Novel insight into genetic impacts on neurodegenerative dementia

Dementia can be broadly categorized into neurodegenerative dementias and non-neurodegenerative forms. Neurodegenerative dementias include Alzheimer’s disease (AD), frontotemporal lobar degeneration (FTLD), neuronal intranuclear inclusion disease (NIID), dementia with Lewy bodies (DLB), Huntington’s disease (HD), and prion diseases. Genetic factors play a central role in the etiology of neurodegenerative dementias. In AD, heritability estimates range from 58%-79% for late-onset AD (LOAD) and over 90% for early-onset AD, with causal genes including APP, PSEN1, and PSEN2. LOAD is a complex polygenic disease. Genome-wide association studies have identified more than 70 susceptibility loci, among which APOE ε4 is the most established genetic risk factor; carriers of the APOE ε4/ε4 genotype are now considered genetically predisposed to AD. However, the known heritability of AD remains incomplete, with rare variants in dozens of genes contributing substantially to disease risk. FTLD often presents with behavioral and language impairments, with MAPT, C9orf72, and GRN being the most commonly implicated causal genes. DLB, which overlaps clinically with Parkinson’s disease dementia, shares genetic risk factors with both AD and PD, including APOE, BIN1, SNCA, and GBA. NIID is caused by abnormal NOTCH2NLC GGC repeat expansions, which correlate with disease phenotype and age of onset. HD results from abnormal CAG repeat expansions in the HTT gene. Prion diseases arise from variants in the PRNP gene, with M129V being a notable risk factor. These findings underscore the pivotal role of genetic factors in the pathogenesis of neurodegenerative dementias.