Abstract Details

Title A Meta-Analysis of Age of Onset and Disease Course in Autosomal Dominant Alzheimer's Disease Mutations

Topic Aging and Dementia

Presentation(s) (-)

Poster/Presentation
Number 002

Objective

Background ADAD genetics has been highly beneficial to understanding AD pathogenesis, with investigators discovering over 180 different mutations in three genes (APP, PSEN1, and PSEN2) which are now known to be directly involved in production of the amyloid-beta peptide implicated as a primary cause of AD pathology. While these mutations all cause early onset AD with virtually complete penetrance, they demonstrate significant heterogeneity in age of onset and disease course, which has not yet been analyzed in a comprehensive way. Several clinical trials are now preparing to evaluate candidate treatments for presymptomatic AD in ADAD patient populations. If evidence-based criteria can be developed for prospectively estimating disease onset, clinical research in ADAD can provide unique benefits by enrolling patient cohorts at well-defined time points in early disease.

Design/Methods We have compiled individual-level data on age of symptom onset from three independent projects studying ADAD extended families, and combined this with data extracted from 108 peer-reviewed publications of ADAD pedigrees. Our combined dataset contains 337 families including 3011 individuals, of whom 1170 were affected by ADAD with known age of symptom onset. After adjusting for ascertainment bias, we used linear regression in R to assess several measures derived from family history as potential predictors of disease onset in individual patients.

Results We report summary statistics describing disease onset and course for 163 pathogenic mutations in our meta-analysis dataset, and discover highly significant correlations between age of onset of individual patients and adjusted mean onset values for mutation type and family.

Conclusions A significant proportion of variance in symptom onset in ADAD is explained by statistical measures derived from family history and mutation type, providing empirical support for use of these data to estimate onset in clinical research.

Authors/Disclosures
Davis C. Ryman, MD, PhD (Levo Therapeutics) PRESENTER	No disclosure on file
Randall Bateman, MD (Washington Univ School of MedicinE)	Dr. Bateman has received personal compensation in the range of $10,000-$49,999 for serving as a Consultant for C2N Diagnostics . Dr. Bateman has received personal compensation in the range of $0-$499 for serving as an officer or member of the Board of Directors for C2N Diagnostics . Dr. Bateman has received stock or an ownership interest from C2N Diagnostics. The institution of Dr. Bateman has received research support from Alzheimer's SILQ Research Fund/ Barnes Jewish Hospital Foundation . The institution of Dr. Bateman has received research support from National Institutes of Health- R21AG067559. The institution of Dr. Bateman has received research support from Centene Corporation. The institution of Dr. Bateman has received research support from Rainwater Charitable Foundation . The institution of Dr. Bateman has received research support from Cure Alzheimer's Fund. The institution of Dr. Bateman has received research support from Cure Alzheimer's Fund. The institution of Dr. Bateman has received research support from Anonymous Foundation. The institution of Dr. Bateman has received research support from Cure Alzheimer's Fund. The institution of Dr. Bateman has received research support from BrightFocus Foundation. The institution of Dr. Bateman has received research support from Assn for Frontotemporal Degeneration FTD Biomarkers Initiative. The institution of Dr. Bateman has received research support from Rainwater Foundation. The institution of Dr. Bateman has received research support from NIH- R01NS095773. The institution of Dr. Bateman has received research support from AbbVie/Biogen/Eli Lilly. The institution of Dr. Bateman has received research support from NIH/NINDS/NIA- RF1AG061900 (R56AG061900 & R01NS065667). The institution of Dr. Bateman has received research support from Eisai. The institution of Dr. Bateman has received research support from Good Ventures Foundation. The institution of Dr. Bateman has received research support from National Institutes of Health- R01 AG070941. The institution of Dr. Bateman has received research support from National Institutes of Health-. The institution of Dr. Bateman has received research support from National Institutes of Health. The institution of Dr. Bateman has received research support from NIH- P50AG005681-36. The institution of Dr. Bateman has received research support from NIH/NIA- U19AG032438. The institution of Dr. Bateman has received research support from Alzheimer's Association. The institution of Dr. Bateman has received research support from Pharma Consortium. The institution of Dr. Bateman has received research support from Eli Lilly . The institution of Dr. Bateman has received research support from NIH/NIA- NIH R01AG053267. The institution of Dr. Bateman has received research support from Administrative Supplement 01- NIH . The institution of Dr. Bateman has received research support from Administrative Supplement 02- NIH . The institution of Dr. Bateman has received research support from NIH- 1U01AG059798. The institution of Dr. Bateman has received research support from NIH- R01AG068319. The institution of Dr. Bateman has received research support from Alzheimer's Association. The institution of Dr. Bateman has received research support from Alzheimer's Association. The institution of Dr. Bateman has received research support from Alzheimer's Association. The institution of Dr. Bateman has received research support from Roche. The institution of Dr. Bateman has received research support from NIH/NIA- R01AG046179. The institution of Dr. Bateman has received research support from GHR; Anonymous Foundation. The institution of Dr. Bateman has received research support from NIH/NIA- 1U01AG042791, 1U01AG042791. The institution of Dr. Bateman has received research support from Alzheimer's Association. The institution of Dr. Bateman has received research support from NIH/State Government- 5U19AG010483. Dr. Bateman has received intellectual property interests from a discovery or technology relating to health care.
Ronald C. Petersen, MD, PhD, FAAN (Mayo Clinic)	Dr. Petersen has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Roche. Dr. Petersen has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Genentech. Dr. Petersen has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Eli Lilly and Co.. Dr. Petersen has received personal compensation in the range of $0-$499 for serving as a Consultant for Eisai, Inc.. Dr. Petersen has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Novo Nordisk. Dr. Petersen has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Novartis. Dr. Petersen has received publishing royalties from a publication relating to health care. Dr. Petersen has received publishing royalties from a publication relating to health care. Dr. Petersen has received publishing royalties from a publication relating to health care. Dr. Petersen has a non-compensated relationship as a Board of Directors with American Brain Foundation that is relevant to AAN interests or activities.

��ɫ��

��ɫ��