Genetic discoveries of Alzheimer's disease are the drivers of our understanding, and together with polygenetic risk stratification can contribute towards planning of feasible and efficient preventive and curative clinical trials. We first perform a large genetic association study by merging all available case-control datasets and by-proxy study results (discovery n = 409,435 and validation size n = 58,190). Here, we add six variants associated with Alzheimer's disease risk (near APP, CHRNE, PRKD3/NDUFAF7, PLCG2 and two exonic variants in the SHARPIN gene). Assessment of the polygenic risk score and stratifying by APOE reveal a 4 to 5.5 years difference in median age at onset of Alzheimer's disease patients in APOE ɛ4 carriers. Because of this study, the underlying mechanisms of APP can be studied to refine the amyloid cascade and the polygenic risk score provides a tool to select individuals at high risk of Alzheimer's disease.
- MeSH
- Alzheimer Disease epidemiology genetics pathology MeSH
- Amyloid beta-Protein Precursor genetics metabolism MeSH
- Apolipoproteins E genetics MeSH
- Genome-Wide Association Study MeSH
- Datasets as Topic MeSH
- Genetic Predisposition to Disease MeSH
- Heterozygote MeSH
- Risk Assessment methods MeSH
- Polymorphism, Single Nucleotide MeSH
- Cohort Studies MeSH
- Middle Aged MeSH
- Humans MeSH
- Multifactorial Inheritance * MeSH
- Follow-Up Studies MeSH
- Risk Factors MeSH
- Aged, 80 and over MeSH
- Aged MeSH
- Case-Control Studies MeSH
- Age of Onset MeSH
- Check Tag
- Middle Aged MeSH
- Humans MeSH
- Male MeSH
- Aged, 80 and over MeSH
- Aged MeSH
- Female MeSH
- Publication type
- Journal Article MeSH
- Research Support, Non-U.S. Gov't MeSH
- Research Support, N.I.H., Extramural MeSH
- Validation Study MeSH
