The effect of Alzheimer's disease and its progression on pyramidal cell gain and connectivity

Alzheimer's disease affects our cognitive neurophysiology by loss of neurones, synapses and neurotransmitters. An improved mechanistic understanding of the human disease will facilitate new treatments. To this end, biophysically-informed dynamic causal models can support inferences around laminar and cell-specific disease effects from human non-invasive imaging. Based on pre-clinical models and effects of cholinesterase inhibitors, we hypothesised that Alzheimer's disease would affect the modulation of superficial pyramidal cell gain and extrinsic connectivity between pyramidal cells of different regions in hierarchical cognitive networks. Magnetoencephalography (MEG) was recorded during an auditory mismatch negativity task from healthy adults (n=14) and people with symptomatic Alzheimer's disease or mild cognitive impairment (n=45, all amyloid-biomarker positive) at baseline and after 16 months. Fourteen people from the symptomatic group had repeat magnetoencephalography at two weeks to assess test-retest reliability. Sensor-level data were analysed using t-tests of the mismatch negativity amplitude from 140ms to 160ms. The repetition effect was assessed with repeated-measures analysis of covariance, using the average evoked response in the mismatch negativity time window as the repeated measure. An absolute, intraclass correlation model of the test-retest data assessed mismatch negativity amplitude reliability. We then fitted dynamic causal models to the evoked responses over 500ms. Second-level parametric empirical Bayes across participants examined the effect of (1) group, patients vs controls, and (2) progression, baseline vs follow-up, on the model parameters reflecting pyramidal cell gain modulation and extrinsic connectivity. There was a significant effect of both disease and progression on the mismatch negativity amplitude (patients vs controls, T=-1.80, p=0.04; patient baseline vs follow-up, T=-2.72, p=.005), which had excellent reliability (ICC=0.95, p<.001). Parametric empirical Bayes revealed strong evidence (posterior probability>95%) that Alzheimer's disease reduced extrinsic connectivity and superficial pyramidal cell gain modulation, which was reduced further at follow up assessment. The mechanistic modelling confirmed the hypothesis that reduced superficial pyramidal cell gain modulation and extrinsic connectivity can explain the observed neurophysiological effect of Alzheimer's disease. This approach to non-invasive magnetoencephalography data may be used for experimental medicine studies of candidate treatments, and bridge clinical to preclinical models of drug efficacy. ### Competing Interest Statement MT is an employee from Janssen Research & Development, a Division of Janssen Pharmaceutica NV., Beerse, Belgium, and owns stock or stock options in the company. MP is employed by AstraZeneca and may currently hold AstraZeneca stocks or stock options. SL is employed by Eli Lilly and may currently hold Eli Lilly stock. ### Funding Statement This work is primarily funded by the Dementias Platform UK which is funded by the Medical Research Council (MC\_UU\_00030/14 & MR/T033371/1), Janssen, AstraZeneca, Araclon, IXICO, Somalogic, GlaxoSmithKline, Invicro, Cambridge Cognition and Cognetivity. The study has additional support from Alzheimer's Research UK (ARUK-PG2017B-19), the Wellcome Trust (220258), Medical Research Council (SUAG/092 G116788; SUAG/096 G116788), NIHR Cambridge Biomedical Research Centre (NIHR203312) and NIHR Oxford Health Biomedical Research Centre (NIHR203316). The views expressed are those of the authors and not necessarily those of the NIHR or the Department of Health and Social Care. For the purpose of open access, the authors have applied a CC BY public copyright licence to any Author Accepted Manuscript version arising from this submission. ### 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: The study has received a favourable opinion from the East of England Cambridge Central Research Ethics Committee (REC reference 18/EE/0042). I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. 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, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes Imaging data and clinical scores are hosted by Dementias Platform UK Imaging Platform (https://portal.dementiasplatform.uk), using XNAT (https://www.xnat.org). Data will be made available with a managed access process through Dementias Platform UK, subject to requesters agreeing to a Code of Conduct to preserve data security, confidentiality and privacy.