Delft Bioinformatics Lab, Delft University of Technology, Delft, The Netherlands.
Department of Clinical Genetics, Section Genomics of Neurodegenerative Diseases and Aging, Vrije Universiteit Amsterdam, Amsterdam UMC, Amsterdam, The Netherlands.
Alzheimers Dement. 2024 Jun;20(6):3864-3875. doi: 10.1002/alz.13810. Epub 2024 Apr 18.
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.
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.
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), and 2-fold lower compared to age-matched controls (P = 5.83 × 10).
Maintaining cognitive health until extreme ages requires complex genetic protection against AD, which concentrates on the genes associated with the endolysosomal and immune systems.
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.
阿尔茨海默病（AD）的患病率随着年龄的增长而增加，但只有一小部分人在没有认知能力下降的情况下达到 100 岁以上的年龄。我们研究了与这种对 AD 具有抵抗力相关的遗传因素。
全基因组关联研究确定了 86 个与 AD 风险相关的单核苷酸多态性（SNP）。我们估计了 2281 例 AD 病例、3165 名年龄匹配的对照和 346 名认知健康的百岁老人中的 SNP 频率。我们为每个个体计算了多基因风险评分（PRS），并研究了在百岁老人中富集/缺失的 SNP 的功能特性。
认知健康的百岁老人中，与 AD 风险相关的 SNP 的保护性等位基因丰富。保护作用集中在 ANKH、GRN、TMEM106B、SORT1、PLCG2、RIN3 和 APOE 基因中的等位基因上。与 AD 病例相比，百岁老人的 PRS 低 5 倍以上（P=7.69×10），与年龄匹配的对照相比低 2 倍（P=5.83×10）。
保持认知健康直到极端年龄需要针对 AD 的复杂遗传保护，这种保护集中在与内溶酶体和免疫系统相关的基因上。
认知健康的百岁老人中，与阿尔茨海默病（AD）相关的遗传变异的保护性等位基因丰富。保护作用集中在涉及免疫和内溶酶体系统的变异上。将变异组合成多基因风险评分（PRS），与 AD 病例相比，百岁老人的 PRS 低 5 倍以上，与中年健康对照相比低 2 倍左右。
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