Research Paper Volume 12, Issue 21 pp 21202—21219

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

Wei Xu1, &, , Chen-Chen Tan1, , Xi-Peng Cao2, , Lan Tan1, , for the Alzheimer’s Disease Neuroimaging Initiative *, ,

  • 1 Department of Neurology, Qingdao Municipal Hospital, Qingdao University, Qingdao, China
  • 2 Clinical Research Center, Qingdao Municipal Hospital, Qingdao, China
* The population data used in preparation for this article were obtained from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) database ( As such, the investigators within the ADNI contributed to the design and implementation of ADNI and/or provided data but did not participate in the analysis or writing of this report. A complete listing of ADNI investigators can be found at:

Received: March 17, 2020       Accepted: July 20, 2020       Published: November 7, 2020
How to Cite

Copyright: © 2020 Xu et al. This is an open access article distributed under the terms of the Creative Commons Attribution License (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.


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.


AD: Alzheimer’s disease; PICALM: phosphatidylinositol binding clathrin assembly protein; GWAS: genome wide association study; Aβ: β-amyloid; NOS: Newcastle-Ottawa Quality Assessment Scale; CI: confidence intervals; SNP: single nucleotide polymorphism; eQTL: expression quantitative trait loci; CSF: cerebral spinal fluid; NC: normal cognition; MCI: mild cognitive impairment; MP-RAGE: magnetization prepared rapid acquisition gradient echo; HIPPO: hippocampus; PARAH: parahippocampal region; ENTOR: entorhinal cortex; MT: middle temporal lobe; PC: posterior cingulate; PRE: precuneus; ROIs: regions of interest; ICV: intracranial volume; IQR: interquartile range; PFR: promoter flanking region; DMN: default mode network.