Genes play a strong role in Alzheimer’s disease (AD), with late-onset AD showing heritability of 58–79% and early-onset AD showing over 90%. Genetic association provides a robust platform to build our understanding of the etiology of this complex disease. Over 50 loci are now implicated for AD, suggesting that AD is a disease of multiple components, as supported by pathway analyses (immunity, endocytosis, cholesterol transport, ubiquitination, amyloid-β and tau processing). Over 50% of late-onset AD heritability has been captured, allowing researchers to calculate the accumulation of AD genetic risk through polygenic risk scores.
A polygenic risk score predicts disease with up to 90% accuracy and is an exciting tool in our research armory that could allow selection of those with high polygenic risk scores for clinical trials and precision medicine. It could also allow cellular modelling of the combined risk. Here we propose the multiplex model as a new perspective from which to understand AD. The multiplex model reflects the combination of some, or all, of these model components (genetic and environmental), in a tissue-specific manner, to trigger or sustain a disease cascade, which ultimately results in the cell and synaptic loss observed in AD.
翻譯：基因在阿爾茨海默病（AD）中起著重要作用，遲發性AD的遺傳力為58-79％，早發性AD的遺傳率超過90％。遺傳關聯為建立我們對這種複雜疾病的病因學的理解提供了一個強大的平臺。現在有超過50個基因位點與AD有關，表明AD是多種成分的疾病，途徑分析（免疫，內吞，膽固醇轉運，泛素化，β-澱粉樣蛋白和tau加工）支持了這一點。已經捕獲了超過50％的晚期AD遺傳性，使研究人員可以通過多基因風險評分來計算AD遺傳風險的累積。
多基因風險評分能夠以高達90％的準確度預測疾病，並且是我們研究領域中令人興奮的工具，可以選擇具有高多基因風險評分的患者進行臨床試驗和精密醫學。它也可以對綜合風險進行細胞建模。在這裡，我們提出了複用模型，作為理解AD的新視角。多重模型以組織特異性的方式反映了部分或全部這些模型成分（遺傳的和環境的）的組合，以觸發或維持疾病級聯，最終導致AD中觀察到的細胞和突觸喪失。
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