Association of white matter hyperintensities with cognitive decline and neurodegeneration

Background: The relationship between white matter hyperintensities (WMH) and the core features of Alzheimer's disease (AD) remains controversial. Further, due to the prevalence of co-pathologies, the precise role of WMH in cognition and neurodegeneration also remains uncertain. Methods: Herein, we analyzed 1803 participants with available WMH volume data, extracted from the ADNI database, including 756 cognitively normal controls, 783 patients with mild cognitive impairment (MCI), and 264 patients with dementia. Participants were grouped according to cerebrospinal fluid (CSF) pathology (A/T profile) severity. Linear regression analysis was applied to evaluate the factors associated with WMH volume. Modeled by linear mixed-effects, the increase rates (Delta) of the WMH volume, cognition, and typical neurodegenerative markers were assessed. The predictive effectiveness of WMH volume was subsequently tested using Cox regression analysis, and the relationship between WMH/Delta WMH and other indicators such as cognition was explored through linear regression analyses. Furthermore, we explored the interrelationship among amyloid-beta deposition, cognition, and WMH using mediation analysis. Results: Higher WMH volume was associated with older age, lower CSF amyloid-beta levels, hypertension, and smoking history (all p <= 0.001), as well as cognitive status (MCI, p < 0.001; dementia, p = 0.008), but not with CSF tau levels. These results were further verified in any clinical stage, except hypertension and smoking history in the dementia stage. Although WMH could not predict dementia conversion, its increased levels at baseline were associated with a worse cognitive performance and a more rapid memory decline. Longitudinal analyses showed that baseline dementia and positive amyloid-beta status were associated with a greater accrual of WMH volume, and a higher Delta WMH was also correlated with a faster cognitive decline. In contrast, except entorhinal cortex thickness, the WMH volume was not found to be associated with any other neurodegenerative markers. To a lesser extent, WMH mediates the relationship between amyloid-beta and cognition. Conclusion: WMH are non-specific lesions that are associated with amyloid-beta deposition, cognitive status, and a variety of vascular risk factors. Despite evidence indicating only a weak relationship with neurodegeneration, early intervention to reduce WMH lesions remains a high priority for preserving cognitive function in the elderly.