Symptom onset in autosomal dominant Alzheimer disease: A systematic review and meta-analysis

Authors

Davis C. Ryman
Natalia AcostaBaena
Paul S. Aisen
Thomas Bird
Adrian Danek
Nick C. Fox
Alison Goate
Peter Frommelt
Bernardino Ghetti
Jessica B. Langbaum
Francisco Lopera
Ralph Martins, Edith Cowan UniversityFollow
Colin L. Masters
Richard P. Mayeux
Eric McDade
Sonia Moreno
Eric M. Reiman
John M. Ringman
Steve Salloway
Peter R. Schofield
Reisa Sperling
Pierre N. Tariot
Chengjie Xiong
John C. Morris
Randall J. Bateman

Document Type

Journal Article

Publisher

Lippincott Williams and Wilkins

Faculty

Faculty of Health, Engineering and Science

School

School of Medical Sciences

RAS ID

18811

Comments

Ryman D.C., Acosta-Baena N., Aisen P.S., Bird T., Danek A., Fox N.C., Goate A., Frommelt P., Ghetti B., Langbaum J.B.S., Lopera F., Martins R., Masters C.L., Mayeux R.P., McDade E., Moreno S., Reiman E.M., Ringman J.M., Salloway S., Schofield P.R., Sperling R., Tariot P.N., Xiong C., Morris J.C., Bateman R.J. (2014). Symptom onset in autosomal dominant Alzheimer disease: A systematic review and meta-analysis. Neurology, 83(3), 253-260. Available here

Abstract

Objective: To identify factors influencing age at symptom onset and disease course in autosomal dominant Alzheimer disease (ADAD), and develop evidence-based criteria for predicting symptom onset in ADAD. Methods: We have collected individual-level data on ages at symptom onset and death from 387 ADAD pedigrees, compiled from 137 peer-reviewed publications, the Dominantly Inherited Alzheimer Network (DIAN) database, and 2 large kindreds of Colombian (PSEN1 E280A) and Volga German (PSEN2 N141I) ancestry. Our combined dataset includes 3,275 individuals, of whom 1,307 were affected by ADAD with known age at symptom onset. We assessed the relative contributions of several factors in influencing age at onset, including parental age at onset, age at onset by mutation type and family, and APOE genotype and sex. We additionally performed survival analysis using data on symptom onset collected from 183 ADAD mutation carriers followed longitudinally in the DIAN Study. Results: We report summary statistics on age at onset and disease course for 174 ADAD mutations, and discover strong and highly significant (p < 10-16, r2 > 0.38) correlations between individual age at symptom onset and predicted values based on parental age at onset and mean ages at onset by mutation type and family, which persist after controlling for APOE genotype and sex. Conclusions: Significant proportions of the observed variance in age at symptom onset in ADAD can be explained by family history and mutation type, providing empirical support for use of these data to estimate onset in clinical research.

DOI

10.1212/WNL.0000000000000596

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