Cognitively healthy centenarians are genetically protected against Alzheimer's disease
Niccolo’ Tesi (Vrije Universiteit Amsterdam)
Sven van der Lee (TU Delft - Pattern Recognition and Bioinformatics, Vrije Universiteit Amsterdam, Amsterdam UMC)
Marc Hulsman (TU Delft - Pattern Recognition and Bioinformatics, Amsterdam UMC, Vrije Universiteit Amsterdam)
Natasja M. van Schoor (Vrije Universiteit Amsterdam, TU Delft - Pattern Recognition and Bioinformatics, Amsterdam Public Health)
Martijn Huisman (Vrije Universiteit Amsterdam, Amsterdam Public Health)
Yolande Pijnenburg (Vrije Universiteit Amsterdam)
Wiesje M. van der Flier (Vrije Universiteit Amsterdam)
Marcel Reinders (TU Delft - Pattern Recognition and Bioinformatics)
Henne Holstege (Amsterdam UMC, Vrije Universiteit Amsterdam, TU Delft - Intelligent Systems)
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Abstract
BACKGROUND: Alzheimer's disease (AD) prevalence increases with age, yet a small fraction of the population reaches ages > 100 years without cognitive decline. We studied the genetic factors associated with such resilience against AD. METHODS: Genome-wide association studies identified 86 single nucleotide polymorphisms (SNPs) associated with AD risk. We estimated SNP frequency in 2281 AD cases, 3165 age-matched controls, and 346 cognitively healthy centenarians. We calculated a polygenic risk score (PRS) for each individual and investigated the functional properties of SNPs enriched/depleted in centenarians. RESULTS: Cognitively healthy centenarians were enriched with the protective alleles of the SNPs associated with AD risk. The protective effect concentrated on the alleles in/near ANKH, GRN, TMEM106B, SORT1, PLCG2, RIN3, and APOE genes. This translated to >5-fold lower PRS in centenarians compared to AD cases (P = 7.69 × 10−71), and 2-fold lower compared to age-matched controls (P = 5.83 × 10−17). DISCUSSION: Maintaining cognitive health until extreme ages requires complex genetic protection against AD, which concentrates on the genes associated with the endolysosomal and immune systems. Highlights: Cognitively healthy cent enarians are enriched with the protective alleles of genetic variants associated with Alzheimer's disease (AD). The protective effect is concentrated on variants involved in the immune and endolysosomal systems. Combining variants into a polygenic risk score (PRS) translated to > 5-fold lower PRS in centenarians compared to AD cases, and ≈ 2-fold lower compared to middle-aged healthy controls.
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