Gene Expression Differences Between Symptomatic and Asymptomatic Individuals with Neuropathologically Confirmed Alzheimer’s Disease

Abstract Background There has been tremendous interest in molecular signatures of cognitively resilient individuals with neuropathologically confirmed Alzheimer disease. We sought to identify transcriptome signatures derived from brain that distinguish such individuals from those with AD diagnosed clinically and confirmed at autopsy. Methods We performed differential gene expression analysis in participants with neuropathologically confirmed AD who had a clinical diagnosis of AD (AD) and cognitively normal (AsymAD) prior to death using RNA sequencing data from 43 AD and 11 AsymAD participants of the Framingham Heart Study and Boston University Alzheimer’s Disease Research Center (FHS/ADRC) and from 155 AD and 208 AsymAD participants of the Religious Orders Study and Memory and Aging Project (ROSMAP). Differential gene expression transcritome‐wide was compared between AD and AsymAD subjects separately in each dataset using linear regression models including covariates for sex, age at death, and post‐mortem interval. Results were combined by meta‐analysis using sample size as a weight. Significantly (P<10 −5 ) differentially expressed genes (DEGs) were subsequently tested for association with memory, language, executive function, and visuospatial performance, and neuropathological traits. Results We identified 36 significant DEGs among which PPDPF, ZNF592, RPL17, MEIS3, and MTMR10 were transcriptome‐wide significant (P<10 −6 ). Of the 36 DEGs, expression of PPDPF, SLC38A2, and PRELP was significantly associated with memory and language test scores (P<0.05). Expression of KCNJ10 was significantly associated with complement 4b protein (P<0.05) and phosphorylated Tau levels (P<10 −3 ). Conclusions This study identified genes that may be involved in cognitive resilience. Our study also illustrated that expression differences of the top‐ranked genes are associated with cognitive performance in memory and language domains, Tau pathology, and neuroinflammation. These findings may provide insight about cognitive resilience mechanisms as well as novel targets for inhibiting cognitive decline.