Researchers find Alzheimer’s pathology damages neurovascular structures in adipose tissue, linking brain disease to metabolic health

Houston Methodist researchers have uncovered a previously unknown mechanism linking Alzheimer’s disease to cardiovascular and metabolic complications. Using advanced three-dimensional imaging in mouse models, the team demonstrated that the neurodegenerative condition systematically dismantles the organised neurovascular structures within adipose tissue, potentially explaining why patients frequently develop concurrent heart disease, stroke and diabetes alongside cognitive decline.

Brain disease extends reach beyond neural tissue
Alzheimer’s disease has long been recognised primarily as a disorder of the brain, charac­terised by amyloid plaques, neurofibrillary tangles and progressive cognitive deteriora­tion. However, research published in the Journal of Lipid Research on 25 October 2025 reveals that the disease’s pathological influ­ence extends far beyond the central nervous system, disrupting critical communication networks between the autonomic nervous system and peripheral adipose tissue.

The study, led by Stephen Wong, Ph.D., the John S. Dunn Presidential Distin­guished Chair in Biomedical Engineering at Houston Methodist, employed sophisti­cated whole-mount immunostaining and three-dimensional confocal microscopy to visualise the structural organisation of neurovascular bundles within subcutane­ous white adipose tissue. Key contributors included Li Yang, Ph.D., a research asso­ciate, and Jianting Sheng, Ph.D., an as­sistant research professor of computational biology and mathematics in radiology.

“By disrupting the connection between the nervous system and fat tissue, the dis­ease may impair the body’s ability to man­age energy,” explained Li Yang, highlight­ing the metabolic implications of these structural changes.

Neurovascular architecture in adipose tissue
In healthy adipose tissue, sympathetic nerve fibres run in close parallel alignment with blood vessels, forming organised neuro­vascular bundles that serve as conduits for both hormonal signalling and neural con­trol. These structures are fundamental to the brain-fat communication axis, enabling the central nervous system to regulate lipid metabolism, energy expenditure and thermo-genesis through sympathetic innervation.

The researchers utilised anti-endomucin antibodies to label blood vessels and anti-tyrosine hydroxylase antibodies to iden­tify sympathetic nerve fibres. In wild-type control mice at 25 weeks of age, confocal imaging revealed tightly coordinated neu­rovascular bundles throughout the subcu­taneous adipose depots, with sympathetic nerves maintaining intimate spatial prox­imity to the vascular network.

Progressive structural deterioration in Alzheimer’s model
The investigation employed 5XFAD mice, a well-established transgenic model of Al­zheimer’s disease that develops aggressive amyloid pathology and cognitive defi­cits. Comparative analysis between age-matched 5XFAD and wild-type animals revealed striking differences in adipose tis­sue neurovascular organisation.

The research team documented four progressive stages of structural deteriora­tion in the Alzheimer’s disease model. Initially, neurovascular bundle decoupling occurred, with sympathetic nerve fibres beginning to separate from their associated blood vessels whilst maintaining some de­gree of parallel orientation. This progressed to complete loss of spatial proximity and co-localisation, where nerves and vessels became spatially disorganised within the adipose tissue architecture. Ultimately, the most severely affected regions displayed near-complete abrogation of sympathetic nerve signals, suggesting extensive dener­vation of the adipose depot.

High-resolution three-dimensional re­constructions provided unprecedented vi-sualisation of these structural changes, of­fering the first comprehensive view of how Alzheimer’s disease pathology manifests in peripheral metabolic tissues.

Autonomic dysfunction extends metabolic consequences
The disruption of neurovascular bundles in adipose tissue carries significant implications for whole-body metabolic regulation. Sympa­thetic innervation of fat depots plays a crucial role in lipolysis, adipokine secretion and ther­mogenic activation of brown and beige adipo­cytes. Loss of these neural connections would be expected to impair the body’s capacity to mobilise stored energy, respond to metabolic stress and maintain glucose homeostasis.

“Alzheimer’s disease induces autonomic nervous system dysfunction (dysautonomia), which exacerbates cardiovascular and meta­bolic comorbidities, yet the role of dysauto­nomia in metabolic dysregulation remains underexplored,” the authors note in their published work, emphasising the novelty of investigating peripheral autonomic manifes­tations of this neurodegenerative condition.

The autonomic nervous system compris­es both sympathetic and parasympathetic divisions that operate largely outside con­scious control, regulating cardiovascular function, gastrointestinal motility, ther­moregulation and metabolic processes. Dysautonomia in Alzheimer’s disease has been documented through various clini­cal manifestations, including orthostatic hypotension, heart rate variability abnor­malities and impaired cardiovascular re­flexes. However, the cellular and structural basis for these autonomic disturbances has remained poorly characterised.

Clinical implications for comorbidity patterns
Epidemiological studies have consistently demonstrated that Alzheimer’s disease pa­tients experience elevated rates of cardio­vascular events, metabolic syndrome and type 2 diabetes compared with age-matched cognitively normal individuals. These asso­ciations have typically been attributed to shared risk factors, including hypertension, dyslipidaemia and insulin resistance, or to the challenges of disease management in cognitively impaired populations.

The Houston Methodist findings suggest an alternative mechanistic explanation: that Alzheimer’s pathology directly compromises the neural circuits governing metabolic ho­meostasis. This disturbance could help ex­plain why individuals with Alzheimer’s often experience issues such as stroke, heart disease, diabetes, high blood pressure and other health complications alongside cognitive decline.

The progressive nature of neurovascular bundle disruption observed in the 5XFAD model parallels the clinical trajectory of Alzheimer’s disease, raising the possibility that metabolic dysfunction may intensify as neurodegeneration advances. This tem­poral relationship warrants investigation in longitudinal clinical studies that track both cognitive and metabolic parameters throughout disease progression.

Therapeutic implications and research directions
“These insights open new avenues for re­search into how treating or preventing au­tonomic dysfunction might improve overall health outcomes for people with Alzheim­er’s,” stated Wong and Sheng, pointing to­wards potential interventional strategies.

Several therapeutic approaches targeting autonomic function merit consideration based on these findings. Pharmacological enhancement of sympathetic signalling through beta-adrenergic agonists could potentially compensate for denervation­induced metabolic impairment. However, systemic sympathetic activation carries car­diovascular risks that would require careful risk-benefit assessment in elderly popula­tions with pre-existing cardiac disease.

Alternative strategies might focus on pre­serving or restoring neurovascular architec­ture before extensive degeneration occurs. Neurotrophic factors, anti-inflammatory agents or vascular protective compounds could theoretically maintain the structural integrity of adipose tissue innervation. Such interventions would likely require initiation during prodromal disease stages to prevent ir­reversible neural loss.

The findings also suggest that metabolic biomarkers related to adipose tissue func­tion, such as adipokine profiles or measures of lipolytic capacity, might serve as periph­eral indicators of autonomic dysfunction in Alzheimer’s disease. Such markers could potentially aid in early detection or moni­toring of disease progression through mini­mally invasive sampling.

Methodological advances enable discovery
The study’s success depended critically on technical innovations in tissue preparation and imaging. Whole-mount immunostaining of adipose tissue presents substantial chal­lenges due to the tissue’s high lipid content and three-dimensional complexity. The re­search team adapted previously published protocols to achieve adequate antibody pene­tration and optical clearing whilst preserving structural relationships between cellular and extracellular components.

High-resolution confocal microscopy with 20X objectives enabled capture of neurovascular architecture across millime­tre-scale tissue volumes with micron-level resolution. The resulting three-dimension­al datasets permitted quantitative analysis of nerve-vessel spatial relationships and structural integrity that would be impos­sible to assess through conventional two-dimensional histological sections.

These methodological advances open op­portunities for broader investigation of adi­pose tissue innervation in various metabolic and neurological disorders, potentially re­vealing common or distinct patterns of neu­rovascular disruption across disease states.

Future research priorities
The Houston Methodist study establishes a foundation for multiple lines of investigation. Mechanistic studies are needed to determine whether adipose tissue denervation results from direct Alzheimer’s pathology affecting peripheral sympathetic neurons, from loss of central autonomic regulation due to brain neurodegeneration, or from systemic factors such as inflammation or vascular dysfunction.

Translation to human subjects represents another critical priority. Post-mortem ex­amination of adipose tissue from Alzheimer’s patients could confirm whether similar neuro­vascular disruption occurs in human disease. Advanced imaging techniques, including positron emission tomography with tracers for sympathetic innervation, might enable assess­ment of adipose denervation in living patients.

Reference:
Kwong, M., Sheng, J., Yang, L., & Wong, S. T. C. (2025). Alzheimer’s disease disrupts intra-adipose neurovascular contact. Jour­nal of Lipid Research, 66(10), 100886. https://doi.org/10.1016/j.jlr.2025.100886