Association of Alzheimer’s disease risk variants on the PICALM gene with PICALM expression, core biomarkers, and feature neurodegeneration

It is still unclear how PICALM mutations influence the risk of Alzheimer’s disease (AD). We tested the association of AD risk variants on the PICALM gene with PICALM expression and AD feature endophenotypes. Bioinformatic methods were used to annotate the functionalities and to select the tag single nucleotide polymorphisms (SNPs). Multiple regressions were used to examine the cross-sectional and longitudinal influences of tag SNPs on cerebrospinal fluid (CSF) AD biomarkers and neurodegenerations. A total of 59 SNPs, among which 75% were reported in Caucasians, were associated with AD risk. Of these, 73% were linked to PICALM expression in the whole blood (p < 0.0001) and/or brain regions (p < 0.05). Eleven SNPs were selected as tag SNPs in Caucasians. rs510566 (T allele) was associated with decreased CSF ptau and ptau/abeta42 ratio. The G allele of rs1237999 and rs510566 was linked with greater reserve capacities of the hippocampus, parahippocampus, middle temporal lobe, posterior cingulate, and precuneus. The longitudinal analyses revealed four loci that could predict dynamic changes of CSF ptau and ptau/abeta42 ratio (rs10501610, p = 0.0001) or AD feature neurodegeneration (rs3851179, rs592297, and rs7480193, p < 0.005). Overall, the genetic, bioinformatic, and association studies tagged four SNPs (rs3851179, rs7480193, rs510566, and rs1237999) as the most prominent PICALM loci contributing to AD in Caucasians.