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Its high vulnerability to dementia, compared to other prefrontal regions, remains unclear.<\/jats:p>\n <\/jats:sec>\n \n METHODS<\/jats:title>\n \n We analyzed\n post mortem<\/jats:italic>\n brain tissue from 118 older subjects, including post\u2010stroke survivors, Alzheimer's disease; vascular, mixed, and frontotemporal dementia (FTD); and cognitively unimpaired controls. Three\u2010dimensional stereology was used to assess pyramidal neuron densities and volumes in mPFC layers III and V. Immunohistochemistry evaluated metabolic dysfunction via cytochrome\n c<\/jats:italic>\n oxidase subunit 1 (COX1), cytochrome\n c<\/jats:italic>\n oxidase subunit 4 (COX4), and 78\u00a0kDa glucose\u2010regulated protein expression.\n <\/jats:p>\n <\/jats:sec>\n \n RESULTS<\/jats:title>\n Pyramidal neuron densities were lowered by \u2248 45% and volumes by \u2248 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.<\/jats:p>\n <\/jats:sec>\n \n DISCUSSION<\/jats:title>\n The mPFC shows high neuronal vulnerability in dementia, while suggesting a vascular\u2013metabolic mechanism, with implications for targeted therapeutic strategies.<\/jats:p>\n <\/jats:sec>\n \n Highlights<\/jats:title>\n \n \n \n Severe pyramidal neuron loss and atrophy arose in the medial prefrontal cortex.<\/jats:p>\n <\/jats:list-item>\n \n Neuronal morphometric changes correlated with cognitive status or aging effects.<\/jats:p>\n <\/jats:list-item>\n \n Metabolic changes decreased by the greatest extent in vascular\u2010associated dementias.<\/jats:p>\n <\/jats:list-item>\n \n Metabolic neuronal markers correlated with aging and frontal vascular pathology.<\/jats:p>\n <\/jats:list-item>\n <\/jats:list>\n <\/jats:p>\n 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