Handgrip Strength Asymmetry as a Dynamic Functional Phenotype Distinct from Weakness and Associated with Incident Dementia: A Population-Based Cohort and Multi- State Analysis

Abstract Background Handgrip strength asymmetry (HGSA) may represent a distinct hand motor imbalance phenotype beyond handgrip strength weakness (HGSW). However, whether HGSA reflects a distinct dynamic phenotype from overt weakness, and whether these phenotypes differ in their associations with dementia, cognition, and structural brain markers, remain unclear. Methods We analyzed 363,867 UK Biobank participants without pre-existing dementia or musculoskeletal disease, who had baseline handgrip strength (HGS) measurements and up to 13.7 years of follow-up. HGS phenotypes were classified as normal HGS, HGSA, HGSW, and HGSAW (combined HGSA and HGSW). Multi-state Markov models characterized transitions between phenotypes among participants with repeated assessments; Cox models estimated dementia risk; linear regression assessed cognitive performance and structural brain outcomes. Results Among participants with repeated assessments, transitions from normal HGS to HGSA was more frequent (intensity: 0.137 vs. 0.004) than transitions to HGSW, and HGSA showed greater reversibility (intensity: 0.118 vs. 0.015). In fully adjusted models, HGSA was associated with increased risk of all-cause dementia (hazard ratio [HR] = 1.17, 95% confidence interval [CI]: 1.11 to 1.24), although associations were stronger for HGSW (HR = 1.60, 95% CI: 1.39 to 1.84) and HGSAW (HR = 1.69, 95% CI: 1.50 to 1.90). HGSA was associated with Alzheimer’s disease but not vascular dementia, whereas HGSW and HGSAW were associated with both subtypes. Cognitive analyses demonstrated that HGSW and HGSAW were associated with poorer general cognitive ability and multiple cognitive domains, whereas HGSA showed no association with general cognition. Neuroimaging analyses showed no significant associations with total brain volume or hippocampal volume; however, HGS phenotypes were all associated with greater white matter hyperintensity volume. Conclusions HGSA is a common, dynamic and partially reversible handgrip phenotype that is frequently observed before overt weakness in repeated assessments. HGSA and HGSW show partly different associations with dementia, cognition, and structural brain markers, suggesting that they capture overlapping but distinct dimensions of functional impairment. HGSA may provide additional context for characterizing functional heterogeneity, although its clinical utility requires further investigation.