For late-onset AD, the largest known genetic risk factor is the APOE ε4 allele. Extensive prior studies have suggested a number of mechanistic roles for APOE ε4 on Aβ burden, including hindering clearance of soluble Aβ from the brain,24 favoring Aβ aggregation into fibrils,25 and promoting neurodegeneration by directing toxic Aβ oligomers to synapses.26 Among the genes neighboring APOE, we found no significant associations with Aβ burden after including APOE ε4 status as a covariate. While this suggests that these genes did not exhibit independent effects on Aβ deposition, the extensive linkage disequilibrium (LD) structure around APOE makes this difficult to definitively determine.
