Search bioRxiv⌕ Search
Home/Archive/bioRxiv

bioRxiv · 10.64898/2026.11.02.763368

Interpretable Machine Learning Links Group-Specific Plasma Proteomics to Regional Structural Neuroimaging in Alzheimer's Disease

Laugi, H.·Hosseinzadehketilateh, M.·Lee, S.·Weisberg, S. M.·Zhu, X.
View original source ↗Export metadata ↓

Abstract

Background: Alzheimer's disease (AD) pathology begins years before clinical symptoms, highlighting the need for scalable biomarkers that capture biological changes across the AD continuum. Broader plasma proteomics may capture systemic processes that vary with disease stage, yet their relationship to AD-related brain neurodegeneration remains unclear. We aimed to identify plasma proteomic signatures across cognitively normal (CN), mild cognitive impairment (MCI), and AD and evaluate their neuroanatomical associations. Methods: We analyzed 146 plasma analytes from 565 Alzheimer's Disease Neuroimaging Initiative (ADNI) participants (58 CN, 396 MCI, 111 AD). Group-specific proteomic signatures were identified using pairwise classification models with nested 5*5 cross-validation. SHAP quantified feature importance, with the top 15 proteins per comparison being prioritized for MRI association analysis. We analyzed 103 regional structural MRI volumes harmonized across 57 acquisition sites using ComBat. Separate ordinary least squares regression tested protein-MRI associations, adjusting for age, sex, APOE4, diagnosis, and intracranial volume, followed by Benjamini-Hochberg false discovery rate (FDR) correction. Results: Classification models using proteomic data achieved AUC of 0.956 +- 0.017 for CN vs MCI, 0.963 +- 0.011 for MCI vs. AD, and 0.836 +- 0.085 for CN vs. AD. SHAP identified group-dependent proteomic signatures. No protein-MRI associations survived FDR correction for CN vs. MCI. In MCI vs. AD, higher cortisol was associated with lower left precuneus and superior parietal volumes, while higher osteopontin was associated with lower left paracentral and accumbens volumes. In CN vs. AD, higher vitronectin was associated with lower posterior corpus callosum volume. Conclusion: These findings suggest that plasma proteomics capture group-specific systemic biological signals across the AD continuum. Linking ML-prioritized plasma proteins to regional brain structure provides neuroanatomical context for blood-based biomarker discovery.

Explore related subjects

neurosciencePreprint

Keep this discovery

Explore connections, maps & timelines

BibTeXRIS

Laugi, H., Hosseinzadehketilateh, M., Lee, S., Weisberg, S. M., Zhu, X.. 2026-11-04. Interpretable Machine Learning Links Group-Specific Plasma Proteomics to Regional Structural Neuroimaging in Alzheimer's Disease. https://doi.org/10.64898/2026.11.02.763368

Cite the original work for its findings. Save a collection to share your selection of sources.

KEEP EXPLORING

Related preprints

bioRxiv2026

40 Hz visual stimulation increases gamma-band functional connectivity between visual, parietal and frontal regions

Visual stimulation at 40 Hz is being investigated as a non-invasive intervention for Alzheimer's disease. Its neural responses have been reported in regions beyond the visual cortex, and concurrent cognitive tasks have been shown to increase their spatial extent. However, it is unclear whether these responses reflect increased functional connectivity between regions or a common response to the stimulus, and whether a concurrent task changes this connectivity. We recorded EEG from 29 healthy young adults during Regular 40 Hz flicker and Irregular 30-50 Hz flicker, each with and without a target-counting task (2 x 2 within-participant design). Source-space connectivity between visual, parietal, and frontal regions was estimated with the debiased squared weighted phase-lag index (dWPLI). Regular stimulation increased 38-42 Hz connectivity for all three region pairs, with the largest increase between visual and parietal regions (increase in all 29 participants). The increase was specific to the stimulation frequency and was observed with two source reconstruction methods and in sensor space. The visual-parietal increase remained significant after correction for source leakage (spatial mixing between reconstructed sources) and after removal of the estimated stimulus-locked component, whereas the increases in visual-frontal and parietal-frontal connectivity did not. The concurrent task did not modulate the visual-parietal effect. For visual-frontal and parietal-frontal connectivity, the stimulation-by-ask interaction was not significant. These results show that 40 Hz visual stimulation increases gamma-band connectivity beyond the visual cortex, and much of this increase reflects a common stimulus-locked response, and connectivity beyond this response was observed mainly between visual and parietal regions.

neuroscience↗
bioRxiv2026

Feedback Valence, Prediction Error, and the Limits of Computational Attribution in Symptom-Related EEG

Feedback-locked electroencephalography (EEG) responses are often interpreted using model-derived prediction errors (PEs), although signed PE can be strongly coupled to feedback valence in binary-outcome tasks. We revisited a published anxiety-related EEG association using two open probabilistic-learning datasets to examine measurement reliability, predictor separability, and participant-level recovery. In the primary dataset, greater trait anxiety was associated with a larger negative-minus-positive FCz theta response among 46 participants with elevated depressive symptoms after adjustment for depression severity. The association also differed between the sampled depression-symptom groups. The feedback contrast showed useful within-session reliability, but matched delta and P3-minus-N2 analyses did not establish theta specificity. Within participants, feedback valence and signed PE were highly correlated (r = -0.964). Exact-design simulations showed that population-level model discrimination could succeed despite poor recovery of individual neural slopes. Participant-specific learning-model refits recovered overall signed PE more consistently than the within-valence variation needed to distinguish it from feedback valence. An independent dataset reproduced the FCz feedback contrast in untreated and placebo cohorts but lacked trait-anxiety scores. Adding signed PE to valence yielded a small held-out predictive improvement under one reinforcement-learning specification, with limited support across sessions and no comparable support under the dual-rate model or in placebo. Together, these findings support a symptom-related feedback EEG association while constraining its theta-specific and participant-level computational interpretation.

neuroscience↗
bioRxiv2026

An open-access neuroimaging-compatible virtual town task for assessing human spatial navigation

Spatial navigation is a cognitive skill that draws on multiple processes such as learning, decision-making and memory, which are often updated on a second-by-second timescale. However, many existing virtual paradigms designed to assay spatial navigation cannot target these processes as they unfold or are not designed for integration with concurrent neurophysiological recording. Here, we present and demonstrate our open-access task for neuroimaging: NAturalistic Virtual Assessment of Navigation (NAVAN) combining high-resolution behavioural tracking and integration with electroencephalography. We report data from this task, in which fifty-three participants completed a wayfinding navigation paradigm across twenty-four trials. Navigational efficiency improved significantly following repeated exposure to the environment, although efficiency declined across trials within each block. Self-reported spatial ability (assessed by the Santa Barbara Sense of Direction) predicted performance during early environmental exposure, suggesting concurrent validity. We demonstrated the feasibility of recording electroencephalography during the task, with in-game events streamed and aligned to the neural recording. The task provides researchers with access to detailed behavioural measures and can be adapted by modifying features such as trial number and difficulty. We also provide a step-by-step implementation guide to support reuse and customisation across experimental settings.

neuroscience↗