Virtually 90% of the elderly with late-onset dementia exhibit neuropathological features consistent with Alzheimer's disease (AD), vascular dementia (VaD) or dementia with Lewy bodies (DLB), alone or in combination. Both AD and DLB reveal extensive senile plaques containing amyloid [beta] whereas neurofibrillary tangles evident as tau pathology are fewer in DLB, which also bears diffuse cortical Lewy bodies. Interestingly, however, there is considerable overlap between AD and VaD in terms of both risk factors and pathology. Cholinergic deficits are also encountered in VaD, which like AD may respond to cholinergic therapy. Cerebrovascular pathology, ischemic brain damage and autonomic dysregulation resulting in cerebral hypoperfusion appears fundamental in the pathogenesis of late-onset dementias. [Neural Res 2003; 25: 66V664]
Keywords: Alzheimer's disease; cerebrovascular disease; cognitive impairment; dementia with Lewy bodies; vascular dementia; vascular disease
INTRODUCTION
Alzheimer's disease (AD) is the most common form of dementia. It is estimated to comprise 45%-55% of elderly cases. In Japan 50% of the dementia cases are thought to be due to cerebrovascular disease. In developed countries the prevalence of AD is estimated at 3%-11% in 65-year-olds and expected to double every decade thereafter. The prevalence is generally less than 3% in developing and economically impoverished countries. Vascular dementia (VaD), resulting from cerebrovascular disease, also shows similar increases in old age comprising 15%-25% of all dementia cases. It is of interest that 60%-80% of those with mild cognitive impairment will succumb to one of the age-related dementing illnesses.
COMMON RISKS AND FEATURES OF THE DEMENTIAS
Recent considerations suggest that in addition to age, late onset dementias may share several features (Figure 1). This is in keeping with the view that neurodegenerative disorders are part of a complex continuum in concert with aging. Whereas the risk for AD is significantly increased by the presence of Down's syndrome or early-onset AD in the family, head trauma, peripheral vascular disease, heart disease and the apolipoprotein E (APOE)-[epsilon]4 allele, VaD risk is increased by systemic and brain vascular disease. Other factors that have been linked to AD are smoking, parental age at birth, previous history of depression, hypothyroidism, low level of education, occupational attainment and activities in early and middle adult life1,2. The role of gender is not entirely clear but current studies suggest women may have higher susceptibility to AD than men although VaD is more common in men. According to life table studies the higher risk of AD in women than men is not due to greater longevity in women but likely other factors such as estrogen, independently or in concert with certain APOE genotypes3.
Protective factors considered for AD and dementias like VaD include mental and physical activity, hormonal and replacement therapy, nonsteroidal anti-inflammatory medication4 and large head size. Diet and calorie restriction5 have received little attention but independent studies have suggested that fat intake may be a risk factor6 and dietary intake of antioxidant vitamins may be protective for dementia7. Interestingly, recent epidemiological studies suggested that moderate consumption of red wine8 or alcohol9 is protective for AD. It is clear that acquisition of these illnesses entails interaction of both hereditary and environmental factors.
Although the early features of cognitive impairment are considered to be different in AD and VaD, there appears substantial degree of overlap in both clinical and pathological features (Table 1). For example, microvascular lesions and white matter abnormalities may be manifest in AD besides VaD. Alternatively, VaD may not necessarily be free from AD lesions. Similarly, cholinergic neuronal deficits are also evident in VaD.
CEREBROVASCULAR DISEASE, AD AND VaD
Longitudinal studies suggest strong association between vascular factors pre-disposing to cerebrovascular disease and AD. Stroke or severe transient ischemic attacks are three times more likely to increase the risk for acquiring AD. Vascular risk factors such as hypertension, atrial fibrillation, carotid thickening, aortic sclerosis and diabetes10 can substantially increase risk to AD in the elderly over the age of 60 years. Furthermore, brain vascular and neurodegenerative pathologies may be additive in the way in which they influence clinical presentation11.
Available evidence shows that VaD and AD share several pathological features12. At least 40% of patients meeting pathological criteria for VaD have concurrent AD pathology. Furthermore, our findings suggest that the age-related accretion of total extracted amyloid [beta]42 in the brains of VaD patients reaches concentrations similar to those in AD after age 75 years13. Other studies have shown that increases in lumbar cerebrospinal fluid tau are not restricted to AD but also evidently increased in various forms of VaD compared to those in nondemented elderly controls14. A large proportion of AD patients also have significant cerebrovascular lesions, including cerebral amyloid angiopathy, macroscopic infarction, microinfarction, hemorrhage, white matter changes and small vessel disease or profound capillary degeneration15.
VaD is a heterogeneous condition with multiple contributing pathologies. Current studies do not provide a clear achetype of neuropathological and neurochemical substrates of VaD or how these interact to cause significant cognitive impairment11. Cognitive changes are common in elderly subjects with stroke but it is accepted that approximately 30% of stroke survivors develop dementia some months after the event indicating a ten-fold risk over a general population of similar age distribution. Cognitive decline and delayed dementia in stroke survivors also increases much more steeply with age than the risk of recurrent stroke. These findings emphasize that mechanisms other than acute ischemia are important. Interestingly, Nolan et al.16 reported that 87% of VaD diagnosed patients were found to have either AD alone (58%) or in combination with cerebrovascular disease (42%) at autopsy. All of the patients with signs of cerebrovascular disease were also found to have some concomitant neurodegenerative disease.
Recent observations suggest the risk of subsequent dementia is sharply increased in patients with lacunar infarct rather than macroinfarction. Indeed, diffuse white matter changes, microinfarction (
Diffuse neurochemical abnormalities, especially cholinergic deficits in areas distant from the site of infarction, have been identified in VaD or multi-infarct dementia19. The mechanisms of these changes, and their contribution to dementia, have not been investigated. Cholinergic deficits appear central to the cognitive deficits in AD but cholinergic mechanisms are also important in regulating cerebral blood flow10. Given the potential complexity of these interactions, cholinergic replacement therapies may have an important role in vascular and 'mixed dementias' in addition to AD. In addition, deficits in cortical synaptophysin immunoreactivity in VaD of the Binswanger's type were also found to be comparable to AD20. These findings not only suggest that axonal degeneration occurs in VaD as evident in AD but support the notion that ischemic or oligemic events may be early events that lead to increases in recognised markers of Alzheimer pathology.
CONCLUSION
AD and VaD are among the most common causes of dementia as a continuum which shares several features including systemic vascular disease, cardiovascular dysregulation, genetic influences and neuropathological changes such as loss of cholinergic neuronal markers. These common features will be of importance in devising appropriate treatment or preventative measures in the progression of the dementias and to afford brain protection.
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Raj N. Kalaria
MRC, Newcastle General Hospital, Newcastle upon Tyne, UK
Correspondence and reprint requests to: Prof. R. N. Kalaria, Wolfson Centre, Institute for Ageing and Health, Newcastle General Hospital, Westgate Road, Newcastle upon Tyne NE4 6BE, UK.
[r.n.kalaria@ncl.ac.uk] Accepted for publication April 2003.
Copyright Forefront Publishing Group Sep 2003
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