Slide 31

WHITE MATTER LESIONS

1) Long-standing hypertension

2) Hyalinisation of vessel walls

3) Decreased vessel lumen

4) Episodes of hypotension

5) Hypoperfusion/ischemia in vulnerable areas (Deep white matter supplied by long penetrating end-arteries with few collaterals)

6) Demyelination

7) Disconnection of subcortical-cortical association pathways

8) Subcortical dementia

Slide 32

WHITE MATTER LESIONS IN RELATION
TO DEMENTIA IN 85-YEAR-OLDS

Ref. Skoog et al. J Geriatr Psychiatry Neurol 1994

Slide 33

WHITE MATTER LESIONS IN ALZHEIMER'S DISEASE

Slide 34

ODDS RATIO FOR DEMENTIA IN RELATION TO
WMLs AND APOEe4 STATUS IN 85-YEAR OLDS

Skoog, Blennow et al
J Neurol Neurosurgy Psychiatr 1998

Slide 35

VASCULAR RISK FACTORS IN ALZHEIMER'S DISEASE

Hypertension
ApoE e4 allele
Generalized atherosclerosis
Coronary heart disease
Changes in cardiac innervation
Atrial fibrillation
Diabetes mellitus
Stroke
Ischemic white matter lesions
Changes in cerebral microvessels

Skoog 1997

Slide 36

MICROVASCULAR CHANGES AND ALZHEIMER'S DISEASE

• Endothelial degeneration
• Cerebral amyloid angiopathy
• Loss of the perivascular neural plexus
• Changes in the capillary wall structure

Slide 37

POSSIBLE MECHANISMS FOR THE ASSOCIATION BETWEEN
ALZHEIMER'S DISEASE AND VASCULAR FACTORS

• Overdiagnosis of Alzheimer's disease in cases of vascular dementia
  
• Cerebrovascular disease affects the clinical expression of Alzheimer's disease
  
• Shared pathogenesis
  
• Vascular disease causes or stimulates Alzheimer's disease
  
• Alzheimer's disease causes or stimulates vascular diseases

Slide 38

PROPORTION OF VASCULAR DEMENTIA
USING DIFFERENT CRITERIA

Ref. Wetterling et al Stroke 1996

Slide 39

Slide 40

POSSIBLE MECHANISMS FOR THE ASSOCIATION BETWEEN
ALZHEIMER'S DISEASE AND VASCULAR FACTORS

• Overdiagnosis of Alzheimer's disease in cases of vascular dementia
  
• Cerebrovascular disease affects the clinical expression of Alzheimer's disease
  
• Shared pathogenesis
  
• Vascular disease causes or stimulates Alzheimer's disease
  
• Alzheimer's disease causes or stimulates vascular diseases

Slide 41

DEMENTIA IN INDIVIDUALS WITH AD
NEUROPATHOLOGY (THE NUN STUDY)

Slide 42

POSSIBLE MECHANISMS FOR THE ASSOCIATION BETWEEN
ALZHEIMER'S DISEASE AND VASCULAR FACTORS

• Overdiagnosis of Alzheimer's disease in cases of vascular dementia
  
• Cerebrovascular disease affects the clinical expression of Alzheimer's disease
  
• Shared pathogenesis
  
• Vascular disease causes or stimulates Alzheimer's disease
  
• Alzheimer's disease causes or stimulates vascular diseases

Slide 43

SHARED PATHOGENIC PATHWAYS
BETWEEN AD AND VASCULAR DISORDER

• Apolipoprotein e4
  
• Oxidative stress
  
• Disturbance in the renin-angiotensin system
  
• Apoptosis
  
• Psychological stress

Slide 44

APOLIPOPROTEIN E (APOE)

Three different alleles (Apo e2, e3, e4)
Three isoforms (ApoE2, E3, E4)
Six different phenotypes

ApoE4 associated with:

Increased Cholesterol
Increased LDL
Coronary heart disease
Atherosclerosis
Alzheimer's disease

Slide 45

SHARED PATHOGENIC PATHWAYS
BETWEEN AD AND VASCULAR DISORDER

• Apolipoprotein e4
  
• Oxidative stress
  
• Disturbance in the renin-angiotensin system
  
• Apoptosis
  
• Psychological stress

Slide 46

The Renin-Angiotensin System

--> Vasoconstriction
Aldosterone secretion
Sodium retention
Sympathetic nervous system
Hyperplasia/hypertrophy in vascular smooth muscle cells

Slide 47

THE RENIN-ANGIOTENSIN SYSTEM IN THE BRAIN

--> Tonic control over blood pressure
Autoregulation of CBF
Impair memory functions
Other behaviors

Slide 48

ALZHEIMER'S DISEASE

ACE activity in the brain increased
Arregui et al.
J Neurochem 1982
Barnes et al.
Eur J Pharmacol 1991

ACE activity in CSF decreased
Zubenko et al.
Brain Res 1985

Slide 49

SHARED PATHOGENIC PATHWAYS
BETWEEN AD AND VASCULAR DISORDER

• Apolipoprotein e4
  
• Oxidative stress
  
• Disturbance in the renin-angiotensin system
  
• Apoptosis
  
• Psychological stress

Slide 50

OXIDATIVE STRESS

Free radical production increased
and/or
Antioxidant defenses decreased

Slide 51

OXIDATIVE STRESS

• Normal atom
  contains paired electrons
• Free radical
  contains unpaired electron
  
  Superoxide
  Hydroxyl
  Nitric oxide
  (endothelial relaxing factor)
  Lipid peroxide
• Reactive oxygen species
  Oxygen-centered free radicals
  Non-radical oxygen derivates
  - hydrogen peroxide
  - hypochlorous acid

Slide 52

DAMAGE TO MOLECULAR TARGETS
BY FREE RADICAL CHAIN REACTIONS

FREE RADICALS (X·) ATTACK NONRADICALS (Y) BY

a) Addition
x· + y --> [x - y]·

b) Electron donation
x· + y --> y·- + x+

c) Electron removal
x + y --> x- + y·+

Slide 53

OXIDATIVE STRESS IN HUMAN DISEASE

Tissue damage (e.g. ischemia) --> Reactive oxygen species increase -->

Free radicals increase --> Damage to proteins, DNA, lipids -->

Cell death

Slide 54

OXIDATIVE STRESS AND FREE RADICALS INVOLVED IN:

• Atherosclerosis
• Early hypertension
• Coronary heart disease
• Stroke (ischemia)
• Alzheimer's disease
• Etc., etc.

Slide 55

OXIDATIVE STRESS

Beta-amyloid -->

Receptor for advanced glycation end products (RAGE)
on neurons, microglia, vascular endothelium -->

Reactive oxygen species -->

Damage neurons
Damage the endothelial lining

Yan et al., Nature 1996

Slide 56

SHARED PATHOGENIC PATHWAYS
BETWEEN AD AND VASCULAR DISORDER

• Apolipoprotein e4
  
• Oxidative stress
  
• Disturbance in the renin-angiotensin system
  
• Apoptosis
  
• Psychological stress

Slide 57

APOPTOSIS

Stimulation -->

Internally encoded suicide program in differentiated cells -->

Apoptosis

• Changes in the cytoplasm
• Fragmentation of chromatin
• Cell membranes preserved

Slide 58

APOPTOSIS

• Beta-amyloid+
• Glucocorticoids+
• Free radicals +
• Glutamate +
• Dopamine +
• Ischemia +
• Estrogen +

Slide 59

APOPTOSIS IN THE BRAINS OF
SPONTANEOUSLY HYPERTENSIVE RATS

• Cortex
• Striatum
• Hippocampus
• Thalamus

Hamet et al. Hypertension 1995

Slide 60

SHARED PATHOGENIC PATHWAYS
BETWEEN AD AND VASCULAR DISORDER

• Apolipoprotein e4
  
• Oxidative stress
  
• Disturbance in the renin-angiotensin system
  
• Apoptosis
  
• Psychological stress

Slide 61

HYPOTHESIS

Stress

• Glucocorticoids
• Immunological factors
• Hypertension

Slide 62-63

Slide 64

POSSIBLE MECHANISMS FOR THE ASSOCIATION BETWEEN
ALZHEIMER'S DISEASE AND VASCULAR FACTORS

• Overdiagnosis of Alzheimer's disease in cases of vascular dementia
  
• Cerebrovascular disease affects the clinical expression of Alzheimer's disease
  
• Shared pathogenesis
  
• Vascular disease causes or stimulates Alzheimer's disease
  
• Alzheimer's disease causes or stimulates vascular diseases

Slide 65

MICROVASCULAR CHANGES
IN ALZHEIMER'S DISEASE

• Endothelial degeneration
• Cerebral amyloid angiopathy
• Loss of the perivascular neural plexus
• Changes in the capillary wall structure

Slide 66

BLOOD BARRIER DYSFUNCTION
IN ALZHEIMER'S DISEASE

• Chronic hypertension
  - increased vascular permeability
  - protein extravasation
  Johannson BB. Dementia 1994
  Nag S. Acta Neuropathol 1984
  
• Extravasated plasma proteins in brain
  parenchyma of AD patients
  Eikelenboom et al. Acta Neuropathol (Berlin) 1982
  Licandro et al. Riv Pat Nerv Ment 1983
  Wisniewski et al. Ann NY Acad Sci 1982

Slides 67-69

Slide 70

POSSIBLE MECHANISM BY WHICH
VASCULAR RISK FACTORS MAY CAUSE
ALZHEIMER'S DISEASE

Chronic hypertension, diabetes mellitus -->

Increased vascular permeability -->

Protein extravasation -->

Extravasated plasma proteins -->

Interaction with brain parenchyma -->

"Amyloid cascade"

Slide 71

POSSIBLE MECHANISMS FOR THE ASSOCIATION BETWEEN
ALZHEIMER'S DISEASE AND VASCULAR FACTORS

• Overdiagnosis of Alzheimer's disease in cases of vascular dementia
  
• Cerebrovascular disease affects the clinical expression of Alzheimer's disease
  
• Shared pathogenesis
  
• Vascular disease causes or stimulates Alzheimer's disease
  
• Alzheimer's disease causes or stimulates vascular diseases

Slide 73

Cerebral amyloid angiopathy -->

Hypertension -->

Cerebral infarctions in
patients with Alzheimer's disease

Olichney et al., Arch Neurol 1995; 52:702-708

Slide 74