Abstract
AIM: Frailty increases the risk of cognitive decline in older adults, yet the brain structural patterns associated with different frailty subtypes remain unclear. This study examined white matter (WM) alterations across frailty subtypes in community-dwelling older adults without dementia. METHODS: This cross-sectional study included participants from the Taiwan Precision Medicine Initiative on Cognitive Impairment and Dementia (TPMIC) cohort. Frailty was assessed using Fried's phenotype and classified into mobility, non-mobility, and low physical activity subtypes. Cognitive function (attention, memory, and executive function) was evaluated using standardized neuropsychological tests. WM microstructure was measured using diffusion tensor imaging (DTI) metrics, including fractional anisotropy (FA) and mean diffusivity (MD). RESULTS: Among 297 participants, 91 (30.6%) were pre-frail/frail. The pre-frail/frail group showed widespread WM alterations, with the internal capsule (IC) remaining significant after full adjustment and FDR correction (q < 0.05). The mobility subtype was associated with poorer cognitive performance across all domains (all P < 0.01) and showed lower FA and higher MD primarily in motor and cognitive-related tracts, such as the corpus callosum (all q < 0.05). In contrast, the non-mobility subtype was associated with poorer attention and executive function, with alterations primarily in emotion-regulation tracts, such as the cingulum and forceps major (all q < 0.05). No significant WM differences were found for the low physical activity subtype. CONCLUSION: Frailty subtypes are associated with distinct WM alteration patterns, reflecting potentially different mechanisms of brain aging. These findings highlight the importance of subtype-specific approaches to early detection and intervention.