Genetics of dementia: Update and guidelines for the clinician

• Published in: American journal of medical genetics. Part B, Neuropsychiatric genetics Vol. 159B; no. 6; pp. 628 - 643
• Main Authors: Cohn-Hokke, Petra E., Elting, Mariet W., Pijnenburg, Yolande A.L., van Swieten, John C.
• Format: Journal Article
• Language: English
• Published: Hoboken Wiley Subscription Services, Inc., A Wiley Company 01.09.2012; Wiley-Liss; Wiley Subscription Services, Inc
• Subjects: Adult and adolescent clinical studies; Age of Onset; Algorithms; Alzheimer's disease; Biological and medical sciences; Degenerative and inherited degenerative diseases of the nervous system. Leukodystrophies. Prion diseases; Dementia - genetics; early onset; frontotemporal dementia; General aspects. Genetic counseling; Genetic Association Studies; genetic counseling; Genetic Predisposition to Disease; genetic testing; Genetics; Humans; Medical genetics; Medical sciences; Neurology; Organic mental disorders. Neuropsychology; Physicians; Practice Guidelines as Topic; Psychology. Psychoanalysis. Psychiatry; Psychopathology. Psychiatry; Nervous system diseases; Alzheimer disease; early onset; Recommendation; Cerebral disorder; Genetic counseling; genetic testing; Central nervous system disease; Genetics; Early; Degenerative disease; Frontotemporal dementia; Alzheimer's disease
• ISSN: 1552-4841; 1552-485X; 1552-485X
• DOI: 10.1002/ajmg.b.32080

With 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 the PSEN1 gene are the most common genetic cause of early onset Alzheimer's disease, whereas APP and PSEN2 gene mutations are less frequent. Familial frontotemporal dementia may be associated with a mutation in the MAPT or GRN gene, or with a repeat expansion in the C9orf72 gene. 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 risk relatives. This review provides an overview of the genetic causes of dementia and discusses all aspects relevant for genetic counseling and testing. Furthermore, based on current knowledge, we provide algorithms for genetic testing in patients with early onset Alzheimer's disease or frontotemporal dementia. © 2012 Wiley Periodicals, Inc.