Genetic assessment of age-associated Alzheimer disease risk: Development and validation of a polygenic hazard score

Abstract

BackgroundIdentifying individuals at risk for developing Alzheimer disease (AD) is of utmost importance. Although genetic studies have identified AD-associated SNPs in APOE and other genes, genetic information has not been integrated into an epidemiological framework for risk prediction.Methods and findingsUsing genotype data from 17,008 AD cases and 37,154 controls from the International Genomics of Alzheimer’s Project (IGAP Stage 1), we identified AD-associated SNPs (at p < 10−5). We then integrated these AD-associated SNPs into a Cox proportional hazard model using genotype data from a subset of 6,409 AD patients and 9,386 older controls from Phase 1 of the Alzheimer’s Disease Genetics Consortium (ADGC), providing a polygenic hazard score (PHS) for each participant. By combining population-based incidence rates and the genotype-derived PHS for each individual, we derived estimates of instantaneous risk for developing AD, based on genotype and age, and tested replication in multiple independent cohorts (ADGC Phase 2, National Institute on Aging Alzheimer’s Disease Center [NIA ADC], and Alzheimer’s Disease Neuroimaging Initiative [ADNI], total n = 20,680). Within the ADGC Phase 1 cohort, individuals in the highest PHS quartile developed AD at a considerably lower age and had the highest yearly AD incidence rate. Among APOE ε3/3 individuals, the PHS modified expected age of AD onset by more than 10 y between the lowest and highest deciles (hazard ratio 3.34, 95% CI 2.62–4.24, p = 1.0 × 10−22). In independent cohorts, the PHS strongly predicted empirical age of AD onset (ADGC Phase 2, r = 0.90, p = 1.1 × 10−26) and longitudinal progression from normal aging to AD (NIA ADC, Cochran–Armitage trend test, p = 1.5 × 10−10), and was associated with neuropathology (NIA ADC, Braak stage of neurofibrillary tangles, p = 3.9 × 10−6, and Consortium to Establish a Registry for Alzheimer’s Disease score for neuritic plaques, p = 6.8 × 10−6) and in vivo markers of AD neurodegeneration (ADNI, volume loss within the entorhinal cortex, p = 6.3 × 10−6, and hippocampus, p = 7.9 × 10−5). Additional prospective validation of these results in non-US, non-white, and prospective community-based cohorts is necessary before clinical use.ConclusionsWe have developed a PHS for quantifying individual differences in age-specific genetic risk for AD. Within the cohorts studied here, polygenic architecture plays an important role in modifying AD risk beyond APOE. With thorough validation, quantification of inherited genetic variation may prove useful for stratifying AD risk and as an enrichment strategy in therapeutic trials.

Polygenic hazard scores in preclinical Alzheimer disease

“…For each CN and MCI participant in this study, we calculated their individual PHS, as previously described 7 . In brief, we identified AD associated SNPs (at p < 10 −5 ) using genotype data from 17,008 AD cases and 37,154 controls from Stage 1 of the International Genomics of Alzheimer’s Disease Project.…”

“…Finally, by combining US population based incidence rates, and genotype-derived PHS for each individual, we derived estimates of instantaneous risk for developing AD, based on genotype and age. In this study, the PHS computed for every CN and MCI participant represents the vector product of an individual’s genotype for the 31 SNPs and the corresponding parameter estimates from the ADGC Phase 1 Cox proportional hazard model in addition to the APOE effects (for additional details see 7 ).…”

“…6 Using genome-wide association (GWAS) from AD cases and controls, we have recently developed a novel ‘polygenic hazard score’ (PHS) for predicting age-specific risk for AD dementia that integrates 31 AD-associated SNPs (in addition to APOE ) with US-population based AD dementia incidence rates. 7 Among asymptomatic older adults, in retrospective analyses, we have previously shown that the PHS predicted age of AD onset strongly correlates with the actual age of onset. 7 To evaluate clinical usefulness and further validate PHS, in this study, we prospectively evaluated whether PHS predicts rate of progression to AD dementia and longitudinal cognitive decline in cognitively asymptomatic older adults and individuals with MCI.…”

“…7 Among asymptomatic older adults, in retrospective analyses, we have previously shown that the PHS predicted age of AD onset strongly correlates with the actual age of onset. 7 To evaluate clinical usefulness and further validate PHS, in this study, we prospectively evaluated whether PHS predicts rate of progression to AD dementia and longitudinal cognitive decline in cognitively asymptomatic older adults and individuals with MCI.…”

Polygenic hazard score: an enrichment marker for Alzheimer’s associated amyloid and tau deposition

“…Beyond APOE ε4, numerous single-nucleotide polymorphisms (SNPs) have now been shown to be associated with small increases in AD dementia risk [16]. Based on a combination of APOE and 31 other genetic variants, we have developed and validated a ‘polygenic hazard score’ (PHS) for quantifying AD dementia age of onset [8]. Importantly, PHS was associated with in vivo biomarkers of AD pathology such as reduced CSF Aβ 1–42 and elevated CSF total tau across the AD spectrum (in older controls, MCI and AD dementia individuals).…”