Abstract
BackgroundClusterin, also known as apolipoprotein J (apoJ), is one of the most abundantly expressed apolipoproteins in the brain after apolipoprotein E (apoE). Like the ε4 allele of the apolipoprotein E gene (APOE), the clusterin gene (CLU) is a risk locus for Alzheimer’s disease, and may play additional roles in atherosclerosis pathogenesis. We tested whether genetic variation in CLU was associated with either Alzheimer’s disease or atherosclerosis-related diseases.MethodsWe studied individual data on 103,987 participants from the Copenhagen General Population Study (CGPS) and the Copenhagen City Heart Study (CCHS). We genotyped a common CLU variant (rs9331896) and two common APOE variants (rs7412 and rs429358), defining the ε2, ε3, and ε4, alleles in CGPS and CCHS. All individuals in the CGPS and CCHS cohorts were followed from study inclusion to occurrence of event, death, emigration, or until 10 November 2014, whichever came first. Summary consortia data on 258,351 individuals from the International Genomics of Alzheimer’s Project (IGAP) and the Coronary Artery Disease Genome-wide Replication and Meta-analysis plus the Coronary Artery Disease (C4D) Genetics and 1000-Genomes-based genome-wide association studies (CARDIoGRAMplusC4D) were used in meta-analyses.ResultsIn CGPS and CCHS, multifactorially adjusted hazard ratios for Alzheimer’s disease, all dementia, vascular dementia, ischemic cerebrovascular disease, and ischemic heart disease were 1.18 (1.07–1.30), 1.09 (1.02–1.17), 0.96 (0.80–1.17), 1.02 (0.97–1.07), and 0.97 (0.93–1.01) per T allele, respectively. Multifactorially adjusted hazard ratios for Alzheimer’s disease and all dementia were 2.72 (2.45–3.01) and 2.21 (2.05–2.38) for the APOE ɛ4 allele. There was no interaction between rs9331896 in CLU and rs429358 (defining the ɛ4 allele) in APOE in predicting Alzheimer’s disease or all dementia (P = 0.39 and P = 0.21). In a meta-analysis including consortium data, the overall fixed- and random-effects odds ratios for Alzheimer’s disease per T allele were 1.16 (1.13–1.18) (I2 = 0.0%; P for heterogeneity = 0.89).ConclusionsA common variant in CLU was associated with a high risk of Alzheimer’s disease and all dementia in the general population but not with vascular dementia or ischemic vascular disease. Important novel aspects compared to previous studies are the incorporation of individual risk factor data, the exact causative ε4 allele, and several subtypes of dementia and atherosclerosis-related endpoints.
Highlights
Clusterin, known as apolipoprotein J, is one of the most abundantly expressed apolipoproteins in the brain after apolipoprotein E
Important novel aspects compared to previous studies are the incorporation of individual risk factor data, the exact causative ε4 allele, and several subtypes of dementia and atherosclerosis-related endpoints
Ischemic cerebrovascular disease, and ischemic heart disease are all characterized by atherosclerosis [15, 16], variation in clusterin gene (CLU) may play a role for these atherosclerosis-related diseases in addition to the wellestablished association with Alzheimer’s disease
Summary
Known as apolipoprotein J (apoJ), is one of the most abundantly expressed apolipoproteins in the brain after apolipoprotein E (apoE). Like the ε4 allele of the apolipoprotein E gene (APOE), the clusterin gene (CLU) is a risk locus for Alzheimer’s disease, and may play additional roles in atherosclerosis pathogenesis. Clusterin ( known as apoJ) is one of the most abundantly expressed apolipoproteins, second only to apoE [7] These apolipoprotein particles are synthesized in astrocytes, are pivotal for brain cholesterol metabolism, and are attached to a high-density lipoprotein (HDL)-like particle [7, 8]. The clusterin molecule is a versatile chaperone that has the ability to bind to a wide array of physiological ligands putatively involved in Alzheimer’s disease pathology [9] One of these is βamyloid, for which clusterin mediates clearance from the brain through the blood–brain barrier to the peripheral circulation via megalin [9, 10]. Ischemic cerebrovascular disease, and ischemic heart disease are all characterized by atherosclerosis [15, 16], variation in CLU may play a role for these atherosclerosis-related diseases in addition to the wellestablished association with Alzheimer’s disease
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