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Lookup NU author(s): Dan Jobson, Dr Yoshiki Hase, Dr Lauren Walker, Dr Tuomo Polvikoski, Dr Ahmad Khundakar, Dr Louise Allan, Professor Raj KalariaORCiD
This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).
© 2026 The Author(s). Alzheimer's & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer's Association. INTRODUCTION: The medial prefrontal cortex (mPFC) is critical for executive function, behavioral inhibition, and memory. Its high vulnerability to dementia, compared to other prefrontal regions, remains unclear. METHODS: We analyzed post mortem brain tissue from 118 older subjects, including post-stroke survivors, Alzheimer's disease; vascular, mixed, and frontotemporal dementia (FTD); and cognitively unimpaired controls. Three-dimensional stereology was used to assess pyramidal neuron densities and volumes in mPFC layers III and V. Immunohistochemistry evaluated metabolic dysfunction via cytochrome c oxidase subunit 1 (COX1), cytochrome c oxidase subunit 4 (COX4), and 78 kDa glucose-regulated protein expression. RESULTS: Pyramidal neuron densities were lowered by ≈ 45% and volumes by ≈ 37% within all dementia groups relative to controls, except for FTD densities. COX1 and COX4 mitochondrial markers were consistently reduced across dementias. Neuronal densities declined with age, especially in the sixth decade of life. Other prefrontal areas were less affected. DISCUSSION: The mPFC shows high neuronal vulnerability in dementia, while suggesting a vascular–metabolic mechanism, with implications for targeted therapeutic strategies. Highlights: Severe pyramidal neuron loss and atrophy arose in the medial prefrontal cortex. Neuronal morphometric changes correlated with cognitive status or aging effects. Metabolic changes decreased by the greatest extent in vascular-associated dementias. Metabolic neuronal markers correlated with aging and frontal vascular pathology.
Author(s): Jobson DD, Hase Y, Walker L, Polvikoski T, Khundakar AA, Allan L, Kalaria RN
Publication type: Article
Publication status: Published
Journal: Alzheimer's and Dementia
Year: 2026
Volume: 22
Issue: 2
Online publication date: 12/02/2026
Acceptance date: 30/12/2025
Date deposited: 25/02/2026
ISSN (print): 1552-5260
ISSN (electronic): 1552-5279
Publisher: John Wiley and Sons Inc.
URL: https://doi.org/10.1002/alz.71151
DOI: 10.1002/alz.71151
Data Access Statement: The data are not publicly available due to privacy or ethical restrictions.
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