In the largest analysis yet of Alzheimer’s disease (AD) gene activity in brain tissue from African American donors, researchers identified more than 400 genes expressed differently in those with AD, offering new insight into disease biology in this underrepresented population.

Tissue from those with confirmed AD also showed unusually high expression of ADAMTS2, a gene involved in collagen production. A previous study found similar high expression of ADAMTS2 in brain tissue of people of European ancestry with AD, suggesting the gene could be a new therapeutic target.

The findings are also an important step in elucidating the underlying mechanisms and genetics behind AD risk in African Americans, which has been largely understudied, the investigators added.

“It’s exciting certainly to me…that to my knowledge, this is the first time that a specific genetic finding was the most significant in both African Americans and folks of European ancestry,” principal investigator Lindsay Farrer, PhD, and distinguished professor of genetics at Boston University School of Medicine in Boston, told Medscape Medical News.

The study was published online on October 8 in Alzheimer’s & Dementia.

Filling a Gap

African Americans are roughly twice as likely as White Americans to develop AD. Risk factors that affect this population include socioeconomic disadvantages and higher rates of vascular disease.

This population is often underrepresented in Alzheimer’s research, despite being at disproportionately higher risk of developing the neurodegenerative disease.

To address that issue, researchers worked with 14 brain banks in the nationwide Alzheimer’s Disease Research Center network to analyze postmortem prefrontal cortex tissue from 207 African American brain donors. Of these, 125 had AD and 82 were control individuals.

Investigators found 482 genes that were differentially expressed in AD cases vs control individuals.

Of the 174 genes with higher expression levels in AD cases, ADAMTS2 had the highest, with an expression level 1.52 times higher in those with AD (log2 fold change = 0.60; P = 2.96 × 10^-8).

The sensitivity analyses indicated that excluding postmortem interval data as a covariate and donors below the age of 60 when they died did “not substantively impact the results,” the investigators wrote.

Enrichment analysis showed biological processes and pathways linked to oxidation reduction and energy production. The 10 pathways most strongly affected in AD cases included genes involved in the formation of mitochondrial respiratory complex 1. All of those genes less active in AD cases compared with control individuals.

While those genes had not been implicated previously in AD, “impairments of the mitochondrial complex 1 formed by them have been reported in AD cases,” Farrer said. His lab plans to further investigate the role of these energy pathways in the disease and further explore the link between ADAMTS2 and AD.

The most significantly associated gene network for AD was enriched for genes involved in oxidative phosphorylation and metabolism.

“Studies like this are important to help us better understand the underlying mechanistic ties to risk of disease in ancestrally diverse and minoritized populations, especially those that have historically been excluded from research,” Ozama Ismail, PhD, director of Scientific Programs at the Alzheimer’s Association, who was not involved in the study, told Medscape Medical News.

‘Striking’ Finding

Key strengths of the study include rigorous neuropathological classification and multi-center data integration from 14 brain banks, Dmitry Prokopenko, PhD, assistant professor at the Genetics and Aging Research Unit, McCance Center for Brain Health, Massachusetts General Hospital and Harvard Medical School in Boston, who was not involved in the study, told Medscape Medical News.

“Most striking is the identification of ADAMTS2, which showed elevated expression in AD across both this study of Africans Americans and a previous larger study of European cohorts,” he said, referring to a preprint that has not yet been peer reviewed.

Critical future work includes validating this gene as a therapeutic target and conducting longitudinal studies across disease stages from peripheral tissues to distinguish causal from consequential changes, Prokopenko said.

A limitation of the study was that this sample is smaller than other differential gene expression studies using samples from European ancestry autopsies.

Other limitations were the “use of bulk RNA sequencing that masks cell-type-specific changes and missing clinical covariates relevant to African American health disparities,” Prokopenko said.

Farrer and Prokopenko reported no disclosures. The full list of funding and disclosures can be found in the original article.