Unveiling paths to Alzheimer’s disease: excitation-inhibition ratio shapes hierarchical dynamics
Bibliographic record
Abstract
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.
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.001 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.000 |
| Insufficient payload (model declined to judge) | 0.001 | 0.000 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".