Analyses from the Swedish BioFINDER‐2 study have shown that tau burden change seen via 18F‐RO‐948 tau PET tracer replicates the post‐mortem spreading pattern of tau. The greatest longitudinal changes have thus far been seen in Braak regions I/II for amyloid positive (Aβ+) cognitively unimpaired (CU) subjects, and Braak regions III/IV and V/VI for Aβ+ subjects with mild cognitive impairment (MCI) and AD dementia, respectively. In the design of clinical trials, selecting a composite cortical region with the greatest longitudinal effect size (LES) is a key objective in keeping trial sample size practical. In this study, we employed a Lasso optimization method to determine a combination of brain subregions optimized for maximal effect size in the pre‐symptomatic and early AD populations.