Reduced Effect of APOE4 on White Matter Microstructure in an American Indian Community

Apolipoprotein E4 (APOE4) is central to Alzheimer disease (AD) personalized medicine, yet its link to AD is highly ancestry-dependent. Emerging evidence suggests an attenuated risk of APOE4 on brain health in American Indian (AI) participants. This study examines white matter microstructure, an early indicator of brain health deterioration, among tribal Elders carrying the APOE4 allele.

We performed a cross-sectional, community-based study in partnership with the Bois Forte Band of Chippewa. Tribal Elders (>54 years of age) were evaluated at the Tribal Nation's health clinic or urban office and were recruited via radio, health fairs, social media, and flyers. We preselected 7 MRI white matter tracts that prior work has shown to be consistently associated with APOE4 status and AD in non-Hispanic white (NHW) participants. We compared microstructural integrity between AI and NHW APOE4 carriers vs noncarriers while controlling for age, sex, and hypertension status.

Sixty-two tribal Elders were included. The mean age was 65 years, and the mean Mini-Mental State Examination score was 29. Forty-nine (79%) participants were female, 33 (53%) had hypertension, and 10 (16%) were APOE4 heterozygotes. In contrast to NHW Alzheimer Disease Neuroimaging Initiative participants, tribal Elders had consistently attenuated associations of APOE4 on white matter microstructure.

Tribal elders have an attenuated effect of APOE4 on a neuroimaging measure of brain health. This finding parallels volumetric and neuropsychological findings in other AI populations. Caution is required when interpreting APOE4 for AI patients in clinical settings, where APOE4 status is increasingly used for prognostic, diagnostic, and treatment eligibility purposes.