Hardy John, Escott-Price Valentina
Department of Neurodegenerative Disease, UCL Institute of Neurology, United Kingdom and UK Dementia Research Institute at UCL, London, UK.
Department of Psychological Medicine and Clinical Neuroscience, Cardiff University, United Kingdom and UK Dementia Research Institute at Cardiff, Cardiff University, Cardiff, UK.
Mol Psychiatry. 2025 Jun;30(6):2748-2753. doi: 10.1038/s41380-025-02911-7. Epub 2025 Jan 29.
In this perspective we draw together the data from the genome wide association studies for Alzheimer's disease, Parkinson's disease and the tauopathies and reach the conclusion that in each case, most of the risk loci are involved in the clearance of the deposited proteins: in Alzheimer's disease, the microglial removal of Aβ, in the synucleinopathies, the lysosomal clearance of synuclein and in the tauopathies, the removal of tau protein by the ubiquitin proteasome. We make the point that most loci identified through genome wide association studies are not strictly pathogenic but rather relate to failures to remove age related damage. We discuss these issues in the context of copathologies in elderly individuals and the prediction of disease through polygenic risk score analysis at different ages. Finally, we discuss what analytic approaches are needed now that we have adequately sized case control analyses in white populations.
从这一角度出发，我们汇总了来自阿尔茨海默病、帕金森病和tau蛋白病全基因组关联研究的数据，并得出结论：在每种情况下，大多数风险位点都参与了沉积蛋白的清除过程：在阿尔茨海默病中，小胶质细胞对Aβ的清除；在突触核蛋白病中，溶酶体对突触核蛋白的清除；在tau蛋白病中，泛素蛋白酶体对tau蛋白的清除。我们指出，通过全基因组关联研究确定的大多数位点并非严格意义上的致病位点，而是与清除与年龄相关的损伤失败有关。我们在老年个体共病以及通过不同年龄的多基因风险评分分析预测疾病的背景下讨论这些问题。最后，鉴于我们在白人人群中进行了足够规模的病例对照分析，我们讨论了现在需要哪些分析方法。
