Genetics of dementia: Update and guidelines for the clinician

AbstractWith increased frequency, clinical geneticists are asked for genetic advice on the heredity of dementia in families. Alzheimer's disease is in most cases a complex disease, but may be autosomal dominant inherited. Mutations in thePSEN1gene are the most common genetic cause of early onset Alzheimer's disease, whereasAPPandPSEN2gene mutations are less frequent. Familial frontotemporal dementia may be associated with a mutation in theMAPTorGRNgene, or with a repeat expansion in theC9orf72gene. All these genes show autosomal dominant inheritance with a high penetrance. Although Alzheimer's disease and frontotemporal dementia are clinically distinguishable entities, phenotypical overlap may occur. Rarely, dementia is caused by mutations in other autosomal dominant genes or by genetic defects with autosomal recessive, X‐linked dominant or mitochondrial inheritance. The inherited forms of frontotemporal dementia and Alzheimer's disease show a large phenotypic variability also within families, resulting in many remaining uncertainties for mutation carriers. Therefore, genetic counseling before performing genetic testing is essential in both symptomatic individuals and healthy at ri