Identification of genetic heterogeneity of Alzheimer's disease across age

Abstract

The risk of APOE for Alzheimer's Disease (AD) is modified by age. Beyond APOE, the polygenic architecture may also be heterogeneous across age. We aim to investigate age-related genetic heterogeneity of AD and identify genomic loci with differential effects across age. Stratified genebased genome-wide association studies (GWAS) and polygenic variation analyses were performed in the younger (60-79 years, N = 14,895) and older (≥ 80 years, N = 6,559) age-at-onset groups using Alzheimer's Disease Genetics Consortium data. We showed a moderate genetic correlation (r g = 0.64) between the two age groups, supporting genetic heterogeneity. Heritability explained by variants on chromosome 19 (harboring APOE) was significantly larger in younger than in older onset group (P < 0.05). APOE region, BIN1, OR2S2, MS4A4E and PICALM were identified at the gene-based genome-wide significance (P < 2.73×10 −6) with larger effects at younger age (except MS4A4E). For the novel gene OR2S2, we further performed leave-one-out analyses, which showed consistent effects across subsamples. Our results suggest using genetically more homogeneous individuals may help detect additional susceptible loci.

Age-dependent effect of APOE and polygenic component on Alzheimer's disease

“…The heterogeneity of the polygenic architecture across age in AD was demonstrated by Lo et al. The authors showed that the heritability explained by chromosome 19 was significantly larger in the younger participants ( Lo et al., 2019 ). Similar results have also been presented in previous studies by Escott-Price ( Escott-Price et al., 2015 , Escott-Price et al., 2017 ).…”

“…Numerous studies have demonstrated that APOE ε4 is associated with an earlier age of disease onset ( Blacker et al., 1997 , Bonham et al., 2016 , Frisoni et al., 1998 , Sando et al., 2008 ), longevity ( Deelen et al., 2019 ), and the existence of a gene-dosage effect between increasing copies of ε4 and lower age of AD onset ( Corder et al., 1993 ). This age-dependent genetic heterogeneity was also investigated in the Alzheimer's Disease Genetics Consortium (ADGC) data ( Lo et al., 2019 ); the authors found moderate genetic correlation (r g = 0.64) between the 2 age groups (60–79 years vs. 80+ years), supporting the presence of genetic heterogeneity. Moreover, in their study, the heritability explained by single-nucleotide polymorphisms (SNPs) on chromosome 19, which harbors APOE , was substantially larger at younger relative to older age.…”

Risk prediction of late-onset Alzheimer’s disease implies an oligogenic architecture

“…Except for the difference due to the estimation methods, such differences could also be caused by differences in age distributions between datasets ( Supplementary Fig. 8), since the genetic effect on LOAD was reported to be age-dependent 38 . Based on the same method, the estimated heritability in datasets with younger individuals was found to be larger than that using older individuals (Supplementary Table 3).…”

Harnessing ionic mechanisms to achieve disease modification in neurodegenerative disorders

“…Nonetheless, thanks to progresses made by genetic studies and the widespread utilization of disease animal models, significant steps forward have been taken in the comprehension of the pathogenic pathways underlying NDDs. Besides confirming the high degree of aetiopathogenic diversity across different NDDs, which is hardly surprising, an unexpected level of internal heterogeneity in the pathogenic mechanisms underlying individual NDD classes has emerged [1][2][3][4], thus supporting the proposition that NDDs are mere clinical entities in which defining symptoms arise from diverse molecular pathways. For translational prospects, the mechanistic complexity of NDD pathogenesis implies that multiple targets should be identified for each NDD subtype, to design specific neuroprotective therapies.…”