Metabolic and functional correlates of first transitions to low muscle strength and memory reserve across four longitudinal cohorts

BACKGROUND: Muscle strength and episodic memory are linked in later life, but factors associated with their first transitions to low reserve remain uncertain. METHODS: We analyzed four longitudinal cohorts of adults aged 50-100 years with at least three synchronous strength and memory assessments. Participants entered follow-up when both cohort-standardized residual scores exceeded -1 SD. Continuous-time panel multistate models estimated muscle-first and memory-first transition intensities. Cohort-specific effects were pooled using random-effects meta-analysis with Hartung-Knapp inference. The primary contrast was the ratio of covariate-specific intensity ratios (IRRs) for memory-first versus muscle-first transitions. RESULTS: The primary analysis included 46,356 participants, with 6,036 first observed muscle-first, 8,539 memory-first and 897 both-low transitions. Older age was associated with a relative memory-first pattern (IRR ratio per 5 years 1.110, 95% CI 1.082-1.139); activities of daily living (ADL) limitation was associated with a relative muscle-first pattern (0.664, 95% CI 0.559-0.788). Diabetes was associated with higher intensities in both domains, but its pathway contrast remained uncertain (0.751, 95% CI 0.554-1.019; P=0.058). Age and ADL associations persisted after adjustment for baseline reserve and multimorbidity and when participants with two assessments were included. Age-specific SD thresholds attenuated the age contrast to 1.048 (95% CI 1.016-1.081). Diabetes findings varied with the low-reserve threshold. CONCLUSIONS: Age and ADL limitation were associated with different relative patterns of first low-reserve transitions. Diabetes was associated with higher transition intensities in both domains without a clear pathway difference at the primary threshold. These observational associations do not establish a biological sequence or clinical screening thresholds.