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However, our previous study in the parietal lobe white matter revealed that WML in Alzheimer\u2019s 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<jats:italic>post-<\/jats:italic>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\u00a0from 40 human<jats:italic>post-mortem<\/jats:italic>brains (AD,<jats:italic>n\u2009=\u2009<\/jats:italic>19; controls,<jats:italic>n\u2009=\u2009<\/jats:italic>21) were quantitatively assessed for demyelination, axonal loss, cortical hyperphosphorylated tau (HP\u03c4) and amyloid-beta (A\u03b2) 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<jats:italic>ante-mortem<\/jats:italic>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 HP\u03c4 and calpain levels were associated with increasing A\u03b2 burden in the AD group, suggestive of an additional degenerative influence. To conclude, this pilot data suggest that frontal WML in AD may\u00a0result 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.<\/jats:p>","DOI":"10.1007\/s00401-021-02376-2","type":"journal-article","created":{"date-parts":[[2021,10,5]],"date-time":"2021-10-05T07:47:29Z","timestamp":1633420049000},"page":"937-950","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":103,"title":["Frontal white matter lesions in Alzheimer\u2019s disease are associated with both small vessel disease and AD-associated cortical pathology"],"prefix":"10.1007","volume":"142","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-0212-9823","authenticated-orcid":false,"given":"Kirsty E.","family":"McAleese","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mohi","family":"Miah","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sophie","family":"Graham","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Georgina M.","family":"Hadfield","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lauren","family":"Walker","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mary","family":"Johnson","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sean J.","family":"Colloby","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alan J.","family":"Thomas","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Charles","family":"DeCarli","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David","family":"Koss","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Johannes","family":"Attems","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2021,10,4]]},"reference":[{"key":"2376_CR1","doi-asserted-by":"publisher","first-page":"1347","DOI":"10.3233\/JAD-180017","volume":"63","author":"ML Alosco","year":"2018","unstructured":"Alosco ML, Sugarman MA, Besser LM, Tripodis Y, Martin B, Palmisano JN et al (2018) A Clinicopathological investigation of white matter hyperintensities and alzheimer\u2019s disease neuropathology. 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