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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.
Hu et al. (2025) studied this question.