Alzheimer’s Disease Susceptibility Gene Apolipoprotein E (APOE) and Blood Biomarkers in UK Biobank (N = 395,769)

Article type: Research Article

Authors: Ferguson, Amy C.^a | Tank, Rachana^a | Lyall, Laura M.^a | Ward, Joey^a | Celis-Morales, Carlos^{b; c} | Strawbridge, Rona^{a; d; e} | Ho, Frederick^a | Whelan, Christopher D.^f | Gill, Jason^b | Welsh, Paul^b | Anderson, Jana J.^a | Mark, Patrick B.^b | Mackay, Daniel F.^a | Smith, Daniel J.^a | Pell, Jill P.^a | Cavanagh, Jonathan^a | Sattar, Naveed^a | Lyall, Donald M.^{a; *}

Affiliations: [a] Institute of Health and Wellbeing, University of Glasgow, Scotland, UK | [b] Institute of Cardiovascular and Medical Sciences, University of Glasgow, Glasgow, Scotland, UK | [c] GEEAFyS, Universidad Católica del Maule, Talca, Chile | [d] Health Data Research UK | [e] Department of Medicine Solna, Cardiovascular Medicine, Karolinska Institutet, Stockholm, Sweden | [f] Research and Early Development (RED), Biogen Inc., Cambridge, MA, USA

Correspondence: [*] Correspondence to: Donald M. Lyall, PhD, 1 Lilybank Gardens, Institute of Health and Wellbeing, University of Glasgow, G12 8RZ, Glasgow, UK. Tel.: +44 0 141 330 8547; Fax: +44 0 141 330 1874; E-mail: [email protected]

Abstract: Background:Alzheimer’s disease (AD) is a neurodegenerative condition where the underlying etiology is still unclear. Investigating the potential influence of apolipoprotein E (APOE), a major genetic risk factor, on common blood biomarkers could provide a greater understanding of the mechanisms of AD and dementia risk. Objective:Our objective was to conduct the largest (to date) single-protocol investigation of blood biomarkers in the context of APOE genotype, in UK Biobank. Methods:After quality control and exclusions, data on 395,769 participants of White European ancestry were available for analysis. Linear regressions were used to test potential associations between APOE genotypes and biomarkers. Results:Several biomarkers significantly associated with APOE ɛ4 ‘risk’ and ɛ2 ‘protective’ genotypes (versus neutral ɛ3/ɛ3). Most associations supported previous data: for example, ɛ4 genotype was associated with elevated low-density lipoprotein cholesterol (LDL) (standardized beta [b] = 0.150 standard deviations [SDs] per allele, p < 0.001) and ɛ2 with lower LDL (b = –0.456 SDs, p < 0.001). There were however instances of associations found in unexpected directions: e.g., ɛ4 and increased insulin-like growth factor (IGF-1) (b = 0.017, p < 0.001) where lower levels have been previously suggested as an AD risk factor. Conclusion:These findings highlight biomarker differences in non-demented people at genetic risk for dementia. The evidence herein supports previous hypotheses of involvement from cardiometabolic and neuroinflammatory pathways.

Keywords: Alzheimer’s disease, APOE, cholesterol, dementia, UK Biobank

DOI: 10.3233/JAD-200338

Journal: Journal of Alzheimer's Disease, vol. 76, no. 4, pp. 1541-1551, 2020