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

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. ### Competing Interest Statement AVV and ALH declare that they have no competing interests. PMM acknowledges consultancy fees from Novartis, Bristol Myers Squibb, Celgene and Biogen He has received honoraria or speakers honoraria from Novartis, Biogen and Roche and has received research or educational funds from Biogen, Novartis, GlaxoSmithKline and Nodthera. AM, GR, CB, YL, MH, JP, RNG, EAR are employees of Invicro, a Konica Minolta Company. JBR serves as Editor to Brain; Chief Scientific Advisor to ARUK; and have consultancies with UCB, Asceneuron, Biogen, WAVE, SV Health, Astex unrelated to the current work; and have research grants from Janssen, Lilly, AstraZeneca. LM is an employee of Biogen. RC is an employee and shareholder of AbbVie, Inc. LC is an employee and shareholder of Pfizer, Inc. AJS is a full-time employee and shareholder of Takeda Pharmaceuticals, Ltd. HT is an employee of Hamamatsu Photonics The patent of JP 2014-531670 for [18F]BCPP-EF has been filed by Hamamatsu Photonics KK. RH is a full-time employee and shareholder of Bristol Myers Squibb. ### Funding Statement Alzheimer's Society, grant number 440, AS-CTF-18-006 (AVV) NIHR Biomedical Research Centre, Imperial College London (AVV, PMM) UK Dementia Research Institute NIHR Cambridge Biomedical Research Centre (BRC-1215-20014) (JBR) Medical Research Council (SUAG/051 G101400; MR/L023784/2; MR/N029941/1) (JBR) ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: NHS London - Brighton & Sussex Research Ethics Committee (REC 18/LO/0179) for AD patients and East of England Cambridge Central & South Research Ethics Committee for controls. Radiation safety was approved by the Administration of Radioactive Substances Advisory Committee (ARSAC R92). Local site approval was provided by Imperial College London Joint Research Office. All necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines and uploaded the relevant EQUATOR Network research reporting checklist(s) and other pertinent material as supplementary files, if applicable. Yes The data for this study is managed within the MINDMAPS consortium. Information concerning access is available from the lead, ilan.rabiner{at}invicro.co.uk