Genetic factors in alzheimer disease and dementia

Abstract

Alzheimer disease (AD) is a common and complex disorder affecting several million people world-wide. It is defined clinically as a progressive dementing illness associated with A b -amyloid neuritic plaques and neurofibrillary tangles in the brain. From a genetic standpoint it is a heterogeneous disorder. Three separate genes (APP, PSEN1, PSEN2) each cause an autosomal dominant, highly penetrant, early-onset, familial form of the disease. The three proteins encoded by these genes all influence the production of the toxic α β1-42 form of amyloid. Commercial genetic testing is available for these rare forms of AD. However, mutations in these genes represent less than 2% of all cases of AD. The more common late-onset form of AD is thought to be polygenic and multifactorial. The e 4 allele of apolipoprotein E (ApoE) is a known genetic risk factor for late-onset AD, lowering the average age of onset by unknown mechanisms. Numerous other candidate risk genes are being identified through genome wide association studies, but have been difficult to confirm. Other familial forms of dementia, such as frontotemporal dementia (FTD), prion-associated diseases, and CADASIL, may be caused by autosomal dominant mutations occurring in their respective genes (MAPT, GRN, PRNP, Notch-3).