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Advisory Council July 2015 Meeting Presentation: Vascular Contributions to Dementia

Monday, July 27, 2015

Vascular contributions to dementia: A path to prevention

Rebecca F. Gottesman, MD PhD
Associate Professor of Neurology and Epidemiology
Johns Hopkins University

What is Vascular Dementia?

  • Also called “Multi-infarct dementia”; other types include subcortical vascular dementia, genetic vascular dementias (CADASIL)
  • Classically defined as rapid onset, stepwise progression of symptoms
    • Sometimes occurring after a stroke, but often not
    • Diagnosis requires cognitive disorder AND either clinical stroke or brain vascular disease by neuroimaging (Gorelick et al., 2011)
  • Patients often have problems with attention and executive function; memory may not be affected
  • Clinically it is the second leading cause of dementia (~20% of dementia cases), occurring in 14.6 per 1000 person-yrs (vs 19.2 for AD) (Fitzpatrick et al., 2004)
MRI of brain.


Vascular contributions to dementia may be relevant in a much larger percentage of patients with dementia

Overlapping circles: left, smaller, labeled Vascular dementia; right, larger, labeled Alzheimer's disease; center area labeled Mixed dementia

Vascular and AD overlap: Autopsy evidence

  • Between 55-80% of AD patients have coincident vascular changes in the brain (Bangen et al., Alzheimers & Dementia 2015; Toledo et al., Brain 2013)
  • Multiple studies have found less AD neuropathological changes (plaques, tangles) in patients with vascular changes for an equivalent level of cognitive impairment
Stacked bar chart.
Modified from Toledo et al, Brain 2013
(VP: Vascular Pathology; AD: Alzheimer's Disease)

Possible explanations for a vascular/ AD connection

  • Vascular disease and Alzheimer’s changes are additive, leading to worse cognition when both are present, OR
  • Vascular disease directly leads to AD neuropathological changes

Mechanisms for a vascular/ AD interaction

  • Vascular risk factors lead to alterations in cerebral blood vessels and can lead to low cerebral blood flow, especially in the white matter of the brain
  • The blood brain barrier can be disrupted in the presence of vascular disease
  • Role of the neurovascular unit: Amyloid-ß itself may directly damage blood vessels, further worsening cerebral blood flow (Iadecola)
  • Vascular disease may make clearance of amyloid-ß harder; the “glymphatic system” is around blood vessels and helps remove brain waste (Nedergaard)
Iadecola, Neuron 2015

What do we mean by “vascular disease”?

  • Vascular contributions to dementia include:
    • Vascular risk factors (hypertension, diabetes, smoking, high cholesterol)
    • Microvascular markers (retinal microvascular changes)
    • Macrovascular markers (carotid artery disease)
    • Clinical strokes
    • Brain changes on MRI or on autopsy
      • Brain infarcts
      • White matter ischemic changes
      • Microbleeds
MRI of brain. MRI of brain. MRI of brain.


  • Associations between vascular risk factors and cognitive decline
  • Associations between stroke and cognitive decline
  • Associations between vascular risk factors, brain MRI changes and cognitive decline
Chart: Vascular risk factors. Leads to Brain vascular changes: white matter changes, silent stroke; or Stroke. Leads to Cognitive decline. Leads to Dementia?

Hypertension and Diabetes are Each Associated with Steeper Cognitive Decline

Figure 2. Adjusted Association of Visit 2 (1990-1992) Systolic Blood Pressure Categories and Linear Systolic Blood Pressure With 20-Year Cognitive Change Among Whites
Several line charts.
Gottesman et al., JAMA Neurology 2014


Figure 2. Difference in global cognitive Z score decline by clinical category of HbA1C level compared with decline in persons without diabetes and HbA1C level <5.7%.
High/low chart.
Rawlings et al., Ann Intern Med 2014

Worse cognitive performance noted after stroke (REGARDS study)

Figure 2. Predicted mean Change in Cognitive Function Test Scores Before and After Acute Stroke at Year 3: REGARDS Study, 2003-2013
Several line charts.
From Levine et al., JAMA 2015

Blood Pressure and White-Matter Disease Progression in a Biethnic Cohort

Atherosclerosis risk in Communities (ARIC) Study

Rebecca F. Gottesman, MD, PhD; Josef Coresh, MD, PhD; Diane J. Catellier, DrPH; A. Richey Sharrett, MD, DrPH; Kathryn M. Rose, PhD; Laura H. Coker, PhD; Dean K. Shibata, MD; David S. Knopman, MD; Clifford R. Jack, MD; Thomas H. Mosley, Jr, PhD

Bar chart.
Stroke. 2010;41:3-8.

Worse cognitive performance is found in people with brain vascular changes

Several line charts.
Jokinen et al., Cerebrovasc Dis 2009 (LADIS Study)

ApoE and vascular disease: A synergistic effect?

Bar chart.
Rodrigue et al., JAMA Neurol 2013

Why is the vascular contribution to dementia and AD so important?

  • Vascular disease is preventable
  • Vascular disease is very common
  • Therefore, this may be a way to prevent AD and other dementia cases

Prevention of vascular disease and AD

USA   Prevalence*   PAR (95% CI) Number of attributable
  cases in 2010 (95% CI)†  
Diabetes mellitus 10.3% 4.5% (2.0-7.3) 240 (107-389)
Midlife hypertension 14.3% 8.0% (2.2-15.1) 435 (119-798)
Midlife obesity 13.1% 7.3% (4.3-10.8) 386 (226-570)
Physical inactivity 32.5% 21.0% (5.8-36.6) 1115 (308-1942)
Depression 19.2% 11.1% (7.5-15.0) 588 (395-796)
Smoking 20.6% 10.8% (3.0-19.8) 574 (159-1050)
Low educational attainment   13.3% 7.3% (4.4-10.3) 386 (236-544)
Combined --   52.7% (25.9-72.8)   2796 (1374-3858)
Adjusted combined -- 30.6% (14.5-45.3) 1622 (771-2401)
† in thousands

Combined vascular risk factors account for 9.6 million additional cases of AD worldwide

2 line charts.
From Norton et al., Lancet Neurology 2014

Future directions in the study of vascular contributors to Alzheimer’s Disease

  • Evaluation of shared genetic risks, or differences in genetic factors that effect an individual’s susceptibility to vascular disease and/or AD
  • Study of racial disparities in AD prevalence, which may be partially attributable to differences in vascular disease
  • Use of neuroimaging, animal models to further explore mechanism of an additive versus synergistic effect of vascular disease and AD
NEJM 2009; 360(17):1718-28.


MRI of brain.
Gottesman & Hillis, Lancet Neurology, 2010

Thanks for your attention.