Summary of Epidemiologic Findings

In the past 5 years, a rapidly accumulating epidemiologic literature suggests that classical and novel risk factors for cardiovascular disease - the leading cause of morbidity and mortality in the U.S. -- are also potent risk factors for cognitive decline and dementia. Simply stated, what's good for the heart is also good for the brain. Classical cardiovascular risk factors that appear to affect cognitive function adversely include hypertension, dyslipidemia, obesity, diabetes, and smoking. These factors are inversely associated with cognitive function in persons with and without a history of clinical cardiovascular disease. Subclinical atherosclerosis, as determined by ultrasound assessment of carotid stenosis or ankle-brachial blood pressure index, has also been shown to correlate inversely with cognitive function. Novel cardiovascular risk factors that have been linked to cognitive dysfunction in aging populations include inflammatory biomarkers such as the acute-phase reactant C-reactive protein and the cytokines interleukin-6 and tumor necrosis factor-alpha, as well as thrombotic markers such as fibrinogen and fibrin D-dimer.

Various hormones have been investigated as predictors of cognitive decline or dementia. Elevated levels of glucocorticoids, which are indicative of hypothalamic-pituitary-adrenal (HPA) axis dysregulation, have been inversely related to cognitive function, but findings have been inconsistent (for example, associations between urinary cortisol and cognitive function have been found in women but not men in the MacArthur Study of Successful Aging). The catecholamines epinephrine and norepinephrine have been examined in relation to total mortality and physical functional decline, but not (to our knowledge) to cognitive decline in large epidemiologic studies. The metabolic syndrome, a constellation of lipid and nonlipid metabolic risk factors closely linked with insulin resistance, and allostatic load, a broader concept that encompasses not only components of the metabolic syndrome but also glucocorticoid and catecholamine parameters, show promise as predictors of cognitive decline in a few community-based studies. Postmenopausal hormone therapy does not appear to protect against cognitive decline or dementia in large clinical trials.

Dietary factors, such as intake of antioxidant vitamins, folate and other B-vitamins, and omega-3 and omega-6 fatty acids, have been related to cognitive function in observational studies, but clinical trials are lacking. Light-to-moderate alcohol use appears to be protective in observational studies.

A high level of self-reported physical activity and a high level of cardiorespiratory fitness as assessed by a treadmill test have emerged as strong protective factors against cognitive decline in recent observational studies.

The past 5 years have also brought advances in our understanding of brain structural and functional correlates of cognitive decline or dementia, as well as genetic determinants of these outcomes.

General reviews/multiple risk factors:

Albert M, Jones K, Savage C, Berkman L, Seeman T, Blazer D, Rowe J. Predictors of cognitive change in older persons: MacArthur Studies of Successful    Aging. Psychol & Aging 1995;10: 578-589.

Anstey K, Christensen H. Education, activity, health, blood pressure and apolipoprotein E as predictors of cognitive change in old age: a review. Gerontology    2000;46:163-77.

Ball LJ, Birge SJ. Prevention of brain aging and dementia. Clin Geriatr Med 2002;18:485-503.

Berkman L, Seeman T, Albert M, Blazer D, Kahn R, Mohs R, Finch C, Schneider E, Cotman C, McClearn G, Nesselroade J, Featherman D, Garmezy N,    McKhann G, Brim G, Prager D, Rowe JW. High, usual and impaired functioning in community-dwelling older men and women: Findings from the MacArthur    Foundation Network on Successful Aging. J Clin Epidemiol 1993; 46: 1129-1140.

Breteler MM, Bots ML, Ott A, Hofman A. Risk factors for vascular disease and dementia. Haemostasis 1998;28:167-73.

Cerhan JR, Folsom AR, Mortimer JA, Shahar E, Knopman DS, McGovern PG, Hays MA, Crum LD, Heiss G. Correlates of cognitive function in middle-aged    adults. Atherosclerosis Risk in Communities (ARIC) Study Investigators. Gerontology 1998; 44:95-105.

Crimmins EM, Seeman T. Integrating biology into demographic research on health and aging. In Finch CE, Vaupel JW, Kinsella K (eds)., Cells & Surveys:    Should Biological Measures Be Included in Social Science Research? National Research Council, Commission on Behavioral and Social Sciences and    Education. Washington DC: National Academy Press, 2000.

DeKosky ST. Pathology and pathways of Alzheimer's disease with an update on new developments in treatment. J Am Geriatr Soc 2003; 51:S314-20.

Elias MF, Elias PK, Robbins MA, Wolf PA, D'Agostino RB. Cardiovascular risk factors and cognitive functioning: An epidemiologic perspective. In: SR    Waldstein SR, Elias MF (eds.), Neuropsychology of Cardiovascular Disease. Mahwah NJ: Lawrence Erlbaum Associates, 2001.

Fillit HM, Butler RN, O'Connell AW, Albert MS, Birren JE, Cotman CW, Greenough WT, Gold PE, Kramer AF, Kuller LH, Perls TT, Sahagan BG, Tully T.    Achieving and maintaining cognitive vitality with aging. Mayo Clin Proc 2002;77:681-96.

Kuller LH, Lopez OL, Newman A, Beauchamp NJ, Burke G, Dulberg C, Fitzpatrick A, Fried L, Haan MN.Risk factors for dementia in the Cardiovascular Health    Cognition Study. Neuroepidemiology 2003;22:13-22.

Knopman D, Boland LL, Mosley T, Howard G, Liao D, Szklo M, McGovern P, Folsom AR. Cardiovascular risk factors and cognitive decline in middle-aged    adults. Neurology 2001;56:42-8.

Lopez OL, Jagust WJ, DeKosky ST, Becker JT, Fitzpatrick A, Dulberg C, Breitner J, Lyketsos C, Jones B, Kawas C, Carlson M, Kuller LH. Prevalence and    classification of mild cognitive impairment in the Cardiovascular Health Study Cognition Study: part 1. Arch Neurol 2003;60:1385-9.

Lopez OL, Jagust WJ, Dulberg C, Becker JT, DeKosky ST, Fitzpatrick A, Breitner J, Lyketsos C, Jones B, Kawas C, Carlson M, Kuller LH. Risk factors for    mild cognitive impairment in the Cardiovascular Health Study Cognition Study: part 2. Arch Neurol 2003;60:1394-9.

Waldstein SR, Elias MF. Introduction to the special section on health and cognitive function. Health Psychol 2003;22:55-8.

Zelinksi E, Crimmins E, Reynolds S, Seeman T. Do medical conditions affect cognition in older adults? Health and Psychology 1999;17:504-512.

Mechanisms by which psychosocial factors may affect cardiovascular disease, and, by extension, cognitive dysfunction:

Kaplan GA, Keil JE. Socioeconomic factors and cardiovascular disease: A review of the literature. Circulation 1993;88:1973-1998.

Knox SS, Uvnas-Moberg K. Social isolation and cardiovascular disease: an atherosclerotic pathyway? Psychoneuroendocrinology 1998;23:877-890.

Pickering T. Cardiovascular pathways: Socioeconomic status and stress effects on hypertension and cardiovascular function. In Adler NE, Marmot M,    McEwen BS, Stewart J (eds.), Socioeconomic Status and Health in Industrial Nations. Annals of the New York Academy of Sciences. 1999:262-277.

Uchino BN, Cacioppo JT, Kiecolt-Glaser JK. The relationship between social support and physiological processes: A review with emphasis on underlying    mechanisms and implications for health. Psychological Bulletin 1996;119:488-531.