APOE*E2 allele delays age of onset in PSEN1 E280A Alzheimer’s disease

Abstract

Alzheimer's disease (AD) age of onset (ADAOO) varies greatly between individuals, with unique causal mutations suggesting the role of modifying genetic and environmental interactions. We analyzed ~50 000 common and rare functional genomic variants from 71 individuals of the ‘Paisa' pedigree, the world's largest pedigree segregating a severe form of early-onset AD, who were affected carriers of the fully penetrant E280A mutation in the presenilin-1 (PSEN1) gene. Affected carriers with ages at the extremes of the ADAOO distribution (30s–70s age range), and linear mixed-effects models were used to build single-locus regression models outlining the ADAOO. We identified the rs7412 (APOE*E2 allele) as a whole exome-wide ADAOO modifier that delays ADAOO by ~12 years (β=11.74, 95% confidence interval (CI): 8.07–15.41, P=6.31 × 10−8, PFDR=2.48 × 10−3). Subsequently, to evaluate comprehensively the APOE (apolipoprotein E) haplotype variants (E1/E2/E3/E4), the markers rs7412 and rs429358 were genotyped in 93 AD affected carriers of the E280A mutation. We found that the APOE*E2 allele, and not APOE*E4, modifies ADAOO in carriers of the E280A mutation (β=8.24, 95% CI: 4.45–12.01, P=3.84 × 10−5). Exploratory linear mixed-effects multilocus analysis suggested that other functional variants harbored in genes involved in cell proliferation, protein degradation, apoptotic and immune dysregulation processes (i.e., GPR20, TRIM22, FCRL5, AOAH, PINLYP, IFI16, RC3H1 and DFNA5) might interact with the APOE*E2 allele. Interestingly, suggestive evidence as an ADAOO modifier was found for one of these variants (GPR20) in a set of patients with sporadic AD from the Paisa genetic isolate. This is the first study demonstrating that the APOE*E2 allele modifies the natural history of AD typified by the age of onset in E280A mutation carriers. To the best of our knowledge, this is the largest analyzed sample of patients with a unique mutation sharing uniform environment. Formal replication of our results in other populations and in other forms of AD will be crucial for prediction, follow-up and presumably developing new therapeutic strategies for patients either at risk or affected by AD.

Presenilin-1 mutations and Alzheimer’s disease

“…Sun et al next examined the relationship between the Aβ42/Aβ40 ratio and the age of disease onset associated with individual mutations and found no significant correlation, further arguing against the pathogenicity of a heightened Aβ42/Aβ40 ratio. However, it should be noted that age of onset is an imperfect proxy for the pathogenicity of individual mutations; for example, the age of onset ascribed to a given FAD mutation is often based on small numbers of affected individuals and can vary substantially based on APOE genotype and possibly other modifier effects (16,17). In contrast, mean ages of onset derived from large numbers of mutations identified in PSEN1 and APP might offer insight into the relative pathogenicity of mutations in each gene; a recent meta-analysis of 1,300 individuals with PSEN or APP mutations demonstrated that PSEN1 mutations cause FAD with a significantly earlier mean age of onset than APP mutations (18).…”

Epigenetic dysregulation of brainstem nuclei in the pathogenesis of Alzheimer’s disease: looking in the correct place at the right time?

“…environmental agents, dietary factors, and lifestyle habits, accumulate, leading to aberrant-pathological changes in expression [67, 68]. Evidently, these notions should be taken into consideration for longitudinal studies in populations at high risk of developing AD [69]. Furthermore, research on incipient stages of AD might not be in conflict with other confounding factors, but as the pathology worsens, the epigenome seems to change dramatically.…”

Variants regulating ZBTB4 are associated with age‐at‐onset of Alzheimer's disease

“…The shared genetic basis of EOAD and LOAD has been revealed by targeted sequencing analyses, where AD risk variants in probands ascertained from LOAD families have been identified (Cruchaga et al , 2012). Furthermore, APOE , the most well-established genetic modifier of AAO of AD, influences AAO of AD in families affected by EOAD (Marchani et al , 2010, Pastor et al , 2003, Velez et al , 2016b) and persons affected by LOAD (Naj et al , 2014). …”