White matter injury, plasma Alzheimer's disease, and neurodegenerative biomarkers on cognitive decline in community‐dwelling older adults: A 10‐year longitudinal study

Abstract INTRODUCTION This study aimed to investigate the synergistic impact of white matter injury, Alzheimer's disease, and neurodegenerative pathology on long‐term cognitive decline and dementia risk in older adults. METHODS We included 262 dementia‐free participants with baseline and follow‐up interviews (2010–2021). At baseline, peak width of skeletonized mean diffusivity (PSMD) was assessed from diffusion tensor imaging. Plasma phosphorylated tau 217 (p‐tau217) and neurofilament light chain (NfL) were measured using a single‐molecule immune‐array assay. Cognitive function was evaluated using Mini‐Mental State Examination (MMSE) and domain‐specific cognitive tests. RESULTS Participants with high‐level PSMD, p‐tau217, and NfL showed the fastest decline of MMSE (β = −0.30) and the highest dementia incidence of 3.54/100 person‐years. A combination model with three markers demonstrated a good predictive value for dementia, incorporating age, sex, education, and apolipoprotein E (area under the curve = 0.93, 95% confidence interval = 0.86, 0.99). DISCUSSION Combining co‐pathology markers may identify individuals with a high risk of cognitive decline. Highlights Peak width of skeletonized mean diffusivity (PSMD) was correlated with long‐term cognitive decline, and this correlation was modified by plasma phosphorylated tau (p‐tau)217 and neurofilament light chain (NfL). Participants with high levels of PSMD, p‐tau217, and NfL showed the fastest cognitive decline and the highest risk of dementia. A combination of the three markers exhibited a good predictive value of incident dementia over a 10‐year follow‐up period.