Treating and Managing Alzheimer’s

There is no cure for Alzheimers disease (AD), however, disease progression can be altered with non-pharmacologic and pharmacologic treatment options.¹^,2 AD is a neurodegenerative condition that typically gets worse over time, and treatments are generally most effective in the early stage of the disease process.³

Non-Pharmacologic Interventions for Alzheimer's Disease

Non-pharmacologic interventions do not change the underlying disease course, however, are often implemented to help maintain or improve cognitive function as well as reduce behavioral symptoms.² Such intervention can include cognitive stimulation, music-based therapy, psychological treatment (ie, cognitive behavioral therapy), physical therapy/exercise, and a healthy diet.²^,3 Safety, effectiveness and purity of alternative therapies/supplements is largely unknown, although trials evaluating the effectiveness of some “medical foods”, such as medium-chain triglycerides, are being conducted.⁴

Pharmacologic Treatments for Alzheimer's Disease

Mainstays for pharmacologic therapy focus on either temporarily managing AD symptoms or treating the underlying cause of disease.^5,6 In terms of pharmacologic therapy, to date seven drugs have received approval from the US FDA for the treatment of AD. These include three acetylcholinesterse inhibitors (donepezil, rivastigmine, and galantamine), one N-methyl-D-aspratate [NMDA] antagonist (memantine), one combination medications (memantine plus donepezil), and three disease modifying therapies (aducanumab, donanemab and lecanemab).^2,23

Pharmacologic Options for Symptom Control

People with AD have diminished cholinergic function due to decreased acetylcholine synthesis.¹ Cholinesterase inhibitors, like donepezil, rivastigmine, and galantamine, can increase cholinergic transmission leading to an improvement in AD symptoms.¹

People with all stages of AD may benefit from a trial of cholinesterase inhibitors as they may show a small benefit in cognition, neuropsychiatric symptoms, and activities of daily living (ADLs).¹ However, results may be variable, as studies suggest that no observable benefit is seen in up to 30%-50% of people with AD.¹ On the other end of the spectrum, up to 20% of people may see above-average improvement in symptoms.¹ Side effects of cholinesterase inhibitors include nausea, vomiting, diarrhea, sleep disturbances, bradycardia, cardiac conduction defects, and syncope.³ Additionally, avoidance of tricyclic antidepressants for treatment of anxiety, depression and psychosis is key due to their anticholinergic activity.³

Memantine is another therapeutic option for AD that can be given as monotherapy or in combination with cholinesterase inhibitors.³ This agent acts by blocking pathologic stimulation of NMDA receptors by neurotransmitter glutamate and slowing intracellular calcium accumulation.^1,2,3This distinct mechanism of action is considered neuroprotective against glutamate and may restore physiologic neuronal function.¹^,2 Studies also suggest memantine may give patients a small improvement in cognition, dementia, and quality of life.¹Common side effects of memantine include dizziness, body aches, headache, and constipation.³

Alzheimer's Disease Modifying Treatments

The United States Food and Drug Administration (FDA) has approved aducanumab (2021) and lecanemab (2023) through an accelerated approval pathway, and full approval of donanemab (2024).^8,9,23 Aducanumab is a recombinant monoclonal antibody targeting amyloid-beta (EMERGE and ENGAGE trials) approved for people with mild cognitive impairment (MCI) and the mild dementia stage of AD, but is recommended to limit use to those with documented amyloid pathology on amyloid positron emission tomography (PET) scans.¹^,2,7,10 Aducanumab is associated with an increased risk of amyloid-related imaging abnormities (ARIA) which can be an indicator of brain swelling; post-approval trials are required to verify clinical benefit.¹^{, 2} However, it should be noted that aducanumab is being discontinued in 2024. Although no longer available through clinical trial, the manufacturer, Biogen has stated that patients receiving aducanumab via prescription from their treating physicians will have it available until Nov. 1, 2024.⁷ Lecanemab is another monoclonal antibody targeting β-amyloid protofibrils (CLARITY-AD), with approved indications of use in those with MCI and the mild dementia stage of AD, following confirmed presence of amyloid-beta pathology.^5,11 ARIA events have also been associated with lecanemab; post approval trials are required to verify clinical benefit.⁵

Donanemab, also a monoclonal antibody targeting the N-terminal pyroglutamate epitope, a modified form of amyloid-beta present only in established plaques.^14,15 Clinical trials suggest that this new medication not only reduces amyloid plaques as measured by ¹⁸F-florbetapir uptake on PET, but also lowers levels of plasma tau biomarkers (TRAILBLAZER-ALZ and TRAILBLAZER-ALZ2 trials).^14,15 Donanemab has also been shown to have less cognitive and functional decline over placebo.¹⁴ARIA has also been observed with use of donanemab in the clinical trial setting.¹⁴

Emerging Treatments

At the present time a total of 36 agents are being assessed in 55 different AD trials, among which disease modifying agents comprise 67%.¹³ Another theraputic in the research pipeline includes gantenerumab, a monoclonal antibody targeting amyloid-beta.¹⁶ Gantenerumab binds aggregated amyloid beta plaques by phagocytosis, and also showed a robust decrease in amyloid plaques after 2 years of treatment.¹⁶

Embracing a Team Approach in Alzheimer's Disease

Management goals for AD include strategizing to optimize dementia outcomes, focusing on lessening symptoms and maintaining quality of life through maximizing function, cognition, behavior and safety.²⁰ A multidisciplinary approach and collaborative care model focuses on long-term, systematic approaches for management of chronic conditions like AD, possibly utilizing cost-efficient strategies to improve health outcomes and shared decision-making for individualized treatment.²¹ This team can help facilitate adaptation to cognitive and behavioral changes with disease progression as well as refer for participation in dementia-related clinical trials.^20,22 Nonmedical issues related to long-term care planning for changing needs over the course of AD can also be discussed, such as establishing a healthcare power of attorney, creating a living will, determining end-of-life care preferences and reviewing finances.¹⁸
Click here to view and download a cognitive impairment care planning toolkit provided by the Alzheimer’s Association^®.

References

Press, D & Buss, SS. Treatment of Alzheimer Disease. UpToDate. https://www.uptodate.com/contents/treatment-of-alzheimer-disease
2023 Alzheimer’s disease facts and figures. Alzheimers Dement. 2023;19(4):1598-1695.
Kumar A, Sidhu J, Goyal A, et al. Alzheimer Disease. StatPearls. 2022. https://www.ncbi.nlm.nih.gov/books/NBK499922/
Alzheimer’s Association^®. Alternative treatments. https://www.alz.org/alzheimers-dementia/treatments/alternative-treatments
National Institute on Aging (NIA). How is Alzheimer’s Disease Treated. https://www.nia.nih.gov/health/how-alzheimers-disease-treated
Alzheimer’s Association^®. Treatments and research. https://www.alz.org/help-support/i-have-alz/treatments-research
Abeysinghe AADT, Deshapriya RDUS, Udawatte C. Alzheimer’s disease; a review of the pathophysiological basis and therapeutic interventions. Life Sci. 2020;256:117996.
Aducanumab (Aduhelm^®) Prescribing Information. August 2023. https://www.biogencdn.com/us/aduhelm-pi.pdf
Lecanemab (Leqembi^®) Prescribing Information. July 2023. https://www.leqembi.com/-/media/Files/Leqembi/Prescribing-Information.pdf?hash=3d7bf1a2-5db2-4990-8388-81086f415676
Tampi RR, Forester BP, Agronin M. Aducanumab: evidence from clinical trial data and controversies. Drugs Context. 2021;10:2021-7-3.
Swanson CJ, Zhang Y, Dhadda S, et al. A randomized, double-blind,
phase 2b proof-of-concept clinical trial in early Alzheimer’s disease
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Ten Kate M, Ingala S, Schwarz AJ, et al. Secondary prevention of Alzheimer’s dementia: neuroimaging contributions. Alzheimers Res Ther. 2018:10:112.
Mintun MA, Lo AC, Evans CD, et al. Donanemab in Early Alzheimer’s Disease. N Engl J Med. 2021;384:1691-1704.
Sims JR, Zimmer JA, Evans CD, et al. Donanemab in Early Symptomatic Alzheimer Disease: The TRAILBLAZER-ALZ 2 Randomized Clinical Trial. JAMA. 2023;330(6):512-527.
Cummings J, Zhou Y, Lee G, Zhong K, Fonseca J, Cheng F. Alzheimer’s disease drug development pipeline: 2023. Alzheimers Dement (N Y). 2023;9(2):e12385.
Klein G, Delmar P, Voyle N, et al. Gantenerumab reduces amyloid-β plaques in patients with prodromal to moderate Alzheimer’s disease: a PET substudy interim analysis. Alzheimers Res Ther. 2019;11:101.
Ellison JM. Understanding the healthcare team in Alzheimer’s disease. 8/11/2021. https://www.brightfocus.org/alzheimers/article/understanding-health-care-team-alzheimers-disease
Jurkowski CL. A Multidisciplinary Approach to Alzheimer’s Disease: Who Should Be Members of the Team? Am J Med. 1998;104(suppl 1);13S-16S.
UCSF Department of Radiology & Biomedical Imaging. Radiology’s Role in Determining the Impact of Amyloid PET Imaging on Real-World Alzheimer’s Disease and Dementia Care. 6/19/2019. https://radiology.ucsf.edu/blog/radiologys-role-determining-impact-amyloid-pet-imaging-real-world-alzheimers-disease-and
Alzheimer’s Association^®. Management. https://www.alz.org/professionals/health-systems-medical-professionals/management
Galvin JE, Valois L, Zweig Y. Collaborative transdisciplinary team approach for dementia care. Neurodegener Dis Manag. 2014;4:455-469.
Alzheimer’s Association^®. Clinical trials recruiting. https://www.alz.org/professionals/health-systems-medical-professionals/clinical_trials_recruiting
News release 7/2/24 (https://investor.lilly.com/news-releases/news-release-details/lillys-kisunlatm-donanemab-azbt-approved-fda-treatment-early). Accessed 7/9/24.