Written by Tasnim Sumaita
Edited by Devika Baddhan
A New Player
In a crowded neurology clinic in Abington, Pennsylvania, 67-year-old Robert Williford received an IV line to his left arm. Williford, a patient with early-stage Alzheimer’s disease (AD), was among the first Black patients to take Leqembi—a groundbreaking drug showing promising results in slowing the progression of AD. AD, a terminal neurodegenerative disease affects nearly 7 million Americans annually (Alzheimer’s Association).
The scientific community has recognized limited success in AD drug development and clinical trials over the past two decades (Kim et al., 2022). Given the rapidly growing elderly population, nearly 14 million individuals are projected to be affected by AD within the next 25 years. Alongside this growing patient population, AD treatment imposes a significant financial burden, costing the U.S. healthcare system an estimated $240 billion per year, highlighting the urgent need—by the United States, AD patients, and caregivers—for new solutions.
Enter Leqembi: Approved 6-0 by the FDA on July 6th, 2023, Leqembi, the brand name for the drug Lecanemab, offers hope amid the struggle for relief from a growing AD epidemic. It is a beta-amyloid targeting therapy created by Japanese pharmaceutical company Eisai, whose CEO Haruo Naito claims that they “…are committed to taking this first step towards changing the future of Alzheimer’s disease” (Eisai Co., 2023).
…For Which People?
In 2022, Leqembi’s pivotal clinical trial followed nearly 1,800 early-stage AD patients aged from 50 to 90 years old over an eighteen-month period. Patients were divided into two groups, receiving either intravenous lecanemab or a placebo (van Dyck et al., 2023). This study was double-blinded to both patients and the researchers. The results of lecanemab’s trial garnered excitement: patients on lecanemab demonstrated slower progression of their AD compared to their placebo counterparts. However, critiques emerged regarding the universality of these results, particularly concerning the racial composition of participants; of nearly 1,800 participants, only 47 were Black (2.6%).
Older Black Americans experience Alzheimer's disease and related dementias at roughly twice the rate of older white Americans. They also represent the highest percentage of Alzheimer’s cases within their racial group, with about 14% of Black Americans aged 65 and older affected, compared to 10% of their white counterparts (Fox, 2018). Beyond representing a disproportionately high percentage of Alzheimer’s patients, Black patients face a significantly higher risk of rapid disease progression and related complications. This is often due to late diagnoses, stemming from limited access to early screening, in contrast to their white peers (African-Americans and Alzheimer's Disease: The Silent Epidemic, 2002). Within the statistical context of Black AD patients and AD in America, the clinical trial for Leqembi did not represent an accurate proportion of what the landscape of AD in America looks like. Beyond this critique of Leqembi’s approval lies a broader, perplexing reasoning as to why such a low number of Black Americans participated in the clinical trials: Were Black Americans screened out by the study’s eligibility requirements?
The Amyloid Hypothesis Is Still A Hypothesis—“The Cabal”
For the past three decades, Alzheimer’s disease has been explained using the amyloid hypothesis. To simplify the amyloid hypothesis, imagine the brain as a city with a network of busy roads. Beta-amyloid proteins act as recurring "trash" scattered throughout the city. In a healthy brain (non-AD), this trash is efficiently cleared away, allowing smooth traffic flow. However, in an Alzheimer's brain, the systems responsible for removing and breaking down the trash are impaired. As a result, the trash accumulates into large piles known as beta-amyloid plaques, blocking the roads and preventing brain cells—our “cars”— from reaching their destinations. This disruption in communication between brain cells contributes to the cognitive decline seen in AD. In addition to interfering with messaging, beta-amyloid plaques are toxic and disrupt brain cell function, further contributing to the decline by impairing the communication between neurons in the hippocampus, a region of the brain crucial for memory formation and retrieval. Essentially, the amyloid hypothesis suggests that the accumulation of beta-amyloid proteins and the resulting formation of plaques are central to Alzheimer’s disease (AD) and its progression (Kametani & Hasegawa, 2018).
This AD model is what Eisai used to screen for eligibility during Leqembi’s clinical trial. As a therapy that works to alleviate the progression of AD by targeting beta-amyloids, participants must have had a significant amount of beta-amyloid accumulation in their brains. Interestingly enough, the proportion of Black Americans in the clinical trial was so low because Black Americans with early AD did not express as much elevated levels of beta-amyloids as their white counterparts (Alzheimer's Association, 2024). Of the volunteers for the trial, nearly half of Black volunteers failed to meet the amyloid threshold compared to less than a quarter of white volunteers. A similar trend was observed in other people of color, where volunteers with early AD did not meet the amyloid requirement despite presenting all other symptoms associated with AD.
This realization, on top of a marked history of failure in Alzheimer’s drug trials that were largely reliant on the amyloid hypothesis, questions the accuracy of our current AD model—a question neuroscientists have been working to answer for decades.
Controversy in the research community surrounding the amyloid hypothesis is not new. Several scientists consider the devotion to the amyloid hypothesis a cabal. For years, researchers have invested thousands of hours and millions of dollars into the amyloid theory and have thus systematically denied alternative explanations because of their commitment. Research aligning with the amyloid hypothesis is usually prioritized in publications, funding, backing by biopharmaceutical companies, and conference presentations, while research competing with the amyloid hypothesis is largely suppressed and ultimately unable to be properly pursued. Neurobiologist Rachel Neve at Massachusetts General Hospital states, “The amyloid hypothesis has been one of the most tragic stories in disease research” (Begley, 2023). One of the main reasons behind the increased funding of the amyloid hypothesis is the combination of limited resources and the high risk associated with Alzheimer's research. In 2023, the NIH allocated only about $4 billion to Alzheimer's research, a relatively small amount compared to the scale of the problem. This constrained funding forces scientists to focus on research paths they consider most secure—such as amyloid-targeting therapies—rather than exploring potentially more innovative but riskier avenues. This dynamic has contributed to the dominance of the amyloid hypothesis in the research community, despite the growing recognition of its limitations (Fox, 2018; Kametani & Hasegawa, 2018; Kim et al., 2022).
One potential alternate explanation for the accumulation of beta-amyloid plaques in AD is that they are a response to the hidden, true cause of AD, rather than being the cause themselves. Other scientists are attempting to investigate neuroinflammation as the cause of the neuron and synapse death associated with AD. Internationally, researchers have been working tirelessly to get their foot through the door to stand up against the status quo of the AD model and drive new solutions to finally create impactful change in AD therapies.
Libby Holman, spokesperson of Eisai, states, “If individuals do not have elevated amyloid, they do not have Alzheimer’s disease.” However, when presented with conflicting data on the presentation of AD, especially in the lack of research about racial-ethnic specific presentation and treatment, it is integral that scientists remain open-minded and holistic in their definition of the AD model. Dr. Lisa L. Barnes, a neuropsychologist at Rush University, says “If we are just targeting amyloid, we can just miss a large potential population that might benefit from treatment.” In the desperate drug race for effective Alzheimer’s therapies, we must ensure that our direction of focus when designing these therapies does not exclude the experiences of a large proportion of the community.
The Future: Broadening Treatment
Despite initial excitement for Leqembi as a therapy for AD, its process of development and approval revealed cracks in its efficacy which especially serve to exacerbate health inequities in Black patients. For the percentage of Black AD patients who meet the amyloid threshold, Leqembi works just as effectively as with any other patient—yet even beyond the efficacy of the drug, the tantalizing gleam of Leqembi remains unattainable for most elderly patients. Priced in America at over $26,000 a year, Leqembi remains out of reach for a majority of elderly Black patients, who make up nearly 20% of those beneath the poverty line aged 65 and older in America (Li and Dalaker, 2022).
In addition to financial barriers, the push for accurate representation in clinical trials remains integral to ensuring treatment is effective for everyone. Increasing education and awareness of Alzheimer's disease (AD) among Black Americans through community outreach is crucial. Coupled with access to related services like screenings and treatments, this could help improve early diagnosis rates in Black AD patients. Early diagnosis is essential for the effectiveness of treatments like Leqembi, which is designed for early-stage AD patients. Expanding Black participation in clinical trials could further ensure that these treatments are accessible and beneficial for this underserved population (Alzheimer's Association, 2024; Fox, 2018; Kametani & Hasegawa, 2018). In addition, spreading awareness about the flaws in the current AD model and its participation in neglecting Black AD patients in academia is vital. Combating this begins with discussion; researchers observing new theories for AD’s pathology should receive platforms at academic conferences and incite debate of how exclusively following the amyloid theory fails Black patients. This can spark further interest and funding in research surrounding AD presentation in patients with lower amyloid levels. For patients like Williford, who meet the amyloid threshold and have the financial resources for treatment, Leqembi provides a source of hope for him and his family, offering a potential solution in the fight against Alzheimer's disease. Many other elderly Black Americans are unable to experience the same, and we must remain holistic and adaptive in our approaches to medicine until we can ensure nobody gets left behind.
References
“African-Americans and Alzheimer’s Disease: The Silent Epidemic.” Alzheimer’s Association, 11 Feb. 2002.
“Alzheimer’s Disease Facts and Figures.” Alzheimer’s Disease and Dementia, Alzheimer’s Association, 2024, www.alz.org/alzheimers-dementia/facts-figures.
Begley, Sharon. “The Maddening Saga of How an Alzheimer’s ‘cabal’ Thwarted Progress toward a Cure for Decades.” STAT, 25 July 2023,
Dalaker, Joseph and Li, Zhe, and Joseph Dalaker, Joseph. “Poverty Among the Population Aged 65 and Older.” Congressional Research Service, 6 Dec. 2022.
Fox, Maggie. “Alzheimer’s Cases to Nearly Triple by 2060, CDC Says.” NBCNews.Com, NBCUniversal News Group, 21 Sept. 2018, www.nbcnews.com/health/health-news/alzheimer-s-cases-nearly-triple-2060-cdc-says-n911866.
Kametani, Fuyuki, and Masato Hasegawa. “Reconsideration of amyloid hypothesis and tau hypothesis in Alzheimer’s disease.” Frontiers in Neuroscience, vol. 12, 30 Jan. 2018, https://doi.org/10.3389/fnins.2018.00025.
Kim, C. Kwon, et al. “Alzheimer’s disease: Key insights from two decades of clinical trial failures.” Journal of Alzheimer’s Disease, vol. 87, no. 1, 3 May 2022, pp. 83–100, https://doi.org/10.3233/jad-215699.
Van Dyck, Christopher H., et al. “Lecanemab in early alzheimer’s disease.” New England Journal of Medicine, vol. 388, no. 1, 5 Jan. 2023, pp. 9–21, https://doi.org/10.1056/nejmoa2212948.
“‘LEQEMBI® Intravenous Infusion’ (Lecanemab) for the Treatment of Alzheimer’s Disease to Be Launched in Japan on December 20: News Release：2023.” Eisai Co., Ltd., 13 Dec. 2023, www.eisai.com/news/2023/news202374.html.
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