Introduction: The apolipoprotein E (APOE) ε2 and ε4 alleles have beneficial and adverse impacts on Alzheimer's disease (AD), respectively, with incomplete penetrance, which may be modulated by other genetic variants.
Methods: We examined whether the associations of the APOE alleles with other polymorphisms in the genome can be sensitive to AD-affection status.
Results: We identified associations of the ε2 and ε4 alleles with 314 and 232 polymorphisms, respectively. Of them, 35 and 31 polymorphisms had significantly different effects in AD-affected and -unaffected groups, suggesting their potential involvement in the AD pathogenesis by modulating the effects of the ε2 and ε4 alleles, respectively. Our survival-type analysis of the AD risk supported modulating roles of multiple group-specific polymorphisms. Our functional analysis identified gene enrichment in multiple immune-related biological processes, for example, B cell function.
Discussion: These findings suggest involvement of local and inter-chromosomal modulators of the effects of the APOE alleles on the AD risk.
Keywords: APOE; Cox regression; age at onset; aging; dementia; genetic modulators; genetic polymorphisms; genome-wide association studies; neurodegenerative diseases; sex-specific associations.
© 2021 the Alzheimer's Association.