Effects of regional white matter hyperintensities and β-amyloid on domain-specific cognition and progression to dementia

White matter hyperintensities (WMHs) and cerebral β-amyloid (Aβ) have been characterized as clinically significant biomarkers associated with greater cognitive decline and incidence of Alzheimer's Disease (AD) dementia. However, it remains unclear how their regional manifestations co-contribute to domain-specific cognition and dementia onset. We investigated 200 cognitively normal (CN) and 523 individuals with mild cognitive impairment (MCI). We first quantified regional WMHs and Aβ accumulation in the four cerebral lobes. Next, we evaluated the effects of both WMHs and Aβ in each lobe on memory, executive function (EF), language, and visuospatial function. We used Cox proportional hazard models to determine the contributions of both regional WMHs and Aβ to dementia progression. In CN individuals, greater WMHs in parietal and temporal regions were associated with poorer EF beyond Aβ. In MCI individuals, greater Aβ burden in all lobes were associated with poorer memory, EF, and language abilities beyond WMHs. Lastly, both greater occipital WMHs and Aβ predicted progression to dementia. Temporo-parietal WMHs may drive early decline in EF beyond regional Aβ, while occipital WMHs play a critical role in disease progression to AD dementia beyond regional Aβ, highlighting the complex interplay of regional WMHs and Aβ on domain-specific cognitive and clinical function.