Mutation and association analyses of dementia-causal genes in Han Chinese patients with early-onset and familial Alzheimer's disease

Alzheimer's disease (AD) is the most common cause of dementia in the elderly. It shares clinical and pathological features with other types of dementia, such as vascular dementia (VaD), Lewy body dementia (LBD), and frontotemporal dementia (FTD). We have hypothesized that there might be an overlapping molecular mechanism and genetic basis to the different types of dementia. In this study, we analyzed the mutation pattern of dementia-causal genes in 169 Han Chinese patients with familial and early-onset AD by using whole exome sequencing or targeted resequencing. We identified 9 potentially pathogenic mutations in the AD-causal genes APP, PSEN1, PSEN2, and 6 mutations in a group of non-AD dementia-causal genes including the FTD-causal gene GRN and the VaD-causal gene NOTCH3. A common splice-site variant rs514492 in the FTD-causal gene VCP showed a positive association with AD risk (P = 0.0003, OR = 1.618), whereas the rare missense variant rs33949390 (p. R 1628P) in the LBD-causal gene LRRK2 showed a protective effect on AD risk (P = 0.0004, OR = 0.170). The presence of putative pathogenic mutations and risk variants in these causal genes for different types of dementia in clinically diagnosed familial and early-onset AD patients suggests a need to screen for mutations of the dementia-causal genes in cases of AD to avoid misdiagnosis. These mutations also support the idea that there are overlapping pathomechanisms between AD and other forms of dementia.