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Targeting the Vasculature in Alzheimer's Disease and Vascular Cognitive Impairment

Targeting the Vasculature in Alzheimer's Disease and Vascular Cognitive Impairment
Reported by
Jamie Kass and Collene Lawhorn

Posted August 22, 2012


Alzheimer's disease (AD) is a devastating neurodegenerative disorder that affects millions of people worldwide. For more than 100 years, the presence of "senile plaques" and "neurofibrillary tangles" were considered the primary pathological markers for AD. In the last half-century, a growing amount of evidence to support the role of the vascular system as a major causative or exacerbating factor has forced an expanded definition of the classification of pathology in the AD brain. Because of increases in life expectancy and because of the aging population, the rates of neurovascular abnormalities that could lead to cognitive impairment and dementia are also likely to rise. Therefore, the need to identify effective therapeutic targets that will address these neurovascular complexities is critical. At the Targeting the Vasculature in Alzheimer's Disease and Vascular Cognitive Impairment symposium, held on May 4, 2012 and presented by the Brain Dysfunction Discussion Group and the Alzheimer's Drug Discovery Foundation, scientists from academia and industry met to share their knowledge on pathogenic mechanisms, vascular outcomes in clinical trials, and drug discovery targets for Alzheimer's disease.

Use the tabs above to find a meeting report and multimedia from this event.

Presentations available from:
Howard Fillet, MD (Alzheimer's Drug Discovery Foundation)
Barry W. Festoff, MD (University of Kansas Medical Center and pHLOGISTIX LLC)
Costantino Iadecola, MD (Weill Cornell Medical College)
Kejal Kantarci, MD (Mayo Clinic)
Vincent Marchesi, MD, PhD (Yale School of Medicine)
Bruce R. Reed, PhD (UC, Davis Alzheimer's Disease Research Center)
Gustavo C. Román, MD (Methodist Neurological Institute)
Chris B. Schaffer, PhD (Cornell University)
Sidney Strickland, PhD (The Rockefeller University)
Cheryl Wellington, PhD (University of British Columbia)

Presented by

  • The New York Academy of Sciences
  • Alzheimer's Drug Discovery Foundation

pHLOGISTIX LLC: Strategies Harnessing Neuroinflammation

Barry W. Festoff (University of Kansas Medical Center and pHLOGISTIX LLC)
  • 00:01
    1. Introduction
  • 00:55
    2. Brain injury and Alzheimer's
  • 03:45
    3. Pathological states in BBB breakdown
  • 05:55
    4. Inflammatory balance
  • 08:12
    5. Blood-neural barriers
  • 10:07
    6. Human model of BBB
  • 12:17
    7. Role of Thrombin and PAR-1
  • 18:20
    8. Main domains of Thrombin
  • 19:45
    9. Neuroinflammation links to coagulation
  • 21:04
    10. Inflammatory marker HMGB1
  • 24:42
    11. Q and

Targeting the Vasculature in Alzheimer's Disease and Vascular Coginitive Impairment

Howard Fillit (Alzheimer's Drug Discovery Foundation)
  • 00:01
    1. Introduction
  • 01:01
    2. Pathology of Alzheimer's Disease
  • 03:22
    3. History of Alzheimer's vascularity
  • 07:10
    4. Amyloid deposit in vivo study
  • 11:38
    5. Preventing dementi

The Overlap Between Vascular and Neurodegenerative Factors in Dementia

Costantino Iadecola (Weill Cornell Medical College)
  • 00:01
    1. Introduction
  • 00:30
    2. Dementia to Alzheimer's
  • 01:49
    3. Vascular factors play a role in Alzheimer's?
  • 08:38
    4. In vivo vascular investigation
  • 11:15
    5. Oxidtive stress and hyperemia AB
  • 15:02
    6. Role of CD36
  • 17:06
    7. Hypertension and brain blood vessel
  • 22:18
    8. Q and

The Effects of Aβ Immunotherapy on the Vasculature

Kejal Kantarci (Mayo Clinic)
  • 00:01
    1. Introduction
  • 00:30
    2. Effects of AB on vasculature
  • 01:41
    3. Amyloid abnormalities (ARIA-E, ARIA-H)
  • 03:23
    4. Reversability of ARIA-E
  • 06:21
    5. ARIA-E immunotherapy risk factors
  • 09:07
    6. ARIA-H
  • 11:03
    7. Association of ARIA-E and ARIA-H
  • 14:05
    8. Pathophysiological process of ARIA
  • 17:15
    9. Histopathology/animal model of ARIA
  • 20:54
    10. Interpretation of ARIA-E and H
  • 24:54
    11. Q and

Gain-of-Function Somatic Mutations Initiate the Vascular Damage that Leads to Alzheimer's Dementia: A Hypothesis

Vincent Marchesi (Yale School of Medicine)
  • 00:01
    1. Introduction
  • 01:16
    2. Capillary distribution slide
  • 03:45
    3. Amyloid collection in caillary
  • 05:07
    4. Role of oxidative damage
  • 07:44
    5. RNA oxidation and Alzheimer's disease
  • 10:51
    6. Somatic mutation leads to blood vessel damage?
  • 18:45
    7. Q and

MRI Markers of Vascular Cognitive Impairment

Bruce R. Reed (UC Davis Alzheimer's Disease Research Center)
  • 00:01
    1. Introduction
  • 01:02
    2. Vascular brain injury
  • 06:35
    3. Cortical atrophy as VBI
  • 09:26
    4. Is VBI a factor for dementia?
  • 12:23
    5. Cognitive effects of VBI
  • 20:31
    6. Case study FCRP and PIB correlation
  • 22:20
    7. Q and

Hypertension, Cognitive Decline, and Dementia: The Hidden Role of Obstructive Sleep Apnea

Gustavo C. Román (Methodist Neurological Institute)
  • 00:01
    1. Introduction
  • 02:01
    2. Clinical factors to vascular response
  • 03:44
    3. Polysomnography study
  • 07:32
    4. Cognitive diagnoses and test scores
  • 09:50
    5. Obstructive sleep apnea (OSA)
  • 13:23
    6. OSA and small vessel disease
  • 16:09
    7. Difficulties induced by apneas
  • 20:52
    8. Q and

Leukocyte Plugging of Capillaries Reduces Brain Blood Flow in Mouse Models of Alzheimer's Disease

Chris B. Schaffer (Cornell University)
  • 00:01
    1. Introduction
  • 01:53
    2. Use of two-photon excitation
  • 03:30
    3. What's the microcirculation in AD?
  • 04:36
    4. Capillaries with stalled blood flow
  • 06:41
    5. Is there localized cappilary occlusion?
  • 07:59
    6. What's causing the occlusion?
  • 10:54
    7. Capillary occlusion and blood flow
  • 16:07
    8. Relationship with AB aggregates
  • 18:12
    9. Q and

Rethinking Dementia from Dr. Alzheimer to the Present

Sidney Strickland (The Rockefeller University)
  • 00:01
    1. Introduction
  • 02:10
    2. AD and circulation risk factors
  • 03:45
    3. The blood clotting cascade
  • 05:25
    4. The role of fibrin deposition
  • 06:28
    5. Does AB affect clotting?
  • 09:01
    6. AB and fibrinogen structure binding
  • 10:40
    7. What are the roles of AB?
  • 14:51
    8. Effects of APO-E on AB and fibrinogen
  • 16:14
    9. Disease analysis and treatment
  • 21:05
    10. Q and

Guarding Vascular Health with High Density Lipoproteins

Cheryl Wellington (University of British Columbia)
  • 00:01
    1. Introduction
  • 00:42
    2. Lipoprotein subclasses
  • 02:25
    3. Subspecies of HDL
  • 04:55
    4. ABCA1's role in AD mice
  • 07:27
    5. Regulation of CAA via ApoA-1
  • 09:38
    6. HDL's function/clinical study
  • 15:27
    7. Accent assay to determine HDL
  • 17:24
    8. Q and


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Constantino Iadecola

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Kejal Kantarci

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Vincent Marchesi

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Bruce Reed

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Mungas D, Jagust WJ, Reed BR, et al. MRI predictors of cognition in subcortical ischemic vascular disease and Alzheimer's disease. Neurology 2001;57(12):2229-35.

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Gustavo Román

Ancoli-Israel S, Palmer BW, Cooke JR, et al. Cognitive effects of treating obstructive sleep apnea in Alzheimer's disease: a randomized controlled study. J. Am. Geriatr. Soc. 2008;56(11):2076-81. [Epub 2008 Sep 15.]

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Chris Schaffer

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Sidney Strickland

Cortes-Canteli M, Paul J, Norris EH, Bronstein R, Ahn HJ, Zamolodchikov D, Bhuvanendran S, Fenz KM, Strickland S. Fibrinogen and beta-amyloid association alters thrombosis and fibrinolysis: a possible contributing factor to Alzheimer's disease. Neuron 2010;66(5):695-709.

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Cheryl Wellington

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Howard Fillit, MD

Alzheimer's Drug Discovery Foundation
e-mail | website | publications

Howard Fillit, a geriatrician, neuroscientist, and a leading expert in Alzheimer's disease, is the founding Executive Director of the Alzheimer's Drug Discovery Foundation (ADDF). The ADDF's mission is to accelerate the discovery and development of drugs to prevent, treat and cure Alzheimer's disease, related dementias and cognitive aging.

Fillit has had a distinguished academic medicine career at The Rockefeller University and The Mount Sinai School of Medicine where he is a clinical professor of geriatrics and medicine and professor of neurobiology. He is a co-author of more than 250 scientific and clinical publications, and is the senior editor of the leading international Textbook of Geriatric Medicine and Gerontology. Previously, Fillit was the Corporate Medical Director for Medicare at New York Life, responsible for over 125,000 Medicare-managed care members in five regional markets. Fillit has received several awards and honors including the Rita Hayworth Award for Lifetime Achievement. He also serves as a consultant to pharmaceutical and biotechnology companies, health care organizations and philanthropies.

Jennifer Henry, PhD

The New York Academy of Sciences

Jennifer Henry is the Director, Life Sciences at the New York Academy of Sciences. Henry joined the Academy in 2009, before which she was a Publishing Manager in the Academic Journals division at Nature Publishing Group. She also has eight years of direct editorial experience as Editor of Functional Plant Biology for CSIRO Publishing in Australia. She received her PhD in plant molecular biology from the University of Melbourne, specializing in the genetic engineering of transgenic crops. As Director of Life Sciences, she is responsible for developing scientific symposia across a range of life sciences, including biochemical pharmacology, neuroscience, systems biology, genome integrity, infectious diseases and microbiology, under the auspices of the Academy's Frontiers of Science program. She also generates alliances with organizations interested in developing programmatic content.


Barry W. Festoff, MD

University of Kansas Medical Center and pHLOGISTIX LLC
e-mail | website | publications

Barry W. Festoff is Professor of Neurology, Integrative Physiology and Pharmacology at the University of Kansas Medical Center (KUMC), where he has been since 1976, when he joined KUMC and the VA Medical Center in Kansas City (KCVAMC). He founded the Neurology Service at the VAMC, was its first Chief and Director of the Neurobiology Research Laboratory. His research has focused on connections between CNS trauma and neurodegeneration with an emphasis on coagulation proteases, principally thrombin, its regulation and its expression in the CNS. Thrombin inhibitors and regulators, such as protease nexin I (PN-I) and thrombomodulin (TM,) have featured in his group's studies emphasizing neuroinflammation. He retired from the VA in October 2010 and founded pHLOGISTIX LLC, a Delaware company with strategies to harness neuroinflammation in CNS injury and other conditions.

Philip B. Gorelick, MD, MPH

Hauenstein Neuroscience Center

Philip B. Gorelick is the Medical Director of the Hauenstein Neuroscience Center, Saint Mary's Health Care, Grand Rapids, MI and previously was the John S. Garvin Professor and Head, Department of Neurology and Rehabilitation, University of Illinois College of Medicine at Chicago. Gorelick attended the Cardinal Stritch School of Medicine at Loyola and graduated in 1977. Gorelick is board-certified in Neurology and Vascular Neurology.

Gorelick is well known in national and international circles as a world leader in stroke prevention. He has developed innovative studies for identification of risk factors for stroke, prevention of first and recurrent stroke, and the elucidation of risk factors and mechanisms for vascular forms of cognitive impairment (VCI). Gorelick was awarded a grant from the World Federation of Neurology in 2011 to develop a prototype registry of provision of neurological services worldwide and to develop interventions to improve neurological services and treatment in developing countries. He currently directs the Clinical Coordinating Center for the US DIAS Trial and recently 1st-authored an AHA/ASA guidance statement on the vascular burden of cognitive impairment. He also holds the distinction of continuous funding from the NIH for his research work over an 18-year period. Gorelick has published over 250 peer-reviewed articles and has edited 6 books in his field with 2 more in development.

Steven M. Greenberg, MD, PhD

Harvard Medical School
e-mail | website | publications

Steven Greenberg is Director of the Hemorrhagic Stroke Research Program at Massachusetts General Hospital and Professor of Neurology at Harvard Medical School. Initiated in 1994, the Hemorrhagic Stroke Research Program has become internationally recognized as a leading authority on the causes, diagnosis, and treatment of cerebral amyloid angiopathy. Greenberg has authored over 100 research articles and 50 chapters, reviews, and editorials in the areas of hemorrhagic stroke and small vessel brain disease, served as principal investigator on multiple national research grants, and in leadership positions at national and international conferences on hemorrhagic stroke and vascular cognitive impairment. He currently serves as Chair of the International Stroke Conference, Chair of the NINDS Stroke Progress Review Group's Vascular Cognitive Impairment subsection, and Director of Faculty Development for the Massachusetts General Hospital Department of Neurology.

Costantino Iadecola, MD

Weill Cornell Medical College
e-mail | website | publications

Costantino Iadecola, MD, the G. C. Cotzias Distinguished Professor of Neurology and Neuroscience and Chief of the Division of Neurobiology at Weill Cornell Medical College, is a clinician-scientist who works on the cellular and molecular mechanisms of cerebral ischemia, and on the interface between stroke and dementia. Iadecola has published over 220 peer-reviewed papers and plays a leadership role in several research organizations and funding agencies. He chairs the scientific board of the Fondation Leducq and is an advisor to the European Stroke Network and to the Institute of Stroke and Dementia Research (Munich, Germany). He is a recipient of the Willis Award, the highest honor in stroke research bestowed by the AHA, and of the Zenith Fellow Award from the Alzheimer's Association.

Kejal Kantarci, MD

Mayo Clinic
e-mail | website | publications

Kejal Kantarci is Associate Professor of Radiology in the Division of Neuroradiology at the Mayo Clinic. Kantarci's research focuses on identifying imaging markers for early diagnosis and differential diagnosis of dementia. She has authored 50 peer-reviewed publications and 8 book chapters and given invited lectures in 22 national and international courses and symposia. She is a charter member of the NIH/CSR Biomedical Imaging and Technology Study Section. Kantarci received the New Investigator Award from the Alzheimer's Association in 2003 and in 2007 she received the Paul Beeson Career Development Award in Aging, an award jointly issued by the National Institutes of Aging, the American Federation of Aging Research, the John Hardford Foundation, the Atlantic Philanthropies, and the Starr Foundation. Her research program has been funded continuously by the Alzheimer's Association and the National Institutes of Health since 2003.

Vincent T. Marchesi, MD, PhD

Yale School of Medicine
e-mail | website | publications

Vincent Marchesi is a Professor of Pathology and Director of the Boyer Center for Molecular Medicine at Yale University. He received a BA and MD from Yale and a D.Phil from Oxford University. Marchesi is a member of the National Academy of Sciences and the Institute of Medicine.

Bruce R. Reed, PhD

UC Davis Alzheimer's Disease Research Center
e-mail | website | publications

Bruce Reed is Professor of Neurology at the University of California, Davis and serves as Associate Director of the UC Davis Alzheimer's Disease Center. Reed received his BA from Carleton College and his PhD in Clinical Psychology from SUNY Stony Brook. He has published over 100 peer-reviewed publications on the neuropsychology of cognitive aging and dementia. His work on the contributions of vascular factors to cognitive impairment in aging has been funded by NIA since 1993. He recently served as Chair of the NIH Clinical Neuroscience Neurodegeneration study section and as panel member for the NINDS Stroke Progress Review Group's Vascular Cognitive Impairment subsection.

Gustavo C. Román, MD

Methodist Neurological Institute
website | publications

Gustavo C. Román is Director of the Nantz National Alzheimer Center at the Methodist Hospital. Prior to joining Methodist, Román was Professor of Neurology, University of Texas Health Science Center at San Antonio (UTHSCSA), and Neurologist at the Veterans Administration Audie L. Murphy Hospital in San Antonio, Texas, USA. Román is a medical graduate from the National University of Colombia with training in Neurology at the Salpêtrière Hospital, University of Paris, France, and at the University of Vermont, Burlington, VT. He was Interim Chairman of Neurology and Neurosurgery at Texas Tech University in Lubbock, Texas. He served as Chief of the Neuroepidemiology Branch at the U.S. National Institutes of Health. At the NIH, he organized the international workshop that defined the criteria for Vascular Dementia for research studies (NINDS-AIREN Criteria). He created an international research network in neuroepidemiology, with participants from Latin America, Europe, India, and China that to this day continues to yield data.

Román is fluent in Spanish, English, and French, and has published 16 books, 35 chapters in books and more than 300 journal articles. He organized the International Congress on Vascular Dementia (Geneva, 1999, Salzburg 2002) and Vas-Cog 2007 (San Antonio, Texas, USA). Román is an internationally recognized expert in vascular dementia, cognitive neurology, neuroepidemiology, and tropical neurology. He served as advisor to the FDA and is a current reviewer for the Aging Systems and Geriatrics Study Section of the NIH.

Chris B. Schaffer, PhD

Cornell University
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Chris Schaffer received his undergraduate degree from the University of Florida in 1995 and his PhD from Harvard University, working with Eric Mazur, in 2001. Both of his degrees are in Physics. As a post-doc at UCSD, Schaffer worked with David Kleinfeld in the Physics and Neuroscience departments. He is currently an Associate Professor at Cornell University in the Department of Biomedical Engineering. His research has centered on the development of optical tools for in vivo manipulation of biological structures and the use of these tools to study the role of cortical microvascular lesions in neurological disease, with a current focus on the role of microvascular disruptions in Alzheimer's disease.

Sidney Strickland, PhD

The Rockefeller University
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Sidney Strickland is Professor and Dean of the Graduate School at The Rockefeller University in New York City. He received his BS in chemistry in 1968 from Rhodes College in Memphis, TN. He obtained his PhD in biochemistry from the University of Michigan in 1972 where he studied the biophysics of enzymology with Vincent Massey. He then was a postdoctoral fellow for two years at Rockefeller with Edward Reich, where he initiated his work on plasminogen activators. He joined the faculty of Rockefeller as an Assistant Professor and then Associate Professor. In 1983, he accepted a position as Leading Professor at the State University of New York at Stony Brook. He returned to Rockefeller in 2000 and established the Laboratory of Neurobiology and Genetics. His lab studies mechanisms of neurodegeneration.

Cheryl L. Wellington, PhD

University of British Columbia
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Cheryl Wellington obtained her PhD in Microbiology at the University of British Columbia in 1991 and did postdoctoral training at Harvard Medical School, the University of Calgary, and the University of British Columbia. She joined the Department of Pathology and Laboratory Medicine at the University of British Columbia in 2000 and was promoted to Associate Professor in 2006.

Wellington's research interests encompass include lipid and lipoprotein metabolism in the brain and how this relates to chronic and acute neurological disorders. Wellington's group has made key contributions to the understanding of the role of apolipoprotein E (apoE) in Alzheimer's disease. Wellington's laboratory has shown that the amount of lipids carried on apoE affects the metabolism of Aβ peptides, which are toxic species that accumulate as amyloid plaques in the brains of patients with Alzheimer's disease and also accumulate in individuals who have suffered traumatic brain injury. Specifically, Wellington has identified the cholesterol transporter ABCA1 as the physiological transporter of lipids onto brain apoE. Her group has shown that mice deficient in ABCA1 have poorly-lipidated apoE in the brain and develop more amyloid, whereas transgenic mice that overexpress ABCA1 have lipid-rich apoE and have virtually no amyloid deposits. Her current research projects are aimed at developing methods to increase apoE lipidation in the brain for application to both Alzheimer's disease and traumatic brain injury.


Presented by

  • The New York Academy of Sciences
  • Alzheimer's Drug Discovery Foundation

When Alois Alzheimer first described the "peculiar" condition we today know as Alzheimer's disease (AD), he could not have predicted the large amount of attention it would attract from generations of scientists. Despite this worldwide research effort, AD remains a devastating disorder that has generated as many questions as it has answers. Are the classic "senile plaques" and "neurofibrillary tangles" sufficient to define the full range of pathology that exists in the brains of millions of AD sufferers? What additional biomarkers could support a mechanism to explain the breadth of cognitive outcomes in AD? What mechanistic parallels in AD can inform us about other types of cognitive impairment?

In the last half-century scientists have addressed these questions and others through careful examination of the blood–brain relationship. The brain, engulfed in miles of deep penetrating arteries, capillaries, and veins, has a rich vascular architecture that creates an environment where neurons are highly susceptible to vascular insult. Multiple lines of evidence support the role of neurovascular mechanisms as a major factor in AD pathogenesis. And although scientists have yet to determine whether the vascular dysfunction leads to neuronal damage or whether the vascular pathology stems from the neurodegenerative process, there are results from human imaging, mouse models, and postmortem studies that support a critical role for the vascular dysfunction in AD. Affirming the correlation is the fact that the elderly have the highest rates of AD and other dementias as well as the highest rates of vascular-associated illnesses. Therefore, as this population grows so does the need to identify effective therapeutic targets that will address the complexity of these interactions. At the Targeting the Vasculature in Alzheimer's Disease and Vascular Cognitive Impairment symposium scientists from academia and industry met to share their knowledge on clinical and translational approaches to the study of vascular contributions to AD and to other forms of cognitive decline.

In his meeting introduction, Howard Fillit, from the Alzheimer's Drug Discovery Foundation, noted that although scientists first described blood vessel damage in the AD brain more than 100 years ago, this particular aspect of AD pathology has not always received the same attention as have other neurodegenerative descriptors since that time. Sharing an historical perspective on some of the earliest depictions of vascular involvement and explaining some of the developments in the field since then, Fillit reminded the audience that while more work on vasculature and AD are needed, current findings have far progressed from the superficial depictions of 100 years ago. Studies using electron microscopy show marked capillary damage in AD patient tissue and show that fibrillary plaques may in fact flow out of blood vessels. Evidence from studies using immunohistochemical stains for capillaries, as well as PET and FDG neuroimaging studies also show significant capillary-vessel interactions. Work in animal models reveals perivascular deposits of amyloid in the brain, suggesting a critical role for the blood brain barrier. Finally, clinical evidence reveals increasingly high comorbidity rates of older patients with diabetes and/or hypertension and AD—supporting a role of neurovascular dysfunction as a contributor to cognitive decline.

Philip Gorelick, Hauenstein Neuroscience Center
Costantino Iadecola, Weill Cornell Medical College
Vincent T. Marchesi, Yale University
Steven Greenberg, Harvard Medical School
Bruce Reed, University of California, Davis Alzheimer's Research Center


  • A guidance statement on neurovascular contributions to cognitive impairment includes treatment of blood pressure and other cardiovascular risk factors and lifestyle changes that could reduce the probability of cognitive impairment or dementia and cardiovascular disease.
  • Oxidative stress contributes to the dysfunction of cerebral blood vessels via amyloid-beta (Aβ) activation of NADPH oxidase.
  • Somatic mutations may yield mutant proteins that contribute to blood vessel damage.
  • Multimodal imaging studies can be used to define causal pathways between small vessel disease and neuropathology.
  • Elderly individuals with VCI show direct and detectable cognitive changes, even without the presence of Aβ.

Review of cerebrovascular disease in AD

Philip Gorelick from the Hauenstein Neuroscience Center kicked off the discussion on neurovascular contributions to cognitive impairment by reviewing the development of a guidance statement on this issue from the American Heart Association and the American Stroke Association. Gorelick noted that in the 1980s there was a major debate on how to classify Alzheimer's disease (AD). Should it be operationally defined as a distinct entity or should it be considered an open-ended disorder until more data were collected? In 1984 a working group led by Guy M. McKhann ultimately outlined a set of criteria to diagnose probable, possible, and definite AD. These criteria generally focused on evidence of neurodegeneration, thereby moving the field away from considering vascular risk factors.

However, a number of clinical studies over the years in patients with both marked cognitive impairments and vascular problems including unilateral infarctions, elevated body mass index, and chronic conditions like hypertension, heart disease, and diabetes, lent strong support to the idea that vascular dysfunction contributes to cognitive impairment. Given these findings Gorelick and his colleagues, on behalf of the American Heart Association and the American Stroke Association, developed an overall guide "for practitioners to gain a better understanding of vascular cognitive impairment (VCI) and dementia, prevention, and treatment." They defined VCI as a syndrome where there is evidence of clinical stroke or subclinical vascular brain injury and cognitive impairment affecting at least one cognitive domain. Gorelick noted that it can be difficult to diagnose VCI because of the presence of other cerebral or systemic disorders. Specifically, both Alzheimer’s disease and stroke are common as we age, and these disorders co-exist in many elderly persons causing a “mixed”-type of dementia or cognitive impairment.

The guidelines outlined by the group include choices that at a minimum could reduce the probability of stroke and other cardiovascular diseases such as: smoking cessation, controlling hypertension, lowering cholesterol and hyperglycemia, adopting a Mediterranean diet, and increasing exercise. Evaluation of research on potential pharmacological interventions suggest that off-label Donepezil might be useful for treating some cases, while the benefits of antiplatelet therapy, the cholinesterase inhibitor rivastigmine, and the NMDA receptor antagonist memantine are less clear.

Oxidative stress and blood flow homeostasis

Costantino Iadecola from Weill Cornell Medical College began his presentation by reminding the audience that the brain is a unique organ with respect to blood. Unlike other organs, the brain has no energy reserves and is therefore dependent on blood flow to deliver oxygen and remove waste. To maintain homeostasis, the brain is subject to several neurovascular regulatory processes that maintain blood flow to sufficient levels. Autoregulation buffers cerebral blood flow from the deleterious effects of changes in blood pressure. Functional hyperemia links neural activity to cerebral blood flow, assuring that active neurons receive sufficient blood flow to support their increased energy needs. One critical factor in this regulation is the signaling from endothelial cells to the myocytes in the cerebrovasculature. For example, endothelial cells release nitric oxide, a potent vasodilator when increased blood flow is required. These neurovascular regulatory components are compromised in hypertension (high blood pressure), in aging, and in AD. In addition, some patients with AD tend to have atherosclerosis, microvessel alterations, and altered patterns of cerebral blood flow.

Iadecola's group studies neurovascular regulation in mice overexpressing the amyloid precursor protein (APP), a condition that produces an AD-like condition in these mice. They found that all major neuroregulatory processes that maintain blood flow (autoregulation, functional hyperemia, and endothelial regulation) were disrupted in APP mice at very early timepoints—even before the onset of plaques and cognitive decline.

Furthermore, the group found that oxidative stress contributes to this dysfunction of cerebral blood vessels via amyloid-beta (Aβ) activation of NADPH oxidase. A scavenger receptor, CD36, mediates this activation. Deletion of NADPH oxidase genes or the CD36 gene blocks the development of neurovascular dysfunction in the mouse model. In aged APP mice, the neurovascular rescue is independent of effects on amyloid plaques and results in improved cognitive performance of the mice.

The interaction of Aβ with CD36 leads to the activation of NADPH oxidase, and ultimately oxidative stress. (Image courtesy of Costantino Iadecola)

Additionally, findings from a model of angiotensin-induced hypertension shows that some of the hallmark changes reported in other AD models are also observed in hypertension. For example, there are clear alterations in cerebral blood flow that are related to failure of endothelial and neural mechanisms.

Sources of damage to blood vessels and the sequelae

Vincent Marchesi of Yale University took a genetic approach to investigate neurovascular contributions to AD. In studies of older adults with and without AD, the angioarchitecture of both these groups shows a global reduction in capillaries and blood flow when compared to younger subjects. Marchesi's work aims to determine the mechanisms that underlie the diffuse small blood vessel damage seen in aged individuals. He posited that oxidative damage of nucleic acids causes somatic mutations and yields mutant proteins that contribute to blood vessel damage. Mutations in certain proteins can enhance acute and chronic inflammation or can affect endothelial cell function. Mutations may also affect known players in AD pathology, such as APP, presenilins, and tau. Hence somatic mutations may be the precursor of a cascade that eventually signals inflammatory responses and poor vascular outcomes such as ischemia, and subsequently amyloid dysregulation.

Steven Greenberg of Harvard Medical School addressed the issue of how small vessel disease eventually results in cognitive decline. Stroke is a huge risk factor for dementia, and small vessel pathology is the fundamental basis for many kinds of stroke. Greenberg is interested in examining the relationship between bleeding or brain injury from small blood vessels in the brain and cerebral amyloid angiopathy (CAA), a condition in which amyloid builds up in these vessels. Greenberg's group used T2*-weighted magnetic resonance imaging (MRI) and noninvasive amyloid imaging with Pittsburgh Compound B (PiB) to analyze the spatial relationship between CAA and microbleeds. They found that amyloid deposition gives rise to local islands of increased vascular amyloid with impaired physiology that have increased predilection for microbleeds. fMRI studies showed that people with CAA have smaller and slower responses to visual stimulation, indicating that there are behavioral consequences to the damage caused by the condition.

Classic neuropathology studies that used dyes injected into the brain have contributed to the understanding of how amyloid gains access to the outer walls of small vessels and smooth muscle. In addition, Greenberg said, work by Roy Wellers's group at the University of Southampton School of Medicine, UK, showed that after Aβ is degraded by proteases it crosses the blood brain barrier and drains from the brain with interstitial fluid along basement membranes of capillaries and arteries, resulting in deposition of Aβ in vessels as CAA.

Because of the pervasiveness and multiple sequelae associated with amyloid angiopathy in AD, Greenberg posited that any study of AD is in fact a study in amyloid angiopathy, and that moderate to severe CAA may be an independent contributor to cognitive dysfunction.

Cortical atrophy in vascular cognitive impairment

Bruce Reed of the UC Davis Alzheimer's Research Center focused on the next part of the puzzle—the relationship between vascular brain injury and vascular cognitive impairment (VCI), which ranges from the mild impairment that comes with normal aging through dementia. Epidemiological data show that cerebrovascular disease is the result of chain of pathological events that starts off with risk factors like hypertension, diabetes and smoking, moves through atherosclerosis and vascular brain injury and stroke, and ends with enormous damage to the brain.

Generally, the progression of damage due to these risk factors is mostly linear over time. However, there is a marked shift to later onset and more rapid progression when all-cause dementia is considered, which parallels the increasing presence of Aβ. While these data seem to cast doubt on the contribution of cerebrovascular damage to dementia a study by Bennett and Schneider—the community-based Memory and Aging Project—showed that postmortem samples from demented subjects had a higher prevalence of mixed pathology, a combination of vascular and AD lesions compared to those with Aβ deposition or infarction alone.

Reed proposed that the cortical atrophy often observed in the AD brain is in fact a type of vascular brain injury, and that this atrophy is a big driver of cognitive dysfunction. In MRI studies that looked at brain volumes prior to death, patients with either vascular or AD lesions had less gray matter than normal controls, but otherwise were not strikingly different from each other. Patients with mixed lesions had the most neurodegeneration—so the mixture of vascular and AD lesions in the brain may have doubled the impact on the cognitive processing areas.

Interestingly, Reed's group used tests of executive dysfunction and memory in combination with or PET imaging or post mortem neuropathology to assess the correlation of cognitive dysfunction with VCI and AD. They found that in VCI there are direct and detectable cognitive changes in normal elderly, even without the presence of Aβ. Furthermore, the spectrum of cognitive consequences from VCI was highest in normal aging, intermediate in those with mild cognitive impairment (MCI), and indistinct in those with dementia.

Kejal Kantarci, Mayo Clinic
Gustavo C. Román, Methodist Neurological Institute


  • Immunotherapy to clear Aβ can lead to microhemorrhages in the brain.
  • Obstructive sleep apnea is a significant risk factor in the early cognitive decline in the elderly.

Complications of Aβ immunotherapy

To date, there are no effective treatments for Alzheimer's disease, and clinical trials have revealed potential problems with some approaches. Kejal Kantarci of the Mayo Clinic discussed one of these: the effects of Aβ immunotherapy on the vasculature. Efforts to combat AD by using antibodies against Aβ led the disturbing finding that this treatment apparently caused microhemorrhages in the brain in some individuals. The Alzheimer's Association Research Roundtable Workgroup was tasked with addressing the FDA's concerns on the abnormalities that stemmed from immunotherapy.

Two major classes of abnormalities were observed—amyloid-related imaging abnormalities with edema/effusions (ARIA-E), and amyloid-related imaging abnormalities with hemosiderin deposition (ARIA-H). ARIA-E is characterized by extravasation of protein-rich fluid, vasogenic edema, and sulcal effusion/exudate. The abnormality, which may be accompanied by transient symptoms of headache, confusion, and visual disturbances, is reversible. ARIA-E resembles CAA-related inflammation, and the risk factors associated with the condition are high-dose immunotherapy, increased clearance of Aβ, and the presence of the APOE ε4 allele.

Immunotherapy to clear Aβ is complicated by the finding that increased clearance is associated with ARIA-E. (Ostrowitzki et al. Mechanism of amyloid removal in patients with Alzheimer disease treated with Gantenerumab. Archives of Neurology 2012)

ARIA-H is more prevalent in AD and increases with age. It may be influenced by CAA and appears as a microhemorrhage with superficial siderosis, a condition of iron deposition in neuronal tissues thought to represent residual leakage of blood. ARIA-H risk factors include the prevalence of microhemorrhage, CAA, and vascular events. Interestingly, studies have shown that 35% of subjects with microhemorrhages developed ARIA-E, making ARIA-H a risk factor for ARIA-E. Close to 50% of subjects with ARIA-E were found to have microhemorrhages.

What pathophysiological processes underlie ARIA? One hypothesis is that ARIA is related to the processes associated with the clearance and movement of amyloid into vessel walls. For example, rapid clearance of amyloid from parenchyma to the perivascular space may cause a drainage backup and excess fluid shifts. Another explanation is that movement of amyloid into cerebral vessel walls may damage the vessels leading to microhemorrhages, a process described by other speakers at the symposium.

Unfortunately, there are no well-established models for ARIA in animals. The AD roundtable recommended that further clinical trials for Aβ immunotherapy should be accompanied by MRI to detect ARIA. The roundtable offered recommendations about ways to increase the sensitivity of MRI and to determine the frequency of scanning. Kantarci noted that future studies to investigate the pathophysiology, natural history, risk factors, and clinical course of ARIA are needed.

Obstructive sleep apnea

The second session was wrapped up with a talk by Gustavo C. Román of Methodist Neurological Institute on the role of obstructive sleep apnea in hypertension, cognitive decline, and dementia. Approximately 20% of middle-aged adults suffer from obstructive sleep apnea (OSA). OSA is a form of periodic breathing that can induce a variety of physiological responses including: altered oxygen states, muscle contractions, pressure dysfunction, arterial receptor activation, and cardiovascular arrhythmias. Several studies have shown that sleep is critical for cognitive function and OSA is a significant risk factor in the early cognitive decline in the elderly. OSA can also exacerbate the effects from vascular risk factors, such as obesity and hypertension, on small vessel brain disease.

A study that evaluated sleep in 106 older adults in an AD and dementia clinic revealed that the majority of patients had moderate to severe OSA, suggesting elderly patients may have a predisposition to airway obstruction. Possibilities for this disparity in the elderly might include relaxed musculature, less sleep requirements, as well as greater sensitivities to medicines and to noise disturbances. In addition, while the population in this study was not overwhelmingly obese, a significant percentage of subjects suffered from hypertension, hypercholesterolemia, cardiovascular disease, and diabetes. The cognitive status of subjects ranged from those with mild cognitive impairment (MCI) to various forms of dementia, AD, and normal pressure hydrocephalus. The findings also revealed that the worse the sleep apnea a person suffered, the more severe their cognitive deficits. In addition, MRI results revealed that 86% of subjects also suffered from small vessel disease, and subjects with multi-infarct dementia were shown to have a higher prevalence of OSA than AD subjects or controls. Though treatment for OSA can be challenging, the considerable improvements on cognitive tests and cortical volume measurements in those who have been treated are promising.

Barry W. Festoff, University of Kansas Medical Center and pHLOGISTIX LLC
Chris B. Schaffer, Cornell University
Sidney Strickland, The Rockefeller University
Cheryl L. Wellington, University of British Columbia


  • Thrombomodulin is a potent anti-inflammatory with potential as a therapeutic target for traumatic brain injury.
  • The decreased brain blood flow seen in AD patients may be due to dysfunction at the capillary level and may exacerbate AD pathology by decreasing Aβ clearance.
  • Aβ binding to fibrinogen affects clot structure and clot lysis.

Vascular coagulation-inflammatory pathways and therapeutic targets

Traumatic brain injury (TBI) and chronic traumatic encephalopathy (CTE) in particular are significant risk factors for Alzheimer's disease (AD). Barry W. Festoff of University of Kansas Medical Center and pHLOGISTIX LLC presented his group's work on determining the ways in which these injuries can lead to AD. The human body has evolved innate immune responses to detect and combat invading pathogens and physical damage and an importance component of these responses is the activation of coagulation and inflammatory cascades via the protein thrombin and its receptors—proteinase-activated receptors (PARs). Although some level of inflammation and clotting is useful as a protective response, thrombin can also be damaging because it disrupts vascular barriers. Thus, through a negative feedback loop the proteins thrombomodulin and activated Protein C (APC) ultimately dampen the inflammatory and anticoagulatory response initiated by thrombin by inhibiting the activity of that protein.

Mechanical injury leads to the activation of thrombin, which cleaves fibrinogen to release fibrin. Thrombomodulin inhibits the cascade. (Image courtesy of Barry Festoff)

Festoff decided to investigate the role of thrombin in blood brain barrier (BBB) disruption because it had been shown that the protein disrupts vascular barriers in the gut, lung, and other organs. In a cell culture BBB model, thrombin and PAR1-agonist peptides were shown by a variety of criteria to affect the BBB. Festoff's group went on to demonstrate that thrombomodulin can counter this effect.

Festoff's group designed a controlled cortical impact model that could recapitulate some of the conditions associated with CTE and TBI, and allowed them to record the speed of an impact as well as the depth of that impact on the brain. They found that in response to cortical impact, there is an increase in the levels of hgmb1 protein, a protein that binds to TLRs and RAGE to activate a pro-inflammatory response. Furthermore thrombomodulin binds to hgmb1 to counter this response. Hence thrombomodulin might prove useful for treating conditions that stem from TBI or CTE, and could eventually prove useful as a target therapy for AD.

Leukocyte plugging of capillary segments in AD mice

Several mouse models for AD have been developed that successfully recapitulate many aspects of AD pathology and symptoms. Because small vessel diseases play a significant role in AD patient populations, Chris Schaffer of Cornell University is using mouse models of AD to investigate microcirculatory deficits and small vessel dysfunction. Two-photon excited fluorescence microscopy through glass-covered craniotomies allows Schaffer and his group to observe the flow of red blood cells through individual capillaries in wild-type mice and mouse models of AD.

Schaffer's team observed stalled blood flow in only a very small percentage of capillaries in wild-type mice (0.3%). In AD mice, this number increased to approximately 2%. Furthermore, in wild-type mice, these stalls in blood flow resolved in a few minutes but in the mutant mice, only half of stalls resolved while the remaining half continued for multiple hours. AD mice also had increased variability in stall rate, stalls tended to reappear in the same capillaries, and the fraction of capillaries stalled decreased as age advanced.

What could be the reason for these stalls? In vivo imaging revealed that more than 60% of the stalls in the AD mice were caused by leukocytes, specifically monocytes, that were plugging a capillary segment. This suggests vascular inflammation, likely due to the inflammatory effects of Aβ, may underlie the capillary stalling phenomena. But why is it that stalling in only 2% of capillaries makes such a significant difference? A single stalled capillary causes reduced blood flow in multiple downstream vessel branches, so that increases in the number of stalled capillaries not only decreases the number of flowing vessels, but causes decreased flow in the remaining vessels as well. A simple model revealed that the 2% differential in stalled capillaries between wild-type and AD mice predicts a 30% decrease in blood flow, which recapitulates findings from clinical studies. As a result of this decreased blood flow Aβ clearance would decrease, producing a positive feedback loop where microvascular problems and AD pathology mutually exacerbate each other.

Thrombosis and fibrinolysis in AD

Sidney Strickland from the Rockefeller University continued the discussion on potential therapeutic targets for cerebrovascular dysfunction in AD. In addition to the cardiovascular lifestyle risk factors for AD outlined by Gorelick, other factors include high fibrinogen levels, atrial fibrillation, and the genetic disease associated with coagulation—Factor 5 Leiden, Strickland said. The molecular clotting cascade, described earlier by Festoff, suggests that upon injury a protease cascade that leads to thrombin, which cleaves fibrinogen to yield fibrin. Strickland's work using mouse models has shown that the inability to clear fibrin from the blood can have serious consequences. By 6 months of age, mice with a genetic condition that results in fibrin tissue deposits waste and die. They also show delayed wound healing, greater incidences of arthritis, glomerulonephritis, venous thrombosis, and conjunctivitis.

Strickland's working model is that in AD, Aβ binds to fibrinogen and affects clot structure and lysis. Because abnormal clots are resistant to degradation, the result is marked blood vessel damage and inflammation. In addition, when clotting is induced in vivo using ferric chloride, AD mutant mice were more prone than wild-type mice to clotting and the clotting persisted even after application of a clot-dissolving compound. Reducing fibrin levels was shown to boost memory performance in AD mouse models.

Aβ and fibrinogen show colocalization in vessels of AD patients. (Image courtesy of Sidney Strickland)

Studies that examined Aβ-fibrinogen co-localization in human brain revealed that the ApoE ε4/ε4 genotype was associated with increased fibrinogen deposition in CAA-positive vessels in AD patients. In terms of possible therapies, a logical question is could inhibiting the Aβ-fibrinogen interaction be beneficial in AD? And if the issue is a clotting irregularity, could clotting inhibition work? While interesting mechanistically, the possibility of hemorrhage makes this a less attractive option; a targeted inhibition of Aβ's action on fibrinogen is more likely. High-throughput screening identified the RU505 compound, which has shown some promise in controlling clotting and altering cognitive performance in a contextual fear conditioning experiment on AD mutant mice.

Cheryl Wellington of the University of British Columbia closed with a discussion of high-density lipoproteins (HDLs) and the HDL-like ApoA1. While much research has examined the role of HDL, also known as "the good cholesterol," as a fundamental component of cardiovascular health, less is known about the role of lipoproteins in the brain. HDLs are heterogeneous particles that differ in size, density, shape, surface charge, and composition. These particles act through several mechanisms to mediate reverse cholesterol transport, suppress inflammation, enhance immunity, and promote endothelial health. ApoE the brain's major HDL-like lipoprotein—accessing the brain through the cerebral spinal fluid—is one of the major genetic risk factors for AD.

ABCA1 is a cholesterol transporter that is the physiological transporter of lipids onto brain apoE. Wellington's group showed that in AD mouse models ABCA1 levels and corresponding lipidation levels of apo E affects amyloid load. ABCA1 knockout mice showed increased amyloid while transgenic mice overexpressing ABCA1 showed negligible amounts of amyloid deposits.

Coronal mouse sections through the hippocampus show that when ABCA1 reduced, mice have increased amyloid staining (left panel). Coronal sections from a transgenic AD mouse overexpressing ABCA1 showed increased amyloid staining (right panel). (Image courtesy of Cheryl Wellington)

Furthermore additional CNS effects were demonstrated in the ApoA-I knockout mice: CAA and behavioral deficits increased, while in overexpressing ApoA-I transgenic mice CAA decreased. These findings support the idea that ApoA1 has a beneficial effect on the CNS.

Novel probes developed by the company Accent Assays can be used to measure the exchange of lipid free ApoA1, on and off HDL particles. The assays can also help distinguish healthy patients from those with metabolic syndromes or diabetes. Future studies on cohorts with AD, an MCI with and without diabetes can help further explore their effectiveness. Because HDL dysfunction underlies many diseases including those known to be comorbid with AD, like type-2 diabetes, a method by which to measure HDL functionality has many potential uses.