•National Alzheimer's Coordinating.Center. [1] Participants with genetic data and longitudinal cognitive assessments (NACC, N=11,531; aged 73 ± 8 years; 56% female; 40% APOE*ε4)

•Clinical Risk Score (CRS): modified CAIDE score (age, sex, education, obesity, hypertension, and hypercholesterolemia. [2]

•Polygenic Risk Score (PRS): PRS-CSx cross-ancestry AD PRS. [3]

•Harmonized memory, executive function, and language domain scores (ADSP-PHC). [4]

•Secondary: Incident MCI or dementia.

•Linear mixed-effects models with age as the time scale. Models adjusted for APOE ε4 and genetic PCs.

•Predicted trajectories and contrasts estimated at low (−1 SD), mean, and high (+1 SD) CRS and PRS.

•Secondary: Cox proportional hazards models for incident MCI or dementia.

Conclusions:

Clinical and genetic risk were independently associated with cognitive decline and dementia risk. Joint consideration of these risk domains identified consistent gradients of risk across cognitive and clinical outcomes, supporting the value of integrating clinical and genetic information when characterizing disease susceptibility. Findings were largely consistent with additive effects of CRS and PRS, with limited evidence for multiplicative interaction. Future studies leveraging larger and more diverse populations, earlier longer follow-up, and joint modeling of cognitive trajectories and clinical conversion may further clarify how clinical and genetic risk jointly influence disease progression.