Abstract
Cognitive frailty has emerged as an important concept in research and clinical practice, yet the combined effect of cognitive reserve and frailty on neurodegenerative disease risk remains unexplored. This study included 346,025 UK Biobank participants followed for up to 15 years. Cognitive reserve indicators were generated using latent class analysis based on educational level, occupational achievement, confiding in others, social contact, leisure activities, and television viewing time. The primary outcome was neurodegenerative disease, with secondary outcomes including Parkinson's disease, Alzheimer's disease, and all-cause dementia. During a median follow-up of 13.7 years, 5,590 new cases of neurodegenerative diseases were diagnosed. Compared to non-frail individuals, pre-frail and frail individuals had 1.47-fold (95% CI: 1.39-1.55) and 2.74-fold (95% CI: 2.46-3.06) increased risk, respectively, while high cognitive reserve conferred protection (HR = 0.82, 95% CI: 0.76-0.87). In joint effect analysis, individuals with low levels of cognitive reserve and frailty had the highest risk (HR = 3.13, 95% CI: 2.70-3.63), demonstrating significant additive interaction. Cross-sectional neuroimaging analyses showed that lower cognitive reserve levels was associated with reduced total brain volume (β = -0.161), reduced hippocampal volumes (βleft = -0.085, βright = -0.097), and increased white matter hyperintensities (β = 0.045). These findings emphasize maintaining cognitive reserve and managing frailty as modifiable factors for preventing neurodegenerative diseases.