March 23, 2017 – For sure across the United States, but by a fair assumption worldwide also, late-onset Alzheimer’s disease (AD) is the most common form of dementia. There is a strong need for in vivo markers for AD risk stratification and cohort enrichment in therapeutic trials and eventually in the selection of treatment options for patients from the general at risk population. Although numerous studies have identified several genetic risk factors, including the E4 allele of apolipoprotein E (APOE), genetic variants have not been integrated with genetic epidemiology for quantifying age of AD onset.
In a very recent study, just published in the open access journal PLOS Medicine, genetic assessment of age-associated Alzheimer disease risk has been undertaken in order to develop and validate polygenic hazard scores for identifying individuals at risk for developing Alzheimer’s disease (AD).
Using genotype data from 17,008 AD cases and 37,154 controls from the International Genomics of Alzheimer’s Project (IGAP Stage 1), the researchers identified AD-associated SNPs (at p <10−5). They 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, they 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 E3/3 individuals, the PHS modified expected age of AD onset by more than 10 years 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 populations outside of the US, and possibly of different ethnic backgrounds along with prospective community-based cohorts are necessary in order to confirm a global applicability of these findings and make them validated for generalised clinical use in prospective disease risk examination and. possibly, prospective use of preventative therapeutic intervention in patients at high risk for the development of AD, particularly at early age.
About the Author
Ph.D.; Professor in Pharmacology and Toxicology.
Senior expert in theragenomic and personalized medicine and individualized drug safety.
Senior expert in pharmaco- and toxicogenetics.
Senior expert in human safety of drugs, chemicals, environmental pollutants, and dietary ingredients.
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