The Era of Disease-Changing Alzheimer’s Disease Treatments

Inside first articleGreg Cooper, MD, PhD, discussed the early symptoms of Alzheimer’s disease and the barriers to early diagnosis.

The era of long-awaited disease-modifying therapies in the field of Alzheimer’s disease has finally arrived. In the past few years, 3 drugs have received FDA approval for the treatment of Alzheimer’s disease or mild cognitive impairment (MCI) due to Alzheimer’s disease.

The first of these was aducanumab, which received accelerated approval from the FDA in 2021 based primarily on evidence of amyloid removal.1 It has not been widely adopted by experts and will be phased out in late 2024.2,3 However, 2 newer agents (lecanemab and donanemab) have become available. was presented. has received full FDA approval with clinical trial evidence for both amyloid elimination and clinical benefit.4,5 Although these treatments do not reverse the cognitive symptoms of Alzheimer’s disease, they significantly slow the progression; Some evidence suggests that early treatment is most effective.

Drug Mechanisms

Both lecanemab and donanemab are monoclonal antibodies that target beta-amyloid; lecanemab more specifically targets amyloid fibrils. These agents have been shown to reduce cerebral amyloid levels with high efficacy, typically over a period of 12 to 18 months. According to the amyloid cascade hypothesis, beta-amyloid accumulation leads to a cascade of subsequent events that ultimately result in the development of clinical symptoms of Alzheimer’s disease, making it a logical target for treatment. According to the amyloid cascade hypothesis, beta-amyloid deposition is followed by the production of neurofibrillary tangles or hyperphosphorylated tau aggregates. As would be predicted based on this hypothesis, tau levels are reduced in patients treated with anti-amyloid agents, indicating the expected downstream effect of these treatments. These treatments also show a modest but significant slowing of cognitive decline, again consistent with what would be expected based on the amyloid cascade hypothesis.

Drug Indications

However, these disease-modifying treatments are now approved and have been shown to be effective very early in the clinical course of Alzheimer’s disease, at the MCI or mild dementia stage. In the MCI phase, when there is no significant impairment in activities of daily living, we would expect a mild impairment in memory. In the mild dementia stage, we expect memory to worsen as well as needing at least a little help with daily activities. Unfortunately, these medications are not known to be effective when symptoms extend beyond these stages. In fact, there is preliminary evidence to suggest that the earlier treatment is started, the greater the effect. So, similar to what is said about stroke, this may be another situation where “time is brain.”

Despite these drugs’ significant promise, they also face significant challenges. First, we need to develop systems that will facilitate the early identification of suitable patients and their referral to specialists and centers that can administer these drugs. Centers administering these medications must coordinate among various departments and stakeholders to facilitate necessary evaluations (e.g., clinical examinations, imaging studies, biomarker studies) and treatment. These medications are intravenous infusions that require coordination with the pharmacy and infusion center, among others.

Additionally, although effective, these medications are not without risks. Of greatest concern are amyloid-associated imaging abnormalities (ARIA), which essentially mean swelling (ARIA-E) or bleeding (ARIA-H) in the brain. ARIA-H typically consists of microbleeds seen only on MRI but may also include larger hemorrhages. Experts warn of the potential for rare deaths from these drugs. Therefore, careful monitoring systems, including frequent MRI examination, ideally in coordination with well-trained radiology partners, are required. In our experience, creating order sets in our electronic medical records and establishing additional in-office protocols has helped ensure that all regularly recommended safety MRI examinations are scheduled at the time treatment is initiated. Following discussions among all stakeholders, we established additional safeguards to prevent further infusions without confirmation that required MRI examinations were reviewed, significant and/or symptomatic ARIA was absent, and continued compliance was confirmed. Establishing these processes at the beginning can help prioritize security and run the entire program efficiently.

Despite these challenges, the development and institutionalization of an anti-amyloid program comes with significant rewards. We have found that patients and their families are extremely enthusiastic and grateful for the opportunity to receive these medications. While they understand that these treatments are not a cure, they do provide significant hope. For many, these treatments offer the hope of preserving a higher quality of life that you can enjoy with friends and family for longer than would normally be expected, and this has proven to be very meaningful. In our experience, the value of such a program goes well beyond studies, especially with careful planning, involvement of multiple stakeholders, and careful and open communication from the beginning of treatment and continuing throughout treatment.

Greg Cooper, MD, PhD, is chief of adult neurology and director of the Memory Center at the Norton Neuroscience Institute. He briefly led the dementia clinic at the University of Iowa before joining the Sanders-Brown Center on Aging at the University of Kentucky and later founded and directed the Baptist Health Memory Care Program until joining Norton in 2021. Cooper was also actively involved in research. has served as principal investigator on a number of clinical trials and has a strong interest in education and caregiver support.

References

1. FDA grants accelerated approval for Alzheimer’s drug. FDA. Newsletter. June 7, 2021. Access date: November 1, 2024. https://www.fda.gov/news-events/press-announcements/fda-grants-accelerated-approval-alzheimers-drug

2. Stefanacci RG. The curse of being first: Lessons from the pharmaceutical industry’s blockbuster drugs. AJMC^®. 8 March 2024. Access date: 1 November 2024. https://www.ajmc.com/view/the-curse-of-being-first-lessons-from-pharma-s-blockbuster-drugs

3. Joszt L. Biogen discontinues aducanumab and focuses on lecanemab for Alzheimer’s disease. AJMC. 31 January 2024. Access date: 1 November 2024. https://www.ajmc.com/view/biogen-abandons-aducanumab-pivots-focus-to-lecanemab-for-alzheimer-disease

4. Joszt L. FDA grants full approval for Alzheimer’s drug lecanemab. AJMC. July 6, 2023. Access date: November 1, 2024. https://www.ajmc.com/view/fda-grants-full-approval-for-alzheimer-drug-lecanemab

5. Jeremias S. FDA approves donanemab for early Alzheimer’s disease. AJMC. 2 July 2024. Access date: 1 November 2024.