bioRxiv Science⌕ Search
Home/Archive/bioRxiv

bioRxiv · 10.1101/2025.04.29.651293

Frontal Vulnerability vs. Temporal Resilience: Neuro-compensatory mechanisms underline differential language aging trajectories

Jain, P.·Akhter, A.·Banerjee, A.
View original source ↗Export metadata ↓

Abstract

Age-related decline underlies cognitive functions such as sensorimotor control, executive functioning, memory, and language production (LP), whereas language comprehension (LC) tends to remain intact or improve across healthy adult lifespan. This preservation likely stems from structural and functional integrity within core language network (cLAN) regions. To investigate this hypothesis, we analyzed the relationships among brains resting-state functional connectivity (FC), structural connectivity (SC), and language behaviour (LC and LP) using a cross-sectional cohort of healthy adults (N = 652; M/F = 322/330; aged 18-88) from the Cambridge Centre for Ageing and Neuroscience (Cam-CAN) dataset. Six cognitive tasks assessing LC and LP were employed, with neuroimaging measures focused on region-specific connections within the cLAN. Using generalized additive mixed models (GAMMs), complex brain-behaviour interactions were identified. Behavioral analyses revealed established age-related dichotomy, LC abilities in vocabulary and proverb comprehension improved and in syntactic and semantic comprehension remained stable, whereas LP tasks, e.g., verbal fluency, picture priming, and tip of tongue exhibited significant decline across the lifespan. SC exhibited decline in both intra-and inter-hemispheric fronto-temporal and frontal lobe connections, contrasted by preserved or enhanced temporal lobe connectivity, supporting a pattern of frontal vulnerability concomitant with temporal resilience. Age-related FC patterns demonstrated overall preservation, reflecting compensatory mechanisms to sustain functional integrity despite structural degradation. GAMM analyses revealed complex relationships between brain connectivity and language performance across age. Thus, integrating knowledge of brain structure, function, and language abilities, we identified the brain network mechanisms associated with dichotomous language behavior along lifespan. SignificanceUnderstanding age-related changes in language abilities is vital for early detection of cognitive decline and intervention development. This study reveals heterogeneous language aging trajectories: language production often declines, while comprehension remains stable or improves. Notably, comprehension tasks with high executive and working memory demands also show resilience, suggesting compensatory mechanisms beyond crystallized knowledge. Using multimodal neuroimaging in a large adult lifespan cohort, we link behavioral patterns to distinct network dynamics within the core language system. We uncover relative vulnerability in frontal brain regions, with pronounced structural decline in fronto-temporal pathways, contrasted by resilience in temporal connectivity, which is preserved or strengthened. These findings highlight regionally specific vulnerabilities and compensatory functional adaptations, refining current models and providing a framework to guide research promoting healthy cognitive aging.

Source connections

Explore related subjects

neurosciencePreprint

Keep this discovery

Explore connections, maps & timelines

BibTeXRIS

Jain, P., Akhter, A., Banerjee, A.. 2025-05-02. Frontal Vulnerability vs. Temporal Resilience: Neuro-compensatory mechanisms underline differential language aging trajectories. https://doi.org/10.1101/2025.04.29.651293

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

KEEP EXPLORING

Related preprints

bioRxiv2026

The Unreasonable Effectiveness of Cell Types in Describing Neuronal Physiological Features

Single-cell RNA sequencing (scRNA-seq) captures detailed gene expression profiles at scale, while patch-clamp recordings measure intrinsic neuronal electrophysiological properties. Modeling the relations between these two modalities remains a challenge. Here, we compare how well electrophysiological features can be predicted by traditional transcriptomic cell type classification, representations derived from a foundational model (scGPT) pretrained on large-scale scRNA-seq datasets, ion channel-coding genes, and highly variable genes. Using paired transcriptomic and electrophysiological patch-sequencing data from 495 human neurons from neurosurgical tissue, we find that cluster-level cell type representations consistently outperform highly variable gene selection, ion channel gene selection, and context-enriched scGPT embeddings. Notably, performance varies across model architectures and initializations, and the best results are obtained by combining the outputs of separate cell type and scGPT-based models. Together, these findings suggest that traditional discrete cellular classification is highly effective in predicting physiological features. For maximum performance it can be complemented by pretrained transformer models.

neuroscience↗
bioRxiv2026

A nonlinear inhibition pathway underlying cortical responses to tuned holographic optogenetic perturbations

Optogenetics enables causal manipulation of cortical activity. Perturbation responses can be counterintuitive due to network interactions, making theory essential for predicting them. Existing approaches often rely on linear approximations, which fail for many biologically relevant perturbations. Here we develop a nonlinear theory of responses to holographic perturbations in cell-type-specific recurrent networks with structured connectivity. We fit a nonlinear model to mouse V1 data, which shows cotuned-ensemble suppression: perturbing spatially clustered neurons with similar preferred orientations yields markedly stronger short-range suppression than perturbing untuned ensembles. We show that cotuned-ensemble suppression arises from a feature-tuned, nonlinear inhibition pathway implicating somatostatin-positive (SST) interneurons. The theory predicts that cotuned ensembles suppress parvalbumin-positive (PV) neurons but facilitate SST neurons, and links the degree of cotuned-ensemble suppression or facilitation to the variance of the SST response. This framework identifies mechanisms by which nonlinear inhibition sculpts cortical dynamics and establishes a predictive basis for targeted optogenetic interventions.

neuroscience↗
bioRxiv2026

Proteomic signatures of APOE ε4 across human tissues and cell types in Alzheimers disease

The apolipoprotein E {varepsilon}4 (APOE {varepsilon}4) allele is the strongest genetic risk factor for late-onset Alzheimers disease (AD). However, the underlying molecular mechanisms remain unclear. This study included 1691 participants from the Religious Orders Study and Rush Memory and Aging Project (ROSMAP), 1226 participants from the Accelerating Medicines Partnership - Alzheimers Disease (AMP-AD) Diverse Cohorts Study, and 735 participants from the Alzheimers Disease Neuroimaging Initiative (ADNI). To characterise APOE {varepsilon}4 molecular effects, we analysed proteomic data from plasma, cerebrospinal fluid (CSF), and induced pluripotent stem cell (iPSC)-derived astrocytes and neurons, as well as transcriptomic and proteomic data from multiple brain regions. The association of APOE {varepsilon}4 with AD neuropathology was also examined. APOE {varepsilon}4 carriers shared a plasma proteomic signature enriched for immune processes, irrespective of AD diagnosis. A machine learning classifier trained on this signature discriminated APOE {varepsilon}4 carriers from non-carriers in an independent cohort using CSF proteomics. APOE {varepsilon}4 carriage was associated with higher Braak stages and Consortium to Establish a Registry for Alzheimers Disease (CERAD) score. However, only limited APOE {varepsilon}4-associated transcriptomic and proteomic changes were observed in bulk brain tissue, with poor cross-layer concordance. Proteomic analyses of iPSC-derived astrocytes and neurons further revealed cell-type-specific APOE {varepsilon}4-associated changes. APOE {varepsilon}4 is associated with a consistent proteomic signature across plasma and CSF. Its molecular effects in the brain differ across cell types, brain regions and molecular layers. These findings support the need for cell-type-resolved multi-omic studies to elucidate how APOE {varepsilon}4 confers AD risk.

neuroscience↗