Tsapanou A, Mourtzi N, Gu Y, Habeck C, Belsky D, Stern Y
Cognitive Neuroscience Division, Department of Neurology, Columbia University Irving Medical Center, New York, NY, USA.
1st Department of Neurology, Aiginition Hospital, National and Kapodistrian University of Athens Medical School, Athens, Greece.
Neuroimage Rep. 2023 Mar;3(1). doi: 10.1016/j.ynirp.2022.100153. Epub 2022 Dec 20.
Genome-wide association studies (GWAS) have identified large numbers of genetic variants associated with cognition. However, little is known about how these genetic discoveries impact cognitive aging.
We conducted polygenic-index (PGI) analysis of cognitive performance in n = 168 European-ancestry adults aged 20-80. We computed PGIs based on GWAS of cognitive performance in young/middle-aged and older adults. We tested associations of the PGI with cognitive performance, as measured through neuropsychological evaluation. We explored whether these associations were accounted for by magnetic resonance imaging (MRI) measures of brain-aging phenotypes: total gray matter volume (GM), cortical thickness (CT), and white matter hyperintensities burden (WMH).
Participants with higher PGI values performed better on cognitive tests (B = 0.627, SE = 0.196, = 0.002) (age, sex, and principal components as covariates). Associations remained significant with inclusion of covariates for MRI measures of brain aging; B = 0.439, SE: 0.198, = 0.028). PGI associations were stronger in young and middle-aged (age<65) as compared to older adults. For further validation, linear regression for Cog PGI and cognition in the fully adjusted model and adding the interaction between age group and Cog PGI, showed significant results (B = 0.892, SE: 0.325, = 0.007) driven by young and middle-aged adults (B = -0.403, SE: 0.193, = 0.039). In ancillary analysis, the Cognitive PGI was not associated with any of the brain measures.
Genetics discovered in GWAS of cognition are associated with cognitive performance in healthy adults across age, but most strongly in young and middle-aged adults. Associations were not explained by brain-structural markers of brain aging. Genetics uncovered in GWAS of cognitive performance may contribute to individual differences established relatively early in life and may not reflect genetic mechanisms of cognitive aging.
全基因组关联研究（GWAS）已识别出大量与认知相关的基因变异。然而，对于这些基因发现如何影响认知衰老，我们知之甚少。
我们对168名年龄在20至80岁之间的欧洲裔成年人的认知表现进行了多基因指数（PGI）分析。我们基于年轻人/中年人和老年人认知表现的GWAS计算PGI。我们通过神经心理学评估测试了PGI与认知表现之间的关联。我们探究了这些关联是否由脑老化表型的磁共振成像（MRI）测量指标所解释：总灰质体积（GM）、皮质厚度（CT）和白质高信号负荷（WMH）。
PGI值较高的参与者在认知测试中的表现更好（B = 0.627，标准误 = 0.196，P = 0.002）（以年龄、性别和主成分为协变量）。纳入脑老化MRI测量指标的协变量后，关联仍然显著；B = 0.439，标准误：0.198，P = 0.028）。与老年人相比，PGI关联在年轻人和中年人（年龄<65岁）中更强。为了进一步验证，在完全调整模型中对认知PGI和认知进行线性回归，并加入年龄组与认知PGI之间的交互作用，结果显示由年轻人和中年人驱动的显著结果（B = 0.892，标准误：0.325，P = 0.007）（B = -0.403，标准误：0.193，P = 0.039）。在辅助分析中，认知PGI与任何脑测量指标均无关联。
在认知GWAS中发现的基因与各年龄段健康成年人的认知表现相关，但在年轻人和中年人中关联最为强烈。脑老化的脑结构标志物无法解释这些关联。在认知表现GWAS中发现的基因可能导致生命早期就已确立的个体差异，且可能无法反映认知衰老的遗传机制。
