MMSE-CDR-SB residual as an exploratory indicator of deviation from an Alzheimer's disease-typical cognitive-functional pattern.

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.