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Widespread cell stress and mitochondrial dysfunction in early Alzheimer’s Disease

Lookup NU author(s): Professor David BrooksORCiD

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This is the authors' accepted manuscript of an article that has been published in its final definitive form by American Association for the Advancement of Science (AAAS), 2022.

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Abstract

Cell stress and impaired oxidative phosphorylation are central to mechanisms of synaptic loss and neurodegeneration in the cellular pathology of Alzheimer’s disease (AD). We quantified the in vivo density of the endoplasmic reticulum stress marker, the sigma 1 receptor (S1R) using [¹¹C]SA4503 PET, as well as that of mitochondrial complex I (MC1) with [¹⁸F]BCPP-EF and the pre-synaptic vesicular protein SV2A with [¹¹C]UCB-J in 12 patients with early AD and in 16 cognitively normal controls. We integrated these molecular measures with assessments of regional brain volumes and brain perfusion (CBF) measured with MRI arterial spin labelling. 8 AD patients were followed longitudinally to estimate rates of change with disease progression over 12-18 months. The AD patients showed widespread increases in S1R (≤ 27%) and regional decreases in MC1 (≥ -28%), SV2A (≥ -25%), brain volume (≥ -23%), and CBF (≥ -26%). [¹⁸F]BCPP-EF PET MC1 density (≥ -12%) and brain volumes (≥ -5%) were further reduced at follow up in brain regions consistent with the differences between AD patients and controls at baseline. Exploratory analyses showing associations of MC1, SV2A and S1R density with cognitive changes at baseline and longitudinally with AD, but not in controls, suggested a loss of metabolic functional reserve with disease. Our study thus provides novel in vivo evidence for widespread cellular stress and bioenergetic abnormalities in early AD and that they may be clinically meaningful.

Publication metadata

Author(s): Venkataraman AV, Mansur A, Rizzo G, Bishop C, Lewis Y, Kocagoncu E, LingfordHughes A, Huiban M, Passchier J, Rowe JB, Sukada H, Brooks DJ, Martarello L, Comley RA, Chen L, Schwarz AJ, Hargreaves R, Gunn RN, Rabiner EA, Matthews PM

Publication type: Article

Publication status: Published

Journal: Science Translational Medicine

Year: 2022

Volume: 14

Issue: 658

Print publication date: 17/08/2022

Online publication date: 17/08/2022

Acceptance date: 11/07/2022

Date deposited: 11/07/2022

ISSN (print): 1946-6234

ISSN (electronic): 1946-6242

Publisher: American Association for the Advancement of Science (AAAS)

URL: https://doi.org/10.1126/scitranslmed.abk1051

DOI: 10.1126/scitranslmed.abk1051

ePrints DOI: 10.57711/dghj-cc97

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