A large postmortem gene expression study has identified hundreds of genes and multiple biological pathways associated with Alzheimer’s disease in brain tissue from African American donors, addressing a long-standing gap in neurodegenerative research. The findings, published in Alzheimer’s & Dementia, represent the largest transcriptome-wide analysis of the disease conducted exclusively in this population.
Researchers analyzed RNA sequencing data from the brains of 207 African American donors, including 125 individuals with neuropathologically confirmed Alzheimer’s disease (AD) and 82 controls without significant neurodegenerative disease. Differential gene expression analysis identified 482 genes with significant expression differences between AD cases and controls, even after adjustment for age, sex, RNA quality, batch effects, and estimated brain cell-type proportions.
The most strongly associated gene was ADAMTS2, which showed approximately 1.5-fold higher expression in AD cases. ADAMTS2 encodes a metalloproteinase involved in extracellular matrix processing and has previously been implicated in neurological pathways relevant to AD, including signaling related to reelin, a protein involved in synapse function and resistance to cognitive decline. The same gene has also emerged in recent studies of European-ancestry cohorts, suggesting shared disease mechanisms across populations.
Beyond individual genes, the researchers identified broader biological patterns linked to AD. Many of the genes with altered expression were involved in how cells produce and use energy, particularly within mitochondria. Several genes that help power the mitochondrial respiratory chain were expressed at lower levels in Alzheimer’s brains, supporting previous evidence that disrupted energy metabolism plays a role in neurodegeneration.
The analysis also revealed groups of genes that tend to change together in AD. These gene networks were linked to processes such as cellular signaling, gene regulation, and metabolism. Several networks remained strongly associated with AD after statistical adjustment, suggesting that coordinated changes across multiple genes are involved rather than isolated molecular events.
In addition, the study connected genetic risk to changes in gene activity. Some genetic variants previously linked to AD in African American populations were found to influence the expression of nearby genes in brain tissue. This finding supports the idea that genetic risk can affect disease development by altering how genes are regulated.
The authors note important limitations, including the use of bulk tissue rather than single-cell data and limited availability of detailed clinical histories. However, they emphasize that the results highlight both shared and population-specific molecular features of AD.
The study reinforces the value of integrating molecular data with neuropathologic assessment and the importance of ancestrally diverse cohorts in defining disease mechanisms and identifying potential therapeutic targets.
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