Defining the Genetic Architecture of Alzheimer's Disease: Where Next?

Sims, Rebecca; Williams, Julie

doi:10.1159/000440841

Cited by 16 publications

(14 citation statements)

References 39 publications

(54 reference statements)

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“…At 60% AD risk, APOE ε3/3 individuals in the first decile of the PHS have an expected age of onset of 85 y, whereas for individuals in the tenth decile of the PHS, the expected age of onset is greater than 95 y. These findings are directly relevant to the general population, where APOE ε4 accounts for only a fraction of AD risk [3], and are consistent with prior work [26] indicating that AD is a polygenic disease where non- APOE genetic variants contribute significantly to disease etiology.…”

Section: Discussionsupporting

confidence: 86%

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

et al. 2017

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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.

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Section: Discussionsupporting

confidence: 86%

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

et al. 2017

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“…At 60% AD risk APOE ε3/3 individuals in the 1 st decile of PHS have an expected age of onset of 85 whereas for individuals in the 10 th decile of PHS, the expected age of onset is greater than 95. These findings are directly relevant to the general population where APOE ε4 only accounts for a fraction of AD risk 3 and are consistent with prior work 21 indicating that AD is a polygenic disease where non- APOE genetic variants contribute significantly to disease etiology.…”

Section: Discussionsupporting

confidence: 90%

Personalized genetic assessment of age associated Alzheimer’s disease risk

Rs¹,

Wang

et al. 2016

Preprint

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78 79 80 *Data used in preparation of this article were obtained from the Alzheimer's Disease Neuroimaging 81 Initiative (ADNI) database (adni.loni.usc.edu). As such, the investigators within the ADNI contributed to 82 the design and implementation of ADNI and/or provided data but did not participate in analysis or writing 83 of this report. A complete listing of ADNI investigators can be found at: http://adni.loni.usc.edu/wp-84 content/uploads/how_to_apply/ADNI_Acknowledgement_List.pdf 85 86 87 Manuscript = 3,095 words 88 89 90 ABSTRACT 91 Importance: Identifying individuals at risk for developing Alzheimer's disease (AD) is 92 of utmost importance. Although genetic studies have identified APOE and other AD 93 associated single nucleotide polymorphisms (SNPs), genetic information has not been 94 integrated into an epidemiological framework for personalized risk prediction. 95 Objective: To develop, replicate and validate a novel polygenic hazard score for 96 predicting age-specific risk for AD. 97 Setting: Multi-center, multi-cohort genetic and clinical data. 98

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“…Although ApoE remains the most potent susceptibility gene, the advent of genome wide association studies have identified 25 loci known to associate with late-onset sporadic AD, and the advent of polygenic risk scores are now available and will further refine our understanding of genetic contributions to AD progression (for review, see Sims & Williams, 2016). …”

Section: The 1990s: Neuropsychological Characterization Of Alzheimer’mentioning

confidence: 99%

Alzheimer’s Disease: Past, Present, and Future

Bondi

Edmonds

Salmon

2017

J Int Neuropsychol Soc

478

314

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Although dementia has been described in ancient texts over many centuries (e.g., “Be kind to your father, even if his mind fail him.” – Old Testament: Sirach 3:12), our knowledge of its underlying causes is little more than a century old. Alzheimer published his now famous case study only 110 years ago, and our modern understanding of the disease that bears his name, and its neuropsychological consequences, really only began to accelerate in the 1980s. Since then we have witnessed an explosion of basic and translational research into the causes, characterizations, and possible treatments for Alzheimer’s disease (AD) and other dementias. We review this lineage of work beginning with Alzheimer’s own writings and drawings, then jump to the modern era beginning in the 1970s and early 1980s and provide a sampling of neuropsychological and other contextual work from each ensuing decade. During the 1980s our field began its foundational studies of profiling the neuropsychological deficits associated with AD and its differentiation from other dementias (e.g., cortical vs. subcortical dementias). The 1990s continued these efforts and began to identify the specific cognitive mechanisms affected by various neuropathologic substrates. The 2000s ushered in a focus on the study of prodromal stages of neurodegenerative disease before the full-blown dementia syndrome (i.e., mild cognitive impairment). The current decade has seen the rise of imaging and other biomarkers to characterize preclinical disease before the development of significant cognitive decline. Finally, we suggest future directions and predictions for dementia-related research and potential therapeutic interventions.

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Defining the Genetic Architecture of Alzheimer's Disease: Where Next?

Cited by 16 publications

References 39 publications

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

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

Personalized genetic assessment of age associated Alzheimer’s disease risk

Alzheimer’s Disease: Past, Present, and Future

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