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Hypometabolism, Alzheimer’s Disease, and Possible Therapeutic Targets: An Overview

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Raut, Snehal, Bhalerao, Aditya, Powers, Michael, Gonzalez, Minelly, Mancuso, Salvatore, Cucullo, Luca·2023·Cells
DOI 10.3390/cells12162019PMC PMC10453773
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Abstract

The brain is a highly dynamic organ that requires a constant energy source to function normally. This energy is mostly supplied by glucose, a simple sugar that serves as the brain’s principal fuel source. Glucose transport across the blood–brain barrier (BBB) is primarily controlled via sodium-independent facilitated glucose transport, such as by glucose transporter 1 (GLUT1) and 3 (GLUT3). However, other glucose transporters, including GLUT4 and the sodium-dependent transporters SGLT1 and SGLT6, have been reported in vitro and in vivo. When the BBB endothelial layer is crossed, neurons and astrocytes can absorb the glucose using their GLUT1 and GLUT3 transporters. Glucose then enters the glycolytic pathway and is metabolized into adenosine triphosphate (ATP), which supplies the energy to support cellular functions. The transport and metabolism of glucose in the brain are impacted by several medical conditions, which can cause neurological and neuropsychiatric symptoms. Alzheimer’s disease (AD), Parkinson’s disease (PD), epilepsy, traumatic brain injury (TBI), schizophrenia, etc., are a few of the most prevalent disorders, characterized by a decline in brain metabolism or hypometabolism early in the course of the disease. Indeed, AD is considered a metabolic disorder related to decreased brain glucose metabolism, involving brain insulin resistance and age-dependent mitochondrial dysfunction. Although the conventional view is that reduced cerebral metabolism is an effect of neuronal loss and consequent brain atrophy, a growing body of evidence points to the opposite, where hypometabolism is prodromal or at least precedes the onset of brain atrophy and the manifestation of clinical symptoms. The underlying processes responsible for these glucose transport and metabolic abnormalities are complicated and remain poorly understood. This review article provides a comprehensive overview of the current understanding of hypometabolism in AD and potential therapeutic targets.

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  • Cerebral hypometabolism, particularly reduced glucose metabolism, is a consistent and defining feature of AD.

    “Cerebral hypometabolism or a reduction in the metabolic activity of brain cells, particularly glucose metabolism, is a consistent and defining feature of AD [66].”

    From Toward a Unified Framework in Molecular Neurobiology of Alzheimer’s Disease: Revisiting the Pathophysiological Hypotheses (2026) · cites this paper as [66]

    Section 2, “Hypometabolism in AD” (page not provided), calls brain hypometabolism a major feature of AD and describes repeated findings of impaired glucose uptake. But Section 6, “Discussion and Conclusions” (page not provided), says hypometabolism is not specific to AD or a primary diagnostic criterion, so “defining” overstates the source if it implies a distinguishing feature. (LLM, conf=0.84)

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  • Regional metabolic deficits closely mirror mitochondrial bioenergetic decline, suggesting cerebral hypometabolism represents an in vivo biomarker of mitochondrial dysfunction rather than an isolated process.

    “These regional metabolic deficits closely mirror mitochondrial bioenergetic decline, suggesting that cerebral hypometabolism represents an in vivo biomarker of mitochondrial dysfunction rather than an isolated process [66, 68].”

    From Toward a Unified Framework in Molecular Neurobiology of Alzheimer’s Disease: Revisiting the Pathophysiological Hypotheses (2026) · cites this paper as [66]

    Section 2, “Hypometabolism in AD” (page unavailable), describes regional glucose-metabolism deficits; Section 4, “The Potential Therapeutic Targets for Hypometabolism in AD” (page unavailable), associates hypometabolism with mitochondrial impairment. The review does not establish that the regional deficits closely mirror mitochondrial bioenergetic decline or identify cerebral hypometabolism as an in vivo biomarker of mitochondrial dysfunction. (LLM, conf=0.86)

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Cited by

Sorted by citations

Authors
Raut, S., Bhalerao, A., Powers, M., Gonzalez, M., Mancuso, S., & Cucullo, L.
Affiliations
Oakland University (US)
Corresponding author
Cucullo, Luca
ORCID
Venue
Cells
Publisher
MDPI AG
Published
2023-08-08
Volume
12
Issue
16
Pages
2019
ISSN
2073-4409 (ISSN-L)
DOI
10.3390/cells12162019
PMC
PMC10453773
OpenAlex
W4385665874
Cited by
65
References
24
Citations by year
2026: 24 · 2025: 27 · 2024: 14
FWCI
2.18
Type
journal article
Language
en
Open access
Licence
Locations
  • Cells (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders
  • National Institutes of Health/National Institute (2R01DA029121-01A1, 1R01DA049737-01, 1R01NS117906-01)
  • National Institute of Neurological Disorders and Stroke (2R01DA029121-01A1, 1R01DA049737-01, 1R01NS117906-01)
Topics
  • Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
  • Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
  • Life Sciences › Neuroscience › Neurology › Barrier Structure and Function Studies
Keywords
hypometabolism, Alzheimer's disease, brain glucose metabolism, glucose transporters, GLUT1, GLUT3, blood-brain barrier, brain insulin resistance, mitochondrial dysfunction, brain atrophy, therapeutic target, neurodegenerative diseases
MeSH terms
Alzheimer Disease, Blood-Brain Barrier, Brain, Humans, Glucose Transporter Type 1, Glucose Transporter Type 3

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