Contributor: The Era of Disease-Modifying Alzheimer Disease Treatments

In his first article, Greg Cooper, MD, PhD, discussed early symptoms of Alzheimer disease and barriers to earlier diagnosis.

Greg Cooper, MD, PhD

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

The first was aducanumab, which received accelerated approval from the FDA in 2021 primarily based on evidence for amyloid removal.1 It was not widely embraced by specialists and will be discontinued in late 2024.2,3 However, 2 newer agents—lecanemab and donanemab—have received full FDA approval with clinical trial evidence for both removal of amyloid and clinical benefit.4,5 While these treatments don’t reverse the cognitive symptoms of Alzheimer disease, they significantly slow progression, with some evidence suggesting that earlier treatment is most effective.

Drug Mechanisms

Both lecanemab and donanemab are monoclonal antibodies targeting beta-amyloid, with lecanemab targeting amyloid fibrils more specifically. These agents have been shown to reduce levels of cerebral amyloid with high efficacy typically over a 12- to 18-month period. According to the amyloid cascade hypothesis, accumulation of beta-amyloid leads to the subsequent cascade of events ultimately resulting in the development of clinical symptoms of Alzheimer’s disease, making this a logical target for treatment. According to the amyloid cascade hypothesis, neurofibrillary tangles, or the production of hyperphosphorylated tau aggregates, follow the accumulation of beta-amyloid. As would then be predicted based on this hypothesis, levels of tau are reduced in patients treated with anti-amyloid agents, indicating an expected downstream impact 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 currently are only approved and shown to be effective very early in the clinical course of Alzheimer disease, at the stage of MCI or mild dementia. At the MCI stage, we would expect to see mild impairment in memory in the absence of significant impairment of activities of daily living. In the mild dementia stage, we expect worsening memory along with the need for at least minor assistance with daily activities. Unfortunately, once symptoms have progressed beyond these stages, these medications are not known to be effective. In fact, there is preliminary evidence to suggest the earlier treatment is started, the greater the impact. In other words, much like what has been said about stroke, this may be another circumstance where “time is brain.”

Despite the significant promise of these medications, they come with significant challenges. First, we need to develop systems that facilitate the early recognition and triaging of appropriate patients to specialists and centers capable of administering these medications. Those centers administering these medications must coordinate among various departments and stakeholders to facilitate the needed evaluations (eg, 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, while effective, these medications are not without risk. Of greatest concern is amyloid-related imaging abnormalities (ARIA), which essentially means swelling (ARIA-E) or bleeding (ARIA-H) in the brain. ARIA-H typically consists of microhemorrhages seen only on MRI, but can also include larger hemorrhages. Experts warn of the potential for rare deaths with these medications. Therefore, careful monitoring systems, which include frequent MRI examination, are necessary, ideally in coordination with well-trained radiology partners. In our experience, the creation of order sets in our electronic medical record and the institution of additional in-office protocols have helped ensure all regularly recommended safety MRI examinations are scheduled at the time treatment is initiated. After discussion among all stakeholders, we have created additional safeguards, preventing further infusions without affirmation of review of required MRI examinations, absence of significant and/or symptomatic ARIA and ongoing eligibility. Creating these processes initially can help make sure that safety is prioritized and that the entire program runs efficiently.

Despite these challenges, the development and institution of an anti-amyloid program comes with significant rewards. We have found patients and families to be highly enthusiastic and grateful for the opportunity to receive these medications. While they understand these treatments are not a cure, they do provide significant hope. For many, these treatments offer the hope of preservation of a higher quality of life to be enjoyed with friends and family for a longer period of time than otherwise would be expected, and this has proven very meaningful. In our experience, the value of such a program has far exceeded the work involved, particularly with careful planning, engagement of multiple stakeholders, and ongoing careful and open communication from the beginning and throughout treatment.

Greg Cooper, MD, PhD, is chief of adult neurology and director of the Memory Center at Norton Neuroscience Institute. He briefly directed the dementia clinic at the University of Iowa before joining the Sanders-Brown Center on Aging at the University of Kentucky, and later formed and directed the Baptist Health Memory Care Program until joining Norton in 2021. Cooper has also been active in research serving 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. News release. June 7, 2021. Accessed 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 pharma’s blockbuster drugs. AJMC^®. March 8, 2024. Accessed November 1, 2024. https://www.ajmc.com/view/the-curse-of-being-first-lessons-from-pharma-s-blockbuster-drugs

3. Joszt L. Biogen abandons aducanumab, pivots focus to lecanemab for Alzheimer disease. AJMC. January 31, 2024. Accessed November 1, 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 drug lecanemab. AJMC. July 6, 2023. Accessed 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 disease. AJMC. July 2, 2024. Accessed November 1, 2024. https://www.ajmc.com/view/fda-approves-donanemab-for-early-alzheimer-disease