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Cited by 41Alzheimer's disease research and treatmentsMitochondrial Function and PathologyDementia and Cognitive Impairment Research

From Plaques to Pathways in Alzheimer’s Disease: The Mitochondrial-Neurovascular-Metabolic Hypothesis

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Kazemeini, Sarah, Nadeem-Tariq, Ahmed, Shih, Ryan, Rafanan, John, Ghani, Nabih, Vida, Thomas A.·2024·International Journal of Molecular Sciences
DOI 10.3390/ijms252111720PMC PMC11546801
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Abstract

Alzheimer’s disease (AD) presents a public health challenge due to its progressive neurodegeneration, cognitive decline, and memory loss. The amyloid cascade hypothesis, which postulates that the accumulation of amyloid-beta (Aβ) peptides initiates a cascade leading to AD, has dominated research and therapeutic strategies. The failure of recent Aβ-targeted therapies to yield conclusive benefits necessitates further exploration of AD pathology. This review proposes the Mitochondrial–Neurovascular–Metabolic (MNM) hypothesis, which integrates mitochondrial dysfunction, impaired neurovascular regulation, and systemic metabolic disturbances as interrelated contributors to AD pathogenesis. Mitochondrial dysfunction, a hallmark of AD, leads to oxidative stress and bioenergetic failure. Concurrently, the breakdown of the blood–brain barrier (BBB) and impaired cerebral blood flow, which characterize neurovascular dysregulation, accelerate neurodegeneration. Metabolic disturbances such as glucose hypometabolism and insulin resistance further impair neuronal function and survival. This hypothesis highlights the interconnectedness of these pathways and suggests that therapeutic strategies targeting mitochondrial health, neurovascular integrity, and metabolic regulation may offer more effective interventions. The MNM hypothesis addresses these multifaceted aspects of AD, providing a comprehensive framework for understanding disease progression and developing novel therapeutic approaches. This approach paves the way for developing innovative therapeutic strategies that could significantly improve outcomes for millions affected worldwide.

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  • The ensuing glutamate release activates ionotropic receptors and voltage-gated Ca2+ channels, resulting in excessive intracellular Ca2+ influx.

    “The ensuing glutamate release activates ionotropic receptors and voltage-gated Ca2⁺ channels, resulting in excessive intracellular Ca2+ influx.”

    From Toward a Unified Framework in Molecular Neurobiology of Alzheimer’s Disease: Revisiting the Pathophysiological Hypotheses (2026) · cites this paper as [64]

    Section 7.5 says glutamate activates NMDARs, describes their overactivation in Alzheimer’s disease, and links that overactivation to increased intracellular Ca2+. It does not say that glutamate release activates voltage-gated Ca2+ channels, so that part of the claimed pathway is unsupported. (LLM, conf=0.86)

    Experimental — accuracy not yet measured

  • Elevated cytosolic Ca2+ activates phospholipases, proteases, and endonucleases, which degrade membranes, proteins, and nucleic acids, ultimately compromising neuronal integrity.

    “Elevated cytosolic Ca2⁺ activates phospholipases, proteases, and endonucleases, which degrade membranes, proteins, and nucleic acids, ultimately compromising neuronal integrity.”

    From Toward a Unified Framework in Molecular Neurobiology of Alzheimer’s Disease: Revisiting the Pathophysiological Hypotheses (2026) · cites this paper as [64]

    Section 7.5, “NMDAR Antagonists and Calcium Dysregulation” (page unavailable), links increased intracellular Ca2+ to cell death and mitochondrial dysfunction. It does not describe activation of phospholipases, proteases, or endonucleases, or their degradation of membranes, proteins, and nucleic acids; that specific mechanism is unsupported by our copy. (LLM, conf=0.86)

    Experimental — accuracy not yet measured

  • Impaired OXPHOS and ATP depletion compromise Na+/K+-ATPase function, leading to membrane depolarization and reversal of glutamate transporters.

    “Impaired OXPHOS and ATP depletion compromise Na⁺/K⁺-ATPase function, leading to membrane depolarization and reversal of glutamate transporters [64].”

    From Toward a Unified Framework in Molecular Neurobiology of Alzheimer’s Disease: Revisiting the Pathophysiological Hypotheses (2026) · cites this paper as [64]

    Sections 3.1 and 4.5 state that mitochondrial dysfunction and impaired oxidative phosphorylation reduce ATP production; section 4.1 says ATP supports membrane-potential maintenance. Our copy does not describe Na⁺/K⁺-ATPase failure, membrane depolarization, or reversal of glutamate transporters, so it does not support the claimed causal chain. (LLM, conf=0.86)

    Experimental — accuracy not yet measured

  • Aβ and tau oligomers may accumulate within mitochondria, impairing respiratory chain function and increasing ROS production.

    “In this case, Aβ and tau oligomers may accumulate within mitochondria, impairing respiratory chain function and increasing ROS production [64].”

    From Toward a Unified Framework in Molecular Neurobiology of Alzheimer’s Disease: Revisiting the Pathophysiological Hypotheses (2026) · cites this paper as [64]

    Section 4.5 links impaired mitochondrial function in Alzheimer’s disease to reduced oxidative-phosphorylation activity and increased ROS generation. However, the retrieved passages do not say that Aβ and tau oligomers accumulate within mitochondria or that such accumulation causes the impairment. Section 4.2 instead describes mitochondrial alterations as promoting Aβ accumulation and tau hyperphosphorylation. Page numbers were not available in our copy. (LLM, conf=0.86)

    Experimental — accuracy not yet measured

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200 of 243 shown

Cited by

Sorted by citations

Authors
Kazemeini, S., Nadeem-Tariq, A., Shih, R., Rafanan, J., Ghani, N., & Vida, T. A.
Affiliations
University of Nevada, Las Vegas (US)
Corresponding author
Vida, Thomas A.
ORCID
Venue
International Journal of Molecular Sciences
Publisher
MDPI AG
Published
2024-10-31
Volume
25
Issue
21
Pages
11720
ISSN
1422-0067 (ISSN-L)
DOI
10.3390/ijms252111720
PMC
PMC11546801
OpenAlex
W4403946151
Cited by
41
References
33
Citations by year
2026: 20 · 2025: 21
FWCI
2.15
Type
journal article
Language
en
Open access
Licence
Locations
  • International Journal of Molecular Sciences (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
Topics
  • Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Mitochondrial Function and Pathology
  • Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
Keywords
Alzheimer's disease, mitochondrial dysfunction, blood-brain barrier disruption, cerebral blood flow, amyloid-beta, amyloid hypothesis, oxidative stress, bioenergetic failure, glucose hypometabolism, insulin resistance, neurodegeneration, metabolic disorders
MeSH terms
Alzheimer Disease, Animals, Blood-Brain Barrier, Humans, Mitochondria, Amyloid beta-Peptides, Oxidative Stress, Plaque, Amyloid

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