Multimodal Genetic Analysis of Brain Amyloidosis
Authors: Wang Ting‐Chen , Archer Derek B. , Ali Muhammad , Wu Yiyang , Mormino Elizabeth , Buckley Rachel F. , Lee Annie J. , Saykin Andrew J. , De Jager Philip L. , Schneider Julie A. , Bennett David A. , Barnes Lisa L. , Vardarajan Badri N. , Mayeux Richard , Kunkle Brian W. , Bush William S. , Keene C. Dirk , Seshadri Sudha , Sperling Reisa A , Vemuri Prashanthi , Ramanan Vijay K. , Schellenberg Gerard D. , Huentelman Matthew J. , Hamilton‐Nelson Kara L. , Pericak‐Vance Margaret A. , Goate Alison M. , Haines Jonathan L. , Montine Thomas J. , Beecham Gary W , Cruchaga Carlos , Hohman Timothy J. , Dumitrescu Logan C. ,   ADNI, Knight Alzheimer Disease Research Center (Knight ADRC), the Dominantly Inherited Alzheimer Network (DIAN), ADNI‐DOD, the Australian Imaging Biomarkers, Lifestyle (AIBL) Study, A4 Study Team, Alzheimer’s Disease Sequencing Project (ADSP)
Published: January 2025

AbstractBackgroundGenome‐wide association studies (GWAS) in Alzheimer’s disease (AD) leveraging endophenotypes beyond case/control diagnosis, such as brain amyloid β pathology, have shown promise in identifying novel variants and understanding their potential functional impact. In this study, we leverage two brain amyloid β pathology measurement modalities, PET imaging and neuropathology, to address sample size limitations and to discover novel genetic drivers of disease.MethodWe conducted a meta‐analysis on an amyloid PET imaging GWAS (N = 7,036, 35% amyloid positive, 53.67% female, age = 71) and an autopsy GWAS of brain amyloidosis (N = 6,519, 63.08% amyloid positive, 51.34% female, age at death = 83), both adjusted for covariates including age, sex and principal components of genetic ancestry. All participants in both GWAS were unrelated individuals of European descent. We defined amyloid positivity as moderate or frequent neuritic plaques using the Consortium to Establish a Registry for Alzheimer’s Disease (CERAD) staging scores within each autopsy cohort. A Gaussian mixture model (GMM) was applied to each amyloid PET imaging cohort to identify the cohort and tracer‐specific cut‐offs that differentiate amyloid positive and negative populations.ResultThe genome‐wide significant results from the meta‐analysis identified three known AD loci (APOE, CR1, and BIN1) and a novel chromosome 17 locus (rs35635959, intergenic, MAF = 0.27, OR = 1.18, p = 1.47 × 10‐8). The MAGMA gene‐level analysis excluding the APOE region suggests significant associations between rs35635959 and COASY, PLEKHH3, and TUBG2 on chromosome 17, implying the potential roles of these genes on amyloidosis. Functional annotations of rs35635959 leveraging brain eQTL databases indicate its association with differential gene expression of COASY and TUBG2 in AD brains. ROSMAP bulk and single‐nucleus RNAseq analyses link TUBG2 downregulation to the higher amyloid burden and AD diagnosis while suggesting such observations are enriched in excitatory and inhibitory neurons, reaching FDR significance.ConclusionThis study is the most extensive European GWAS of brain amyloidosis, and our findings replicate known AD loci and identify a possible novel locus (index SNP rs35635959) on chromosome 17. Functional annotations of the novel variant indicate TUBG2, implicating in microtubule organization, warrants further assessment. Ongoing efforts aim to validate these novel effects using independent datasets.