MMSE-CDR-SB residual deviation from AD pattern linked to non-AD pathologies in autopsy and clinical cohorts

This cohort study analyzed an autopsy cohort (n=1,981) and a clinical diagnosis cohort (n=3,184) from NACC data. The intervention or exposure was the MMSE-CDR-SB residual, which summarizes deviation from an AD-typical cognitive-functional pattern, using an AD-oriented reference equation as the comparator. The primary outcome was deviation from an AD-typical cognitive-functional pattern.

Lower residual values were associated with lower odds of amyloid and AD-type tau pathology. Positive residual values showed a directional but nonspecific association with non-AD co-pathologies, including TDP-43 and vascular burden. Positive residual values were enriched in PSP and FTLD-other. AD cases clustered near the reference pattern.

No safety or tolerability data were reported. Key limitations include that the residual appears to summarize deviation from an AD-typical pattern rather than indicate one specific pathology, and positive residual values showed a directional but nonspecific association with selected non-AD co-pathologies.

Practice relevance is that this may serve as an exploratory triage-level signal of a less AD-typical presentation. Associations were examined using multivariable logistic regression, and the certainty note is that this is an exploratory indicator.