Abstract
Deposition of amyloid plaques in the brain is one of the two main pathological hallmarks of Alzheimer’s disease (AD). Amyloid positron emission tomography (PET) is a neuroimaging tool that selectively detects in vivo amyloid deposition in the brain and is a reliable endophenotype for AD that complements cerebrospinal fluid biomarkers with regional information. We measured in vivo amyloid deposition in the brains of ~1000 subjects from three collaborative AD centers and ADNI using 11C-labeled Pittsburgh Compound-B (PiB)-PET imaging followed by meta-analysis of genome-wide association studies, first to our knowledge for PiB-PET, to identify novel genetic loci for this endophenotype. The APOE region showed the most significant association where several SNPs surpassed the genome-wide significant threshold, with APOE*4 being most significant (P-meta = 9.09E-30; β = 0.18). Interestingly, after conditioning on APOE*4, 14 SNPs remained significant at P < 0.05 in the APOE region that were not in linkage disequilibrium with APOE*4. Outside the APOE region, the meta-analysis revealed 15 non-APOE loci with P < 1E-05 on nine chromosomes, with two most significant SNPs on chromosomes 8 (P-meta = 4.87E-07) and 3 (P-meta = 9.69E-07). Functional analyses of these SNPs indicate their potential relevance with AD pathogenesis. Top 15 non-APOE SNPs along with APOE*4 explained 25–35% of the amyloid variance in different datasets, of which 14–17% was explained by APOE*4 alone. In conclusion, we have identified novel signals in APOE and non-APOE regions that affect amyloid deposition in the brain. Our data also highlights the presence of yet to be discovered variants that may be responsible for the unexplained genetic variance of amyloid deposition.
Highlights
Electronic supplementary material The online version of this article contains supplementary material, which is available to authorized users.Genomic efforts mainly through large-scale genome-wide association studies (GWAS), as part of the Alzheimer’s Disease Genetics Consortium (ADGC) [1] and the International Genomics of Alzheimer’s Project (IGAP) [2], have identified over 20 genes/loci for late-onset Alzheimer’s disease (AD)
Pittsburgh Compound-B (PiB) retention was measured in four cortical regions of the brain, including medial frontal cortex (MFC; anterior cingulate/ gyrus rectus), lateral frontal cortex (LFC), precuneus cortex (PRC), and parietal cortex (PAR) and expressed as a ratio to the cerebellum
PiB retention was expressed as standardized uptake volume ratio (SUVR) in the PITT and Alzheimer’s Disease Neuroimaging Initiative (ADNI)/Indiana University (IU) data [23, 24] and as binding potential (BP) in the Washington University (WU) data [25]
Summary
Genetic studies focusing on AD-related quantitative phenotypes/endophenotypes may help to identify additional AD-related genes. One such AD-related phenotype is deposition of amyloid-beta (Aβ) in the brain, which is one of the two main pathologic hallmarks of AD; the other being the formation of tau deposits in the form of neurofibrillary tangles, neuropil threads, and dystrophic neurites (tau pathology) in the brain [4]. The in vivo detection of Aβ deposition in the brain, as measured by positron emission tomography (PET) scanning with 11Clabeled Pittsburgh Compound-B (PiB) and the increased retention of PiB observed in the brains of AD patients compared with cognitively normal controls, was first reported by Klunk and colleagues [8, 9] and since has been confirmed in many studies [10]. Multiple studies have shown that amyloid PET has a high value for the clinical diagnosis of AD and in clinical trials aiming to reduce brain Aβ burden [14]
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