PICALM Variation Moderates the Relationships of APOE ɛ4 with Alzheimer’s Disease Cerebrospinal Biomarkers and Memory Function Among Non-Demented Population

Article type: Research Article

Authors: Liu, Yan-Bing^{a; b} | Wang, Xue-Jie^a | Tan, Lan^a | Tan, Chen-Chen^a | Xu, Wei^{a; *} | for the Alzheimer’s Disease Neuroimaging Initiative¹

Affiliations: [a] Department of Neurology, Qingdao Municipal Hospital, Qingdao University, Qingdao, China | [b] Medical college, Qingdao University, Qingdao, China

Correspondence: [*] Correspondence to: Dr. Wei Xu, MD, PhD, Department of Neurology, Qingdao Municipal Hospital, Qingdao, China, Donghai Middle Road, No.5, Qingdao, China. Tel.: +86 0532 15610091257; E-mail: [email protected].

Note: [1] The data used in preparation for this article were obtained from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) database (http://adni.loni.usc.edu). 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 analyses or writing of this report. A complete listing of ADNI investigators can be found at: http://adni.loni.usc.edu/wp-content/uploads/how_to_apply/ADNI_Acknowledgement_List.pdf

Abstract: Background:APOE ɛ4 and PICALM are established genes associated with risk of late-onset Alzheimer’s disease (AD). Previous study indicated interaction of PICALM with APOE ɛ4 in AD patients. Objective: To explore whether PICALM variation could moderate the influences of APOE ɛ4 on AD pathology biomarkers and cognition in pre-dementia stage. Methods: A total of 1,034 non-demented participants (mean age 74 years, 56% females, 40% APOE ɛ4 carriers) were genotyped for PICALM rs3851179 and APOE ɛ4 at baseline and were followed for influences on changes of cognition and cerebrospinal fluid (CSF) AD markers in six years. The interaction effects were examined via regression models adjusting for age, gender, education, and cognitive diagnosis. Results: The interaction term of rs3851179×APOE ɛ4 accounted for a significant amount of variance in baseline general cognition (p = 0.039) and memory function (p = 0.002). The relationships of APOE ɛ4 with trajectory of CSF Aβ42 (p = 0.007), CSF P-tau181 (p = 0.003), CSF T-tau (p = 0.001), and memory function (p = 0.017) were also moderated by rs3851179 variation. Conclusions:APOE ɛ4 carriers experienced slower clinical and pathological progression when they had more protective A alleles of PICALM rs3851179. These findings firstly revealed the gene-gene interactive effects of PICALM with APOE ɛ4 in pre-dementia stage.

Keywords: Alzheimer’s disease, amyloid, APOE ɛ4, cognition, interaction, memory, PICALM , tau protein

DOI: 10.3233/JAD-230516

Journal: Journal of Alzheimer's Disease, vol. 96, no. 4, pp. 1651-1661, 2023