Chronic Microinfarcts Are Associated with Differences in APOE ε4–Braak Tau Stage Relationships in Autopsied Brains

Authors: Obed Okwoli Apochi, Rebecca Bernal, Alice Blanche Sylvie Nono-Djotsa, Yannick N. Wadop, Crystal Wiedner, Biniyam Ayele, Muralidharan Sargurupremraj, Xueqiu Jian, Alfred K. Njamnshi, Cyrille Nkouonlack, Jose E. Cavazos, Sudha Seshadri, Alfred Fonteh†, Bernard Fongang, Jayandra Jung Himali, Margaret E. Flanagan, Agustin Ruiz, on behalf of the African Initiative on Bioinformatics Online Training in Neurodegenerative Diseases (AI-BOND).

Poster ID: P1-9655

Key takeaway: Chronic microinfarcts were associated with differences in the relationship between APOE ε4 genotype and Braak tangle stage. The strongest estimated association was observed among ε44 carriers with microinfarcts, although this estimate was imprecise and should be interpreted cautiously.

Introduction: APOE ε4 is strongly associated with Alzheimer’s disease neuropathology. Older brains often show mixed vascular and neurodegenerative lesions. Chronic microinfarcts may alter vulnerability to tau pathology. The objective of this study was to test whether chronic microinfarcts modify the association between APOE ε4 genotype and Braak tangle stage.

Methods: We analyzed a NACC autopsy-confirmed sample of 7,153 participants. APOE groups were defined as ε4 noncarriers (ε33, ε22, ε23), ε4 heterozygotes (ε24, ε34), and ε4 homozygotes (ε44). Chronic microinfarcts were classified as absent or present. The outcome was Braak tangle stage. Ordinal logistic regression was used, with adjustment for age, age squared, sex, self-reported ancestry, and education. Statistical significance was set at FDR-corrected p < 0.05.

Results: The sample included 7,153 participants. Mean age was 79 years. Overall, 3,405 participants were female, 4,226 had a bachelor’s degree or higher, 6,758 reported White ancestry, and 303 reported Black or African American ancestry. Braak stage V–VI was present in 3,606 participants, and chronic microinfarcts were present in 917 participants. The interaction p-value for microinfarct status and APOE ε4 genotype was 0.0096.

Main findings: Among participants without microinfarcts, ε24/ε34 carriers had higher odds of advanced Braak stage compared with ε4 noncarriers, and ε44 carriers had even higher odds. Among participants with microinfarcts, ε24/ε34 carriers also showed increased odds, while ε44 carriers showed the strongest estimated association. However, the confidence interval for ε44 carriers with microinfarcts was wide, reflecting limited precision.

Limitations: Limitations include the observational autopsy design, grouping of ε24 and ε34 heterozygotes, and reduced precision for ε44 carriers with microinfarcts due to the wide confidence interval.

Conclusion: Chronic microinfarcts were associated with differences in APOE ε4–Braak tangle stage relationships. The strongest estimated association was observed among ε44 carriers with microinfarcts, but the wide confidence interval indicates limited precision. These findings support further investigation of vascular–tau interactions in autopsy-confirmed cohorts.

Acknowledgements: We thank all research volunteers and our funders who made this effort possible. The National Institute on Aging designated South Texas Alzheimer’s Disease Research Center (P30 AG066546). The NACC database is funded by NIA/NIH Grant U24 AG072122 and the ADRCs as the source of the data. The BUILD-FSA NIH UG3AG090675. †In memory of Dr. Fonteh, whose contributions to this work are gratefully acknowledged.

Contact: apochiobed@gmail.com
Website: https://aibond.org