A landscape of the genetic and cellular heterogeneity in Alzheimer disease
Authors: Brase Logan , You Shih-Feng , Albanus Ricardo D’Oliveira , Del-Aguila Jorge L. , Dai Yaoyi , Novotny Brenna C , Soriano-Tarraga Carolina , Dykstra Taitea , Fernandez Maria Victoria , Budde John P , Bergmann Kristy , Morris John C , Bateman Randall J , Perrin Richard J , McDade Eric , Xiong Chengjie , Goate Alison , Farlow Martin , Chhatwal Jasmeer P. , Schofield Peter , Chui Helena ,   Dominantly Inherited Alzheimer Network (DIAN), Sutherland Greg T , Kipnis Jonathan , Karch Celeste M , Benitez Bruno A , Cruchaga Carlos , Harari Oscar 
Published: December 2021

AbstractBackgroundAlzheimer disease (AD) has substantial genetic, molecular, and cellular heterogeneity associated with its etiology. Much of our current understanding of the main AD molecular events associated with the amyloid hypothesis (APP, PSEN1 and PSEN2) and neuroimmune modulation (TREM2 and MS4A) is based on genetic studies including GWAS. However, the functional genes, downstream transcriptional ramifications, and the cell-type-specific effects of many GWAS loci remain poorly understood. Understanding these effects can point us to the cellular processes involved in AD and uncover potential therapeutic targets.MethodsWe applied a genetic-based approach to our sample selection; our cohort included carriers of AD pathogenic mutations (APP, PSEN1), risk variants in TREM2, and the resilience variant (rs1582763) in the MS4A cluster associated with cerebrospinal fluid (CSF) soluble TREM2 levels. We performed single-nucleus RNA-sequencing (snRNA-seq) of 1,102,459 nuclei from the human parietal cortex of these carriers. Following initial unbiased clustering and cell-type annotation, we performed deep subclustering analysis per cell type to identify unique cellular transcriptional states associated with these genetic variants. We identified differentially expressed genes between cell states and genetic variant carriers/controls, and performed differential cell proportion analyses to determine key differences among these carriers. We analyzed sequencing data from human dorsolateral prefrontal cortex and mouse models to replicate the enrichment of unique cell states in genetic variant carriers. Finally, we leveraged these cell-state differential expression results to link genes in AD GWAS loci to their functional cell types.FindingsWe identified cell-specific expression states influenced by AD genetic factors for neurons and glia. Autosomal dominant AD (ADAD) brains exhibited unique transcriptional states in all cell types. TREM2 variant carrier brains were also enriched for specific microglia and oligodendrocyte subpopulations. Carriers of the resilience MS4A variant were enriched for an altered activated-microglia expression state. We mapped AD GWAS genes to their potential functional cell types, and some, including PLCG2 and SORL1, were expressed in a broader range of brain cell types than previously reported.InterpretationAD pathogenic, risk, or resilience variants are sufficient to alter the transcriptional and cellular landscape of human brains. Overall, our results suggest that the genetic architecture contributes to the cortical cellular heterogeneity associated with disease status, which is a critical factor to consider when designing drug trials and selecting the treatment program for AD patients.Our findings suggest that integrating genetic and single-cell molecular data facilitates our understanding of the heterogeneity of pathways, biological processes and cell types modulated by genetic risk factors for AD.FundingUS National Institutes of Health, Hope Center, Archer foundation, Alzheimer Association, CZI.