PARIETAL WHITE MATTER LESIONS IN ALZHEIMER’S DISEASE ARE ASSOCIATED WITH CORTICAL NEURODEGENERATIVE PATHOLOGY AND NOT WITH SMALL-VESSEL DISEASE

Cerebral white matter lesions (WML), as seen histologically, or white matter hyperintensities (WMH) as seen on MRI, are a frequent finding in both demented and non-demented elderly. WML encompass demyelination and axonal loss, and the pathogenesis is assumed to be small vessel disease (SVD)-related ischemia. However, in the posterior region, WML may also occur as the result of degenerative axonal loss secondary to cortical Alzheimer's disease (AD) pathology, i.e., hyperphosphorylated tau (HPτ) and amyloid-beta (Aβ) as a result of Wallerian degeneration. It is not clear whether pathological and molecular signatures in WML seen in AD differ from normal aged, and elucidation of this is paramount for accurate clinical dementia diagnostics. We investigated differences in the composition of parietal WML using post-mortem human brain tissue of AD and aged controls. WML from parietal tissue of 55 post-mortem brains (AD, n = 27; controls, n = 27) were quantitative assessed for severity, axonal loss and demyelination, as well cortical measures of HPτ, Aβ and WM-SVD. Biochemical assessment measured calpain protease (Wallerian degeneration) and myelin proteins MAG (ischemia) and PLP (axonal atrophy). Our findings support the concept of degenerative axonal loss, secondary to cortical AD-pathology, which is a putative mechanism in the pathogenesis of WML in AD. This new understanding of WML/WMH pathogenesis in AD is paramount for the accurate diagnosis of patients with cognitive impairment and future studies are warranted to investigate diagnostic accuracy of WM changes in AD. Our findings support the concept of posterior degenerative axonal loss that is secondary to cortical AD-pathology, which is a putative mechanism in the pathogenesis of WML in AD. This new understanding of WML/WMH pathogenesis in AD is paramount for the accurate diagnosis of patients with cognitive impairment and future studies are warranted to investigate diagnostic accuracy of WM changes in AD.