Jaholkowski Piotr, Bahrami Shahram, Fominykh Vera, Hindley Guy F L, Tesfaye Markos, Parekh Pravesh, Parker Nadine, Filiz Tahir T, Nordengen Kaja, Hagen Espen, Koch Elise, Bakken Nora R, Frei Evgeniia, Birkenæs Viktoria, Rahman Zillur, Frei Oleksandr, Haavik Jan, Djurovic Srdjan, Dale Anders M, Smeland Olav B, O'Connell Kevin S, Shadrin Alexey A, Andreassen Ole A
Center for Precision Psychiatry, Division of Mental Health and Addiction, Oslo University Hospital, Institute of Clinical Medicine, University of Oslo, Oslo, Norway.
Center for Precision Psychiatry, Division of Mental Health and Addiction, Oslo University Hospital, Institute of Clinical Medicine, University of Oslo, Oslo, Norway.
Neurobiol Dis. 2024 Dec;203:106750. doi: 10.1016/j.nbd.2024.106750. Epub 2024 Nov 27.
The observation that the risk of developing Alzheimer's disease is reduced in individuals with high premorbid cognitive functioning, higher educational attainment, and occupational status has led to the 'cognitive reserve' hypothesis. This hypothesis suggests that individuals with greater cognitive reserve can tolerate a more significant burden of neuropathological changes before the onset of cognitive decline. The underpinnings of cognitive reserve remain poorly understood, although a shared genetic basis between measures of cognitive reserve and Alzheimer's disease has been suggested. Using the largest samples to date and novel statistical tools, we aimed to investigate shared genetic variants between Alzheimer's disease, and measures of cognitive reserve; cognition and educational attainment to identify molecular and neurobiological foundations. We applied the causal mixture model (MiXeR) to estimate the number of trait-influencing variants shared between Alzheimer's disease, cognition, and educational attainment, and condFDR/conjFDR to identify shared loci. To provide biological insights loci were functionally characterized. Subsequently, we constructed a Structural Equation Model (SEM) to determine if the polygenic foundation of cognition has a direct impact on Alzheimer's disease risk, or if its effect is mediated through established risk factors for the disease, using a case-control sample from the UK Biobank. Univariate MiXeR analysis (after excluding chromosome 19) revealed that Alzheimer's disease was substantially less polygenic (450 trait-influencing variants) compared to cognition (11,100 trait-influencing variants), and educational attainment (12,700 trait-influencing variants). Bivariate MiXeR analysis estimated that Alzheimer's disease shared approximately 70 % of trait-influencing variants with cognition, and approximately 40 % with educational attainment, with mixed effect directions. Using condFDR analysis, we identified 18 loci jointly associated with Alzheimer's disease and cognition and 6 loci jointly associated with Alzheimer's disease and educational attainment. Genes mapped to shared loci were associated with neurodevelopment, expressed in early life, and implicated the dendritic tree and phosphatidylinositol phosphate binding mechanisms. Spatiotemporal gene expression analysis of the identified genes showed that mapped genes were highly expressed during the mid-fetal period, further suggesting early neurodevelopmental stages as critical periods for establishing cognitive reserve which affect the risk of Alzheimer's disease in old age. Furthermore, our SEM analysis showed that genetic variants influencing cognition had a direct effect on the risk of developing Alzheimer's disease, providing evidence in support of the neurodevelopmental hypothesis of the disease.
病前认知功能较高、教育程度较高和职业地位较高的个体患阿尔茨海默病的风险降低，这一观察结果导致了“认知储备”假说。该假说表明，认知储备较大的个体在认知能力下降之前能够耐受更严重的神经病理变化负担。尽管有人提出认知储备与阿尔茨海默病的测量指标之间存在共同的遗传基础，但认知储备的基础仍知之甚少。我们使用迄今为止最大的样本和新颖的统计工具，旨在研究阿尔茨海默病与认知储备测量指标之间的共同遗传变异；认知和教育程度，以确定分子和神经生物学基础。我们应用因果混合模型（MiXeR）来估计阿尔茨海默病、认知和教育程度之间共享的影响性状变异的数量，并使用条件错误发现率（condFDR）/联合错误发现率（conjFDR）来识别共享位点。为了提供生物学见解，对位点进行了功能表征。随后，我们构建了一个结构方程模型（SEM），使用来自英国生物银行的病例对照样本，以确定认知的多基因基础是否对阿尔茨海默病风险有直接影响，或者其影响是否通过该疾病已确定的风险因素介导。单变量MiXeR分析（排除19号染色体后）显示，与认知（11100个影响性状变异）和教育程度（12700个影响性状变异）相比，阿尔茨海默病的多基因性要低得多（450个影响性状变异）。双变量MiXeR分析估计，阿尔茨海默病与认知共享约70%的影响性状变异，与教育程度共享约40%，且效应方向混合。使用condFDR分析，我们确定了18个与阿尔茨海默病和认知共同相关的位点以及6个与阿尔茨海默病和教育程度共同相关的位点。映射到共享位点的基因与神经发育相关，在生命早期表达，并涉及树突状树和磷脂酰肌醇磷酸结合机制。对已识别基因的时空基因表达分析表明，映射基因在胎儿中期高度表达，进一步表明早期神经发育阶段是建立认知储备的关键时期，这会影响老年时患阿尔茨海默病的风险。此外，我们的SEM分析表明，影响认知的基因变异对患阿尔茨海默病的风险有直接影响，为该疾病的神经发育假说提供了支持证据。
