AbstractBackgroundMany people with clinically diagnosed Alzheimer’s disease (AD) dementia during life show multiple comorbid neuropathologies at autopsy. We sought to develop and evaluate a composite brain pathology score (BPS) score in the Adult Changes in Thought (ACT) study.MethodWe chose nine standard neuropathological variables to derive the BPS: Thal phase, Braak stage, CERAD score, cerebral amyloid angiopathy (CAA) score, presence of Lewy Body disease, presence of hippocampal sclerosis, total microinfarcts, LATE stage, and presence of arteriolosclerosis. We used confirmatory factor analyses (CFA) to derive a composite score for BPS. We compared BPS to the AD Neuropathologic Change (ADNC) score.We performed non‐nested modeling to compare the association of each score (BPS vs ADNC) using the last cognitive score (memory, executive function, language, and visuospatial ability) prior to death, adjusting for age at death and sex. Non‐nested models were compared with the Adjusted‐R2, the Davidson‐MacKinnon J‐test, and the Cox–Pesaran test. We focused on people whose last cognitive data were≤2 years prior to death. We compared associations of ADNC and BPS with last known clinical diagnosis (no dementia vs. any dementia), adjusting for age at death and sex by considering area under receiver operator characteristic (ROC) curves.ResultSample size was 886 with mean age of death was 89 and 57% were female. A bifactor model fit the best (Figure 1) with residual correlations for Thal phase and CERAD score, and for LATE stage and presence of hippocampal sclerosis. The BPS explained more of the variance for each of the cognitive scores (Table 1) and was superior and statistically significant compared to the ADNC score in comparisons of non‐nested models (Table 2). The BPS was also more strongly associated (Odds Ratio = 3.2) with dementia diagnosis than the ADNC score (Odds Ratio = 2.0). The area under the ROC curve for ADNC score was 0.74, while it was 0.78 for BPS score. The difference between the areas under ROC curves was statistically significant (p‐value < 0.0001).ConclusionWe demonstrate an approach to developing a composite brain pathology score which incorporates multiple forms of pathology. Future efforts will be focused on co‐calibrating and harmonizing BPS in other autopsy cohorts.