The genetics of very early onset Alzheimer disease.
OBJECTIVE
This study was undertaken to clarify the genetics of very early onset Alzheimer disease (VEOAD), defined as AD beginning before age 35.


BACKGROUND
Early onset AD (EOAD) is defined by onset of symptoms before age 65, and affected individuals may harbor a mutation in presenilin 1 (PSEN1), presenilin 2 (PSEN2), or amyloid precursor protein. VEOAD is exceedingly rare, and PSEN1 mutations have been implicated. We encountered a man with phenotypic frontotemporal dementia beginning at age 32 and a strong family history of an autosomal dominant dementia who was found at autopsy to have AD.


METHODS
Histologic and genetic analyses of the patient's brain were undertaken, and a review of all published VEOAD cases was performed.


RESULTS
Histologic findings were diagnostic of advanced stage AD. Genetic evaluation of brain tissue identified an intronic PSEN1 polymorphism; no known pathogenic mutation was found. Literature review (1934 to 2007) disclosed 101 cases of VEOAD; the youngest age of dementia onset was 24 years. In all cases in which definitive genetic analysis was available, either a PSEN1 mutation or linkage to chromosome 14 was found.


CONCLUSIONS
VEOAD can present with atypical clinical features, including findings suggestive of frontotemporal dementia. All reported cases of VEOAD with conclusive genetic analysis seem to be associated with PSEN1 mutations. Genetic testing in adults younger than 35 with dementia can identify the genetic defect and assist in diagnosis and family counseling.
Filley
Christopher M
CM
Department of Neurology, University of Colorado School of Medicine, Denver, CO, USA. christopher.filley@uchsc.edu
Rollins
Yvonne D
YD
Anderson
C Alan
CA
Arciniegas
David B
DB
Howard
Katherine L
KL
Murrell
Jill R
JR
Boyer
Philip J
PJ
Kleinschmidt-DeMasters
Belte K
BK
Ghetti
Bernardino
B
D000328:Adult; D000544:Alzheimer Disease / Q000175:diagnosis / Q000235:genetics*; D001284:Atrophy / Q000473:pathology; D001921:Brain / Q000473:pathology; D002878:Chromosomes, Human, Pair 1 / Q000235:genetics; D002891:Chromosomes, Human, Pair 21 / Q000235:genetics; D017809:Fatal Outcome; D006801:Humans; D007438:Introns / Q000235:genetics; D008297:Male; D016874:Neurofibrillary Tangles / Q000473:pathology; D009483:Neuropsychological Tests; D017354:Point Mutation / Q000235:genetics; D011110:Polymorphism, Genetic / Q000235:genetics; D053764:Presenilin-1 / Q000235:genetics*; D053766:Presenilin-2 / Q000235:genetics*
C508853:PSEN1 protein, human; C508861:PSEN2 protein, human; D053764:Presenilin-1; D053766:Presenilin-2