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Relationships of brain cholesterol and cholesterol biosynthetic enzymes to Alzheimer’s pathology and dementia in the CFAS population-derived neuropathology cohort

Lookup NU author(s): Dr Connor Richardson, Professor Fiona MatthewsORCiD



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


Altered cholesterol metabolism is implicated in brain ageing and Alzheimer’s disease. We examined whether key genes regulating cholesterol metabolism and levels of brain cholesterol are altered in dementia and Alzheimer’s disease neuropathological change (ADNC). Temporal cortex (n = 99) was obtained from the Cognitive Function and Ageing Study. Expression of the cholesterol biosynthesis rate-limiting enzyme HMG-CoA reductase (HMGCR) and its regulator, SREBP2, were detected using immunohistochemistry. Expression of HMGCR, SREBP2, CYP46A1 and ABCA1 were quantified by qPCR in samples enriched for astrocyte and neuronal RNA following laser-capture microdissection. Total cortical cholesterol was measured using the Amplex Red assay. HMGCR and SREBP2 proteins were predominantly expressed in pyramidal neurones, and in glia. Neuronal HMGCR did not vary with ADNC, oxidative stress, neuroinflammation or dementia status. Expression of HMGCR neuronal mRNA decreased with ADNC (p = 0.022) and increased with neuronal DNA damage (p = 0.049), whilst SREBP2 increased with ADNC (p = 0.005). High or moderate tertiles for cholesterol levels were associated with increased dementia risk (OR 1.44, 1.58). APOE ε4 allele was not associated with cortical cholesterol levels. ADNC is associated with gene expression changes that may impair cholesterol biosynthesis in neurones but not astrocytes, whilst levels of cortical cholesterol show a weak relationship to dementia status.

Publication metadata

Author(s): Mistry H, Richardson CD, Higginbottom A, Ashford B, Ahamed SU, Moore Z, Matthews FE, Brayne C, Simpson JE, Wharton SB

Publication type: Article

Publication status: Published

Journal: Neuroscience Research

Year: 2024

Pages: epub ahead of print

Online publication date: 24/01/2024

Acceptance date: 17/01/2024

Date deposited: 06/02/2024

ISSN (electronic): 0168-0102

Publisher: Elsevier


DOI: 10.1016/j.neures.2024.01.003

PubMed id: 38278219


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Funder referenceFunder name
Alzheimer’s Research UK (AS-PG2016-1)
MRC U.1052.00.0013