BackgroundMore than 75 common variant loci account for only a portion of the heritability for Alzheimer’s disease (AD). A more complete understanding of the genetic basis of AD can be deduced by exploring associations with AD-related endophenotypes.MethodsWe conducted genome-wide scans for cognitive domain performance using harmonized and co-calibrated scores derived by confirmatory factor analyses for executive function, language, and memory. We analyzed 103,796 longitudinal observations from 23,066 members of community-based (FHS, ACT, and ROSMAP) and clinic-based (ADRCs and ADNI) cohorts using generalized linear mixed models including terms for SNP, age, SNP × age interaction, sex, education, and five ancestry principal components. Significance was determined based on a joint test of the SNP’s main effect and interaction with age. Results across datasets were combined using inverse-variance meta-analysis. Genome-wide tests of pleiotropy for each domain pair as the outcome were performed using PLACO software.ResultsIndividual domain and pleiotropy analyses revealed genome-wide significant (GWS) associations with five established loci for AD and AD-related disorders (BIN1,CR1,GRN,MS4A6A, andAPOE) and eight novel loci.ULK2was associated with executive function in the community-based cohorts (rs157405,P= 2.19 × 10–9). GWS associations for language were identified withCDK14in the clinic-based cohorts (rs705353,P= 1.73 × 10–8) andLINC02712in the total sample (rs145012974,P= 3.66 × 10–8).GRN(rs5848,P= 4.21 × 10–8) andPURG(rs117523305,P= 1.73 × 10–8) were associated with memory in the total and community-based cohorts, respectively. GWS pleiotropy was observed for language and memory withLOC107984373(rs73005629,P= 3.12 × 10–8) in the clinic-based cohorts, and withNCALD(rs56162098,P= 1.23 × 10–9) andPTPRD(rs145989094,P= 8.34 × 10–9) in the community-based cohorts. GWS pleiotropy was also found for executive function and memory withOSGIN1(rs12447050,P= 4.09 × 10–8) andPTPRD(rs145989094,P= 3.85 × 10–8) in the community-based cohorts. Functional studies have previously linked AD toULK2,NCALD, andPTPRD.ConclusionOur results provide some insight into biological pathways underlying processes leading to domain-specific cognitive impairment and AD, as well as a conduit toward a syndrome-specific precision medicine approach to AD. Increasing the number of participants with harmonized cognitive domain scores will enhance the discovery of additional genetic factors of cognitive decline leading to AD and related dementias.Supplementary InformationThe online version contains supplementary material available at 10.1186/s13024-023-00633-4.