Unveiling paths to Alzheimer’s disease: excitation-inhibition ratio shapes hierarchical dynamics

Abstract Alzheimer’s disease is marked by cognitive and memory impairment, with early disruptions in the balance between excitatory and inhibitory neurotransmission, thought to be closely linked to co-occurrent brain changes. The posterior-to-anterior hypothesis posits that functional neurodegeneration begins in critical areas of the default mode network, particularly the hippocampus and posterior cingulate cortex, before extending to more anterior brain regions. This study seeks to evaluate how cortical hierarchy, measured with functional connectivity proxies for excitation/inhibition equilibrium, shapes across the continuum from cognitively unimpaired individuals to symptomatic Alzheimer’s disease. We include 97 participants: 28 patients (including 20 carriers of the Apolipoprotein E allele, ɛ4+), 35 at-risk individuals (ɛ4+), and 34 controls (ɛ4-). Resting-state functional MRI and T1-weighted imaging were collected for all subjects, with a subset of Alzheimer’s patients also undergoing GABA-edited magnetic resonance spectroscopy in posterior cingulate cortex to provide a multimodal description of pathology-related excitation/inhibition disruptions’ impact on cortical hierarchical dynamics. To probe the validity of excitation/inhibition proxies, we (i) investigated the relationship between in-vivo measurements and cognitive profile in Alzheimer’s; (ii) compared default mode network temporal dynamics across groups; (iii) tested its multivariate association with cognitive profile and genetic interactions; (iv) and quantified subject fingerprints related to both pathology presence and genetic risk factors. The in-vivo excitation/inhibition ratio significantly related to cognitive deficits in Alzheimer’s patients, indicating that lower inhibition corresponds to poorer cognitive performance. A voxel-wise analysis demonstrated a positive association between neurometabolism in the posterior cingulate and temporal dynamics across default mode network regions, which can effectively differentiate between patients and controls. Furthermore, network fluctuations showed significant links to cognitive performance metrics, particularly among at-risk individuals. The study identified distinct functional fingerprints based on cortical temporal dynamics, emphasizing the interplay between genetic predisposition and the presence of Alzheimer’s disease. This investigation provides compelling evidence for the clinical importance of functional connectivity proxies related to excitation/inhibition, particularly within the default mode network. Neurodegeneration induces both a temporal and neurometabolic functional regression in higher-order cortical areas, resulting in a loss of specialized function. Consequently, the hierarchical continuum of cortical functions is disrupted, leading to a homogenization of brain activity. Excitation/inhibition proxies can expand our ability to recognize brain fingerprints of at-risk pre-symptomatic and pre-clinical subjects, opening pathways for potential disease-modifying treatments. Competing Interest Statement The authors have declared no competing interest. Funding Statement The IRCCS Fatebenefratelli is partially supported by the Italian Ministry of Health (Ricerca Corrente and grant GR-2018-12368250). 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 been approved by the Ethics Committee of the FBF-BS (approval date 15/05/2019; Number 41-2019) and by the Ethics Committee of the Spedali Civili Brescia (approval date 29/06/2022; NP5395) 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 Footnotes This revision is for the updated submission to Brain Communications Data Availability Data supporting the findings of this study are openly accessible. The analysis code is available on GitHub: https://github.com/ferrariasia06/PATHFIND. For raw material requests related to the Alzheimer's disease cohort (from BrainSync-AD), please contact roberto.gasparotti{at}unibs.it or barbara.borroni{at}unibs.it. Requests concerning raw materials from the cognitively unimpaired subjects cohort (from NEST4AD) should be directed to mpievani{at}fatebenefratelli.eu.