. 2019 Jan;15(1):158-167.

doi: 10.1016/j.jalz.2018.07.222.

Vascular dysfunction-The disregarded partner of Alzheimer's disease

Melanie D Sweeney¹, Axel Montagne¹, Abhay P Sagare¹, Daniel A Nation², Lon S Schneider³, Helena C Chui⁴, Michael G Harrington⁵, Judy Pa⁶, Meng Law⁷, Danny J J Wang⁶, Russell E Jacobs¹, Fergus N Doubal⁸, Joel Ramirez⁹, Sandra E Black¹⁰, Maiken Nedergaard¹¹, Helene Benveniste¹², Martin Dichgans¹³, Costantino Iadecola¹⁴, Seth Love¹⁵, Philip M Bath¹⁶, Hugh S Markus¹⁷, Rustam Al-Shahi Salman⁸, Stuart M Allan¹⁸, Terence J Quinn¹⁹, Rajesh N Kalaria²⁰, David J Werring²¹, Roxana O Carare²², Rhian M Touyz²³, Steve C R Williams²⁴, Michael A Moskowitz²⁵, Zvonimir S Katusic²⁶, Sarah E Lutz²⁷, Orly Lazarov²⁷, Richard D Minshall²⁸, Jalees Rehman²⁹, Thomas P Davis³⁰, Cheryl L Wellington³¹, Hector M González³², Chun Yuan³³, Samuel N Lockhart³⁴, Timothy M Hughes³⁴, Christopher L H Chen³⁵, Perminder Sachdev³⁶, John T O'Brien³⁷, Ingmar Skoog³⁸, Leonardo Pantoni³⁹, Deborah R Gustafson⁴⁰, Geert Jan Biessels⁴¹, Anders Wallin⁴², Eric E Smith⁴³, Vincent Mok⁴⁴, Adrian Wong⁴⁵, Peter Passmore⁴⁶, Frederick Barkof⁴⁷, Majon Muller⁴⁸, Monique M B Breteler⁴⁹, Gustavo C Román⁵⁰, Edith Hamel⁵¹, Sudha Seshadri⁵², Rebecca F Gottesman⁵³, Mark A van Buchem⁵⁴, Zoe Arvanitakis⁵⁵, Julie A Schneider⁵⁵, Lester R Drewes⁵⁶, Vladimir Hachinski⁵⁷, Caleb E Finch⁵⁸, Arthur W Toga⁵⁹, Joanna M Wardlaw⁸, Berislav V Zlokovic⁶⁰

Affiliations

¹ Department of Physiology and Neuroscience, Zilkha Neurogenetic Institute, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA.
² Department of Psychology, University of Southern California, Los Angeles, CA, USA; Alzheimer's Disease Research Center, Keck School of Medicine at the University of Southern California, Los Angeles, CA, USA.
³ Alzheimer's Disease Research Center, Keck School of Medicine at the University of Southern California, Los Angeles, CA, USA; Department of Neurology, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA; Department of Psychiatry and the Behavioral Sciences, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA.
⁴ Alzheimer's Disease Research Center, Keck School of Medicine at the University of Southern California, Los Angeles, CA, USA; Department of Neurology, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA.
⁵ Huntington Medical Research Institutes, Pasadena, CA, USA.
⁶ Laboratory of Neuro Imaging (LONI), Stevens Institute for Neuroimaging and Informatics, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA.
⁷ Alzheimer's Disease Research Center, Keck School of Medicine at the University of Southern California, Los Angeles, CA, USA; Department of Radiology, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA.
⁸ 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.
⁹ LC Campbell Cognitive Neurology Research Unit, Sunnybrook Research Institute, University of Toronto, Toronto, ON, Canada; Hurvitz Brain Sciences Research Program, Sunnybrook Research Institute, University of Toronto, Toronto, ON, Canada; Heart and Stroke Foundation Canadian Partnership for Stroke Recovery, Sunnybrook Health Sciences Centre, University of Toronto, Toronto, ON, Canada.
¹⁰ Department of Medicine (Neurology), Hurvitz Brain Sciences Program, Canadian Partnership for Stroke Recovery, and LC Campbell Cognitive Neurology Research Unit, Sunnybrook Research Institute, Sunnybrook Health Sciences Centre, Toronto Dementia Research Alliance, University of Toronto, Toronto, Canada.
¹¹ Section for Translational Neuroscience, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark; Division of Glia Disease and Therapeutics, Center for Translational Neuromedicine, University of Rochester Medical School, Rochester, NY, USA.
¹² Department of Anesthesiology, Yale School of Medicine, New Haven, CT, USA.
¹³ Institute for Stroke and Dementia Research (ISD), Ludwing-Maximilians-University Munich, Munich, Germany.
¹⁴ Feil Family Brain and Mind Research Institute, Weill Cornell Medicine, New York, NY, USA.
¹⁵ Institute of Clinical Neurosciences, University of Bristol, School of Medicine, Level 2 Learning and Research, Southmead Hospital, Bristol, UK.
¹⁶ Stroke Trials Unit, Division of Clinical Neuroscience, University of Nottingham, City Hospital Campus, Nottingham, UK; Stroke, Nottingham University Hospitals NHS Trust, City Hospital Campus, Nottingham, UK.
¹⁷ Stroke Research Group, Department of Clinical Neurosciences, University of Cambridge, Cambridge Biomedical Campus, Cambridge, UK.
¹⁸ Faculty of Biology, Medicine and Health, Division of Neuroscience and Experimental Psychology, School of Biological Sciences, University of Manchester, Manchester, UK.
¹⁹ Institute of Cardiovascular and Medical Sciences, University of Glasgow, Glasgow, UK.
²⁰ Neurovascular Research Group, Institute of Neuroscience, Newcastle University, Newcastle upon Tyne, UK.
²¹ Stroke Research Centre, Department of Brain Repair and Rehabilitation, UCL Institute of Neurology and the National Hospital for Neurology and Neurosurgery, London, UK.
²² Faculty of Medicine, University of Southampton, Southampton, UK.
²³ British Heart Foundation, Glasgow Cardiovascular Research Centre, Institute of Cardiovascular and Medical Sciences, University of Glasgow, UK.
²⁴ Department of Neuroimaging, Institute of Psychiatry, Psychology & Neuroscience, King's College London, London, UK.
²⁵ Stroke and Neurovascular Regulation Laboratory, Departments of Radiology and Neurology Harvard Medical School, Massachusetts General Hospital, Boston, MA, USA.
²⁶ Department of Anesthesiology and Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic College of Medicine, Rochester, MN, USA.
²⁷ Department of Anatomy and Cell Biology, University of Illinois at Chicago, Chicago, IL, USA.
²⁸ Department of Anesthesiology, University of Illinois at Chicago, Chicago, IL, USA; Department of Pharmacology, University of Illinois at Chicago, Chicago, IL, USA.
²⁹ Department of Pharmacology, The Center for Lung and Vascular Biology, The University of Illinois College of Medicine, Chicago, IL, USA; Department of Medicine, The Center for Lung and Vascular Biology, The University of Illinois College of Medicine, Chicago, IL, USA.
³⁰ Department of Pharmacology, University of Arizona, Tucson, AZ, USA.
³¹ Department of Pathology and Laboratory Medicine, Djavad Mowafaghian Centre for Brain Health, University of British Columbia, Vancouver, British Columbia, Canada.
³² Department of Neurosciences, University of California, San Diego, CA, USA.
³³ Department of Radiology, University of Washington, Seattle, WA, USA.
³⁴ Department of Internal Medicine, Wake Forest School of Medicine, Winston-Salem, NC, USA; Alzheimer's Disease Research Center, Wake Forest School of Medicine, Winston-Salem, NC, USA.
³⁵ Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Memory Aging and Cognition Centre, National University Health System, Singapore; Department of Psychological Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Memory Aging and Cognition Centre, National University Health System, Singapore.
³⁶ Centre for Healthy Brain Ageing, School of Psychiatry, University of New South Wales Australia, Sydney, Australia.
³⁷ Department of Psychiatry, University of Cambridge School of Clinical Medicine, Cambridge, UK.
³⁸ Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, Sahlgrenska Academy, University of Gothenburg, Mölndal, Sweden.
³⁹ "L. Sacco" Department of Biomedical and Clinical Sciences, University of Milan, Milan, Italy.
⁴⁰ Department of Neurology, State University of New York-Downstate Medical Center, Brooklyn, NY, USA.
⁴¹ Department of Neurology, Brain Center Rudolf Magnus, University Medical Center Utrecht, Utrecht, The Netherlands.
⁴² Institute of Neuroscience and Physiology, University of Gothenburg, Gothenberg, Sweden.
⁴³ Hotchkiss Brain Institute, University of Calgary, Alberta, Canada.
⁴⁴ Department of Medicine and Therapeutics, Therese Pei Fong Chow Research Centre for Prevention of Dementia, The Chinese University of Hong Kong, Hong Kong SAR, China; Gerald Choa Neuroscience Centre, Lui Che Woo Institute of Innovative Medicine, The Chinese University of Hong Kong, Hong Kong SAR, China.
⁴⁵ Department of Medicine and Therapeutics, Therese Pei Fong Chow Research Centre for Prevention of Dementia, The Chinese University of Hong Kong, Hong Kong SAR, China.
⁴⁶ School of Medicine, Dentistry and Biomedical Sciences, Queen's University Belfast, Belfast, UK.
⁴⁷ Department of Radiology and Nuclear Medicine, Amsterdam Neuroscience, VU University Medical Center, Amsterdam, The Netherlands; Institutes of Neurology and Healthcare Engineering, University College London, London, UK.
⁴⁸ Section of Geriatrics, Department of Internal Medicine, VU University Medical Center, Amsterdam, The Netherlands.
⁴⁹ Department of Population Health Sciences, German Center for Neurodegenerative Diseases (DZNE), Bonn, Germany; Institute for Medical Biometry, Informatics and Epidemiology (IMBIE), Faculty of Medicine, University of Bonn, Bonn, Germany.
⁵⁰ Department of Neurology, Methodist Neurological Institute, Houston, TX, USA.
⁵¹ Laboratory of Cerebrovascular Research, Montreal Neurological Institute, McGill University, Montréal, QC, Canada.
⁵² The Framingham Heart Study, Framingham, MA, USA; Department of Neurology, Boston University School of Medicine, Boston, MA, USA.
⁵³ Departments of Neurology and Epidemiology, Johns Hopkins University, Baltimore, MD, USA.
⁵⁴ Department of Radiology, Leiden University Medical Center, Leiden, The Netherlands.
⁵⁵ Department of Neurological Sciences, Rush University Medical Center, Chicago, IL, USA; Rush Alzheimer's Disease Center, Rush University Medical Center, Chicago, IL, USA.
⁵⁶ Laboratory of Cerebral Vascular Biology, Department of Biomedical Sciences, University of Minnesota Medical School Duluth, Duluth, MN, USA.
⁵⁷ Division of Neurology, Department of Clinical Neurological Sciences, Western University, London, Ontario, Canada.
⁵⁸ Leonard Davis School of Gerontology, Dornsife College, University of Southern California, Los Angeles, CA, USA.
⁵⁹ Alzheimer's Disease Research Center, Keck School of Medicine at the University of Southern California, Los Angeles, CA, USA; Laboratory of Neuro Imaging (LONI), Stevens Institute for Neuroimaging and Informatics, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA.
⁶⁰ Department of Physiology and Neuroscience, Zilkha Neurogenetic Institute, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA; Alzheimer's Disease Research Center, Keck School of Medicine at the University of Southern California, Los Angeles, CA, USA. Electronic address: zlokovic@usc.edu.

PMID: 30642436
PMCID: PMC6338083
DOI: 10.1016/j.jalz.2018.07.222

Vascular dysfunction-The disregarded partner of Alzheimer's disease

Melanie D Sweeney et al. Alzheimers Dement. 2019 Jan.

. 2019 Jan;15(1):158-167.

doi: 10.1016/j.jalz.2018.07.222.

Authors

Affiliations

¹ Department of Physiology and Neuroscience, Zilkha Neurogenetic Institute, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA.
² Department of Psychology, University of Southern California, Los Angeles, CA, USA; Alzheimer's Disease Research Center, Keck School of Medicine at the University of Southern California, Los Angeles, CA, USA.
³ Alzheimer's Disease Research Center, Keck School of Medicine at the University of Southern California, Los Angeles, CA, USA; Department of Neurology, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA; Department of Psychiatry and the Behavioral Sciences, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA.
⁴ Alzheimer's Disease Research Center, Keck School of Medicine at the University of Southern California, Los Angeles, CA, USA; Department of Neurology, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA.
⁵ Huntington Medical Research Institutes, Pasadena, CA, USA.
⁶ Laboratory of Neuro Imaging (LONI), Stevens Institute for Neuroimaging and Informatics, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA.
⁷ Alzheimer's Disease Research Center, Keck School of Medicine at the University of Southern California, Los Angeles, CA, USA; Department of Radiology, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA.
⁸ 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.
⁹ LC Campbell Cognitive Neurology Research Unit, Sunnybrook Research Institute, University of Toronto, Toronto, ON, Canada; Hurvitz Brain Sciences Research Program, Sunnybrook Research Institute, University of Toronto, Toronto, ON, Canada; Heart and Stroke Foundation Canadian Partnership for Stroke Recovery, Sunnybrook Health Sciences Centre, University of Toronto, Toronto, ON, Canada.
¹⁰ Department of Medicine (Neurology), Hurvitz Brain Sciences Program, Canadian Partnership for Stroke Recovery, and LC Campbell Cognitive Neurology Research Unit, Sunnybrook Research Institute, Sunnybrook Health Sciences Centre, Toronto Dementia Research Alliance, University of Toronto, Toronto, Canada.
¹¹ Section for Translational Neuroscience, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark; Division of Glia Disease and Therapeutics, Center for Translational Neuromedicine, University of Rochester Medical School, Rochester, NY, USA.
¹² Department of Anesthesiology, Yale School of Medicine, New Haven, CT, USA.
¹³ Institute for Stroke and Dementia Research (ISD), Ludwing-Maximilians-University Munich, Munich, Germany.
¹⁴ Feil Family Brain and Mind Research Institute, Weill Cornell Medicine, New York, NY, USA.
¹⁵ Institute of Clinical Neurosciences, University of Bristol, School of Medicine, Level 2 Learning and Research, Southmead Hospital, Bristol, UK.
¹⁶ Stroke Trials Unit, Division of Clinical Neuroscience, University of Nottingham, City Hospital Campus, Nottingham, UK; Stroke, Nottingham University Hospitals NHS Trust, City Hospital Campus, Nottingham, UK.
¹⁷ Stroke Research Group, Department of Clinical Neurosciences, University of Cambridge, Cambridge Biomedical Campus, Cambridge, UK.
¹⁸ Faculty of Biology, Medicine and Health, Division of Neuroscience and Experimental Psychology, School of Biological Sciences, University of Manchester, Manchester, UK.
¹⁹ Institute of Cardiovascular and Medical Sciences, University of Glasgow, Glasgow, UK.
²⁰ Neurovascular Research Group, Institute of Neuroscience, Newcastle University, Newcastle upon Tyne, UK.
²¹ Stroke Research Centre, Department of Brain Repair and Rehabilitation, UCL Institute of Neurology and the National Hospital for Neurology and Neurosurgery, London, UK.
²² Faculty of Medicine, University of Southampton, Southampton, UK.
²³ British Heart Foundation, Glasgow Cardiovascular Research Centre, Institute of Cardiovascular and Medical Sciences, University of Glasgow, UK.
²⁴ Department of Neuroimaging, Institute of Psychiatry, Psychology & Neuroscience, King's College London, London, UK.
²⁵ Stroke and Neurovascular Regulation Laboratory, Departments of Radiology and Neurology Harvard Medical School, Massachusetts General Hospital, Boston, MA, USA.
²⁶ Department of Anesthesiology and Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic College of Medicine, Rochester, MN, USA.
²⁷ Department of Anatomy and Cell Biology, University of Illinois at Chicago, Chicago, IL, USA.
²⁸ Department of Anesthesiology, University of Illinois at Chicago, Chicago, IL, USA; Department of Pharmacology, University of Illinois at Chicago, Chicago, IL, USA.
²⁹ Department of Pharmacology, The Center for Lung and Vascular Biology, The University of Illinois College of Medicine, Chicago, IL, USA; Department of Medicine, The Center for Lung and Vascular Biology, The University of Illinois College of Medicine, Chicago, IL, USA.
³⁰ Department of Pharmacology, University of Arizona, Tucson, AZ, USA.
³¹ Department of Pathology and Laboratory Medicine, Djavad Mowafaghian Centre for Brain Health, University of British Columbia, Vancouver, British Columbia, Canada.
³² Department of Neurosciences, University of California, San Diego, CA, USA.
³³ Department of Radiology, University of Washington, Seattle, WA, USA.
³⁴ Department of Internal Medicine, Wake Forest School of Medicine, Winston-Salem, NC, USA; Alzheimer's Disease Research Center, Wake Forest School of Medicine, Winston-Salem, NC, USA.
³⁵ Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Memory Aging and Cognition Centre, National University Health System, Singapore; Department of Psychological Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Memory Aging and Cognition Centre, National University Health System, Singapore.
³⁶ Centre for Healthy Brain Ageing, School of Psychiatry, University of New South Wales Australia, Sydney, Australia.
³⁷ Department of Psychiatry, University of Cambridge School of Clinical Medicine, Cambridge, UK.
³⁸ Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, Sahlgrenska Academy, University of Gothenburg, Mölndal, Sweden.
³⁹ "L. Sacco" Department of Biomedical and Clinical Sciences, University of Milan, Milan, Italy.
⁴⁰ Department of Neurology, State University of New York-Downstate Medical Center, Brooklyn, NY, USA.
⁴¹ Department of Neurology, Brain Center Rudolf Magnus, University Medical Center Utrecht, Utrecht, The Netherlands.
⁴² Institute of Neuroscience and Physiology, University of Gothenburg, Gothenberg, Sweden.
⁴³ Hotchkiss Brain Institute, University of Calgary, Alberta, Canada.
⁴⁴ Department of Medicine and Therapeutics, Therese Pei Fong Chow Research Centre for Prevention of Dementia, The Chinese University of Hong Kong, Hong Kong SAR, China; Gerald Choa Neuroscience Centre, Lui Che Woo Institute of Innovative Medicine, The Chinese University of Hong Kong, Hong Kong SAR, China.
⁴⁵ Department of Medicine and Therapeutics, Therese Pei Fong Chow Research Centre for Prevention of Dementia, The Chinese University of Hong Kong, Hong Kong SAR, China.
⁴⁶ School of Medicine, Dentistry and Biomedical Sciences, Queen's University Belfast, Belfast, UK.
⁴⁷ Department of Radiology and Nuclear Medicine, Amsterdam Neuroscience, VU University Medical Center, Amsterdam, The Netherlands; Institutes of Neurology and Healthcare Engineering, University College London, London, UK.
⁴⁸ Section of Geriatrics, Department of Internal Medicine, VU University Medical Center, Amsterdam, The Netherlands.
⁴⁹ Department of Population Health Sciences, German Center for Neurodegenerative Diseases (DZNE), Bonn, Germany; Institute for Medical Biometry, Informatics and Epidemiology (IMBIE), Faculty of Medicine, University of Bonn, Bonn, Germany.
⁵⁰ Department of Neurology, Methodist Neurological Institute, Houston, TX, USA.
⁵¹ Laboratory of Cerebrovascular Research, Montreal Neurological Institute, McGill University, Montréal, QC, Canada.
⁵² The Framingham Heart Study, Framingham, MA, USA; Department of Neurology, Boston University School of Medicine, Boston, MA, USA.
⁵³ Departments of Neurology and Epidemiology, Johns Hopkins University, Baltimore, MD, USA.
⁵⁴ Department of Radiology, Leiden University Medical Center, Leiden, The Netherlands.
⁵⁵ Department of Neurological Sciences, Rush University Medical Center, Chicago, IL, USA; Rush Alzheimer's Disease Center, Rush University Medical Center, Chicago, IL, USA.
⁵⁶ Laboratory of Cerebral Vascular Biology, Department of Biomedical Sciences, University of Minnesota Medical School Duluth, Duluth, MN, USA.
⁵⁷ Division of Neurology, Department of Clinical Neurological Sciences, Western University, London, Ontario, Canada.
⁵⁸ Leonard Davis School of Gerontology, Dornsife College, University of Southern California, Los Angeles, CA, USA.
⁵⁹ Alzheimer's Disease Research Center, Keck School of Medicine at the University of Southern California, Los Angeles, CA, USA; Laboratory of Neuro Imaging (LONI), Stevens Institute for Neuroimaging and Informatics, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA.
⁶⁰ Department of Physiology and Neuroscience, Zilkha Neurogenetic Institute, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA; Alzheimer's Disease Research Center, Keck School of Medicine at the University of Southern California, Los Angeles, CA, USA. Electronic address: zlokovic@usc.edu.

PMID: 30642436
PMCID: PMC6338083
DOI: 10.1016/j.jalz.2018.07.222

Erratum in

Erratum.
[No authors listed] [No authors listed] Alzheimers Dement. 2022 Mar;18(3):522. doi: 10.1002/alz.12483. Epub 2022 Feb 2. Alzheimers Dement. 2022. PMID: 35112491 No abstract available.

Abstract

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.

Keywords: Alzheimer's disease; Biomarkers; Blood-brain barrier; Cerebral blood flow; MRI; Vascular.

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Figures

**Figure 1.. Alzheimer’s disease is a multifactorial and heterogeneous disease.**
Alzheimer’s disease (AD) is defined as a unique neurodegenerative disease based on the presence of amyloid-β (Αβ) and tau deposits. Additional factors (red), however, contribute to the onset and progression of AD pathophysiological changes directly affecting brain vascular system (i.e., blood-brain barrier leakages, blood flow shortfalls) and innate immune system, and neuronal health and functioning independently and/or simultaneously with Aβ and tau pathologies. This includes, but is not limited to: genetic risk factors, vascular factors, environmental factors including socioeconomic stress, microbiome, and lifestyle. Aging still remains the key risk factor for AD, and also profoundly affects brain vasculature, innate immune responses and neuronal functions (blue).

Figure 2.. Schematic illustrating key differences in brain metabolic fate of glucose and its non- metabolizable surrogate analog 2-deoxy-D-glucose (2DG) and its radiolabeled form ¹⁸F-fluoro- 2-deoxy-D-glucose (FDG).
Glucose, a key energy metabolite in the brain, is transported across the blood-brain barrier (BBB) via endothelial-specific glucose transporter-1 (GLUT1) hexose transporter. After uptake by brain cells, glucose undergoes glycolysis followed by Krebs cycle and oxidative metabolism providing the fuel for physiological brain functions through the generation of high-energy adenosine-3 phosphate (ATP) molecules, the foundation for neuronal and non-neuronal cell maintenance and the generation of neurotransmitters. On the other hand, glucose surrogate analogs 2DG and FDG, although still transported across the BBB via GLUT1 hexose transporter, cannot enter the glycolytic pathway or Krebs cycle in brain. After the initial hexokinase step, 2DG- 6P and FDG-6P get trapped in the brain, because they are not substrates for glucose-6P isomerase, which is a necessary metabolic step in the glycolytic pathway. Therefore, 2DG and FDG are not metabolized by the glycolytic pathway or Krebs cycle, do not generate any ATP energy-donor molecules in brain, and their net metabolic rate in brain is zero joules.

See this image and copyright information in PMC

Comment in

"Alzheimer's disease" is neither "Alzheimer's clinical syndrome" nor "dementia".
Jagust W, Jack CR Jr, Bennett DA, Blennow K, Haeberlein SB, Holtzman DM, Jessen F, Karlawish J, Liu E, Molinuevo JL, Montine T, Phelps C, Rankin KP, Rowe CC, Scheltens P, Siemers E, Sperling R. Jagust W, et al. Alzheimers Dement. 2019 Jan;15(1):153-157. doi: 10.1016/j.jalz.2018.11.002. Alzheimers Dement. 2019. PMID: 30642435 No abstract available.

References

1. Jack CR, Bennett DA, Blennow K, Carrillo MC, Dunn B, Haeberlein SB, et al. NIA-AA Research Framework: Toward a biological definition of Alzheimer’s disease. Alzheimers Dement J Alzheimers Assoc 2018;14:535–62. doi: 10.1016/j.jalz.2018.02.018. - DOI - PMC - PubMed
1. Montagne A, Zhao Z, Zlokovic BV. Alzheimer’s disease: A matter of blood-brain barrier dysfunction? J Exp Med 2017. doi: 10.1084/jem.20171406. - DOI - PMC - PubMed
1. Sweeney MD, Sagare AP, Zlokovic BV. Blood-brain barrier breakdown in Alzheimer disease and other neurodegenerative disorders. Nat Rev Neurol 2018;14:133–50. doi: 10.1038/nrneurol.2017.188. - DOI - PMC - PubMed
1. Arvanitakis Z, Capuano AW, Leurgans SE, Bennett DA, Schneider JA. Relation of cerebral vessel disease to Alzheimer’s disease dementia and cognitive function in elderly people: a cross-sectional study. Lancet Neurol 2016;15:934–43. doi: 10.1016/S1474-4422(16)30029-1. - DOI - PMC - PubMed
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Vascular dysfunction-The disregarded partner of Alzheimer's disease

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Vascular dysfunction-The disregarded partner of Alzheimer's disease

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