Neurite Degradation Mediates the Effect of Amyloid Deposition on Global Cognition in Asymptomatic Older Adults.

This study investigates whether amyloid deposition is associated with neurite degradation in cognitively unimpaired (asymptomatic) older adults, with a focus on brain regions critical for memory and cognition. Using data from the ADNI3 cohort (n = 65; mean age 69.5±5.5), we examined the relationship between amyloid levels (from PET imaging), neurite density (derived from diffusion MRI-based Neurite Orientation Dispersion and Density Imaging, NODDI), and global cognition (MoCA scores). NODDI is a biophysical diffusion MRI model that quantifies microstructural features of brain tissue through metrics like neurite density index (NDI) that may sensitively capture early neurodegenerative changes leading up to Alzheimer's Disease (AD). Spearman correlation analyses showed significant negative associations between amyloid and NDI in the right entorhinal cortex (ρ = -0.29; p = 0.02) and left fusiform gyrus (ρ = -0.26; p = 0.04). Amyloid also correlated with ODI in the left (ρ = -0.31; p = 0.011) and right fusiform gyrus (ρ = -0.33; p = 0.006). Mediation analyses revealed significant effects for NDI in the left entorhinal cortex (p = 0.02) and left fusiform gyrus (p = 0.006), and for ODI in the left fusiform gyrus (p = 0.044). These findings indicate that even in the absence of clinical symptoms, amyloid deposition may contribute to microstructural degradation in key brain areas, which in turn relates to cognitive function. NDI specifically may hold promise as an early imaging marker for identifying individuals at risk and tracking AD progression. This study demonstrates that neurite degradation, measured by neurite density index (NDI), mediates the relationship between amyloid deposition and global cognitive function in asymptomatic older adults, highlighting NDI as a promising early marker of microstructural vulnerability in preclinical Alzheimer's disease.