Alzheimer’s Drugs: Lack of Racial Diversity in Clinical Trials Raise Concern

In a recent, the United States of America’s Food and Drug Administrator (FDA), has approved the drug Lecanemab (Leqembi ®) for the treatment of early Alzheimer’s Disease (AD). The Alzheimer’s Association, in its release of July 6, said that it celebrates the traditional grant approval of the drug for Alzheimer’s treatment, especially with confirmation of the elevated amount of amyloid beta in the brain. Lecanemab is developed by Eisai/Biogen. Similarly, another drug candidate, Donanemab, is waiting for its approval. 

Before one drug is approved for use, it has to undergo stringent clinical trials. Lecanemab’s clinical trial report appeared at NEJM (New England Journal of Medicine) in January this year, where it was claimed that the drug (a monoclonal antibody) is effective in reducing amyloid in early Alzheimer’s disease. Similarly, the result of the Donanemab clinical trial was published in a JAMA journal recently, on July 17, which also claims the effectivity of the drug in early AD, and here also, the target is amyloid along with tau protein. 

However, experts have raised concerns about the racial profile of the participants in these trials. The Lecanemab trial, as written by Sara Reardon in Nature,  consists of only 20% of the participants who are people of colour.  Again, in the Donanemab trial having participants of 1736, only 19 (less than even 10%) are black. Donanemab is developed by the pharma company Eli Lilly, based in the USA. 

The low numbers of people of colour are making experts apprehensive. These two drugs are thought to be the first to have shown positive clinical outcomes amongst AD patients. Now, with the racial disparities in the trial participants, experts doubt whether these drugs will work for people of colour or address the cause of dementia at all because the causes of dementia may vary demographically.

Criticising the trials, University of California neurologist Gil Rabinovici was quoted to have said in Sara Reardon’s article as—“ I don’t think it should be acceptable that clinical trials are so non-representative. This is a call to arms.”

Notably, the US FDA recommended that clinical trials reflect demographic diversity as different people will use a drug, which is not apparently reflected in AD drug trials. One aspect of it lies in the cause that these drugs are focused on. The participants in these drug trials should have sufficient amyloid protein accumulated in their brains with the development of AD. This implies that amyloid protein has been the main target of these drugs as this has been considered the primary cause of developing AD.

New Studies Challenge the Amyloid Theory.

The amyloid theory has long been considered the hallmark of AD development, and apparently, this has become the basis of many drug development strategies. The research paper in Nature in 2006 became prominent over time and saw over 2000  citations. This paper linked amyloid-beta accumulation in the brain to memory loss and AD. 

The amyloid-beta is a protein, and in ageing brains, a large accumulation of it leads to plaque formation, which impairs memory formation- the core of the theory that drove AD research. However, over time researchers have obtained findings which suggest that it may not be the full truth. 

In a research published in the journal Alzheimer’s & Dementia in December 2022, the researchers claimed that higher levels of Amyloid-beta in the brain is a natural process and may not always be a sign of AD. However, the researchers said that Amyloid-beta's soluble form is unrelated to AD progression, whereas the fibrillar form is associated with the disease. 

Similarly, another research published in the Journal of Alzheimer’s Disease researchers claimed to have found that depletion of the amyloid-beta 42 (this is the functional form of amyloid-beta protein) is more harmful than the number of insoluble amyloid plaques formed in the brain as far as the progression of AD is concerned. In an article about the research published in The Conversation, three of the researchers of the study wrote, “When amyloid-beta protein accumulates in the form of plaques (insoluble clumps), the original soluble form of the protein, which performs important functions in the brain, is consumed and lost. Some studies have shown that reduced levels of soluble amyloid-beta – called amyloid-beta 42 – have led to patients having worse clinical outcomes.” 

Moreover, in July last year, Science reported dozens of research articles on AD altering images and also duplication, which supported the leading Amyloid-beta theory. The article author Charles Piller wrote, “A neuroscience image sleuth finds signs of fabrication in scores of Alzheimer’s articles, threatening a reigning theory of the disease.” This, as experts opine, increased the doubts about AD progression, especially the leading theory. 

Sara Reardon’s article also mentions studies which found that people of colour have less amyloid protein in the brain with AD than their white counterparts. This also impacted the recruitment of the trial participants. The article includes the version of John Sima, a senior medical director of Eli Lilly, which suggests that the Donanemab trial was difficult as only one in eight black and one in 17 Hispanic people had sufficient amyloid and tau protein to be qualified to be included in the trial. The drug only focuses on amyloid and tau proteins, and it follows the traditional amyloid theory. 

However, counter to this, Joshua Grill, an AD researcher at the University of California, said, " The field needs to understand why this keeps happening. It is unclear why people of colour would have lower amyloid or tau levels than their white counterparts with the same cognitive impairment.” Grill suggests that dementia amongst people of colour may be due to other factors like vascular disorders or inflammation. Other evidence suggests that AD may have certain genetic factors that differ among European and African people. 

“Amyloid levels are not the only reason Alzheimer’s trials lack racial diversity. We need to look at all our inclusion and exclusion criteria: necessary and contributing to disparities in who we bring in,”—commented Reisa Sperling, a Harvard University neurologist.