Neuropsychiatric Epidemiology Unit, Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, the Sahlgrenska Academy, Centre for Ageing and Health (AGECAP) at the University of Gothenburg, Sweden; Region Västra Götaland, Sahlgrenska University Hospital, Psychiatry, Cognition and Old Age Psychiatry Clinic, Gothenburg, Sweden; Department of Human Genetics, Genomics of Neurodegenerative Diseases and Aging at the Amsterdam University Medical Center, Amsterdam, the Netherlands.
Department of Psychology, and Centre for Ageing and Health (AGECAP), at the University of Gothenburg, Sweden.
Neurobiol Dis. 2023 Dec;189:106357. doi: 10.1016/j.nbd.2023.106357. Epub 2023 Nov 15.
Polygenic risk scores for Alzheimer's disease (AD-PRSs) have been associated with cognition. However, few studies have examined the effect of AD-PRS beyond the APOE gene, and the influence of genetic variants related to level of cognitive ability (COG-PRS) on cognitive performance over time in the general older population.
A population-based sample of 965 individuals born in 1930, with genetic and standardized cognitive data on six psychometric tests (Thurstone's picture memory, immediate recall of 10 words, Block design, word fluency, figure identification, delayed recall of 12 items), were examined at age 70, 75, 79, and 85 years. Non-APOE AD-PRSs and COG-PRSs (P < 5e, P < 1e, P < 1e, P < 1e) were generated from recent genome-wide association studies. Linear mixed effect models with random intercepts and slope were used to analyze the effect of APOE ε4 allele, AD-PRSs, and COG-PRSs, on cognitive performance and rate of change. Analyses were repeated in samples excluding dementia.
APOE ε4 and AD-PRS predicted change in cognitive performance (APOE ε4*age: β = -0.03, P < 0.0001 and AD-PRS *age: β = -0.01, P = 0.02). The results remained similar in the sample excluding those with dementia. COG-PRS predicted level of cognitive performance, while APOE ε4 and AD-PRS did not. COG-PRSs did not predict change in cognitive performance.
We found that genetic predisposition of AD predicted cognitive decline among 70-year-olds followed over 16 years, regardless of dementia status, while polygenic risk for general cognitive performance did not.
阿尔茨海默病（AD）的多基因风险评分（AD-PRS）与认知能力相关。然而，很少有研究在 APOE 基因之外考察 AD-PRS 的影响，也很少有研究在一般老年人群中考察与认知能力水平相关的遗传变异（COG-PRS）对认知表现随时间变化的影响。
本研究基于人群的样本包括 965 名出生于 1930 年的个体，这些个体在 70、75、79 和 85 岁时接受了六项心理测试（Thurstone 图片记忆、10 个单词的即时回忆、积木设计、词语流畅性、图形识别、12 个项目的延迟回忆）的遗传和标准化认知数据。从最近的全基因组关联研究中生成非 APOE AD-PRS 和 COG-PRS（P<5e，P<1e，P<1e，P<1e）。采用具有随机截距和斜率的线性混合效应模型，分析 APOE ε4 等位基因、AD-PRS 和 COG-PRS 对认知表现和变化率的影响。在排除痴呆症的样本中重复了分析。
APOE ε4 和 AD-PRS 预测认知表现的变化（APOE ε4年龄：β=-0.03，P<0.0001 和 AD-PRS年龄：β=-0.01，P=0.02）。在排除痴呆症的样本中，结果仍然相似。COG-PRS 预测认知表现水平，而 APOE ε4 和 AD-PRS 则没有。COG-PRS 不预测认知表现的变化。
我们发现，AD 的遗传易感性预测了 70 岁人群在 16 年随访期间的认知下降，无论痴呆状态如何，而一般认知表现的多基因风险则没有。
