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

Abstract 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. Significance Statement 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. Competing Interest Statement The authors have declared no competing interest. Funding Statement No funding to disclose at this moment. Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: Alzheimers Disease Neuroimaging Initiative publicly available data were used in this study. I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes Data Availability Alzheimers Disease Neuroimaging Initiative publicly available data were used in this study.