Abstract Details

Title Identification of Novel Genetic Risk Factors for Cerebral Amyloid Angiopathy

Topic Aging, Dementia, and Behavioral Neurology

Presentation(s) P5 - Poster Session 5 (11:45 AM-12:45 PM)

Poster/Presentation
Number 13-005

Objective To investigate the genetic risk factors of Cerebral Amyloid Angiopathy (CAA)

Background

CAA is characterized by the accumulation of amyloid-beta in the cerebrovasculature, affects blood vessel integrity leading to brain hemorrhages and an accelerated cognitive decline in Alzheimer’s Disease (AD) patients. Our previous genome-wide association study (GWAS) identified a LINC-PINT splice variant associated with lower CAA levels in individuals without APOEe4 and higher levels of LINC-PINT expression in the brain of AD cases. In this study, we expand our GWAS to include additional AD and non-AD donors.

Design/Methods

We analyzed 1350 AD and 502 non-AD donors from the Mayo Clinic Brain Bank, scored for CAA. We performed QC and imputation. We conducted GWAS in all donors (N=1,852) by testing imputed variant dosages for association with square root transformed CAA using linear regression, adjusting for relevant covariates.To assess associations with major CAA risk factors, we performed interaction analysis with APOEe4 presence and sex; and pursued stratified analyses.

Results Variants at the APOE locus were identified as the most significant in our study. In addition, several other variants approached genome-wide significance after adjusting for AD neuropathology. The LINC-PINT splice variant remained associated with lower CAA scores in AD donors without the APOEe4 risk allele. To enhance the robustness of our findings, we are pursuing further expansion of our study cohort to include other available datasets. To explore putative functional consequences of key variants, we collected peripheral gene expression measures in participants from Mayo Clinic with neuroimaging measures including microhemorrhages.

Conclusions We expect this study will provide further insights into the genetic architecture underlying risk for CAA, both in the context of significant AD pathology, and without. Characterization of genetic variants and functional outcomes in the context of neuropathology may lead to new avenues of research aimed at identifying biomarkers and therapies to treat CAA, and AD.

Authors/Disclosures
Merve Atik, MD (Mayo Clinic) PRESENTER	Dr. Atik has nothing to disclose.
Joseph S. Reddy, PhD	Dr. Reddy has nothing to disclose.
Thuy Nguyen	Mrs. Nguyen has nothing to disclose.
Katie D. Sotelo	Ms. Sotelo has nothing to disclose.
Frederick Q. Tutor-New	Mr. Tutor-New has received personal compensation for serving as an employee of Mayo Clinic.
Minerva Carrasquillo (Mayo Clinic Florida)	The institution of Minerva Carrasquillo has received research support from NIA. The institution of Minerva Carrasquillo has received research support from Carl Angus DeSantis Foundation. The institution of Minerva Carrasquillo has received research support from Florida Department of Health. Minerva Carrasquillo has received personal compensation in the range of $500-$4,999 for serving as a Reviewer for Study Section with NIH.
Jonathan Graff-Radford, MD, FAAN	Dr. Graff-Radford has received personal compensation for serving as an employee of Mayo Clinic. Dr. Graff-Radford has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for NINDS/NIH. Dr. Graff-Radford has received personal compensation in the range of $10,000-$49,999 for serving as an Editor, Associate Editor, or Editorial Advisory Board Member for JAMA Neurology. Dr. Graff-Radford has received personal compensation in the range of $5,000-$9,999 for serving as an Editor, Associate Editor, or Editorial Advisory Board Member for Open evidence . The institution of Dr. Graff-Radford has received research support from NIH. The institution of Dr. Graff-Radford has received research support from Eisai. The institution of Dr. Graff-Radford has received research support from Cognition therapeutics. Dr. Graff-Radford has received personal compensation in the range of $5,000-$9,999 for serving as a Faculty Member with IMPACT AD .
Neill R. Graff-Radford, MD, FAAN (Mayo Clinic Jacksonville)	The institution of Dr. Graff-Radford has received research support from Biogen. The institution of Dr. Graff-Radford has received research support from Lilly. The institution of Dr. Graff-Radford has received research support from Eisai. The institution of Dr. Graff-Radford has received research support from Biogen. Dr. Graff-Radford has received publishing royalties from a publication relating to health care.
Kejal Kantarci, MD (Mayo Clinic)	The institution of Dr. Kantarci has received research support from Eli Lilly. The institution of Dr. Kantarci has received research support from NIH. The institution of Dr. Kantarci has received research support from ADDF. The institution of Dr. Kantarci has received research support from Eisai. The institution of Dr. Kantarci has received research support from BioArctic.
Michael DeTure, PhD	Mr. DeTure has nothing to disclose.
Dennis W. Dickson, MD (Mayo Clinic)	Dr. Dickson has nothing to disclose.
Mariet Allen, PhD (Mayo Clinic)	The institution of Dr. Allen has received research support from NIH. The institution of Dr. Allen has received research support from Florida Department of Health. Dr. Allen has received personal compensation in the range of $0-$499 for serving as a Reviewer with NIH.
Nilufer Taner, MD, PhD, FAAN (Mayo Clinic)	The institution of Dr. Taner has received research support from NIH.

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