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Alzheimer's Disease Study Traces Factors Affecting APOE Variant Risk, Protective Effects

NEW YORK – New research has started untangling the extent to which individuals' ancestry, race, biological sex, and age can impact the effects of variants in the apolipoprotein E-coding genes APOE*4 and APOE*2, which have been linked to enhanced and decreased risk of late-onset Alzheimer disease (AD), respectively.

"When consulting individuals on their genetic risk for Alzheimer's disease, APOE status is a core variable," Stanford University neurology and neurological sciences researcher Michael Belloy said in an email. "Our study shows that race, ethnicity, ancestry, sex, and age all matter to provide an individualized answer."

For a paper published in JAMA Neurology on Monday, Belloy and colleagues from Stanford, Washington University, and elsewhere brought together APOE profiles assessed by array-based genotyping, exome sequencing, or whole-genome sequencing in nearly 68,800 participants, including 21,852 individuals of East Asian ancestry, 7,145 non-Hispanic Black individuals, and 5,738 Hispanic individuals.

"One important aspect of our work is that we really increased sample sizes for non-Hispanic Black, Hispanic, and East Asian individuals, so that we now have better understanding of the associations of APOE genotypes with Alzheimer's disease risk in these groups," Belloy explained, noting that the "scale of our study was thus a critical factor in generating novel insights."

Along with clinical, diagnostic, and pathological clues for 68,756 unique individuals participating in the study, the genetic data pointed to a progression of AD risk related to individuals' self-reported ancestry and race, sex, and age.

"There was a general, stepwise pattern of [odds ratios] for APOE*4 genotypes and AD risk across race and ethnicity groups," the authors reported.

Their results pointed to a dramatic reduction in AD risk in African ancestry participants with APOE*4 risk variants in their germlines, for example. That effect was less pronounced in individuals classified as "non-Hispanic Black" in a related racial analysis, Belloy explained, reflecting differences between race, a social construct, and ancestry, which more closely reflects an individual's geographic history and related genetic variation.

The team also found that both the risky and protective APOE variants had the most muted ties to Alzheimer's risk in Hispanic individuals, while a risk-enhancing genotyping known as APOE*34 appeared to have a particularly pronounced effect in female carriers in the non-Hispanic White group — an effect that was subsequently described in females from the Hispanic and non-Hispanic Black groups as well.

While at least one of the risky APOE genotypes showed strong ties to late-onset AD in individuals with East Asian ancestry, on the other hand, some protective APOE genotypes did not coincide with AD risk in the East Asian individuals.

"We showed clearly that the effect of APOE*2 is less protective in non-Hispanic Black compared to non-Hispanic White individuals," Belloy said, "and there appears to be little to no effect in Hispanic and East Asian individuals."

Together with their age-focused analyses, the investigators suggested that the ancestry- and race-based distinctions in APOE genotype relationships to AD point to the need for additional research to understand and further parse out the protective and risk genotype variability found in the current study.

The results may also inform the design of upcoming clinical trials, Belloy noted, where "subjects may be recruited based on expected risk conferred due to APOE genotypes."

Even so, the authors cautioned that the findings so far relied on relatively broad ancestry classifications, and may benefit from more refined research done at the local ancestry level, which can "provide insight into the ancestral origin of the genetic information surrounding APOE, which may differ from the global average ancestry assessed across an individual's entire genome."

In a related commentary article in JAMA Neurology, VU Amsterdam researchers Rik Ossenkoppele and Wiesje van der Flier considered the team's epidemiological findings in combination with results from another new JAMA Neurology study focused on APOE*4 relationships to amyloid-beta and tau levels found in the brain by neuroimaging.

In particular, they suggested that the studies may prove useful for treating AD with monoclonal antibodies that target amyloid-beta, since prior clinical trials suggest that the amyloid-beta plaque-decreasing antibody drugs also interact with APOE genotypes.

Together, the new papers "highlight the clinical relevance of considering APOE genotype in treatment-related decision-making," they wrote. "Key steps for the future include advancing our understanding of APOE interactions with age, sex, gender, race, ethnicity, and socioeconomic factors and the efficacy and risks associated with these treatments in real-world clinical practice."