---
title: "MALDI-TOF imaging reveals sex- and age-dependent shifts in brain lactate metabolism in an Alzheime"
id: "biorxiv-17-maldi-tof-imaging-mass-spectrometry-demonstrates-sex-and-age-dependent-spatial"
canonical_url: "https://medichelpline.com/clinical-feed/biorxiv-17-maldi-tof-imaging-mass-spectrometry-demonstrates-sex-and-age-dependent-spatial"
content_type: "clinical_feed_article"
specialty: "Neurology"
source_name: "bioRxiv (Biomedical Preprints)"
source_url: "https://www.biorxiv.org/content/10.64898/2026.09.14.750669v1?rss=1"
published_at: "2026-09-21T12:00:00.000Z"
evidence_level: "Verified Feed"
license: "CC-BY-NC-4.0 / Informational Use"
---
# MALDI-TOF imaging reveals sex- and age-dependent shifts in brain lactate metabolism in an Alzheime
## Provenance & Clinical Metadata
- **Canonical URL:** https://medichelpline.com/clinical-feed/biorxiv-17-maldi-tof-imaging-mass-spectrometry-demonstrates-sex-and-age-dependent-spatial
- **Specialty:** [Neurology](https://medichelpline.com/clinical-feed/neurology.md)
- **Primary Source:** bioRxiv (Biomedical Preprints)
- **Source URL:** [Original Journal Publication](https://www.biorxiv.org/content/10.64898/2026.09.14.750669v1?rss=1)
- **Published At:** 2026-09-21T12:00:00.000Z
- **Evidence Rating:** Verified Feed
## Executive GIST (TL;DR)
- The study used **MALDI-TOF imaging mass spectrometry** and immunofluorescence to spatially map brain metabolites and epigenetic marks in wild type and Alzheimer’s disease (AD) transgenic mice at 6 and 18 months of age. - Measured metabolites included **lactate**, glutamate, pyruvate, and citrate; histone lactylation was assessed as an epigenetic correlate of lactate signaling. - Young mice (6 months) exhibited higher lactate and glutamate, which declined with age; pyruvate increased with age, showing an inverse pattern to lactate. - These metabolic shifts were more pronounced in females; females maintained higher **lactate** and glutamate than males at both ages, indicating a persistent sex-specific metabolic phenotype. - Ratios (pyruvate-to-lactate and pyruvate-to-citrate) indicated a progressive, region-specific shift from glycolytic toward oxidative metabolism with aging and/or amyloid stress. - Elevated lactate in aged females paralleled increased **histone lactylation**, especially in cortex and the CA2/CA3 hippocampal subregion. - In AD transgenic females, histone lactylation was enriched in putative microglia located near amyloid plaques. - In wild type mice, lactate levels correlated positively with histone lactylation, consistent with a lactate-driven epigenetic mechanism; this correlation was weakened or absent in transgenic mice despite plaque-adjacent lactylation. - The dissociation in transgenic mice suggests amyloid pathology may decouple metabolic state from epigenetic regulation. - The authors conclude that **sex** is a major variable shaping brain metabolic–epigenetic coupling during aging and amyloid stress, and that sex-specific lactate metabolism and lactylation signaling may contribute to differential AD vulnerability.
## Clinical Analysis & Structured Key Points
MALDI-TOF imaging mass spectrometry demonstrates sex- and age-dependent spatial changes in brain energy metabolism in response to amyloid stress using a mouse model of Alzheimers Disease | bioRxiv Skip to main content New Results MALDI-TOF imaging mass spectrometry demonstrates sex- and age-dependent spatial changes in brain energy metabolism in response to amyloid stress using a mouse model of Alzheimers Disease Sandra Grahovac-Nemeth , Kristina Jurcic , Marc Courchesne , Karen Nygard , Grace Callahan , Ariel K Frame , Reza Khazaee , Wenxuan Wang , Moganatharsa Ganeshalingam , Raymond Thomas , Shawn N Whitehead , Robert C Cumming doi: https://doi.org/10.64898/2026.09.14.750669 Sandra Grahovac-Nemeth Western University Find this author on Google Scholar Find this author on PubMed Search for this author on this site Kristina Jurcic Western University Find this author on Google Scholar Find this author on PubMed Search for this author on this site Marc Courchesne Western University Find this author on Google Scholar Find this author on PubMed Search for this author on this site Karen Nygard Western University Find this author on Google Scholar Find this author on PubMed Search for this author on this site Grace Callahan Western University Find this author on Google Scholar Find this author on PubMed Search for this author on this site Ariel K Frame Western University Find this author on Google Scholar Find this author on PubMed Search for this author on this site Reza Khazaee Western University Find this author on Google Scholar Find this author on PubMed Search for this author on this site Wenxuan Wang Western University Find this author on Google Scholar Find this author on PubMed Search for this author on this site Moganatharsa Ganeshalingam Western University Find this author on Google Scholar Find this author on PubMed Search for this author on this site Raymond Thomas Western University Find this author on Google Scholar Find this author on PubMed Search for this author on this site Shawn N Whitehead Western University Find this author on Google Scholar Find this author on PubMed Search for this author on this site Robert C Cumming Western University Find this author on Google Scholar Find this author on PubMed Search for this author on this site For correspondence: rcummin5{at}uwo.ca Abstract Info/History Metrics Supplementary material Preview PDF Abstract Alzheimer's disease (AD) is the most common form of dementia, and no therapies currently exist that prevent or slow its progression. Lactate has recently emerged as both an energy substrate and a signaling molecule required for memory formation, acting in part through a novel epigenetic mechanism termed histone lactylation. Here, we used matrix-assisted laser desorption/ionization time-of-flight (MALDI-TOF) imaging mass spectrometry and immunofluorescence microscopy to spatially map lactate, glutamate, pyruvate, and citrate levels, alongside histone lactylation, in the brains of wild type and AD transgenic mice at 6 and 18 months of age. Lactate and glutamate were highest in young animals and declined with age, while pyruvate showed the inverse pattern. These shifts were most pronounced in females, and pyruvate-to-lactate and pyruvate-to-citrate ratios suggested a progressive, region-specific shift from glycolytic to oxidative metabolism. Sex was a dominant determinant of cerebral metabolite distribution: females maintained consistently higher lactate and glutamate than males at both ages, indicating a sex-specific metabolic phenotype that persists across physiological aging. Elevated lactate levels were paralleled by increased histone lactylation in aged females, particularly within the cortex and CA2/CA3 hippocampal subregion, and in transgenic females lactylation was enriched in putative microglia near amyloid plaques. Lactate and histone lactylation were positively correlated in wild type mice, consistent with a lactate-driven epigenetic mechanism possibly in microglia, but this relationship was weakened or absent in transgenic mice despite elevated plaque-adjacent lactylation, suggesting amyloid pathology decouples metabolic state from epigenetic regulation. These findings identify sex as a major, underappreciated variable shaping brain metabolic-epigenetic coupling during aging and amyloid stress. Together, these results implicate sex-specific lactate metabolism and lactylation signaling as potential contributors to differential AD vulnerability, and underscore the need to incorporate sex as a biological variable in future studies of metabolic-epigenetic mechanisms and therapeutic targeting in AD. Competing Interest Statement The authors have declared no competing interest. Funder Information Declared Natural Sciences and Engineering Research Council of Canada , RGPIN/06893-2019 Canadian Consortium on Neurodegeneration in Aging , 37794 (Phase I) and 163902 (Phase 2) Copyright The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY 4.0 International license . Back to top Previous Next Posted September 21, 2026. Download PDF Supplementary Material Email Thank you for your interest in spreading the word about bioRxiv. 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Share MALDI-TOF imaging mass spectrometry demonstrates sex- and age-dependent spatial changes in brain energy metabolism in response to amyloid stress using a mouse model of Alzheimers Disease Sandra Grahovac-Nemeth , Kristina Jurcic , Marc Courchesne , Karen Nygard , Grace Callahan , Ariel K Frame , Reza Khazaee , Wenxuan Wang , Moganatharsa Ganeshalingam , Raymond Thomas , Shawn N Whitehead , Robert C Cumming bioRxiv 2026.09.14.750669; doi: https://doi.org/10.64898/2026.09.14.750669 Share This Article: Copy Citation Tools MALDI-TOF imaging mass spectrometry demonstrates sex- and age-dependent spatial changes in brain energy metabolism in response to amyloid stress using a mouse model of Alzheimers Disease Sandra Grahovac-Nemeth , Kristina Jurcic , Marc Courchesne , Karen Nygard , Grace Callahan , Ariel K Frame , Reza Khazaee , Wenxuan Wang , Moganatharsa Ganeshalingam , Raymond Thomas , Shawn N Whitehead , Robert C Cumming bioRxiv 2026.09.14.750669; doi: https://doi.org/10.64898/2026.09.14.750669 Citation Manager Formats BibTeX Bookends EasyBib EndNote (tagged) EndNote 8 (xml) Medlars Mendeley Papers RefWorks Tagged Ref Manager RIS Zotero Tweet Widget Facebook Like Google Plus One Subject Areas All Articles Animal Behavior and Cognition (8015) Biochemistry (18744) Bioengineering (14890) Bioinformatics (44453) Biophysics (22610) Cancer Biology (19728) Cell Biology (26906) Clinical Trials (138) Developmental Biology (13970) Ecology (21008) Epidemiology (2067) Evolutionary Biology (25457) Genetics (16171) Genomics (23513) Immunology (18717) Microbiology (42520) Molecular Biology (18064) Neuroscience (93479) Paleontology (700) Pathology (2982) Pharmacology and Toxicology (5100) Physiology (8116) Plant Biology (16000) Scientific Communication and Education (2095) Synthetic Biology (4560) Systems Biology (10237) Zoology (2391)
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