Alzheimer’s disease (AD) is characterized by progressive synaptic dysfunction, neuronal death, and brain atrophy, with amyloid-β (Aβ) plaque deposits and hyperphosphorylated tau neurofibrillary tangle accumulation in the brain tissue, which all lead to loss of cognitive function. Pathogenic mutations in the well-known AD causal genes including APP, PSEN1, and PSEN2 impair a variety of pathways, including protein processing, axonal transport, and metabolic homeostasis. Here we identified a missense variant rs117916664 (c.896T>C, p.Asn299Ser [p.N299S]) of the acetyl-CoA acyltransferase 1 (ACAA1) gene in a Han Chinese AD family by whole-genome sequencing and validated its association with early-onset familial AD in an independent cohort. Further in vitro and in vivo evidence showed that ACAA1 p.N299S contributes to AD by disturbing its enzymatic activity, impairing lysosomal function, and aggravating the Aβ pathology and neuronal loss, which finally caused cognitive impairment in a murine model. Our findings reveal a fundamental role of peroxisome-mediated lysosomal dysfunction in AD pathogenesis.

阿尔茨海默病 (AD) 的特征是进行性突触功能障碍、神经元死亡和脑萎缩，伴有淀粉样蛋白-β (Aβ) 斑块沉积和脑组织中过度磷酸化的 tau 神经原纤维缠结积累，这些都会导致认知功能丧失。众所周知的 AD 致病基因（包括APP、PSEN1和PSEN2 ）中的致病突变会损害多种途径，包括蛋白质加工、轴突运输和代谢稳态。在这里，我们鉴定了乙酰辅酶A 酰基转移酶 1 ( ACAA1) 基因在汉族 AD 家族中通过全基因组测序，并在一个独立队列中验证了其与早发家族性 AD 的关联。进一步的体外和体内证据表明，ACAA1 p.N299S 通过扰乱其酶活性、损害溶酶体功能、加重 Aβ 病理和神经元损失而导致 AD，最终导致小鼠模型的认知障碍。我们的研究结果揭示了过氧化物酶体介导的溶酶体功能障碍在 AD 发病机制中的基本作用。