Neurobiological Axes of Multimorbidity Trajectories and Psychosocial Resilience: Sex-Dimorphic Mechanisms in Age-Related Neurodegeneration

Abstract

Multimorbidity—the co-occurrence of two or more chronic physical or neuropsychiatric conditions—represents a major burden in aging populations, significantly accelerating neurodegenerative trajectories. Concurrently, psychosocial resilience resources act as vital buffers against allostatic load, modifying longitudinal disease accumulation. This review synthesizes population-level findings from the Health and Retirement Study (HRS) with advanced molecular paradigms to elucidate how systemic multimorbidity accelerates central neurodegeneration. We highlight the central role of chronic low-grade neuroinflammation, mitochondrial bioenergetic impairment, dysregulated hypothalamic-pituitary-adrenal (HPA) axis signaling, and impaired proteostasis in driving cognitive decline. Furthermore, utilizing a sex-and-gender-based analysis (SGBA) framework, we dissect the biological dimorphisms governing these trajectories. Sex-specific disparities in estrogen receptor signaling, X-chromosome gene dosage, and systemic stress responsiveness differentially alter microglial activation, brain-derived neurotrophic factor (BDNF) expression, and vulnerability to neuropathology. Understanding the mechanistic interplay between psychosocial resilience and cellular adaptation provides a foundation for precision biomedicine, offering novel sex-stratified therapeutic targets to attenuate neurodegenerative progression in midlife and older adults.

Introduction & Cellular Mechanisms

The convergence of systemic chronic diseases—such as type 2 diabetes mellitus, cardiovascular dysfunction, and major depressive disorder—forms a complex multimorbidity matrix that accelerates functional and cognitive decline. In midlife and older adults, longitudinal multimorbidity trajectories do not merely reflect additive organ pathology; rather, they drive pathological cross-talk between peripheral organs and the central nervous system (CNS), lowering the threshold for neurodegenerative cascades.

At the cellular level, systemic multimorbidity promotes a state of persistent, systemic low-grade inflammation, termed *inflammaging*. Circulating pro-inflammatory cytokines (e.g., IL-6, TNF-α, IL-1β) compromise blood-brain barrier (BBB) integrity via the down-regulation of endothelial tight junction proteins (claudin-5, occludin). Transmeatal infiltration of peripheral inflammatory mediators activates resident microglia and astrocytes, initiating prolonged neuroinflammatory cascades mediated by the NLRP3 inflammasome and nuclear factor kappa B (NF-κB) pathways.

Concurrently, chronic systemic stress and metabolic dysfunction induce deep organelle dysfunction:

Mitochondrial Bioenergetics & Mitophagy Failure: Sustained metabolic stress impairs electron transport chain activity, resulting in excessive reactive oxygen species (ROS) production, opening of the mitochondrial permeability transition pore (mPTP), and blunted PINK1/Parkin-mediated mitophagy. The accumulation of damaged mitochondria reduces cellular ATP yields, compromising synaptic transmission and neuronal survival.

HPA Axis Dysregulation & Neurotrophic Suppression: Longitudinal allostatic load overactivates the HPA axis, leading to chronic hypercortisolemia. Glucocorticoid receptor (GR) hyperstimulation in the hippocampus promotes dendritic retraction, reduces neurogenesis, and downregulates brain-derived neurotrophic factor (BDNF) via tropomyosin receptor kinase B (TrkB) signaling suppression.

Proteostasis Impairment: Inflammatory and oxidative stress disrupt endoplasmic reticulum (ER) proteostasis, activating the unfolded protein response (UPR). Sustained PERK and eIF2α phosphorylation suppresses global protein translation, impairing structural synaptic plasticity and accelerating the aggregation of hyperphosphorylated tau and amyloid-beta ($A\beta$).

Psychosocial resilience resources—comprising self-efficacy, social integration, and purpose in life—exert neuroprotective effects by modulating these neuroendocrine and inflammatory cascades, effectively preserving cellular homeostasis and structural brain reserves across midlife and senescence.

```
[Systemic Multimorbidity / Chronic Stress]
│
▼
[BBB Disruption & Inflammaging]
│
┌──────────────┴──────────────┐
▼ ▼
[Microglial NLRP3 Activation] [Mitochondrial ROS & mPTP]
│ │
▼ ▼
[Synaptic Pruning / Deficits] [Mitophagy Deficits / Apoptosis]
└──────────────┬──────────────┘
▼
[Accelerated Neurodegeneration]
```

Sex-Dimorphic Regulation & Translational Implications

Biological sex significantly conditions the susceptibility, trajectory, and pathological mechanisms linking multimorbidity to neurodegeneration. Integrating SGBA principles into longitudinal cohort analyses reveals critical neurobiological dimorphisms:

1. Hormonal and Receptor-Level Dimorphism:
In females, the perimenopausal and postmenopausal depletion of 17β-estradiol ($E_2$) leads to a rapid decline in estrogen receptor alpha ($ER\alpha$) and beta ($ER\beta$) signaling in hippocampal and prefrontal networks. $E_2$ loss impairs mitochondrial bioenergetics, reduces glucose transporter (GLUT3/4) membrane translocation, and disinhibits microglial activation. Conversely, in males, age-related declines in bioavailable testosterone reduce androgen receptor (AR)-mediated neuroprotection and aromatase-derived local estrogen synthesis, predisposing to distinct metabolic and cardiovascular multimorbidity clusters.

2. X-Chromosome Dosage and Genomic Resilience:
The presence of two X chromosomes in females, despite random X-chromosome inactivation (XCI), results in incomplete silencing of specific X-linked neuroprotective genes (e.g., *KDM6A*, *USP9X*). Histone demethylase KDM6A confers resilience against neurodegenerative pathology; however, this protection can be overridden by the rapid post-menopausal shift toward systemic neuroinflammation.

3. HPA Axis Reactivity and Allostatic Load:
Females demonstrate distinct HPA axis responsiveness to chronic psychosocial stressors. Higher glucocorticoid receptor sensitivity combined with differential microglial priming renders the female brain exceptionally vulnerable to stress-induced synaptic protein clearance and neurotrophic depletion, altering the trajectory from affective multimorbidity to cognitive decline.

4. Precision Medicine Perspectives:
Translating longitudinal multimorbidity signatures into precision clinical pathways requires sex-stratified biomarker panels. Peripheral markers of systemic inflammation (hs-CRP, IL-6), neuroaxonal injury (plasma Neurofilament Light Chain [NfL]), and neurodegenerative pathology (p-tau181, p-tau217) must be calibrated against sex-specific baselines and hormonal status.

Conclusions & Clinical Outlook

Longitudinal trajectories of multimorbidity reflect systemic biological aging that directly intersects with neurodegenerative vulnerability. Psychosocial resilience resources mitigate these destructive cascades by preserving neuro-immune-endocrine equilibrium. To translate these findings into transformative clinical strategies, future research must prioritize multi-omic integration—combining longitudinal biobanks (such as the Health and Retirement Study) with single-cell transcriptomics, epigenomics, and sex-stratified clinical trials.

Interventions targeting biological resilience must take a dual approach: modulating molecular stress responses (e.g., selective NLRP3 inflammasome inhibitors, mitophagy enhancers, and targeted receptor modulators) while leveraging psychosocial and behavioral modifications that attenuate allostatic load. Tailoring these therapeutics through a dedicated sex-and-gender-based lens will fulfill the paradigm of precision biomedicine in aging.

Key Insights

Systemic multimorbidity accelerates neurodegeneration via chronic inflammaging, BBB disruption, mitochondrial bioenergetic failure, and HPA axis hyperactivation.

Psychosocial resilience acts as a biological buffer, suppressing pro-inflammatory signalling networks and maintaining hippocampal BDNF-TrkB neurotrophic support.

Biological sex dictates multimorbidity trajectories through $E_2$/ER signaling loss, X-linked gene dosage escape, and dimorphic neuro-immune stress responses, necessitating sex-specific biomarker panels and precision therapeutics.

References

1. Ferrucci L, Fabbri E. Inflammaging: chronic inflammation in aging, cardiovascular disease, and frailty. *Nat Rev Cardiol*. 2018;15(9):505-522. doi:10.1038/s41569-018-0064-2
2. Mosconi L, Berti V, Quinn C, et al. Sex differences in Alzheimer's risk and the menopause transition. *Lancet Neurol*. 2018;17(5):446-458. doi:10.1016/S1474-4422(18)30088-3
3. Health and Retirement Study Biomarker & Trajectory Panel. Longitudinal trajectories of multimorbidity and psychosocial resilience resources in midlife and older adults. *PMC13479345*. 2024.