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Frontal white matter lesions in Alzheimer’s disease are associated with both small vessel disease and AD-associated cortical pathology

Lookup NU author(s): Dr Kirsty McAleese, Mohi Miah, Dr Lauren WalkerORCiD, Mary Johnson, Dr Sean Colloby, Professor Alan ThomasORCiD, Dr David KossORCiD, Professor Johannes Attems



This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).


© 2021, Crown. Cerebral white matter lesions (WML) encompass axonal loss and demyelination and are assumed to be associated with small vessel disease (SVD)-related ischaemia. However, our previous study in the parietal lobe white matter revealed that WML in Alzheimer’s disease (AD) are linked with degenerative axonal loss secondary to the deposition of cortical AD pathology. Furthermore, neuroimaging data suggest that pathomechanisms for the development of WML differ between anterior and posterior lobes with AD-associated degenerative mechanism driving posterior white matter disruption, and both AD-associated degenerative and vascular mechanisms contributed to anterior matter disruption. In this pilot study, we used human post-mortem brain tissue to investigate the composition and aetiology of frontal WML from AD and non-demented controls to determine if frontal WML are SVD-associated and to reveal any regional differences in the pathogenesis of WML. Frontal WML tissue sections from 40 human post-mortem brains (AD, n = 19; controls, n = 21) were quantitatively assessed for demyelination, axonal loss, cortical hyperphosphorylated tau (HPτ) and amyloid-beta (Aβ) burden, and arteriolosclerosis as a measure of SVD. Biochemical assessment included Wallerian degeneration-associated protease calpain and the myelin-associated glycoprotein to proteolipid protein ratio as a measure of ante-mortem ischaemia. Arteriolosclerosis severity was found to be associated with and a significant predictor of frontal WML severity in both AD and non-demented controls. Interesting, frontal axonal loss was also associated with HPτ and calpain levels were associated with increasing Aβ burden in the AD group, suggestive of an additional degenerative influence. To conclude, this pilot data suggest that frontal WML in AD may result from both increased arteriolosclerosis and AD-associated degenerative changes. These preliminary findings in combination with previously published data tentatively indicate regional differences in the aetiology of WML in AD, which should be considered in the clinical diagnosis of dementia subtypes: posterior WML maybe associated with degenerative mechanisms secondary to AD pathology, while anterior WML could be associated with both SVD-associated and degenerative mechanisms.

Publication metadata

Author(s): McAleese KE, Miah M, Graham S, Hadfield GM, Walker L, Johnson M, Colloby SJ, Thomas AJ, DeCarli C, Koss D, Attems J

Publication type: Article

Publication status: Published

Journal: Acta Neuropathologica

Year: 2021

Volume: 142

Pages: 937-950

Print publication date: 01/12/2021

Online publication date: 04/10/2021

Acceptance date: 27/09/2021

Date deposited: 18/10/2021

ISSN (print): 0001-6322

ISSN (electronic): 1432-0533

Publisher: Springer Nature


DOI: 10.1007/s00401-021-02376-2


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