References

1. van Dyck CH, et al. Lecanemab in early Alzheimer's disease. N Engl J Med. 2023;388(1):9-21.

2. Haeberlein SB, et al. Two randomized phase 3 studies of aducanumab in early Alzheimer's disease. J Prev Alzheimers Dis. 2022;9(2):197-210.

3. Sims JR, et al. Donanemab in early symptomatic Alzheimer's disease: the TRAILBLAZER-ALZ2 randomized clinical trial. JAMA. 2023;330(6):512-527.

4. Porsteinsson AP, et al. Diagnosis of early Alzheimer's disease: clinical practice in 2021. J Prev Alz Dis. 2021;3(8):371-386.

5. Alzheimer’s Association special report: More Than Normal Aging: Understanding Mild Cognitive Impairment. Available at alz.org. Published 2022.

6. MoCA cognition FAQs. Available at mocacognition.com. Published 2023.  

7. Deak MC, Stickgold R. Sleep and cognition. Wiley Interdiscip Rev Cogn Sci. 2010;1(4):491-500.

For decades, clinicians have been unable to offer a treatment to slow the cognitive and functional decline of their patients with Alzheimer’s disease (AD). Cholinesterase inhibitors are formulated to preserve memory by preventing acetylcholine breakdown, but these agents lose effectiveness as the disease progresses and less acetylcholine is produced.¹ The N-methyl-D-aspartate receptor antagonist memantine has shown some clinical benefit in moderate to severe AD, but no efficacy in early-stage AD.²

Investigators, however, have continued to search for answers, probing alternative treatment targets to attempt to slow or even halt AD’s debilitating effects. One such target, the amyloid-beta cascade, is in the forefront of research. Through this pathway, amyloid-beta proteins proliferate, aggregate and lead to amyloid plaques and, ultimately, tau tangles that diminish cognition and function. Newer agents on the market and in the pipeline have shown efficacy in mild to moderate AD by targeting this pathway and eliminating amyloid plaques, and these findings are providing patients and their families with new hope against a difficult-to-manage disease.

“It is essential to control amyloid-beta as the place to start to find the right therapy to prevent or treat dementia,” says Samuel E. Gandy, MD, PhD, a professor of Alzheimer’s disease research and Associate Director of the Alzheimer’s Disease Research Center at Mount Sinai Medical Center in New York City.

The amyloid-beta pathway

Researchers have been following the amyloid-beta pathway since the mid-1980s, when the protein and its amino acid sequence were strongly associated with Down syndrome and, soon after, AD.³ Through the 1990s and early 2000s, studies that focused on autosomal dominant AD genes, genetic risk factors for amyloid-beta accumulation and AD-related biomarkers provided evidence that AD pathophysiology begins to develop decades before the onset of symptoms.³

“There are believers in this hypothesis, and there are disbelievers,” says Pierre N. Tariot, MD, Institute Director of the Banner Alzheimer’s Institute in Phoenix and co-director of the International Alzheimer’s Prevention Initiative. “The bottom line is that there is strong genetic evidence that amyloid is in some cases sufficient to cause Alzheimer’s dementia and in other cases necessary, but some say that this hasn’t been fully determined.”

What is known is that many people accumulate amyloid deposits in the brain as they age. As part of the normal molecular life cycle, the amyloid precursor proteins (APPs) from which amyloid-beta is developed are cleaved by alpha-secretase proteolytic enzymes, resulting in harmless amyloid fragments. Alternatively, some APPs are processed by gamma-secretase and beta-secretase enzymes, causing the resulting amyloid fragments to misfold and proliferate, leading to an imbalance in amyloid-beta production and breakdown common among people with AD.³

Misfolded amyloid-beta proteins initially are produced as soluble monomers; these monomers then proliferate and aggregate into larger soluble forms, including dimers and trimers, oligomers and protofibrils. Some of these aggregations later become insoluble fibrils that ultimately develop into insoluble plaques; both formations are associated with synaptic dysfunction in AD.³

Aside from proliferation, other factors that contribute to brain amyloid-beta buildup in AD include changes in receptor expression that dictate amyloid-beta movement between the brain and blood, as well as altered flow and absorption of cerebrospinal fluid during aging.³    

Delaying the progression of AD

As amyloid plaques keep developing and proliferating into an “amyloid bloom,” Dr. Tariot notes, they initiate the abnormal processing and accumulation of tau proteins and, ultimately, tau tangles. “It’s the tangle severity, not the amyloid burden, that is correlated with the degree of cognitive impairment in a patient who has symptoms,” he adds.    

Through decades of investigation, researchers identified amyloid protein accumulation in the brain as an upstream process that begins decades before AD symptoms develop (see Figure 1). This has led investigators to hypothesize that if the amyloid-beta cascade and plaque production could be detected and disrupted, the progression of AD and its devastating effects could be delayed and perhaps halted.

Researchers have responded by developing agents formulated to disrupt specific segments of the cascade. Since 2016, several molecules have been created to either prevent amyloid proteins from aggregating or inhibit the beta-secretase and gamma-secretase enzymes that misfold amyloid proteins. But so far, neither mechanism of action has shown efficacy in slowing AD-related cognitive and functional decline.⁴

Clinical trials on early-stage AD

A more recent mechanism for disrupting the pathogenesis that leads to plaque has involved development of amyloid-targeting agents, synthetic monoclonal antibodies that interact with different aspects of the cascade and prompt the immune system to detect and destroy soluble and insoluble amyloid formations, including plaques. While earlier amyloid-targeting antibodies have not shown efficacy, more recently developed agents in this class have been shown in clinical trials to slow clinical progression of early-stage AD compared with placebo.^5-7 One of these anti-amyloid antibodies recently received Food and Drug Administration (FDA) approval, and another is awaiting FDA approval.⁸

“In an 18-month trial period, persons on one of these agents are likely to have about 5 to 6 more months of preserved higher level of functioning compared with patients not receiving the treatment,” Dr. Tariot says. “That is, patients receiving these agents are about a third better off after 18 months, and there is thinking that if the treatment were to be continued, that treatment difference might continue to increase over time.”

Adds Dr. Gandy, “The data on treatments targeting amyloid-beta are very encouraging. It is the most hopeful mechanism of action we have seen so far.”   

Importance of genetic testing

It is important to note that amyloid-targeting antibodies carry a risk of amyloid-related imaging abnormalities (ARIA), the most common adverse effect of these agents. ARIA is believed to be caused by neuroinflammation or vascular rupture associated with plaque removal.⁹  

ARIA usually is asymptomatic, but in some, it can cause headaches, worsening confusion, dizziness, visual disturbances, nausea and seizures.⁹ It is most commonly associated with edema (ARIA-E) or hemorrhage (ARIA-H), and either subtype has been reported in about 40% of patients receiving these agents based on imaging tests, with one-quarter of patients reporting symptoms.¹⁰

Researchers also have found that ARIA-E is more prevalent at treatment initiation, when prescribed at higher dosages, among patients with more than four microhemorrhages at baseline, and among patients who carry the ApoE4 gene.⁹ Therefore, genetic testing for the ApoE4 gene is strongly recommended before administering an amyloid-targeting antibody, Dr. Tariot advises. In addition, studies have found that the risk of ARIA-H increases with age and cerebrovascular disease.⁹

Autoinjectors could be a game-changer

Targeting the amyloid-beta cascade holds significant promise for AD treatment and is among the most common mechanisms of action of AD agents now in development. About 25 therapies targeting different aspects of the cascade are in various clinical trial stages, as are agents that target alternative pathways associated with AD pathophysiology such as inflammation, oxidative stress and synaptic function.¹¹

Currently, anti-amyloid antibodies are administered by intravenous infusion, but subcutaneous formulations also are being developed. One subcutaneous molecule has received FDA fast-track designation,¹² while others are in early-stage clinical trials. “This could be a major game-changer,” Dr. Tariot says. “Patients wouldn’t need to go into an infusion center. You could use an autoinjector at home.” He adds that, in addition to convenience, ease of use and cost-effectiveness, subcutaneous amyloid-targeting antibodies may reduce ARIA-E incidence compared with intravenous formulations, as peak drug levels would be lower with the subcutaneous versus the intravenous version.    

More studies on AD prevention

As research into slowing AD progression continues, some investigators are turning their attention to stopping the disease before it develops. There are large clinical trials studying whether amyloid-targeting antibodies can prevent AD in people who are at known risk of the disease but who don’t yet have cognitive or functional symptoms.

For example, in one AD prevention trial, the AHEAD-345 study, unimpaired participants ages 55 to 80 with elevated or intermediate levels of amyloid confirmed by brain imaging will receive an amyloid-targeting therapy or placebo to determine if the agent can prevent plaques and tau tangles from developing and thereby prevent AD in older persons at risk of the disease. Study completion is scheduled for 2027.^13,14    

Additionally, in the TRAILBLAZER-ALZ3 study, unimpaired participants ages 55 to 80 who are at risk of future AD based on blood biomarkers will receive an amyloid-targeting therapy or placebo to determine if the agent can prevent AD in older persons at risk of the disease. Study completion is scheduled for 2027.^15,16

Although previous AD prevention studies have not panned out, Drs. Tariot and Gandy say the concept still is worth exploring given the performance of amyloid-targeting antibodies in removing brain plaques in clinical trials. “Can you stave off the so-called downstream effects on tau and inflammation and membrane function and essentially arrest the disease course?” Dr. Tariot asks. “That’s an unknown, but we should soon be getting those answers.”

—by Pete Kelly

References

1. National Institute on Aging. How is Alzheimer's disease treated? Updated April 1, 2023. Available at nia.nih.gov.

2. McShane R, et al. Memantine for dementia. Cochrane Database Syst Rev. 2019;2019(3):CD003154.

3. Hampel H, et al. The amyloid-b pathway in Alzheimer's disease. Mol Psychiatry. 2021;26(10):5481-5503.

4. Huang L-K, et al. Clinical trials of new drugs for Alzheimer's disease. J Biomed Sci. 2020;27(1):18.

5. van Dyck CH, et al. Lecanemab in early Alzheimer's disease. N Engl J Med. 2023;388(1):9-21.

6. National Institute on Aging. NIA statement on report of lecanemab reducing cognitive decline in Alzheimer’s clinical trial. July 6, 2023. Available at nia.nih.gov.

7. Sims JR, et al. Donanemab in early symptomatic Alzheimer’s disease. JAMA. 2023;330(6):512-527.

8. National Institute on Aging. NIA statement on report of donanemab results: more Alzheimer’s research progress. July 17, 2023. Available at nia.nih.gov.

9. Withington CG, Turner RS. Amyloid-related imaging abnormalities with anti-amyloid antibodies for the treatment of dementia due to Alzheimer's disease. Front Neurol. 2022;13:862369.

10. Salloway S, et al. Amyloid-related imaging abnormalities in 2 phase 3 studies evaluating aducanumab in patients with early Alzheimer disease. JAMA Neurol. 2022;79(1):1-10.

11. Cummings J, et al. Alzheimer's disease drug development pipeline: 2023. Alzheimers Dement (N Y). 2023;9(2):e12385.

12. Cummings J. Anti-amyloid monoclonal antibodies are transformative treatments that redefine Alzheimer’s disease therapeutics. Drugs. 2023;83(7):569-576.

13. The AHEAD-345 study. Available at clinicaltrials.gov.

14. The TRAILBLAZER-ALZ3 study. Available at clinicaltrials.gov.

Changes in cognitive function are common in aging patients and can affect a variety of cognitive domains including memory, learning and decision-making. Unfortunately, some patients and even healthcare professionals have a fatalistic attitude about the effects of aging on the brain, including the belief that dementia is often an inevitable consequence of getting older. However, research shows that simple lifestyle modifications can help slow the progression of cognitive decline, especially in the early stages. “It’s so important for people to be proactive about brain health because, while there are many potential treatments on the horizon, nothing is going to replace taking care of our brain to preserve brain function and reduce the risk of developing mild cognitive impairment (MCI), Alzheimer’s disease, stroke and other brain disease,” says Marie Pasinski, MD, Assistant Professor of Neurology at Harvard Medical School in Cambridge, MA. “The studies are powerful, showing that more than 40% of dementia cases are due to modifiable risk factors.”¹

Assessing modifiable risks

To start, Dr. Pasinski recommends using tools that can identify modifiable risk factors. “Brain health is all about understanding how we are currently caring for our brain and knowing what things we need to focus on,” she explains. When it comes to assessing brain health, she recommends the McCance Brain Care Score, which can be calculated using a short questionnaire developed at the Massachusetts General Hospital McCance Center for Brain Health. The Brain Care Score was developed to serve as an evidence-based tool to evaluate modifiable risk factors (e.g., hypertension, dyslipidemia, overweight/obesity, etc.) that have been shown to affect brain health, cognitive function and dementia risk. In a study involving nearly 400,000 adults, the Brain Care Score was found to be significantly predictive of risk for future dementia.²

Counseling patients on lifestyle modifications

“It’s never too early or too late to change our brain for the better,” says Dr. Pasinski. To help improve brain function in all patients, including those without brain disease and those with cognitive decline, Dr. Pasinski advocates for addressing modifiable risks outlined in the Brain Care Score. Specifically, counsel patients on adopting these healthy habits:

1. Follow the MIND diet.

Nutrition plays a key role in the health of the brain, affecting a variety of factors such as inflammation, energy and blood supply. For optimal brain health, Dr. Pasinski recommends the MIND diet (Mediterranean-DASH Diet Intervention for Neurodegenerative Delay). As the name suggests, this is modeled after the Mediterranean diet and Dietary Approaches to Stop Hypertension (DASH) promoted by the National Heart, Lung and Blood Institute. The DASH diet also incorporates evidence-based recommendations that focus specifically on brain health.

“What I like about the MIND diet is that it not only provides guidelines for how many servings of specific brain-healthy foods people should be eating per week, but also what unhealthy foods to limit,” explains Dr. Pasinski. For instance, the MIND diet specifically recommends 6 or more servings of green leafy vegetables per week. Other brain-healthy foods include whole grains, nuts, berries, poultry, fish and olive oil as the primary fat. Sodium should be limited to 1,500 mg per day, and restricting foods such as pastries, sweets, red meat, cheese and butter is recommended.

Rigorous adherence to the MIND diet was shown to lower the risk of Alzheimer’s disease by 53%, while those who followed it moderately reduced their risk by 35%.³ Additional research found that the MIND diet is associated with a lower risk for Alzheimer’s disease and delayed rates of cognitive decline, even among individuals who are considered genetically high risk for Alzheimer’s disease.⁴

2. Limit alcohol consumption.

“We used to think alcohol was part of the brain-healthy diet and red wine is often cited as part of the Mediterranean diet,” explains Dr. Pasinski. “But those studies were confounded by the fact that alcohol is a luxury item. People who can afford alcohol also tend to have access to better healthcare and have lower rates of dementia risk factors. Alcohol is a known neurotoxin to the brain.” She adds, “We recommend limiting it. None is best, and that’s what I advocate for, especially with patients who are experiencing memory problems.”

3. Quit smoking.

Smoking affects vascular health, which is known to play an important role in the development of Alzheimer’s disease. Research has found that, among older adults (>65 years), smoking increases the risk for dementia by up to 60%. Smoking cessation, on the other hand, has been found to reduce the risk for dementia by up to 10% after at least 4 years.⁴ Support your patients who smoke by giving them resources to help them kick the habit, such as 1-800-QUIT-NOW or smokefree.gov.

4. Be physically active—and avoid prolonged sitting.

For adults, 150 minutes of moderate-intensity physical activity, or 75 minutes of high-intensity physical activity, per week is recommended by most major health organizations. Alongside these recommendations, Dr. Pasinski suggests her patients avoid sitting for long periods. “We know that with prolonged sitting, cortisol levels rise and blood sugar rises,” she explains. “Weaving more physical activity throughout your day, or just getting up for a couple of minutes and walking around, can bring those levels down.”    

For added benefits, Dr. Pasinski encourages patients to engage in activities that they enjoy. “When it’s fun, it boosts the benefits in the brain,” she says. She suggests combining physical activity with mental stimulation and socialization by learning a new sport such as pickleball or joining a team.

5. Get restorative sleep.

“We know that sleep is critical for brain health,” says Dr. Pasinski. “During sleep, the brain rejuvenates itself, fortifies synapses, and stores new information learned during the day. It’s also when the toxic plaque-forming beta-amyloid that accumulates in Alzheimer’s disease is cleared from the brain. When we miss out on sleep, we’re missing out on a great chance to boost our brain health.”                         

Research suggests that insufficient sleep (≤6 hours per night) in adults over the age of 50 is associated with a 30% increased risk for dementia.⁵ To help improve sleep, Dr. Pasinski urges healthcare providers to check patients for underlying sleep disorders, particularly in those who report snoring or poor-quality sleep. Addressing untreated sleep problems can have profound effects on cognitive health. “I’ve had many patients who present with memory problems that turn out to have an untreated sleep disorder like obstructive sleep apnea,” she notes. “And once this is treated, their memory improves.”

6. Stay engaged, control stress and socialize.

“Mental health is an important component of brain health,” says Dr. Pasinski, adding that research has revealed a significant link between depression and anxiety and the risk of developing Alzheimer’s disease. Similarly, loneliness is also strongly associated with dementia.⁶ In addition to stress management and addressing mental health needs, Dr. Pasinski recommends encouraging patients to nurture social relationships and become more involved in their community. “The brain is hardwired to bond with others,” she says. “When we emotionally connect with others, a potent cocktail of feel-good neurotransmitters—including serotonin and dopamine, the brain’s natural antidepressants—is released. Socializing has also been shown to lower cortisol levels, ease anxiety and improve overall health.” According to Dr. Pasinski, “Having a rich social network is not only wonderful for the brain, but it’s also one of the best predictors of happiness, longevity and well-being.”

—by Morgan Meissner

References

1. Livingston G, et al. Dementia prevention, intervention, and care: 2020 report of the Lancet Commission. Lancet. Aug 8 2020;396(10248):413-446.

2. Singh SD, et al. The predictive validity of a Brain Care Score for dementia and stroke: data from the UK Biobank cohort. Front Neurol. 2023;14:1291020.

3. Morris MC, et al. MIND diet associated with reduced incidence of Alzheimer's disease. Alzheimers Dement. Sep 2015;11(9):1007-1014. 

4. Vu THT, et al. Adherence to MIND diet, genetic susceptibility, and incident dementia in  three US cohorts. Nutrients. Jul 3 2022;14(13).

5. Sabia S, et al. Association of sleep duration in middle and old age with incidence of dementia. Nat Commun. Apr 20 2021;12(1):2289.  

6. Sutin AR, et al. Loneliness and risk of dementia. J Gerontol B Psychol Sci Soc Sci. 2020 Aug 13;75(7):1414-1422.

PATIENT: DON, 77, HAD A GRADUAL COGNITIVE DECLINE OVER 1 YEAR. A NEUROPSYCHIATRIC HISTORY ALSO REVEALED UNCHARACTERISTIC IRRITABILITY.

“Don’s early-stage AD pathology made him a candidate for anti-amyloid therapy”

PHYSICIAN:
Pierre N. Tariot, MD,
Director, Banner Alzheimer’s Institute, Phoenix, and Co-Director, Alzheimer’s Prevention Initiative

History:
Around mid-2021, Don’s wife first noticed that he repeated questions and forgot about recent events. This became more noticeable over the next year, but Don was unaware of his memory lapses. In May 2022, Don saw his primary care physician, who performed a brief history and examination that showed no focal findings or parkinsonism, and a Mini Mental State Examination with a score of 23. Routine labs were normal. He was referred 2 months later to our institute, where a cognitive history revealed recent memory lapses, difficulty finding words and trouble making financial decisions. A functional history uncovered errors in managing his personal affairs, and a neuropsychiatric history revealed uncharacteristic irritability. A neurological exam was normal except for mild high-frequency hearing loss. Montreal Cognitive Assessment score was 22. Don had had a TIA more than 2 years earlier.  

An unenhanced brain MRI showed mild atrophy and nonspecific white matter changes. Neuropsychological testing also was performed. Don was diagnosed with mild cognitive impairment (MCI), probably due to Alzheimer’s pathology, that was mainly amnestic with some changes in language, executive function and mood. There was no other relevant medical history.

Initiating treatment:
First, Don was prescribed an acetylcholinesterase inhibitor. Family members reported that he “seemed more like himself,” was less irritable and more fluent. Four months later, Don and his family asked to explore anti-amyloid AD therapy. We reviewed Don’s medical eligibility and determined he had no major contraindications, including a cerebrovascular accident, seizure, or TIA in the previous year; severe microvascular disease or vasogenic edema; a macro hemorrhage that exceeded 10 mm; or anticoagulant or thrombolytic agent use. I also discussed the need for genotyping, biomarker confirmation, biweekly infusions and surveillance MRIs.

In addition, I reviewed infusion-related reactions including headache, dizziness, flu-like symptoms and blood pressure changes, as well as potential amyloid-related imaging abnormalities with edema (ARIA-E), or with microhemorrhage (ARIA-H). ARIA-E can be asymptomatic or can cause symptoms such as headaches, confusion, unsteady gait, visual disturbances, nausea and, rarely, seizures that are usually mild and resolve with treatment interruption. In rare cases, ARIA-E can be persistent and severe.

Don underwent cerebrospinal fluid testing, which revealed amyloid and tau proteins indicative of AD pathology. Genotyping uncovered both the APOE 3 and 4 alleles, the latter of which contributes to ARIA-E risk. However, Don was still eligible for anti-amyloid treatment and began the infusions. To monitor for asymptomatic ARIA, he had brain MRIs before the fifth, seventh and 14th infusions. He experienced a mild infusion reaction with the first dose, which resolved with NSAIDs and antihistamines. After 5 months, Don’s family reports that he is stable. We will repeat cognitive and functional assessments at month 6.

Considerations:
Early AD diagnosis can help explain unusual signs and symptoms and enhance quality of life for the patient and their family. It allows them both to participate in care decisions and state preferences and to access educational and supportive resources sooner. Neuropsychiatric symptoms can be addressed, and treatment of AD and comorbidities can be optimized.

Fortunately, today’s increased knowledge of AD pathology and the advent of anti-amyloid agents provide new hope for slowing AD progression. FDA-approved monoclonal antibodies work by targeting and removing certain forms of beta-amyloid, a signature protein of AD pathology. Importantly, evidence suggests that anti-amyloid treatment should start in the early stages of AD to be effective, so timing and early recognition are critical.

KOL on Demand