Abstract：
BACKGROUND: 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.
METHODS: 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-8, P < 1e-5, P < 1e-3, P < 1e-1) 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.
RESULTS: 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.
CONCLUSIONS: 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.
METHODS: 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-8, P < 1e-5, P < 1e-3, P < 1e-1) 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.
RESULTS: 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.
CONCLUSIONS: 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.
摘要：
背景：阿尔茨海默病（AD-PRS）的多基因风险评分与认知相关。然而,很少有研究检查过AD-PRS超出APOE基因的作用，以及与认知能力水平（COG-PRS）相关的遗传变异对一般老年人群认知表现的影响。
方法：以人口为基础的样本，包括1930年出生的965个人，在六个心理测量测试中获得了遗传和标准化的认知数据（Thurstone的图片记忆，立即回忆10个字，块设计,单词流利,图识别,延迟召回12项)，在70、75、79和85岁时进行检查。非APOEAD-PRS和COG-PRS（P<5e-8，P<1e-5，P<1e-3，P<1e-1）来自最近的全基因组关联研究。采用随机截距和斜率的线性混合效应模型分析APOEε4等位基因的效应,AD-PRS,和COG-PRS，认知表现和变化率。在不包括痴呆的样品中重复分析。
结果：APOEε4和AD-PRS可预测认知能力的变化（APOEε4*年龄：β=-0.03，P<0.0001，AD-PRS*年龄：β=-0.01，P=0.02）。除痴呆症患者外，样本中的结果仍然相似。COG-PRS预测认知表现水平，而APOEε4和AD-PRS没有。COG-PRS不能预测认知表现的变化。
结论：我们发现，在70岁的人群中，AD的遗传易感性可以预测16岁以上的认知能力下降。不管痴呆状态如何,而一般认知表现的多基因风险没有。
方法：以人口为基础的样本，包括1930年出生的965个人，在六个心理测量测试中获得了遗传和标准化的认知数据（Thurstone的图片记忆，立即回忆10个字，块设计,单词流利,图识别,延迟召回12项)，在70、75、79和85岁时进行检查。非APOEAD-PRS和COG-PRS（P<5e-8，P<1e-5，P<1e-3，P<1e-1）来自最近的全基因组关联研究。采用随机截距和斜率的线性混合效应模型分析APOEε4等位基因的效应,AD-PRS,和COG-PRS，认知表现和变化率。在不包括痴呆的样品中重复分析。
结果：APOEε4和AD-PRS可预测认知能力的变化（APOEε4*年龄：β=-0.03，P<0.0001，AD-PRS*年龄：β=-0.01，P=0.02）。除痴呆症患者外，样本中的结果仍然相似。COG-PRS预测认知表现水平，而APOEε4和AD-PRS没有。COG-PRS不能预测认知表现的变化。
结论：我们发现，在70岁的人群中，AD的遗传易感性可以预测16岁以上的认知能力下降。不管痴呆状态如何,而一般认知表现的多基因风险没有。
