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

The long-awaited era of disease-modifying treatments in the field of Alzheimer’s disease has finally arrived. In recent 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 FDA approval in 2021, primarily based on evidence of amyloid clearance.1 It has not been widely adopted by specialists and will be discontinued late 2024.2,3 However, two newer agents – lecanemab and donanemab – have been adopted. has received full FDA approval with clinical trial evidence for amyloid clearance and clinical benefit.4,5 Although these treatments do not reverse the cognitive symptoms of Alzheimer’s 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 more specifically targeting amyloid fibrils. These agents have been shown to reduce brain amyloid levels with high effectiveness, usually over a period of 12 to 18 months. According to the amyloid cascade hypothesis, the accumulation of beta-amyloid leads to a subsequent cascade of events ultimately resulting in 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 the accumulation of beta-amyloid. As might 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.

Medication Indications

However, these disease-modifying treatments are currently approved and have only proven effective very early in the clinical course of Alzheimer’s disease, at the stage of MCI or mild dementia. In the MCI stage, mild memory impairment would be expected in the absence of significant impairment in activities of daily living. In the mild dementia stage, we expect memory deterioration as well as the need for at least minor assistance with daily activities. Unfortunately, once symptoms have progressed beyond these stages, these medications are no longer effective. In fact, there is preliminary evidence to suggest that the earlier treatment is started, the greater the impact. In other words, just like what was said about stroke, this may be another situation where “time is brains.”

Despite the considerable 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 medications. Centers administering these medications must coordinate efforts across departments and stakeholders to facilitate necessary assessments (e.g., clinical examinations, imaging studies, biomarker studies) and treatment. These medications are intravenous infusions that require, among other things, coordination with the pharmacy and the infusion center.

Additionally, although effective, these medications are not without risk. Of greatest concern are amyloid-related imaging abnormalities (ARIA), which basically means swelling (ARIA-E) or bleeding (ARIA-H) in the brain. ARIA-H usually consists of microhemorrhages seen only on MRI, but can also include larger hemorrhages. Experts warn of the risk of rare deaths linked to these drugs. Therefore, careful monitoring systems, including frequent MRI scans, are necessary, ideally in coordination with well-trained radiology partners. In our experience, creating order sets in our electronic medical record and implementing additional in-office protocols has helped ensure that all regularly recommended safety MRI scans are scheduled at the time of treatment initiation. After discussion among all stakeholders, we created additional safeguards, preventing further infusions without confirmation of required MRI scans, absence of significant and/or symptomatic ARIA, and continued eligibility. Creating these processes upfront can help ensure that security is a priority and that the entire program operates efficiently.

Despite these challenges, developing and implementing an anti-amyloid program comes with significant rewards. We have found that patients and their families are very enthusiastic and grateful for the opportunity to receive these medications. Although they understand that these treatments are not a cure, they nevertheless provide significant hope. For many, these treatments offer the hope of preserving a better quality of life, which they can enjoy with friends and family for a longer period of time than might otherwise be expected, and this has proven to be very significant. In our experience, the value of such a program far outweighed the work involved, especially with careful planning, multiple stakeholder engagement, and ongoing, attentive, and open communication from the beginning and throughout the 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, then formed and directed the Baptist Health Memory Care Program until joining Norton in 2021. Cooper has also been active in research. he is a principal investigator on a number of clinical trials and has a keen interest in caregiver education and support.

References

1. FDA grants accelerated approval for Alzheimer’s drug. FDA. Press 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 the pharmaceutical industry’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 and focuses on lecanemab for the treatment of Alzheimer’s 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 to Alzheimer’s disease 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 treatment of Alzheimer’s disease. AJMC. July 2, 2024. Accessed November 1, 2024.