Late-onset Alzheimer’s risk variants in memory decline, incident mild cognitive impairment, and Alzheimer’s disease

Abstract

Background Genome-wide association studies (GWAS) of late-onset Alzheimer's disease (LOAD) identified risk variants. We assessed the association of nine variants with memory and progression to mild cognitive impairment (MCI) or LOAD (MCI/LOAD). Methods Older Caucasians, cognitively normal at baseline and longitudinally evaluated at Mayo Clinic Rochester and Jacksonville, were assessed for associations of genetic variants with memory decline (n=2,262) using linear mixed models and for incident MCI/LOAD (n=2,674) with Cox proportional hazards models. Each variant was tested both individually and collectively using a single weighted risk score. Results APOE-ε4 was significantly associated with worse memory at baseline (β=-0.88, p=2.78E-03) and increased rate of 5-year decline (β=-1.43, p=3.71E-06) with highly significant overall effect on memory (p=3.88E-09). CLU-locus risk allele rs11136000-G was associated with worse memory at baseline (β=-0.51, p=0.012), but not with increased rate of decline. CLU allele was also associated with incident MCI/LOAD (hazard ratio=HR=1.14, p=0.049) in sensitivity analysis. MS4A6A-locus risk allele rs610932-C was associated with increased incident MCI/LOAD in primary analysis (HR=1.17, p=0.016) and had suggestive association with lower baseline memory (β=-0.35, p=0.08). PICALM-locus risk allele rs3851179-G had nominally significant HR in both primary and sensitivity analysis, but with a protective estimate. LOAD risk alleles ABCA7-rs3764650-C and EPHA1-rs11767557-A associated with increased rates of memory decline in the subset of subjects with a final diagnosis of MCI/LOAD. Risk scores excluding APOE were not significant, whereas APOE-inclusive risk scores associated with worse memory and incident MCI/LOAD. Conclusions The collective influence of the nine top LOAD GWAS variants on memory decline and progression to MCI/LOAD appears limited. Given the significant associations observed with APOE-ε4, discovery of the biologically functional variants at these loci may uncover stronger effects on memory and incident disease.

Microglial Malfunction: The Third Rail in the Development of Alzheimer's Disease

“…The Erythropoietin-producing hepatocellular (Eph) receptor ( EPHA1 ) is associated with LOAD risk (Carrasquillo et al, 2015, Naj et al, 2011, Wang et al, 2015a). The Eph receptors are receptor tyrosine kinases and their ligands, ephrins, are involved in mediating cell adhesion and migration, and may function in immune cell migration.…”

Evaluation of a Genetic Risk Score to Improve Risk Prediction for Alzheimer’s Disease

“…Since the effect sizes associated with individual genetic variants are small, ranging from a 23% reduction to a 22% increase in risk, an aggregated genetic risk score (GRS) could perform better than any individual variant. Such an approach has been successfully used to replicate association of genetic variants with AD, [17–23] but also to show associations of AD-related genetic variants with mild cognitive impairment [21, 22] and endophenotypes such as brain volumes measured by MRI, [24–27] cognitive tests, [18, 20, 22, 28] age at onset [23, 29], or CSF biomarkers of AD [23, 30]. These results hinted at potential benefits of using genetic information to improve the selection of asymptomatic, at-risk participants in preclinical biomarker or drug trials.…”

Genetic variants in Alzheimer disease — molecular and brain network approaches

“…For example, out of 13 single nucleotide polymorphisms associated with general cognitive function , four ( TOMM40 , APOE , MEF2C and ABCG1 ) have been consistently implicated in AD 248 , and others were associated with the rate of cognitive decline ( CR1) 249 , episodic memory ( PICALM ) 250 and working memory performance tasks ( BIN1) 251 . The most consistent finding, by far, was the association of APOE with various cognitive phenotypes and the rate of cognitive decline with age 252,253 . However, some of this overlap in the genetic bases of cognitive function and that of AD-associated dementia might be due to the fact that decline in cognitive ability can occur naturally with time or with AD.…”