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

The long-awaited era of disease-modifying treatments in Alzheimer’s disease has finally arrived. In the past few years, 3 drugs have received FDA approval for the treatment of mild cognitive impairment (MCI) due to Alzheimer’s disease or mild Alzheimer’s 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 accepted by specialists and will be discontinued at the end of 2024.2,3 However, 2 newer agents—lecanemab and donanemab—have received full FDA approval with clinical trial evidence for both amyloid clearance and clinical benefit.4,5 Although these treatments do not reverse the cognitive symptoms of Alzheimer’s disease, they significantly slow progression, some evidence suggesting that earlier treatment is most effective.

Drug mechanisms

Both lecanemab and donanemab are monoclonal antibodies that target beta-amyloid, with lecanemab targeting amyloid fibrils more specifically. These agents have been shown to reduce brain amyloid levels with high efficacy, usually over a period of 12 to 18 months. According to the amyloid cascade hypothesis, the accumulation of beta-amyloid leads to the subsequent cascade of events that ultimately lead to the development of clinical symptoms of Alzheimer’s disease, making it a logical target for treatment. According to the amyloid cascade hypothesis, neurofibrillary tangles or the production of hyperphosphorylated tau aggregates follow beta-amyloid accumulation. As would then be predicted based on this hypothesis, tau levels 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.

Medicinal indications

However, these disease-modifying treatments are currently only approved and have been shown to be effective very early in the clinical course of Alzheimer’s disease, at the stage of MCI or mild dementia. In the MCI stage, we would expect to see mild memory impairment in the absence of significant impairment in activities of daily living. In the mild dementia stage, we expect memory to deteriorate, 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 that the earlier treatment is started, the greater the impact. In other words, like what was said about stroke, this may be another circumstance where “time is brain.”

Despite the significant promise of these drugs, they come with significant challenges. First, we need to develop systems that facilitate early recognition and triage of appropriate patients to specialists and centers capable of administering these drugs. Those centers administering these drugs must coordinate across departments and stakeholders to facilitate the necessary assessments (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.

In addition, although effective, these drugs are not without risks. The biggest concern is amyloid-related imaging abnormalities (ARIA), which essentially means swelling (ARIA-E) or bleeding (ARIA-H) in the brain. ARIA-H usually consists of microhemorrhages seen only on MRI, but may also include larger hemorrhages. Experts warn of the potential for rare deaths with these drugs. Careful monitoring systems are therefore required, including frequent MRI examinations, ideally in coordination with well-trained radiological partners. In our experience, creating order sets in our electronic medical record and instituting additional office protocols have helped ensure that all regularly recommended safety MRI examinations are scheduled at the time of treatment initiation. After discussion among all stakeholders, we created additional safeguards, preventing further infusions without affirming review of required MRI examinations, absence of significant and/or symptomatic ARIA, and continued eligibility. Creating these processes up front can help ensure that safety is prioritized and that the entire program runs efficiently.

Despite these challenges, developing and instituting an anti-amyloid program comes with significant rewards. We have found that patients and families are very excited and grateful for the opportunity to receive these medications. While I understand that these treatments are not a cure, they offer significant hope. For many, these treatments offer the hope of maintaining a higher quality of life that can be enjoyed with friends and family for a longer period of time than would otherwise be expected, and this has proven very significant. In our experience, the value of such a program far outweighed the work involved, especially with careful planning, multi-stakeholder involvement, 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 the 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 before joining Norton in 2021. Cooper was also active in research. serves as principal investigator on a number of clinical trials and has a strong interest in caregiver education and support.

reference

1. FDA grants accelerated approval for Alzheimer’s drug. FDA. Press release. 7 June 2021. Retrieved 1 November 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. Retrieved 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, focuses on lecanemab for Alzheimer’s disease. AJMC. 31 January 2024. Accessed 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. 6 July 2023. Retrieved 1 November 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. Retrieved 1 November 2024.