The Tangled Story of Plaques and Arteries

Newman et al., in their article entitled ‘‘Dementia and Alzheimer’s Disease Incidence in Relationship to Cardiovascular Disease in the Cardiovascular Health Study Cohort,’’ have examined associations between cardiovascular disease, other than stroke, in older adults with dementia and Alzheimer’s disease (AD). This study joins a number of others that question the basic origins of AD. There is increasing evidence of an association between AD and atherosclerosis, as well as with a number of risk factors for atherosclerotic disease. The nature of this association remains unclear. It has been suggested that vascular factors that lead to brain hypoperfusion, discrete microinfarctions in the brain, or direct toxic effects of the same risk factors that lead to atherosclerosis acting on the microvasculature of susceptible brain regions such as the medial temporal lobe actually cause AD. It has also been suggested that AD and atherosclerosis are independent processes with common elements in the causative pathway. An alternative explanation is that the presence of vascular disease or stroke (subclinical or clinically diagnosed) accelerates the decline in cognitive function in those with already existing subclinical AD. Thus, the clinical recognition of AD occurs at an earlier point than it might otherwise. It is likely that more than one of these pathologies affects what is seen clinically in the patient. Perhaps different combinations of factors contribute to an apparently similar clinical course in different patients. The fact that atherosclerotic-related diseases and AD only become clinically apparent after a lengthy period in which subclinical disease is present but not diagnosed significantly complicates understanding which factors are involved, and to what extent. Pathologic studies have confirmed that brains in young individuals can exhibit the neuropathological changes associated with AD. Studies have also revealed that teenagers may have asymptomatic beginnings of atherosclerosis. Measures of subclinical atherosclerosis, such as the arterial brachial index and intimal medial thickness measured using carotid ultrasound, as well as coronary calcium detected using computed tomography scan, have become available for the diagnosis of subclinical atherosclerosis, but there is no similar diagnostic procedure for AD. Although the rate of medial temporal lobe atrophy in the brain as determined using magnetic resonance imaging is predictive of AD under research conditions, it is not specific for AD and therefore cannot be used as conclusive evidence for AD. There is little question that vascular dementia (VaD) and clinical stroke have similar relationships to atherosclerotic risk factors. If VaD was a large proportion of the reported total dementia in a population, it would not be surprising that atherosclerotic risk factors were related to total dementia. A high prevalence of VaD misdiagnosed as AD could conceivably lead to results indicating that dementia overall was related to atherosclerotic risk factors. Thus, it is important to differentiate dementia into subtypes in the process of investigating the relationship between atherosclerosis and its risk factors for dementia. As in the study reported by Newman et al., in most studies, the classification of dementia is accomplished using clinical and neuropsychological examinations and testing in addition to medical imaging studies. Nevertheless, many of the various clinical diagnostic criteria used to classify dementia into subcategories have subjective elements and are dependent on subjective interpretation. It is becoming increasingly apparent that a large proportion of individuals who have dementia have mixed dementia, defined as having features of both VaD and AD. Ultimately the criterion standard for the diagnosis of dementia is the presence of plaques and tangles in the appropriate areas of the brain. This can only be confirmed by pathologic examination after death. Thus, for most studies, pathologic confirmation is not an option, and risk factor associations are determined based on a clinical diagnosis. The risk factors for atherosclerosis are well established. The association between these factors and risk for AD is less clear, but the overlap between the well-defined risk factors for atherosclerosis and those more recently associated with dementia or AD is significant. Although the importance of most of these factors in AD pathogenesis is not as well established, prospective population-based studies of the long-term risk attributable to exposures in middle age suggest that an association exists between most atherosclerotic risk factors and AD. In the Honolulu Asia Aging Study, low-level chronic inflammation (measured using a high-sensitivity assay of C-reactive protein), high-density lipoprotein cholesterol, apolipoprotein E e4, diabetes mellitus metabolic syndrome, and blood pressure were found to be related to AD. Several of these were ascertained using pathologic confirmation in the unique autopsy study associated with the study. Others have reported similar findings, and in addition, cholesterol, homocysteine, smoking, increased fat intake, and obesity have also been related to AD. Factors that may modify and confound associations are also central to understanding these relationships, but in complex situations such as that existing for the association seen between atherosclerosis and dementia in older people, caution in interpreting the effects of these factors is needed. For example, because of the consistent and significant DOI: 10.1111/j.1532-5415.2005. 53365.x