Hutton M, Pérez-Tur J, Hardy J
Neurogenetics Laboratory, Mayo Clinic Jacksonville, FL 32224, USA.
Essays Biochem. 1998;33:117-31. doi: 10.1042/bse0330117.
Mutations in any one of three genes can cause autosomal dominant, early-onset Alzheimer's disease: these genes are the amyloid precursor protein (APP) gene on chromosome 21, the presenilin-1 (PS-1) gene on chromosome 14 and the presenilin-2 (PS-2) gene on chromosome 1. Pathogenic mutations at all these loci cause mismetabolism of APP such that more of the peptide A beta 42 is produced. This peptide is deposited in the plaques in the brains of Alzheimer's patients. These facts have led to the dominant hypothesis for the disease process: the 'amyloid cascade hypothesis', which proposes that overproduction or failure to clear the peptide A beta 42 is always central to the disease. Genetic variability at the apoliprotein E locus is a major determinant of late onset Alzheimer's disease. The mechanism by which apoliprotein E is involved in the pathogenesis of Alzheimer's disease is not yet known. There are likely to be other genetic factors which impinge on Alzheimer's disease.
这三个基因分别是位于21号染色体上的淀粉样前体蛋白（APP）基因、位于14号染色体上的早老素-1（PS-1）基因和位于1号染色体上的早老素-2（PS-2）基因。所有这些位点的致病突变都会导致APP代谢异常，从而产生更多的Aβ42肽。这种肽沉积在阿尔茨海默病患者大脑的斑块中。这些事实导致了关于疾病进程的主流假说：“淀粉样蛋白级联假说”，该假说认为Aβ42肽的过量产生或清除失败始终是该疾病的核心。载脂蛋白E基因座的遗传变异性是晚发性阿尔茨海默病的主要决定因素。载脂蛋白E参与阿尔茨海默病发病机制的具体机制尚不清楚。可能还有其他遗传因素影响阿尔茨海默病。
