Vascular dysfunction—The disregarded partner of Alzheimer's disease
Open accessAbstract
Increasing evidence recognizes Alzheimer's disease (AD) as a multifactorial and heterogeneous disease with multiple contributors to its pathophysiology, including vascular dysfunction. The recently updated AD Research Framework put forth by the National Institute on Aging–Alzheimer's Association describes a biomarker‐based pathologic definition of AD focused on amyloid, tau, and neuronal injury. In response to this article, here we first discussed evidence that vascular dysfunction is an important early event in AD pathophysiology. Next, we examined various imaging sequences that could be easily implemented to evaluate different types of vascular dysfunction associated with, and/or contributing to, AD pathophysiology, including changes in blood‐brain barrier integrity and cerebral blood flow. Vascular imaging biomarkers of small vessel disease of the brain, which is responsible for >50% of dementia worldwide, including AD, are already established, well characterized, and easy to recognize. We suggest that these vascular biomarkers should be incorporated into the AD Research Framework to gain a better understanding of AD pathophysiology and aid in treatment efforts.
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The two-hit vascular hypothesis proposes that cerebrovascular dysfunction plays an important role in the progression of AD.
“Accordingly, cerebrovascular dysfunction has been put forward three decades ago, and two‐hit vascular hypothesis was proposed to demonstrate the important role of cerebrovascular dysfunction in the progression of AD.[ 5 ]”
From Multifunctional Nanostructure RAP‐RL Rescues Alzheimer's Cognitive Deficits through Remodeling the Neurovascular Unit (2021) · cites this paper as [5]
The section “Vascular dysfunction and vascular biomarkers in AD” says cerebrovascular dysfunction is prominent in AD and describes vascular factors acting with amyloid burden to promote cognitive decline. This supports the claimed importance of vascular dysfunction, but our copy does not identify a “two-hit vascular hypothesis” or substantiate the sentence’s “three decades ago” dating. (LLM, conf=0.84)
Experimental — accuracy not yet measuredClinical distinctions between Alzheimer's and vascular dementias are often blurred by frequent co-association.
“It is no wonder then that the clinical distinctions between Alzheimer’s and the vascular dementias often is blurred by their frequent co-association (102).”
From Glymphatic failure as a final common pathway to dementia (2020) · cites this paper as [102]
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Flagged first, then by citations
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- Authors
- Sweeney, M. D., Montagne, A., Sagare, A. P., Nation, D. A., Schneider, L. S., Chui, H. C., Harrington, M. G., Pa, J., Law, M., Wang, D. J. J., Jacobs, R. E., Doubal, F. N., Ramirez, J., Black, S. E., Nedergaard, M., Benveniste, H., Dichgans, M., Iadecola, C., Love, S., Bath, P. M., Markus, H. S., Al‐Shahi Salman, R., Allan, S. M., Quinn, T. J., Kalaria, R. N., Werring, D. J., Carare, R. O., Touyz, R. M., Williams, S. C. R., Moskowitz, M. A., Katusic, Z. S., Lutz, S. E., Lazarov, O., Minshall, R. D., Rehman, J., Davis, T. P., Wellington, C. L., González, H. M., Yuan, C., Lockhart, S. N., Hughes, T. M., Chen, C. L. H., Sachdev, P., O'Brien, J. T., Skoog, I., Pantoni, L., Gustafson, D. R., Biessels, G. J., Wallin, A., Smith, E. E., Mok, V., Wong, A., Passmore, P., Barkof, F., Muller, M., Breteler, M. M. B., Román, G. C., Hamel, E., Seshadri, S., Gottesman, R. F., van Buchem, M. A., Arvanitakis, Z., Schneider, J. A., Drewes, L. R., Hachinski, V., Finch, C. E., Toga, A. W., Wardlaw, J. M., & Zlokovic, B. V.
- Affiliations
- University of Southern California (US)
- Huntington Medical Research Institutes (US)
- UK Dementia Research Institute (GB)
- Sunnybrook Health Science Centre (CA)
- University of Toronto (CA)
- University of Copenhagen (DK)
- Yale University (US)
- Institut für Schlaganfall- und Demenzforschung (DE)
- Weill Cornell Medicine (US)
- Southmead Hospital (GB)
- Nottingham University Hospitals NHS Trust (GB)
- University of Cambridge (GB)
- Neuroimaging Sciences and Brain Research Imaging Center Division of Neuroimaging Sciences Center for Clinical Brain Sciences UK Dementia Research Institute at the University of Edinburgh UK
- University of Manchester (GB)
- University of Glasgow (GB)
- Neurovascular Research Group Institute of Neuroscience Newcastle University Newcastle upon Tyne UK
- National Hospital for Neurology and Neurosurgery (GB)
- University of Southampton (GB)
- British Heart Foundation (GB)
- Department of Neuroimaging Institute of Psychiatry Psychology & Neuroscience King's College London London UK
- Harvard University (US)
- Department of Anesthesiology and Molecular Pharmacology and Experimental Therapeutics Mayo Clinic College of Medicine Rochester MN USA
- University of Illinois Chicago (US)
- University of Arizona (US)
- University of British Columbia (CA)
- University of California San Diego (US)
- University of Washington (US)
- Wake Forest University Health Sciences (US)
- National University of Singapore (SG)
- UNSW Sydney (AU)
- University of Gothenburg (SE)
- University of Milan (IT)
- SUNY Downstate Health Sciences University (US)
- University Medical Center Utrecht (NL)
- University of Calgary (CA)
- Chinese University of Hong Kong (HK)
- Queen's University Belfast (GB)
- Amsterdam Neuroscience (NL)
- Amsterdam UMC Location Vrije Universiteit Amsterdam (NL)
- University of Bonn (DE)
- Houston Methodist (US)
- Laboratory of Cerebrovascular Research Montreal Neurological Institute McGill University Montréal QC Canada
- Boston University (US)
- Johns Hopkins University (US)
- Department of Radiology Leiden University Medical Center Leiden The Netherlands
- Rush University Medical Center (US)
- University of Minnesota (US)
- Western University (CA)
- Department of Physiology and Neuroscience Zilkha Neurogenetic Institute Keck School of Medicine University of Southern California Los Angeles CA USA
- ORCID
- Sweeney, Melanie D.
- Montagne, Axel
- Sagare, Abhay P.
- Nation, Daniel A.
- Schneider, Lon S.
- Chui, Helena C.
- Harrington, Michael G.
- Pa, Judy
- Law, Meng
- Wang, Danny J. J.
- Jacobs, Russell E.
- Doubal, Fergus N.
- Ramirez, Joel
- Black, Sandra E.
- Nedergaard, Maiken
- Benveniste, Helene
- Dichgans, Martin
- Iadecola, Costantino
- Love, Seth
- Bath, Philip M.
- Markus, Hugh S.
- Allan, Stuart M.
- Quinn, Terence J.
- Werring, David J.
- Carare, Roxana O.
- Touyz, Rhian M.
- Moskowitz, Michael A.
- Lutz, Sarah E.
- Lazarov, Orly
- Minshall, Richard D.
- Rehman, Jalees
- Davis, Thomas P.
- Wellington, Cheryl L.
- González, Hector M.
- Yuan, Chun
- Lockhart, Samuel N.
- Hughes, Timothy M.
- Chen, Christopher L. H.
- Sachdev, Perminder
- O'Brien, John T.
- Skoog, Ingmar
- Pantoni, Leonardo
- Gustafson, Deborah R.
- Biessels, Geert Jan
- Wallin, Anders
- Smith, Eric E.
- Mok, Vincent
- Wong, Adrian
- Passmore, Peter
- Muller, Majon
- Breteler, Monique M. B.
- Román, Gustavo C.
- Seshadri, Sudha
- Gottesman, Rebecca F.
- Arvanitakis, Zoe
- Schneider, Julie A.
- Drewes, Lester R.
- Hachinski, Vladimir
- Finch, Caleb E.
- Toga, Arthur W.
- Wardlaw, Joanna M.
- Venue
- Alzheimer's & Dementia
- Publisher
- Wiley
- Published
- 2019-01
- Volume
- 15
- Issue
- 1
- Pages
- 158-167
- ISSN
- 1552-5260 (ISSN-L)
- 1552-5279
- PMC
- PMC6338083
- OpenAlex
- W2910508414
- Cited by
- 711
- References
- 106
- Citations by year
- 2026: 73 · 2025: 92 · 2024: 96 · 2023: 91 · 2022: 99 · 2021: 111 · 2020: 92 · 2019: 56 · 2018: 1
- FWCI
- 71.30
- Type
- journal article
- Language
- en
- Update notices
- erratum (2022-02-02)
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- Locations
- Alzheimer s & Dementia (publishedVersion)
- Research at the University of Copenhagen (University of Copenhagen) (publishedVersion, other-oa)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Bristol Research (University of Bristol) (acceptedVersion, cc-by-nc-nd)
- Explore Bristol Research (submittedVersion, cc-by-nc-nd)
- Data Archiving and Networked Services (DANS) (submittedVersion, cc-by)
- Archivio Istituzionale della Ricerca (Universita Degli Studi Di Milano) (submittedVersion, other-oa)
- Leiden Repository (Leiden University) (submittedVersion, cc-by)
- Utrecht University Repository (Utrecht University) (submittedVersion, other-oa)
- ePrints Soton (University of Southampton) (submittedVersion)
- eScholarship (California Digital Library) (submittedVersion)
- Research Portal (King's College London) (submittedVersion)
- DZNE Pub (submittedVersion)
- Pure Amsterdam UMC (submittedVersion, other-oa)
- Amsterdam UMC (VU Amsterdam) - Institutional Repository (submittedVersion)
- Edinburgh Research Explorer (University of Edinburgh) (submittedVersion, cc-by-nc-nd)
- Utrecht University Repository (Utrecht University) (submittedVersion)
- Data Archiving and Networked Services (DANS) (submittedVersion)
- Newcastle University ePrints (Newcastle Univesity)
- Funders
- National Institutes of Health (R01AG023084, R01NS090904, R01NS034467, R01AG039452, 1R01NS100459, 5P01AG052350, P50AG005142)
- Topics
- Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
- Life Sciences › Neuroscience › Neurology › Neurological Disease Mechanisms and Treatments
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Keywords
- Alzheimer's disease, vascular dysfunction
- MeSH terms
- Alzheimer Disease, Blood-Brain Barrier, Brain, Cerebrovascular Circulation, Humans, United States, Vascular Diseases, Biomarkers, Amyloid beta-Peptides, National Institute on Aging (U.S.), White Matter
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
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