MMSE–CDR‐SB residual as an exploratory indicator of deviation from an Alzheimer's disease–typical cognitive–functional pattern
Abstract INTRODUCTION In clinical practice, patients with Alzheimer's disease (AD) often present with cognitive and functional profiles that diverge from what is expected. We tested whether the Mini‐Mental State Examination Clinical Dementia Rating Sum of Boxes (MMSE–CDR‐SB) residual, defined as observed minus expected CDR‐SB from a published MMSE–CDR‐SB reference equation, reflects clinically meaningful deviation from the expected cognitive–functional relationship. METHODS Using National Alzheimer's Coordinating Center data, we analyzed an autopsy cohort (n = 1981) and a separate clinical diagnosis cohort (n = 3184). Negative residual values indicated less functional impairment than expected for a given cognitive score, and positive values indicated greater functional impairment than expected. Associations were examined using multivariable logistic regression adjusted for MMSE score range, age, sex, and education. RESULTS Lower residual values were associated with lower odds of amyloid and AD‐type tau pathology. Higher residual values showed a directional association with transactive response DNA binding protein 43 kDa; vascular burden was also associated with the residual index but across a broader range. In the clinical cohort, higher residual values were enriched in progressive supranuclear palsy and frontotemporal lobar degeneration (other), whereas AD cases clustered near the reference pattern. DISCUSSION The MMSE–CDR‐SB residual may help flag less AD‐typical presentations for further etiologic evaluation, but cannot be interpreted as a pathology‐specific marker due to substantial overlap across diagnostic groups.