MMSE-CDR-SB residual as an exploratory indicator of deviation from an AD-typical cognitive-functional pattern

INTRODUCTIONWe tested whether the MMSE-CDR-SB residual, defined as observed minus expected CDR-SB from an Alzheimers disease-oriented reference equation, reflects deviation from an AD-typical cognitive-functional pattern. METHODSUsing NACC data, we analyzed an autopsy cohort (n=1,981) and a separate clinical diagnosis cohort (n=3,184). Associations were examined using multivariable logistic regression adjusted for MMSE band, age, sex, and education. RESULTSLower residual values were associated with lower odds of amyloid and AD-type tau pathology. Positive residual values showed a directional but nonspecific association with selected non-AD co-pathologies, including TDP-43 and vascular burden. In the clinical cohort, positive residual values were enriched in PSP and FTLD-other, whereas AD cases clustered near the reference pattern. DISCUSSIONThe residual appears to summarize deviation from an AD-typical cognitive-functional pattern rather than indicate one specific pathology, and may serve as an exploratory triage-level signal of a less AD-typical presentation. HighlightsO_LIMMSE-CDR-SB residual summarizes deviation from an AD-typical pattern. C_LIO_LILower residuals were associated with lower odds of amyloid and AD-type tau. C_LIO_LIPositive residuals were clinically enriched in PSP and FTLD-other. C_LIO_LIResidual has potential as a triage-level signal of a less AD-typical presentation. C_LI Research in ContextO_ST_ABSSystematic reviewC_ST_ABSWe reviewed PubMed and reference lists for studies on MMSE-CDR-SB crosswalks, mixed dementia pathology, and syndrome-specific differences in cognitive-functional severity. Prior work mainly mapped scores across instruments and did not test whether deviation from an AD-oriented MMSE-CDR-SB reference relationship was associated with neuropathological or clinical heterogeneity. InterpretationIn NACC, the MMSE-CDR-SB residual behaved as a summary of deviation from an AD-typical cognitive-functional pattern rather than as a specific pathology marker. Negative residuals were associated with lower odds of core AD pathology, whereas positive residuals were enriched in PSP and FTLD-other and showed only directional, nonspecific signals for selected non-AD co-pathologies. Future directionsProspective validation should test generalizability, refine practical thresholds, and determine whether this simple bedside metric improves etiologic triage for mixed pathology and non-AD syndromic features, especially where biomarker access is limited.