This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Identifying remediable risk factors and developing strategies for preventing age-related cognitive decline and dementia in diverse population groups is an urgent public health priority. We have developed both retrospective and prospective methods for distinguishing individuals with normal cognitive aging and individuals with preclinical dementia focusing on Alzheimer's disease (AD) as well as AD and Vascular Dementia (VaD) in combination, a condition we refer to as AD/VaD. We have retrospectively identified three stages in the evolution of AD and AD/VaD using change point models: a stage of relative cognitive stability, a stage of accelerated cognitive decline, and a stage of diagnosable dementia. The progression to dementia is often conceptualized in a stages of disease model. We consider cognitive stability, cognitive impairment (ACI and NACI), and dementia as crucial stages in this model. Longitudinal aging studies usually focus on candidate risk factors for dementia rather than evaluating their influence on transitions from cognitive stability to cognitive impairment and from cognitive impairment to dementia. None-the-less, preventive interventions are usually tested using the implicit framework of a staging model. STAGING MODELS OF COGNITIVE DECLINE The application of staging models to the study of dementia is important for several reasons. A large group of individuals have Cognitive Impairment but do not meet criteria for dementia. Because subgroups of these individuals develop AD at elevated rates they have become the targets of intervention studies. As a consequence, most studies of intermediate stages, such as amnestic MCI, have been conducted in highly selected samples from memory disorder clinics or centers for dementia treatment. These studies have focused on individuals with prevalent MCI who have had the condition for an uncertain period. Other studies focus on clinically diagnosable dementia, ignoring intermediate states which precede diagnosis. If risk factors and protective factors have effects that depend critically on the stage of illness, risk factors for dementia from epidemiologic studies may not be effective in secondary prevention trials; they may well be effective in primary prevention. As a corollary, candidate interventions for secondary prevention should be identified in studies that examine the transition from intermediate stage to dementia. Thus, one of our goals is to provide a conceptual framework for linking the study of risk factors to prevention trials. CHANGE POINT MODELS The preclinical onset of AD and AD/VaD takes place over many years. Change point models use the time of dementia diagnosis as a temporal referent, retrospectively describing the preclinical course. We have identified three stages of decline in subjects who develop AD and AD/VaD. There is a stage of relative cognitive stability, a stage of accelerated cognitive decline, and a stage of clinically diagnosable dementia. This pattern of cognitive decline is obscured if age or study year are used as the temporal referent, rather than time of dementia diagnosis. While change point models rely on retrospective analysis, prospective definitions of intermediate cognitive stages are required for preventive interventions and have been proposed. Amnestic MCI is the most widely used conceptualization of the transitional phase between cognitive normality and dementia. The transition from amnestic MCI to dementia has been well studied in prevalent MCI cases identified in subspecialty centers. The transition from normal to MCI has been less well explored. As an alternative to amnestic MCI, we have defined an intermediate stage of memory impairment termed Amnestic Cognitive Impairment (ACI) using cut-scores that empirically predict future dementia. We use unadjusted memory cut-scores and included age and education as candidate predictors of dementia in our models; this approach more powerfully predicts the development of dementia than traditional definitions of MCI. Our definition of ACI is based on a cut-score of 24 on the Sum of Free Recall Score from the Free and Cued Selective Reminding Test (FCSRT). This approach does not require informant histories and is therefore simple to apply in a variety of clinical and research settings. It identifies a high-risk group with a prevalence of 21%, several times larger than the 5% prevalence of amnestic MCI in our sample (with a median age over 80) while maintaining a high conversion probability for dementia. Subjects with ACI develop dementia at the rate of about 10% per year. VASCULAR RISK FACTORS FOR COGNITIVE DECLINE AND DEMENTIA Growing evidence suggests that many remediable vascular risk factors (hypertension, diabetes, metabolic syndrome [MS], hyperlipidemia) are associated with cognitive decline and with the risk of AD, VaD and AD/VaD. In 1990, our group observed that myocardial infarction was a risk factor for AD in women. In post-mortem series, AD and vascular pathology commonly occur in the same individuals. Vascular risk factors may exert their influence on AD by increasing vascular lesions which may exacerbate cognitive decline related to AD pathology33 or by directly contributing to the progression of AD pathology. Diabetes and the MS have emerged as important risk factors for dementia and cognitive decline. Components of MS include insulin resistance, visceral adiposity, dyslipidemia, hypertension, elevated levels of inflammatory markers, as well as prothrombotic and inflammatory peptides. The influence of blood pressure on the risk of developing dementia may be age-dependent. In middle-aged individuals, hypertension has been reported to be an important risk factor for developing coronary heart disease and stroke. The relationship between blood pressure and the risk of dementia in older populations is less clear. Treatment of systolic hypertension in the elderly is associated with reduced incidence of dementia. On the other hand, blood pressure is said to decline in the years leading up to dementia. The association between hypotension and dementia in the elderly has been said to be dependent on cognitive status at the time of blood pressure measurement.38 The relationship of dyslipidemia to AD and dementia risk are limited and have yielded conflicting results. In a Dutch population-based study of 561 subjects age 85 or older, subjects in the lowest tertile of HDL levels had an elevated risk for a clinical diagnosis of dementia, which remained significant after controlling for a history of cardiovascular disease, stroke, education, gender, and age. Socioeconomic status (SES) is a complex variable that has several domains including education, income, wealth, occupation, and social prestige. In the field of cognitive aging and dementia, education has been the best studied of the indicators of SES. Education is a powerful predictor of cognitive function above and beyond the independent role of intelligence. To explain the inverse association between AD risk and education, Katzman (1993) postulated that higher levels of education increase neuronal synaptic complexity, and thus increasing the individual's 'cognitive reserve'. Greater reserve might be associated with a later diagnosis of clinical dementia than in subjects with lower education, but cognitive decline might be more rapid both before and after diagnosis. Consistent with this hypothesis, subjects with higher education have accelerated cognitive decline past the point of clinical diagnosis of dementia. Individuals with lower SES, based on measures other than education, also have a higher risk of AD. Occupational status and income also appear to be associated with cognitive function, independent of education. Race/ethnicity has been shown to influence the risk of cognitive decline and dementia although confounding by low SES may explain part of the association. In EAS data, the incidence of dementia in African Americans is 1.6 times higher than in Caucasians. In addition, type of dementia has been shown to vary by race; VaD and AD/VaD are more common in African American populations than in Caucasians. Because vascular risk factors, including hypertension, diabetes, the metabolic syndrome of aging, and hyperlipidemia occur with elevated prevalence in African Americans, race-related differences in vascular risk factors may contribute to differences in dementia incidence by race. BIOLOGICAL MARKERS Inflammation and Thrombosis: There is increasing evidence that inflammatory mechanisms may play an important role in the development of AD and AD/VaD. Systemic and local inflammatory responses not only play a role in cardiovascular disease and stroke, but also have been proposed as mechanisms in the initiation and progression of dementia. Several studies described increased levels of proinflammatory cytokines in the serum of AD patients. Raised levels of various inflammatory markers in the brains and serum in patients with AD have been noted. Large-scale prospective studies have shown that high-sensitivity C-reactive protein (hs-CRP) is a risk factor for vascular disease. Plasma A 42 and 40 may be useful plasma markers during the preclinical onset of AD. Accordingly, in collaboration with Stephen Younkin, at Mayo Clinic Jacksonville, we propose to measure Plasma A 42 and 40 using well established methods. Genetic Risk Factors The ApoE gene is well known to influence cognitive function and risk of neurodegenerative changes late in life; the high-risk allele, ApoE- 4, has direct effects and may also act as an effect modifier influencing the impact of exogenous insults. Apolipoprotein E is found in senile plaques and neurofibrillary tangles and growing evidence suggests that ApoE genotype influences the rate of cerebral amyloidogenesis. There is also emerging evidence that the influence of the 4 isoform may be mediated, in part, by its interaction with the amyloid peptide and promotion of amyloid deposition. The ApoE genotype is an independent risk factor for neuropsychological dysfunction in later life. It is 50% more common among African Americans than whites, yet the association of the ApoE- 4 allele with AD is weaker in African Americans and Hispanics than Caucasians.
SPECIFIC AIMS Aim 1: To examine the role of remediable vascular risk factors (i.e., hypertension, diabetes, metabolic syndrome, hyperlipidemia) on the transitions from relative cognitive stability to Cognitive Impairment and from Cognitive Impairment to AD as well as AD/VaD.
Aim 2 : To examine the role of sociodemographic and behavioral factors, especially engagement in cognitively stimulating activities, education, and race (in particular, African American vs. Caucasian) on transitions from relative cognitive stability to Cognitive Impairment and from Cognitive Impairment to AD as well as AD/VaD.
Aim 3 : To examine biological markers associated with transitions among the stages leading from relative cognitive stability to Cognitive Impairment and from Cognitive Impairment to AD as well as AD/VaD. Specifically we will focus on markers of inflammation/thrombosis (IL-6, CRP, homocysteine, fibrinogen), as well as plasma A 40 and A 42. We will also extract DNA and establish cell lines for current and future genetic analyses.
Aim 4 : To explore the influence of risk factors on rates of cognitive decline within the stage of normality and the stage of cognitive impairment.
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