Ischemia as a common trigger for Alzheimer’s disease
Open accessAbstract
Alzheimer’s disease has various potential etiologies, all culminating in the accumulation of beta -amyloid derivatives and significant cognitive decline. Vascular-related pathology is one of the more frequent etiologies, especially in persons older than 65 years, as vascular risk factors are linked to both cerebrovascular disease and the development of AD. The vascular patho-mechanism includes atherosclerosis, large and small vessel arteriosclerosis, cortical and subcortical infarcts, white matter lesions, and microbleeds. These insults cause hypoperfusion, tissue ischemia, chronic inflammation, neuronal death, gliosis, cerebral atrophy, and accumulation of beta-amyloid and phosphorylated tau proteins. In preclinical studies, hyperbaric oxygen therapy has been shown to reverse brain ischemia, and thus alleviate inflammation, reverse the accumulation of beta-amyloid, induce regeneration of axonal white matter, stimulate axonal growth, promote blood–brain barrier integrity, reduce inflammatory reactions, and improve brain performance. In this perspective article we will summarize the patho-mechanisms induced by brain ischemia and their contribution to the development of AD. We will also review the potential role of interventions that aim to reverse brain ischemia, and discuss their relevance for clinical practice.
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Instances of ischemia are a major risk factor for Alzheimer's disease.
“Instances of ischemia are a major risk factor for Alzheimer's disease, and increased sensitivity to hypoxic insult may play a role in driving pathology in APOE4 (Elman-Shina and Efrati 2022).”
From APOE traffics to astrocyte lipid droplets and modulates triglyceride saturation and droplet size (2024) · cites this paper as Elman-Shina and Efrati 2022
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Ngandu, T., Lehtisalo, J., Solomon, A., Levälahti, E., Ahtiluoto, S., Antikainen, R., Bäckman, L., Hänninen, T., Jula, A., Laatikainen, T., et al. (2015) · The Lancet · doi:10.1016/s0140-6736(15)60461-5 · Cited by 3,689 · see citing works
Snowdon, D. A. (1997) · JAMA: The Journal of the American Medical Association · doi:10.1001/jama.1997.03540340047031 · Cited by 1,590 · see citing works
Obesity and Vascular Risk Factors at Midlife and the Risk of Dementia and Alzheimer Disease
Kivipelto, M., Ngandu, T., Fratiglioni, L., Viitanen, M., Kåreholt, I., Winblad, B., Helkala, E.-L., Tuomilehto, J., Soininen, H., & Nissinen, A. (2005) · Archives of Neurology · doi:10.1001/archneur.62.10.1556 · Cited by 1,291 · see citing works
Tau-targeting therapies for Alzheimer disease
Congdon, E. E., & Sigurdsson, E. M. (2018) · Nature Reviews Neurology · doi:10.1038/s41582-018-0013-z · Cited by 1,113 · cited 2× · see citing works
“The tau protein has received growing attention in recent years (Congdon and Sigurdsson, 2018).”
BackgroundThe overlap between vascular disease and Alzheimer’s disease - lessons from pathology
Attems, J., & Jellinger, K. A. (2014) · BMC Medicine · doi:10.1186/s12916-014-0206-2 · Cited by 739 · cited 5× · see citing works
“of vascular pathology are recognized in AD: small vessel disease and cerebral amyloid angiopathy (CAA) (Attems and Jellinger, 2014).”
BackgroundInfluentialRole of Amyloid-β and Tau Proteins in Alzheimer’s Disease: Confuting the Amyloid Cascade
Gulisano, W., Maugeri, D., Baltrons, M. A., Fà, M., Amato, A., Palmeri, A., D’Adamio, L., Grassi, C., Devanand, D. P., Honig, L. S., et al. (2018) · Journal of Alzheimer's Disease · doi:10.3233/jad-179935 · Cited by 313 · see citing works
Mediterranean Diet, Alzheimer Disease Biomarkers, and Brain Atrophy in Old Age
Ballarini, T., Melo van Lent, D., Brunner, J., Schröder, A., Wolfsgruber, S., Altenstein, S., Brosseron, F., Buerger, K., Dechent, P., Dobisch, L., et al. (2021) · Neurology · doi:10.1212/wnl.0000000000012067 · Cited by 153 · see citing works
Mixed dementia: A review of the evidence
Custodio, N., Montesinos, R., Lira, D., Herrera-Pérez, E., Bardales, Y., & Valeriano-Lorenzo, L. (2017) · Dementia & Neuropsychologia · doi:10.1590/1980-57642016dn11-040005 · Cited by 148 · cited 3× · see citing works
“Vascular risk factors are tightly linked to both cerebrovascular disease and the development of AD (Custodio et al., 2017; Rost et al., 2022).”
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Flagged first, then by citations
Research works printed but not linked: 45
- Aliev G. Priyadarshini M. Reddy V. P. Grieg N. H. Kaminsky Y. Cacabelos R. (2014). Oxidative stress mediated mitochondrial and vascular lesions as markers in the pathogenesis of Alzheimer disease. Curr. Med. Chem. 21 2208– 2217. 10.2174/0929867321666131227161303 24372221 · DOI · Paper page
- Boussi-Gross R. Golan H. Volkov O. Bechor Y. Hoofien D. Beeri M. S. (2015). Improvement of memory impairments in poststroke patients by hyperbaric oxygen therapy. Neuropsychology 29 610– 621. 10.1037/neu0000149 25384125 · DOI
- Breijyeh Z. Karaman R. (2020). Comprehensive Review on Alzheimer’s Disease: Causes and Treatment. Molecules 25: 5789. 10.3390/molecules25245789 33302541 PMC7764106 · DOI · Paper page
- Caprio F. Z. Sorond F. A. (2019). Cerebrovascular disease: Primary and secondary stroke prevention. Med. Clin. North Am. 103 295– 308. 10.1016/j.mcna.2018.10.001 30704682 · DOI
- Chen J. Zhang F. Zhao L. Cheng C. Zhong R. Dong C. (2020). Hyperbaric oxygen ameliorates cognitive impairment in patients with Alzheimer’s disease and amnestic mild cognitive impairment. Alzheimers Dement 6: e12030. 10.1002/trc2.12030 32548235 PMC7293997 · DOI
- Chen W. H. Jin W. Lyu P. Y. Liu Y. Li R. Hu M. (2017). Carotid Atherosclerosis and Cognitive Impairment in Nonstroke Patients. Chin. Med. J. 130 2375– 2379. 10.1002/trc2.12030 28937045 PMC5634090 · DOI
- Chen Y. H. Lin M. S. Lee J. K. Chao C. L. Tang S. C. Chao C. C. (2012). Carotid stenting improves cognitive function in asymptomatic cerebral ischemia. Int. J. Cardiol. 157 104– 107. 10.1016/j.ijcard.2011.10.086 22088226 · DOI
- Cuartero M. I. Garcia-Culebras A. Torres-Lopez C. Medina V. Fraga E. Vazquez-Reyes S. (2021). Post-stroke neurogenesis: Friend or foe? Front. Cell. Dev. Biol. 9: 657846. 10.3389/fcell.2021.657846 33834025 PMC8021779 · DOI
- Cunningham C. O. Caserotti S. R. P. Tully M. A. (2020). Consequences of physical inactivity in older adults: A systematic review of reviews and meta-analyses. Scand. J. Med. Sci. Sports 30 816– 827. 10.1111/sms.13616 32020713 · DOI · Paper page
- de la Torre J. C. (2016). Cerebral perfusion enhancing interventions: A new strategy for the prevention of alzheimer dementia. Brain Pathol. 26 618– 631. 10.1111/bpa.12405 27324946 PMC8029146 · DOI
- Efrati S. Ben-Jacob E. (2014). Reflections on the neurotherapeutic effects of hyperbaric oxygen. Expert Rev. Neurother. 14 233– 236. 10.1586/14737175.2014.884928 24471697 · DOI
- Efrati S. Fishlev G. Bechor Y. Volkov O. Bergan J. Kliakhandler K. (2013). Hyperbaric oxygen induces late neuroplasticity in post stroke patients–randomized, prospective trial. PLoS One 8: e53716. 10.1371/journal.pone.0053716 23335971 PMC3546039 · DOI
- Hadanny A. Daniel-Kotovsky M. Suzin G. Boussi-Gross R. Catalogna M. Dagan K. (2020). Cognitive enhancement of healthy older adults using hyperbaric oxygen: A randomized controlled trial. Aging 12 13740– 13761. 10.18632/aging.103571 32589613 PMC7377835 · DOI
- Hadanny A. Efrati S. (2015). Oxygen–a limiting factor for brain recovery. Crit. Care 19: 307. 10.1186/s13054-015-1034-2 26329929 PMC4556415 · DOI
- Hadanny A. Efrati S. (2020). The Hyperoxic-Hypoxic Paradox. Biomolecules 10: 958. 10.3390/biom10060958 32630465 PMC7355982 · DOI
- Hadanny A. Golan H. Fishlev G. Bechor Y. Volkov O. Suzin G. (2015). Hyperbaric oxygen can induce neuroplasticity and improve cognitive functions of patients suffering from anoxic brain damage. Restor. Neurol. Neurosci. 33 471– 486. 10.3233/RNN-150517 26409406 PMC4923708 · DOI
- He J. T. Zhao X. Xu L. Mao C. Y. (2020). Vascular Risk Factors and Alzheimer’s Disease: Blood-Brain Barrier Disruption, Metabolic Syndromes, and Molecular Links. J. Alzheimers Dis. 73 39– 58. 10.3233/JAD-190764 31815697 · DOI
- Iadecola C. Anrather J. (2011). The immunology of stroke: From mechanisms to translation. Nat. Med. 17 796– 808. 10.1038/nm.2399 21738161 PMC3137275 · DOI · Paper page
- Judge C. Ruttledge S. Murphy R. Loughlin E. Gorey S. Costello M. (2020). Aspirin for primary prevention of stroke in individuals without cardiovascular disease-A meta-analysis. Int. J. Stroke 15 9– 17. 10.1177/1747493019858780 31237833 PMC7003154 · DOI
- Kandiah N. Ong P. A. Yuda T. Ng L. L. Mamun K. Merchant R. A. (2019). Treatment of dementia and mild cognitive impairment with or without cerebrovascular disease: Expert consensus on the use of Ginkgo biloba extract, EGb 761((R)). CNS Neurosci. Ther. 25 288– 298. 10.1111/cns.13095 30648358 PMC6488894 · DOI
- Lee H. Kim K. Lee Y. C. Kim S. Won H. H. Yu T. Y. (2020). Associations between vascular risk factors and subsequent Alzheimer’s disease in older adults. Alzheimers Res. Ther. 12: 117. 10.1186/s13195-020-00690-7 32979926 PMC7520023 · DOI
- Luks A. M. Hackett P. H. (2022). Medical Conditions and High-Altitude Travel. Reply. N. Engl. J. Med. 386 1866– 1867. 10.1056/NEJMc2203182 35544405 · DOI
- Masamoto K. Tanishita K. (2009). Oxygen transport in brain tissue. J. Biomech. Eng. 131: 074002. 10.1115/1.3184694 19640134 · DOI
- Mullard A. (2021). Failure of first anti-tau antibody in Alzheimer disease highlights risks of history repeating. Nat. Rev. Drug. Discov. 20 3– 5. 10.1038/d41573-020-00217-7 33303932 · DOI
- Nishio K. Ihara M. Yamasaki N. Kalaria R. N. Maki T. Fujita Y. (2010). A mouse model characterizing features of vascular dementia with hippocampal atrophy. Stroke 41 1278– 1284. 10.1161/STROKEAHA.110.581686 20448204 · DOI
- Piegza M. Wieckiewicz G. Wierzba D. Piegza J. (2021). Cognitive Functions in Patients after Carotid Artery Revascularization-A Narrative Review. Brain Sci. 11: 1307 10.3390/brainsci11101307 34679372 PMC8533732 · DOI
- Pluta R. Januszewski S. Czuczwar S. J. (2021b). Neuroinflammation in post-ischemic neurodegeneration of the brain: Friend, Foe, or Both? Int. J. Mol. Sci. 22: 4405. 10.3390/ijms22094405 33922467 PMC8122836 · DOI
- Pluta R. Januszewski S. Czuczwar S. J. (2021a). Brain Ischemia as a Prelude to Alzheimer’s Disease. Front. Aging Neurosci. 13: 636653. 10.3389/fnagi.2021.636653 33679381 PMC7931451 · DOI
- Pluta R. Ulamek-Koziol M. Czuczwar S. J. (2018). Neuroprotective and Neurological/Cognitive Enhancement Effects of Curcumin after Brain Ischemia Injury with Alzheimer’s Disease Phenotype. Int. J. Mol. Sci. 19: 4002. 10.3390/ijms19124002 30545070 PMC6320958 · DOI
- Reijmer Y. D. van Veluw S. J. Greenberg S. M. (2016). Ischemic brain injury in cerebral amyloid angiopathy. J. Cereb. Blood Flow Metab. 36 40– 54. 10.1038/jcbfm.2015.88 25944592 PMC4758563 · DOI
- Rost N. S. Brodtmann A. Pase M. P. van Veluw S. J. Biffi A. Duering M. (2022). Post-Stroke Cognitive Impairment and Dementia. Circ. Res. 130 1252– 1271. 10.1161/CIRCRESAHA.122.319951 35420911 · DOI
- Rusek M. Pluta R. Ulamek-Koziol M. Czuczwar S. J. (2019). Ketogenic Diet in Alzheimer’s Disease. Int. J. Mol. Sci. 20: 3892. 10.3390/ijms20163892 31405021 PMC6720297 · DOI · Paper page
- Saito S. Yamamoto Y. Ihara M. (2019). Development of a multicomponent intervention to prevent alzheimer’s disease. Front. Neurol. 10: 490. 10.3389/fneur.2019.00490 31139139 PMC6518668 · DOI
- Scopa C. Marrocco F. Latina V. Ruggeri F. Corvaglia V. La Regina F. (2020). Impaired adult neurogenesis is an early event in Alzheimer’s disease neurodegeneration, mediated by intracellular Abeta oligomers. Cell Death Differ. 27 934– 948. 10.1038/s41418-019-0409-3 31591472 PMC7206128 · DOI
- Sengupta U. Nilson A. N. Kayed R. (2016). The Role of Amyloid-beta Oligomers in Toxicity, Propagation, and Immunotherapy. EBioMedicine 6 42– 49. 10.1016/j.ebiom.2016.03.035 27211547 PMC4856795 · DOI · Paper page
- Shapira R. Efrati S. Ashery U. (2018). Hyperbaric oxygen therapy as a new treatment approach for Alzheimer’s disease. Neural Regen. Res. 13 817– 818. 10.4103/1673-5374.232475 29863011 PMC5998622 · DOI
- Sims N. R. Anderson M. F. (2002). Mitochondrial contributions to tissue damage in stroke. Neurochem. Int. 40 511– 526. 10.1016/S0197-0186(01)00122-X 11850108 · DOI
- Tal S. Hadanny A. Berkovitz N. Sasson E. Ben-Jacob E. Efrati S. (2015). Hyperbaric oxygen may induce angiogenesis in patients suffering from prolonged post-concussion syndrome due to traumatic brain injury. Restor. Neurol. Neurosci. 33 943– 951. 10.3233/RNN-150585 26484702 · DOI
- Utter S. I Tamboli Y. Walter J. Upadhaya A. R. Birkenmeier G. Pietrzik C. U. (2008). Cerebral small vessel disease-induced apolipoprotein E leakage is associated with Alzheimer disease and the accumulation of amyloid beta-protein in perivascular astrocytes. J. Neuropathol. Exp. Neurol. 67 842– 856. 10.1097/NEN.0b013e3181836a71 18716559 · DOI
- Waldau B. Shetty A. K. (2008). Behavior of neural stem cells in the Alzheimer brain. Cell Mol. Life Sci. 65 2372– 2384. 10.1007/s00018-008-8053-y 18500448 PMC3612503 · DOI
- Walsh S. Merrick R. Milne R. Brayne C. (2021). Aducanumab for Alzheimer’s disease? BMJ 374: n1682. 10.1136/bmj.n1682 34226181 PMC8258645 · DOI
- Wendell C. R. Waldstein S. R. Ferrucci L. O’Brien R. J. Strait J. B. Zonderman A. B. (2012). Carotid atherosclerosis and prospective risk of dementia. Stroke 43 3319– 3324. 10.1161/STROKEAHA.112.672527 23103489 PMC3508298 · DOI
- Yan X. Zhang J. Gong Q. Weng X. (2011). Prolonged high-altitude residence impacts verbal working memory: An fMRI study. Exp. Brain Res. 208 437– 445. 10.1007/s00221-010-2494-x 21107542 · DOI
- Yang J. L. Mukda S. Chen S. D. (2018). Diverse roles of mitochondria in ischemic stroke. Redox Biol. 16 263– 275. 29549824 PMC5854930
- Zhang J. Chen J. Fan C. Li J. Lin J. Yang T. (2017). Alteration of spontaneous brain activity after hypoxia-reoxygenation: A resting-state fmri study. High Alt. Med. Biol. 18 20– 26. 10.1089/ham.2016.0083 28266873 · DOI
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APOE traffics to astrocyte lipid droplets and modulates triglyceride saturation and droplet size
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“These conditions are a common trigger for AD development when the NOS output seems to have reached its maximum threshold [73,80].”
- Authors
- Elman-Shina, K., & Efrati, S.
- Affiliations
- Tel Aviv University (IL)
- Corresponding author
- Elman-Shina, Karin
- Venue
- Frontiers in Aging Neuroscience
- Publisher
- Frontiers Media SA
- Published
- 2022-09-26
- Volume
- 14
- Pages
- 1012779-1012779
- ISSN
- 1663-4365 (ISSN-L)
- PMC
- PMC9549288
- OpenAlex
- W4297237395
- Cited by
- 48
- References
- 8
- Citations by year
- 2026: 8 · 2025: 18 · 2024: 12 · 2023: 10
- FWCI
- 6.04
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- Frontiers in Aging Neuroscience (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- 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 ischemia, vascular risk factors, cerebrovascular disease, amyloid-beta, tau phosphorylation, atherosclerosis, cortical infarction, white matter lesions, cerebral microbleeds, hypoperfusion, neuroinflammation, gliosis, hyperbaric oxygen therapy, blood-brain barrier, cognitive decline
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