The genetics of very early onset Alzheimer disease

Christopher M. Filley, Yvonne D. Rollins, C. Alan Anderson, David B. Arciniegas, Katherine L. Howard, Jill R. Murrell, Philip J. Boyer, Belte K. Kleinschmidt-DeMasters, Bernardino Ghetti

Research output: Contribution to journalArticle

32 Citations (Scopus)

Abstract

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.

Original languageEnglish
Pages (from-to)149-156
Number of pages8
JournalCognitive and Behavioral Neurology
Volume20
Issue number3
DOIs
StatePublished - Sep 2007

Fingerprint

Presenilin-1
Alzheimer Disease
Mutation
Dementia
Frontotemporal Dementia
Presenilin-2
Chromosomes, Human, Pair 14
Amyloid beta-Protein Precursor
Brain
Genetic Testing
Age of Onset
Counseling
Young Adult
Autopsy

Keywords

  • Dementia
  • Genetic testing
  • Presenilin 1
  • Very early onset Alzheimer disease

ASJC Scopus subject areas

  • Neuropsychology and Physiological Psychology
  • Behavioral Neuroscience
  • Cognitive Neuroscience

Cite this

Filley, C. M., Rollins, Y. D., Alan Anderson, C., Arciniegas, D. B., Howard, K. L., Murrell, J. R., ... Ghetti, B. (2007). The genetics of very early onset Alzheimer disease. Cognitive and Behavioral Neurology, 20(3), 149-156. https://doi.org/10.1097/WNN.0b013e318145a8c8

The genetics of very early onset Alzheimer disease. / Filley, Christopher M.; Rollins, Yvonne D.; Alan Anderson, C.; Arciniegas, David B.; Howard, Katherine L.; Murrell, Jill R.; Boyer, Philip J.; Kleinschmidt-DeMasters, Belte K.; Ghetti, Bernardino.

In: Cognitive and Behavioral Neurology, Vol. 20, No. 3, 09.2007, p. 149-156.

Research output: Contribution to journalArticle

Filley, CM, Rollins, YD, Alan Anderson, C, Arciniegas, DB, Howard, KL, Murrell, JR, Boyer, PJ, Kleinschmidt-DeMasters, BK & Ghetti, B 2007, 'The genetics of very early onset Alzheimer disease', Cognitive and Behavioral Neurology, vol. 20, no. 3, pp. 149-156. https://doi.org/10.1097/WNN.0b013e318145a8c8
Filley CM, Rollins YD, Alan Anderson C, Arciniegas DB, Howard KL, Murrell JR et al. The genetics of very early onset Alzheimer disease. Cognitive and Behavioral Neurology. 2007 Sep;20(3):149-156. https://doi.org/10.1097/WNN.0b013e318145a8c8
Filley, Christopher M. ; Rollins, Yvonne D. ; Alan Anderson, C. ; Arciniegas, David B. ; Howard, Katherine L. ; Murrell, Jill R. ; Boyer, Philip J. ; Kleinschmidt-DeMasters, Belte K. ; Ghetti, Bernardino. / The genetics of very early onset Alzheimer disease. In: Cognitive and Behavioral Neurology. 2007 ; Vol. 20, No. 3. pp. 149-156.
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N2 - 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.

AB - 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.

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