Critical threshold cerebral hypoperfusion causes Alzheimer's disease?
Abstract
After nearly a century of inquiry, the cause of Alzheimer's disease (AD) remains to be found. In this review, basic and clinical evidence is presented that assembles and hypothetically explains most of the key pathologic events associated with the development of AD. These pathologic events are triggered in AD by an impaired cerebral perfusion originating in the microvasculature which affects the optimal delivery of glucose and oxygen and results in a breakdown of metabolic energy pathways in brain cells such as in the biosynthetic and synaptic pathways. We propose that two factors need to be present before cognitive dysfunction and neurodegeneration is expressed in AD brain: advanced aging, and the presence of a condition that lowers cerebral perfusion. The first factor introduces a normal but potentially menacing process that lowers cerebral blood flow in correlation to increased aging, while the second factor adds a crucial element which further lowers brain perfusion and establishes the heterogeneic disease profile observed in AD patients. These two factors will lead to a critical threshold cerebral hypoperfusion. Critical threshold cerebral hypoperfusion is a self-perpetuating, contained and progressive circulatory insufficiency that will destabilize neurons, synapses, neurotransmission and cognitive function, creating in its wake a neurodegenerative process characterized by the formation of senile plaques, neurofibrillary tangles, and amyloid angiopathy. A discussion of target therapy based on the proposed pathogenesis of AD is also briefly reviewed.
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GRP78 has previously exhibited several neuroprotective roles within endoplasmic reticulum-stress response pathways, by guarding against oxidative stress and glutamate excitotoxicity due to prolonged cerebral ischemia.
“whereas GRP78 has previously exhibited several neuroprotective roles within endoplasmic reticulum–stress response pathways, by guarding against oxidative stress and glutamate excitotoxicity due to prolonged cerebral ischemia.”
From High vulnerability of medial prefrontal pyramidal neurons in post-stroke, vascular, Alzheimer's disease, and aging-related dementias (2026) · cites this paper as [17]
One common pathway reported as significantly changed within post-stroke dementia cases was metabolic functioning, specifically involving impaired mitochondrial energy production, as reported within chronic hypoperfusive areas leading to cellular dysfunction.
“One common pathway reported as significantly changed within PSD cases was metabolic functioning, specifically involving impaired mitochondrial energy production, as reported within chronic hypoperfusive areas leading to cellular dysfunction.”
From High vulnerability of medial prefrontal pyramidal neurons in post-stroke, vascular, Alzheimer's disease, and aging-related dementias (2026) · cites this paper as [17]
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- Authors
- de la Torre, J. C.
- Venue
- Acta Neuropathologica
- Published
- 1999-07-02
- Volume
- 98
- Issue
- 1
- Pages
- 1-8
- ISSN
- 0001-6322 (ISSN-L)
- 1432-0533
- OpenAlex
- W2136989768
- Cited by
- 124
- References
- 46
- Citations by year
- 2026: 1 · 2025: 2 · 2024: 4 · 2023: 2 · 2022: 7 · 2021: 1 · 2020: 3 · 2019: 5 · 2018: 3 · 2017: 1 · 2016: 1 · 2015: 3 · 2014: 12 · 2013: 5 · 2012: 4
- FWCI
- 5.03
- Type
- journal article
- Language
- en
- Open access
- closed
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Acta Neuropathologica (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Life Sciences › Neuroscience › Neurology › Neurological Disease Mechanisms and Treatments
- Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
- Keywords
- Alzheimer's disease, cerebral hypoperfusion, cerebral blood flow, cerebral microvasculature, brain energy metabolism, neurodegeneration, cognitive impairment, aging, amyloid plaques, neurofibrillary tangles, amyloid angiopathy, disease heterogeneity, therapeutic target
- MeSH terms
- Alzheimer Disease, Animals, Blood Flow Velocity, Cerebral Cortex, Cerebrovascular Circulation, Glucose, Humans, Microcirculation, Oxygen, Proteins, Genetic Predisposition to Disease, Rats
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