Abstract
INTRODUCTION: Dual cognitive and mobility decline is more strongly associated with dementia risk than cognitive decline only. It remains unknown whether this syndrome is associated with brain atrophy patterns, white matter (WM) damage, or pathology. METHODS: In the Baltimore Longitudinal Study of Aging participants with and without dual decline, we used linear mixed-effects models to compare up to 13-year longitudinal changes in MRI-derived atrophy patterns, WM hyperintensities (n = 339), microstructure (n = 307), plasma glial fibrillary acidic protein (GFAP), neurofilament light chain (NfL), amyloid beta 42/40 (Aβ(42/40)) ratio (n = 349), and phosphorylated tau 181 (pTau181) (n = 258). RESULTS: Those experiencing dual decline showed accelerated atrophy in medial temporal (p = .004), parietotemporal (p = .029), and perisylvian regions (p = .028), whereas gait decline only showed accelerated parietotemporal atrophy (p = .035) and memory decline only showed perisylvian atrophy (p = .021). Dual decline was also associated with unique microstructural deterioration in several WM tracts (p < .05), a greater decrease in Aβ(42/40) ratio (p = .015), and greater increases in GFAP (p = .009) and NfL (p < .001). DISCUSSION: Individuals experiencing dual decline are at an increased risk for regional brain atrophy, microstructural degradation, and biomarker-defined molecular changes underlying dementia. HIGHLIGHTS: Those experiencing dual decline showed several accelerated brain atrophy patterns. Those experiencing dual decline showed unique microstructural deterioration. Dual decline showed a greater decline in plasma Aβ(42/40) ratio. Dual decline showed greater increases in plasma GFAP and NfL. Dual decline may indicate brain and blood markers underlying dementia.