Future Clinical Trials to Test Promising Approaches for Reducing Vascular Contributions to Cognitive Impairment and Dementia

November 4 - 5, 2019
NIH Neurosciences Building, Room NSC 2172, Bethesda, MD


The National Heart, Lung, and Blood Institute (NHLBI); the National Institute of Neurological Disorders and Stroke (NINDS); and National Institute on Aging (NIA) convened a multidisciplinary working group on Future Clinical Trials to Test Promising Approaches for Reducing Vascular Contributions to Cognitive Impairment and Dementia (VCID). The objectives of the working group are to examine lessons learned from recently completed VCID trials and the promise of ongoing trials, and to identify gaps and opportunities for additional trials that may deliver more potent interventions, including both pharmacological and lifestyle interventions that target vascular and other risk factors.



Dementia is a constellation of neurodegenerative disorders characterized by cognitive impairment that is sufficiently severe to interfere with daily function. The societal burden of dementia is expected to increase in the U.S. and globally in the foreseeable future. Alzheimer’s Disease (AD) is the most common dementia diagnosis, with an estimated 5.8 million Americans currently living with the disease. Growing evidence suggests that dementia has mixed pathology. Clinical AD often has vascular pathology, and epidemiological studies suggest that up to one-third of cases of dementia may be attributed to modifiable vascular risk factors such as smoking, blood pressure, blood sugar, cholesterol, diet, and exercise. Thus, vascular contributions to cognitive impairment and dementia (VCID) are an important target for prevention trials. The Systolic Blood Pressure Intervention Trial (SPRINT) Memory and Cognition in Decreased Hypertension (SPRINT MIND) results showed that intensive lowering of blood pressure reduced risks for mild cognitive impairment (MCI), but did not significantly reduce dementia risk. It is possible that treatment of any single vascular risk factor may be insufficient to cause a large reduction in the risk of clinically significant cognitive impairment or dementia.  The Finnish FINGER trial suggested that interventions on multiple vascular risk factors may need to be targeted, including physical activity, nutritional counseling, and cognitive and social stimulation. The FINGER trial provided the impetus for the U.S. POINTER trial, which is currently underway.  

Working Group Purpose and Objectives

This workshop is timely given that the  NIH Alzheimer’s Disease-Related Dementias Summit in 2019 highlighted the need for clinical trials addressing VCID. The main goal of the workshop was to determine if there are compelling research opportunities for clinical trials to test single or combined interventions for the primary and secondary prevention of vascular contributions to VCID and that align with the following Summit recommendations under the Human-Based Studies focus area.  

  • Develop, validate and longitudinally track: (1) cognitive, physical, or other functional assessment components that indicate the presence of VCID; (2) VCID biomarkers, including when VCID is accompanied by pathological AD (3-5 y).
  • Test for efficacy across the spectrum of VCID severity: (1) interventions proven to reduce cardio- and cerebrovascular risk; (2) established care models (3-5 y).

Concise Summary of Discussions

Rich interdisciplinary discussions were held to inform the design of future clinical trials and also to sharpen the needs for additional epidemiological and basic science studies. Presentations and discussions were centered around the following areas.  

  • What are the most important unanswered scientific questions from the current epidemiological studies and recently completed trials that address VCID risk factors for the prevention of cognitive impairment and dementia?
  • What questions are being answered by some of the ongoing trials, including the rrAD, U.S. POINTER, MIND, and SMARRT trials?
  • What is known about mechanisms of VCID that can inform VCID trials, and what are the opportunities to address mechanistic hypotheses in future VCID trials?

The working group identified several important questions that might be answered by new trials as well as challenges and research opportunities.  

  • In future trials of younger participants who are at lower risk for MCI and dementia, validated surrogate markers of MCI and dementia with good correlation to clinical outcomes would be useful trial endpoints. Although there has been progress in developing validated biomarkers, currently there are limitations for their use as primary outcome measures in efficacy trials.
  • In future trials involving high-risk participants, it may be useful to combine MCI and dementia endpoints.   
  • Continuous measures of cognitive function have been used in observational studies, but their utility in efficacy trials has not yet been established .   

Publication Plans

The meeting participants will develop a workshop report for publication in a peer-reviewed journal. The report will highlight discussions that occurred at the workshop and the research opportunities identified by the working group.

NHLBI Contact

Lawrence J. Fine, MD, DrPH
Division of Cardiovascular Sciences, NHLBI

Working Group Participants


  • Rebecca Gottesman, MD, PhD, Johns Hopkins University 
  • Jeff D. Williamson, MD, MHS, Wake Forest School of Medicine

Organizing Committee

  • Jue Chen, MB, PhD, NHLBI   
  • Roderick A. Corriveau, PhD, NINDS
  • Lawrence J. Fine, MD, DrPH, NHLBI  
  • Jordan T. Gladman, PhD, NINDS
  • Kristina A McLinden, PhD, NIA
  • Claudia S. Moy, PhD, NINDS
  • Laurie Ryan, PhD, NIA
  • Joni Snyder, RN, BSN, MA, NHLBI

Presenters and Discussants

  • David C. Goff, Jr., MD, PhD, NHLBI
  • Clinton B. Wright, MD, MS, NINDS 
  • Eliezer Masliah, MD, NIA  
  • Rebecca Gottesman, MD, PhD, Johns Hopkins University 
  • Jeff D. Williamson, MD, MHS, Wake Forest School of Medicine
  • Rong Zhang, PhD, University of Texas Southwestern Medical Center
  • Rachel Whitmer, PhD, University of California Davis
  • Eric B. Larson, MD, MPH, Kaiser Permanente
  • Steven M. Greenberg, MD, PhD, Massachusetts General Hospital and Harvard Medical School
  • David S. Knopman, MD, Mayo Clinic
  • Karen Bandeen-Roche, PhD, Johns Hopkins University
  • Lenore Joy Launer, PhD, NIA
  • Eric Smith, MD, MPH, University of Calgary
  • Ann Marie Navar, MD, PhD, Duke University
  • Jackson T. Wright, Jr., MD, PhD, Case Western Reserve University
  • Cora E. (Beth) Lewis, MD, MSPH, University of Alabama at Birmingham
  • Donna Wilcock, PhD, University of Kentucky
  • Jin-Moo Lee, MD, PhD, Washington University 

Scholar Awardees

  • C. Elizabeth Shaaban, University of Pittsburgh
  • Allision Arai, University of Maryland
  • Behnam Sabayan, Northwestern University
  • Faria Sanjana, University of Delaware
  • Lauren Oberlin, Weill Cornell Medicine
  • Michael Maniskas, University of Texas Health Sciences Center
  • Swathi Gujral, University of Pittsburgh
  • Kristen George, University of California, Davis
  • Rebecca Fleeman, Penn State College of Medicine
  • Theodore DeConne, University of Delaware

Other Attendees

  • Marc Charette, PhD, NHLBI
  • Zorina Galis, PhD, NHLBI
  • Lijuan Liu, PhD, NHLBI
  • Michelle Olive, PhD, NHLBI
  • Heather Snyder, PhD, Alzheimer’s Association