4,068 posters, 219 videos, 101 topics, 69 sessions, 14,365 authors, 6,128 institutions

Alzheimer's Association International Conference 2026

July 12-15, 2026 | London, United Kingdom, and Online

9748

Genetic Contributors To Amyloid-related And Non-amyloid Related Memory Performance

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Poster Presenter

Emily Mahoney

Authors

Emily R. Mahoney, Alaina Durant, Karen Crawford, Michael L. Cuccaro, Jesse Mez, Thomas J. Montine, Elizabeth C. Mormino, Arthur W. Toga, Duygu Tosun, Andrew J Saykin, Marilyn S. Albert, Susan M Resnick, Sarah A. Biber, Walter A. Kukull, David A. Bennett, Philip L. De Jager, Julie A. Schneider, Corinne D. Engelman, Sterling C. Johnson, Qiongshi Lu, C. Dirk Keene, Eric B. Larson, Shubhabrata Mukherjee, Paul K. Crane, Rachel Buckley, Reisa Sperling, Richard Mayeux, Logan Dumitrescu, Timothy J. Hohman, Derek Archer, Leslie S. Gaynor

Affiliations

Department of Neurology, Washington University in St. Louis, St. Louis, MO, Department of Medicine, University of Washington, Seattle, WA, Vanderbilt Memory and Alzheimer’s Center, Vanderbilt Health, Nashville, TN, University of Southern California, Los Angeles, CA, The John P Hussman Institute for Human Genomics, University of Miami Miller School of Medicine, Miami, FL, Department of Neurology, Boston University School of Medicine, Boston, MA, Department of Pathology, Stanford University, Stanford, CA, Department of Neurology, Stanford University, Stanford, CA, Laboratory of Neuroimaging, University of Southern California Stevens Neuroimaging and Informatics Institute, Keck School of Medicine, University of Southern California, Los Angeles, CA, Department of Radiology, University of California, San Francisco, San Francisco, CA, Indiana Alzheimer’s Disease Research Center and Department of Radiology and Imaging Sciences, Indiana University School of Medicine, Indianapolis, IN, Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD, National Institute on Aging, National Institutes of Health, Baltimore, MD, Rush Alzheimer’s Disease Center, Rush University Medical Center, Chicago, IL, Center for Translational and Computational Neuroimmunology, Department of Neurology, Columbia University Medical Center, New York City, NY, Departments of Neurology and Pathology, Rush University Medical Center, Chicago, IL, Department of Population Health Sciences, University of Wisconsin-Madison School of Medicine and Public Health, Madison, WI, Department of Biostatistics and Medical Informatics, University of Wisconsin-Madison, Madison, WI, Department of Pathology, University of Washington, Seattle, WA, Department of Neurology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, The Taub Institute for Research on Alzheimer's Disease and The Aging Brain, Columbia University Medical Center, New York City, NY

Part of Topic

Background:

Approximately 15-40% of clinical dementia cases diagnosed as Alzheimer’s disease (AD) do not have elevated amyloid deposition despite presenting with clinical and cognitive symptoms concordant with AD dementia. Memory decline is closely associated with the development of amyloid pathology. Thus, the etiology of memory decline in the absence of amyloid is less clear. Characterizing factors contributing to amyloid- and non-amyloid-related memory decline is critical to deconstructing the complexity of clinical dementia. Here, we perform the largest study to date investigating the genetic architecture of memory performance stratified by the presence of amyloid pathology.

Methods:

Data from ten cohorts of aging and AD were included: the Anti-Amyloid Treatment in Asymptomatic Alzheimer’s (A4) study; the Adult Changes in Thought (ACT) study; the Alzheimer’s Disease Neuroimaging Initiative (ADNI); Knight AD Research Center (Knight ADRC); the National Alzheimer’s Coordinating Center (NACC); the National Institute on Aging Alzheimer’s Disease Family Based Study (NIA-AD FBS); the 3 harmonized cohorts of the Religious Orders Study and the Rush Memory and Aging Project (ROS/MAP); the Wisconsin Registry for Alzheimer’s Prevention (WRAP) study; the Biomarkers of Cognitive Decline Among Normal Individuals (BIOCARD) study; and the Baltimore Longitudinal Study of Aging (BLSA). Except the last two, these studies are a part of the AD Sequencing Project – Phenotype Harmonization Core (ADSP-PHC).

Participants were ages 50+, of European ancestry, and with cognitive assessments available <5 years ante-mortem for autopsy cohorts. Amyloid positivity definitions were drawn from cerebrospinal fluid (CSF) amyloid-β42 positivity, positive amyloid positron emission tomography (PET) scan, or presence amyloid pathology (CERAD moderate to severe) at neuropathological examination. Memory scores were harmonized across cohorts to be on the same scale.

GWAS on cross-sectional memory performance were run in amyloid positive and negative sets while SNP*amyloid status interaction models assessed statistical differences between the sets for observed associations. Covariates included age, sex, years of education, amyloid source, and the first 5 principal components. GNOVA (GeNetic cOVariance Analyzer) was used to assess what phenotypes had shared genetic structure with amyloid-related and non-amyloid-related decline using summary statistics from GWAS on 65 other phenotypes.

Results Summary:

The APOE variant rs7412 on chromosome 19 was associated with memory only among amyloid positive participants, not amyloid negative (Table 2, Figure 2). This signal is attenuated when including an APOE-e4 count covariate (p=0.01). An intergenic chromosome 13 variant was negatively associated in amyloid negative participants but was not associated at all in amyloid positive ones (Table 2, Figure 3). GNOVA demonstrated that while amyloid-related and non-amyloid-related memory performance share genetic correlations with some traits (like heart function phenotypes and negatively with AD), they have divergent genetic correlations with others, particularly some immune-related phenotypes (see Figure 4).

Conclusions:

In this study, we explored genetic factors associated with amyloid and non-amyloid-related decline. Specifically, we observed an amyloid-specific association of APOE with memory decline, that corresponds to previous reports. Genetic correlation results observed here suggest that heterogeneity may be impacted by differing contributions of immune function to dementia in the presence and absence of amyloid. The current analysis has limited power due to sample size and to the relatively low frequency of the variants with observed associations. Future studies with additional studies will increase the power to detect meaningful associations. Accounting for amyloid heterogeneity may improve mechanistic understanding of memory decline and inform precision medicine strategies.

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