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[Preprint]. 2023 Jul 20:2023.04.21.23288938.
doi: 10.1101/2023.04.21.23288938.

APOE - ε 4 and BIN1 increase risk of Alzheimer's disease pathology but not specifically of Lewy body pathology

Seth Talyansky  1 , Yann Le Guen  1   2 , Nandita Kasireddy  1 , Michael E Belloy  1 , Michael D Greicius  1
Affiliations

APOE - ε 4 and BIN1 increase risk of Alzheimer's disease pathology but not specifically of Lewy body pathology

Seth Talyansky et al. medRxiv. .

Update in

Abstract

Lewy body (LB) pathology commonly occurs in individuals with Alzheimer's disease (AD) pathology. However, it remains unclear which genetic risk factors underlie AD pathology, LB pathology, or AD-LB co-pathology. Notably, whether APOE - ε 4 affects risk of LB pathology independently from AD pathology is controversial. We adapted criteria from the literature to classify 4,985 subjects from the National Alzheimer's Coordinating Center (NACC) and the Rush University Medical Center as AD-LB co-pathology (AD + LB + ), sole AD pathology (AD + LB - ), sole LB pathology (AD - LB + ), or no pathology (AD - LB - ). We performed a meta-analysis of a genome-wide association study (GWAS) per subpopulation (NACC/Rush) for each disease phenotype compared to the control group (AD - LB - ), and compared the AD + LB + to AD + LB - groups. APOE - ε 4 was significantly associated with risk of AD + LB - and AD + LB + compared to AD - LB - . However, APOE - ε 4 was not associated with risk of AD - LB + compared to AD - LB - or risk of AD + LB + compared to AD + LB - . Associations at the BIN1 locus exhibited qualitatively similar results. These results suggest that APOE - ε 4 is a risk factor for AD pathology, but not for LB pathology when decoupled from AD pathology. The same holds for BIN1 risk variants. These findings, in the largest AD-LB neuropathology GWAS to date, distinguish the genetic risk factors for sole and dual AD-LB pathology phenotypes. Our GWAS meta-analysis summary statistics, derived from phenotypes based on postmortem pathologic evaluation, may provide more accurate disease-specific polygenic risk scores compared to GWAS based on clinical diagnoses, which are likely confounded by undetected dual pathology and clinical misdiagnoses of dementia type.

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Conflict of interest statement

Declarations

Competing interests

The authors declare that they have no competing interests.

Figures

Figure 1.
Figure 1.. Schemes used to classify individuals.
a. Criteria from Tsuang et al. (2013) [52]. b. Criteria from Kaivola et al. (2022) [28]. c. Criteria in the present study.
Figure 2.
Figure 2.. Manhattan plots of genetic association with pathology contrasts.
a. Association with AD+LB+ pathology versus AD−LB− pathology. b. Association with AD+LB− pathology versus AD−LB− pathology. c. Association with AD−LB+ pathology versus AD−LB− pathology. d. Association with AD+LB+ pathology versus AD+LB− pathology. Variants at two novel loci exhibited genome-wide significant associations in the AD−LB+ versus AD−LB− analysis (rs112017605 on both an intron of AC024598.1 and an intron of AC067752.1 on chromosome 10 and rs116691607 on an intron of BLMH on chromosome 17) (c; Suppl. Table 2), but we do not discuss these candidates in the main text because neither was flanked by a set of nearby variants in linkage disequilibrium, raising concern that these could be spurious signals.
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