI/early symptomatic AD, and, in some cases, preclinical or presymptomatic AD. While AADvac1, ACI24, UB-311 and Alzinova are mainly being studied in early or mild AD, JNJ-2056

is distinctive because it is being studied in preclinical/presymptomatic AD, and ALZN002 is different because it enrolls mildto-moderate symptomatic AD dementia patients. Most use repeated immunization with boosters; however, ALZN002 is distinct as an autologous dendritic-cell therapy that requires leukapheresis.194 In this process, the patient’s blood cells are collected, white blood cells are separated and engineered outside the body, and the modified cells are returned to the body to help the immune system recognize and target amyloid. Repurposing is an important strategy in AD drug development, with repurposed agents playing a role in Phase 2 trials.195 Studying therapies already approved for other indications offers several advantages, including substantially shorter development timelines, lower costs, a greater likelihood of success and an established safety profile. The repurposed AD/dementia agents span symptomatic, behavioral and diseasebiology approaches. Cholinergic/muscarinic agents — such as rivastigmine, donepezil combinations, xanomeline and xanomeline/ trospium (Cobenfy) — focus mainly on cognition, psychosis or agitation, while AXS-05 is positioned for agitation in AD dementia. Other repurposed approaches target broader disease biology, including cromolyn sodium plus ibuprofen (ALZT-OP1) for amyloid/neuroinflammation, semaglutide for GLP-1/metabolic-neuroinflammatory

pathways, sodium benzoate for D-amino acid oxidase (DAAO)/NMDA signaling and nilotinib for tyrosine-kinase/autophagyrelated mechanisms. Overall, most are not yet clearly disease-modifying, but several may offer symptom control or benefit in defined AD/dementia subgroups.195 Researchers used a computational drug-repurposing approach to identify FDA-approved medications that may be relevant to AD.196 They first mapped genes linked to AD pathology, focusing specifically on genes associated with both amyloid plaques and tau tangles. They then compared this AD-related molecular network with the target profiles of more than 1,600 FDA-approved drugs. This analysis identified 66 drugs with strong connections to AD-associated genes, several of which are already being evaluated in AD clinical trials. Sildenafil, marketed as Viagra and Revatio, emerged as the top candidate after additional review. Sildenafil is currently approved for erectile dysfunction and pulmonary hypertension. The researchers also analyzed insuranceclaims data from more than 7 million Americans and found that sildenafil users, mostly men, had a 69% lower risk of developing AD over six years compared with nonusers. This association remained after adjusting for factors such as age, sex and other medical conditions. Overall, the findings suggest a potential association between sildenafil use and reduced AD risk.

However, the researchers emphasized that the study does not prove sildenafil prevents or treats AD, and other factors may explain the observed relationship. Further clinical studies are needed to determine whether sildenafil has a causal benefit in AD.

What is the role of AI in the management of Alzheimer’s disease? As the role and capabilities of artificial intelligence (AI) quickly advance, it is important to address its place in the management of AD. In a 2023 symposium by the National Institute on Aging (NIA) and the Johns Hopkins AI and Technology Collaboratory for Aging Research, AI was discussed as a means to improve dementia diagnosis rates, create personalized care plans, and provide coaching and recommendations to caregivers.197 A 2024 study funded by the NIA found that AI machine-learning algorithms using electronic health records were about 70% accurate at predicting AD diagnosis seven years prior and about 80% accurate at predicting diagnosis one year prior.198,199 These predictions improved even further when demographic and visit-related information was available. A 2025 review of 109 studies found that AI is quickly advancing PET and MRI imaging in AD, with benefits including enhanced segmentation, staging and early diagnosis.200

In 2024, the FDA approved a first-in-class clinical test called BrainSee, a software that uses AI and whole-brain imaging analysis to predict the likelihood of progression from amnestic MCI to AD within five years in patients 55–95 years of age. 201–203 The test, which is manufactured by Darmiyan, uses MRI data to pull information related to braintissue degeneration, along with demographic information and cognitive assessment scores, to generate a score between 0 and 100. Scores below 50 indicate a lower likelihood of progression to clinical AD dementia in the next five years, while scores above 50 show higher likelihood of progression. The program also includes a printable analysis report that physicians can share with patients which includes the patient’s prognostic scores and instructions for interpretating them. AI may also play a key role in AD research, potentially leading to faster advances in detection, diagnosis and treatment. 204 While AD research has historically relied on specialized data (e.g., CSF, biomarkers, MRI, PET), AI may have the ability to predict AD using new methods, such as eyetracking data, retinal imaging, near-infrared technology, and speech and language biomarkers, offering less invasive and more accessible paths to early intervention. It is inevitable that the capabilities of AI will continue to evolve with time, along with its potential to advance and transform the current landscape of AD care.

NIA Alzheimer’s and Related Dementias Education and Referral (ADEAR) Center

Resources for caregivers

What resources are available for the caregivers and families of those living with Alzheimer’s disease? The Alzheimer’s Association website is a helpful starting point for families looking for resources, offering a 24/7 helpline that is free for caregivers.205 The website includes tips for nutrition and eating, hygiene, and caregiver health and safety. A detailed explanation of the behaviors of AD patients, with strategies to manage each behavior, as well as financial planning, communitybased and housing resources are also readily available. Additionally, educational webinars for caregivers and AD-related publications can all easily be found on the website, free of charge.

Best Programs for Caregiving is a free, online database providing education for caregivers, support groups and activities for dementia patients.206 In addition to location-based tools for assisting caregivers with finding an individualized living situation, managing finances and addressing needs, the database offers information regarding regionally available adult respite care, or adult day care programs, where dementia patients can interact, socialize and participate in activities concordant with their level of functioning. Many counties have resource lines available for any sort of resource listed in a specific community and are accessible via telephone.

800.438.4380 adear@nia.nih.gov www.nia.nih.gov/alzheimers The ADEAR Center offers information and publications for download (PDFs) about AD and related dementias for families, caregivers and health professionals. ADEAR Center staff answer telephone, email and written requests and make referrals to local and national resources.

Alzheimers.gov www.alzheimers.gov This website provides information and resources from across the federal government on AD and related dementias.

Eldercare Locator 800.677.1116 eldercarelocator@USAging.org https://eldercare.acl.gov

MedlinePlus National Library of Medicine www.medlineplus.gov

Alzheimer’s Association 800.272.3900 866.403.3073 (TTY) info@alz.org www.alz.org

Alzheimer’s Foundation of America 866.232.8484 info@alzfdn.org www.alzfdn.org

Best Programs for Caregiving https://bpc.caregiver.org/caregivers/

Prime's perspective

Summary

What is Prime’s perspective on the management of Alzheimer’s disease?

AD innovation is entering a transformative era fueled by unprecedented advances in our

We are guided by three primary tenets of practice for AD: evidence, innovation and outcomes.

understanding of the human brain, accelerated progress in diagnostic technologies, the emergence of breakthrough disease-modifying therapies, a robust next-generation clinical pipeline and growing recognition of the role of lifestyle factors in brain health. Although a cure remains elusive, the rising prevalence of AD and its profound personal, societal and economic impact underscore the urgency for continued scientific progress. As the field advances, AD remains one of the most vital and compelling challenges in medicine, inviting continued innovation, evidence-based discovery, and renewed hope for patients, caregivers and future generations.

Evidence

Innovation

Outcomes

Ensure recommendations for treatments are supported by clinical evidence

Monitor and prepare for the rapidly evolving drug pipeline and advancements

Power better medicine by connecting care with better outcomes

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Appendices

Appendix A: Commonly used herbal supplements for AD

Supplement

Description

Select evidence

Huperzine A

• Club moss extract

• P hase 2 clinical trial showed no cognitive benefit of huperzine A 200 mcg twice daily compared with placebo in treatment of mild-to-moderate AD.

Supplement

Description

Select evidence

• Similar properties to cholinesterase inhibitors

Apoaequorin

• Active ingredient in Prevagen

• Madison Memory Study showed improvement in cognitive function with apoaequorin versus placebo after 90 days in community-dwelling adults, but this finding was not supported by post hoc analyses.

• Used for centuries in Chinese medicine

• Calcium-binding protein originally found in jellyfish

B vitamins

• Vitamin B12, B6, folic acid • Water-soluble vitamins • May reduce homocysteine levels (a risk factor for dementia)

Caprylic acid

• Active ingredient of Axona • Medium-chain triglyceride from coconut oil or palm kernel oil

• The Federal Trade Commission (FTC) charged the marketers of Prevagen with making false and unsubstantiated claims regarding brain health benefits in 2017.

• Extract of turmeric • Targets inflammatory and antioxidant pathways

• Plant extract • Potential antioxidant and antiinflammatory properties • Used for centuries in Chinese medicine

• Potential protective antioxidant effect on cell membranes

• Phase 2 clinical trial showed improved memory testing (ADAS-Cog score) compared with placebo in patients with mild-to-moderate AD who were also taking FDA-approved AD drugs.

• Cochrane review of three RCTs found no efficacy of omega-3 polyunsaturated fatty acids in treatment of mild-to-moderate AD. • Systematic review and meta-analysis of 38 RCTs found little to no effect of long-chain omega-3 supplements on new neurocognitive outcomes or cognitive impairment. • Meta-analysis of 48 longitudinal studies found lower risk of all-cause dementia or cognitive decline with dietary intake of omega-3 fatty acids, but no definitive conclusion could be drawn.

• Meta-analysis of 95 studies found evidence of slowed cognitive decline with B-vitamin supplementation, especially with early and long-term use. Probiotics

• Living microorganisms • Modulate inflammatory processes and modify gut microbiota

Tramiprosate

• Modified form of the amino acid taurine • Active ingredient in ViviMind and Alzhemed

• RCT with 96 cognitively healthy older adults found limited influence of 1,500 mg/ day curcumin on cognitive function, mood or general quality of life at 12 months.

• Meta-analysis of 15 RCTs found that probiotic supplementation significantly improved cognitive function compared with placebo, particularly with singlestrain formulations, duration of supplementation ≥12 weeks and higher doses.

• Phase 3 extension study found sustained cognitive and functional benefits with tramiprosate 150 mg twice daily over 2.5 years in patients with mild-to-moderate AD who were APOE ε4/ε4 homozygotes.

• May inhibit toxic amyloid formation and amyloid aggregation

• May stimulate amyloid clearance in AD Ginkgo biloba

• Type of polyunsaturated fatty acid

• Cochrane review of five trials showed no evidence of cognitive benefit with 6–24 months of B-vitamin supplementation.

• Ketogenic compound Curcumin

Omega-3 fatty acids (DHA and EPA)

• Phase 3 GEM clinical trial showed no benefit of ginkgo biloba 120 mg twice daily compared with placebo in reducing overall incidence rate of dementia or AD in participants ≥75 years of age with normal cognition or MCI. • Systematic review and meta-analysis of nine RCTs found ginkgo biloba 240 mg daily showed stabilized or slowed decline in cognition, function, behavior and global change at 22–26 weeks in patients with cognitive impairment and dementia.

Vitamin E

• Group of eight fat-soluble compounds • Antioxidant properties

• Cochrane review of two RCTs found no evidence that the alpha-tocopherol form of vitamin E prevents progression to dementia in patients with MCI, but moderate evidence from a single study showed that it may slow functional decline in AD. • Systematic review and meta-analysis of five cohort studies and three RCTs did not find conclusive evidence on association between vitamin E and AD.

Alzheimer’s disease (AD); Alzheimer’s Disease Assessment Scale–Cognitive Subscale (ADAS-Cog); Food and Drug Administration (FDA); randomized controlled trial (RCT); mild cognitive impairment (MCI); docosahexaenoic acid (DHA); eicosapentaenoic acid (EPA); apolipoprotein E (APOE) 58

Appendix B: Phase 2 pipeline AD drugs Generic name/active pharmaceutical ingredient (API)

Manufacturer

Route of administration

Target

Generic name/API

Manufacturer

Scyllo-Inositol (ELND005)

Acumen Pharmaceuticals

Intravenous (IV), Subcutaneous (SC)

Target

Cell/Gene therapy

Amyloid sabirnetug (ACU-193)

Route of administration

Anti-Aβ oligomer (AβO) antibody

LX1001

Lexeo Therapeutics

Intrathecal

Apolipoprotein E4 (APOE4) ε4 gene therapy

RB-ADSC

Regeneration Biomedical

Intraventricular

Stem cell therapy

troculeucel (SNK01)

NKGen Biotech

Natural killer (NK) stem cell immunotherapy

Transition Therapeutics/ Perrigo

By mouth (PO)

Aβ protein inhibitor

varoglutamstat

Vivoryon Therapeutics

Glutaminyl cyclase (QC) inhibitor

zervimesine (Elayta; CT1812)

Cognition Therapeutics

Amyloid beta/amyloid plaques; progesterone receptor; sigma-2 (σ-2) receptor modulator

bryostatin

TAO Synergies

Protein kinase C (PKC) enzyme activator

MW150

NeuroKine Therapeutics

p38 mitogen-activated protein (MAP) kinase inhibitor

Cannabinoid receptor agonist

neflamapimod

EIP Pharma/Vertex/ CervoMed

p38 MAP kinase inhibitor

vafidemstat (ORY-2001)

Oryzon Genomics

Lysine-specific demethylase 1 (LSD1) inhibitor

Kinase regulation

Cannabinoid NTRX-07

NeuroTherapia

PO Cell/Gene therapy

AstroStem

Nature Cell

Stem cell therapy Infection-linked

debamestrocel (NurOwn)

BrainStorm Cell Therapeutics

Intramuscular (IM), Intrathecal

Stem cell therapy

HB-adMSC

Hope Biosciences

Stem cell therapy

laromestrocel (Lomecel-B)

Longeveron

Stem cell therapy

LHP588

Lighthouse Pharmaceuticals

Lysine-gingipain (Kgp) inhibitor

Metabolic/Lipid β-nicotinamide mononucleotide (MIB-626)

Metro International Biotech

Microcrystalline form of β-nicotinamide mononucleotide

pegylated exenatide (pegsebrenatide; NLY01)

D&D Pharmatech

Glucagon-like peptide-1 (GLP-1) receptor agonist

Appendix B: Phase 2 pipeline AD drugs (continued) Generic name/API

Manufacturer

Route of administration

Target

Generic name/API

Manufacturer

Metabolic/Lipid

Route of administration

Target

Neuroinflammation/Neuroimmune

piromelatine

Neurim Pharmaceuticals

Melatonin receptor agonist

senicapoc

Biossil

Potassium channel blocker

2-hydroxypropyl-beta-cyclodextrin (Trappsol Cyclo)

Rafael Holdings

Fatty acids; cholesterol mobilizer

VHB937

Novartis AG

TREM2 agonist

T3D-959

T3D Therapeutics

Peroxisome proliferator-activated receptor (PPAR) agonist

AL001 (Alzamend)

Alzamend Neuro

Neuroprotective agent; ionic cocrystal of lithium

Tricarboxylic acid (TCA) cycle/citric acid cycle (CAC)

allopregnanolone

NeuTherapeutics

Gamma-aminobutyric acid (GABA)-A receptor modulator; progesterone receptor

LM11A-31

PharmatrophiX

Nerve growth factor (NGF) receptor

traneurocin (NA-831)

NeuroActiva

Neuroprotective and neurogenic agent

S-equol

Ausio Pharmaceuticals

Estrogen receptor agonist

tricaprilin

emestedastat (Xanamem)

Cerecin

Actinogen Medical

Neuroprotection/Growth-factor signaling

Blocks 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1)

Neuroinflammation/Neuroimmune AL002

Alector/AbbVie

Triggering receptor expressed on myeloid cells 2 (TREM2) agonist

COYA-301 (interleukin-2)

Coya Therapeutics

Interleukin-2 (IL-2)

Synaptic/Cognition enhancers CSTC1-BAC (also called CSTC1, CHARSIRE Trauma Complex 1)

Charsire Biotechnology/ Botanicure

Topical

Anti-inflammatory agent

foralumab

Tiziana Life Sciences

Inhaled, Intranasal

Anti-cluster of differentiation (CD)3 epsilon subunit of T-cell receptor complex antibody

leronlimab (Vyrologix)

CytoDyn

Chemokine receptor 5 (CCR5)-targeting monoclonal antibody

pegipanermin (Quellor)

INmune Bio

Tumor necrosis factor-alpha (TNF-alpha)

pepinemab (VX15/2503)

Vaccinex/Merck & Co/EMD Serono

Semaphorin 4D/CD100 (SEMA4D) inhibitor

ABBV-552

AbbVie

Synaptic vesicle (SV2A) protein modulator

CST-2032/CST-107 + nadolol

CuraSen Therapeutics

Eta adrenergic agonist; beta adrenergic blocking agent

ismidenon (AD101)

AmyriAD Therapeutics

Calcium channel modulation

mevidalen (LY3154207)

Eli Lilly

Dopamine 1 (D1) receptor allosteric modulator

Appendix B: Phase 2 pipeline AD drugs (continued) Generic name/API

Manufacturer

Route of administration

Target

Generic name/API

Manufacturer

Route of administration Vaccine

Synaptic/Cognition enhancers MK-1167

Merck & Co/Neuphoria Therapeutics

Nicotinic acetylcholine receptor (nAChR) positive allosteric modulator (PAM)

PRX-3140

Nanopharmaceutics

5-hydroxytryptamine receptor 4 (5-HT4) receptor

troriluzole (Vyglxia; BHV-4157)

Biohaven ALS Biopharma

Glutamate modulator

zatolmilast (BPN14770)

Tetra Therapeutics/ Shionogi

Phosphodiesterase-4 (PDE4) inhibitor

Tau bepranemab (UCB0107)

UCB

Target

Microtubule binding region (MTBR) tau; anti-tau protein antibody

BMS-986446

Bristol Myers Squibb

IV, SC

MTBR tau; anti-tau protein antibody

diranersen (BIIB080/EXV-802)

Ionis Pharmaceuticals/ Biogen

Intrathecal

Tau proteins targeting antisense oligonucleotide

MK-2214

Merck & Co

MTBR tau; anti-tau antibody

VY7523

Voyager Therapeutics

MTBR anti-tau antibody

AADvac1

Axon Neuroscience

Tau aggregation inhibitor (TAI) vaccine

ACI-24

AC Immune

IM, SC

Anti-amyloid beta (Aβ) vaccine

ALZN002

Alzamend Neuro

Injectable

Cell-based anti-Aβ vaccine

Alzinova (ALZ-101)

Alzinova

Intranasal/injectable regimen under investigation

Oligomeric Aβ vaccine

JNJ-2056 (formerly ACI-35.030)

AC Immune/Johnson & Johnson

Anti-tau liposome-based vaccine

UB-311

Vaxxinity

Anti-amyloid beta vaccine

Miscellaneous NRCT-202XR

Neurocentria

N/A

Unknown

ONO-2020

Ono Pharmaceutical

Epigenetic regulator

*This table is not all-inclusive.

Clinical Insights: Alzheimer's in Focus