For the first time in Alzheimer’s research, scientists examining brain tissue from African American donors have identified the same top genetic suspect that appears in white populations, a finding that could reshape how researchers approach treatments for a disease that strikes Black Americans at twice the rate of whites.
The gene, called ADAMTS2, showed up with striking consistency. In deceased African American patients with Alzheimer’s, this gene was cranked up to 1.5 times its normal activity level. That alone would be noteworthy. But when Boston University researchers compared their results to a separate study of white brain donors, ADAMTS2 topped that list too.
To our knowledge, this is the first time in similarly designed AD genetics studies that the most significant finding was the same in both white and African Americans.
The comment from Lindsay Farrer, chief of biomedical genetics at Boston University School of Medicine, understates what amounts to a small revelation in Alzheimer’s research. Despite examining tissue from 207 African American brain donors (the largest such study to date), and analyzing over 33,000 genes, the researchers kept circling back to ADAMTS2. The finding suggests that beneath all the differences in how Alzheimer’s affects various populations, some core biological mechanisms may be universal.
The Reelin Connection
ADAMTS2 does not operate in isolation. The gene produces an enzyme that chops up a protein called reelin, which acts like a cellular traffic controller in the brain’s prefrontal cortex and hippocampus. When ADAMTS2 activity increases, it disrupts reelin’s protective functions. Mouse studies have linked lower reelin levels to more tau tangles and amyloid plaques, the two hallmark features of Alzheimer’s pathology.
The reelin pathway gained attention recently when researchers discovered a Colombian woman who carried a devastating early-onset Alzheimer’s mutation but somehow stayed cognitively sharp into her late 60s. She had a rare variant in the gene that makes reelin, which appeared to shield her brain from damage. If ADAMTS2 is sabotaging reelin in Alzheimer’s patients, blocking that process might offer a treatment strategy.
But ADAMTS2 was just the headline. The study identified 482 genes behaving differently in Alzheimer’s brains, many of them involved in the mundane work of keeping neurons powered up. Eleven genes that help mitochondria generate energy were all dialed down in diseased tissue. Three genes involved in cellular respiration showed the same pattern. The brain, it seems, is running out of fuel.
When Ancestry Matters (And When It Does Not)
The overlap between African American and white populations was substantial but incomplete. About 6% of genes flagged as significant in the white study also showed up in the African American analysis, far more than random chance would predict. Yet plenty of genes appeared only in one group or the other, reflecting genuine biological differences or possibly just the quirks of smaller sample sizes.
Some of these ancestry-specific findings make intuitive sense. A variant in the TREM2 gene that is relatively common in African Americans (affecting about 5% of the population) but rare in whites showed clear effects on gene expression in this study. The researchers also found that several genetic variants previously linked to Alzheimer’s risk in African Americans were acting as molecular dimmer switches, turning gene activity up or down.
The fact that expression of ADAMTS2 is significantly and substantially higher in brain tissue from both Whites and Blacks with AD not only points to a shared biological process leading to AD, but also elevates the priority of further research involving this gene which could determine its suitability as a potential therapeutic target.
The study drew tissue from 13 brain banks scattered across the country, pooling resources to assemble a cohort that included 125 Alzheimer’s cases and 82 controls. Even so, the sample remains modest compared to studies in white populations, which can draw from thousands of donors. That imbalance reflects deeper problems: African Americans have historically been underrepresented in medical research, and brain donation rates remain lower in Black communities.
What the researchers could not determine is whether differences in gene activity cause Alzheimer’s or result from it. Diseased brains are messy places, and teasing apart cause and effect requires experiments that post-mortem tissue cannot provide. Still, the convergence on ADAMTS2 across two independent studies, in two different populations, using two different analytical approaches, suggests the finding is not a statistical fluke.
The research also highlights how social and biological factors intertwine in Alzheimer’s risk. African Americans face higher rates of diabetes, cardiovascular disease, and limited access to quality healthcare, all of which increase dementia risk. But the genetic architecture matters too, and understanding how genes behave differently (or similarly) across populations could lead to treatments that work for everyone.
Alzheimer’s & Dementia: 10.1002/alz.70629
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