White Matter Hyperintensity as a Vascular Contribution to the AT(N) Framework

The AT(N) framework enables the classification of an individual within the biological Alzheimer's disease (AD) continuum by pairing the cognitive stage with the biomarker status of amyloid-beta (Aβ, A), tau (T) and neurodegeneration (N). AD is a multifactorial disease that may involve different pathogenic mechanisms such as cerebrovascular disease (CVD). Therefore, biomarkers of these mechanisms can be added to the AT(N) framework to enhance the biomarker characterization of individuals within the AD continuum. In AD, white matter hyperintensities (WMH) which are postulated to develop as a result of chronic ischemia from small vessel CVD are shown to play a role in the aetiology. However, the interplay of WMH with Aβ and tau pathophysiology in AD remains unclear. In this review, we summarized the studies that evaluated the associations between WMH and AD pathophysiology (Aβ and tau). We found that the evidence supporting the association of WMH with Aβ was mixed, and this may be explained by the relative contributions of WMH due to its differential load and anatomical distribution. More studies are also needed to determine the association of WMH with tau pathology. Future longitudinal studies with harmonized methodologies to quantify WMH and account for the anatomical differences of WMH are required to validate the relationship between WMH and AT(N) biomarkers. This will allow a clearer understanding of the utility of WMH as a vascular biomarker in the AT(N) framework. Novel CVD biomarkers will also have the potential to further elucidate the contributions of CVD to the AD pathophysiology.