- Email: [email protected]
Cardiovascular Disease Risk Factors and Cognitive Impairment
Cardiovascular Disease Risk Factors and Cognitive Impairment David T. Nash, MDa,*, and Howard Fillit, MDb The role of cardiovascular disease risk factors in the occurrence and progression of cognitive impairment has been the subject of a significant number of publications but has not achieved widespread recognition among many physicians and educated laymen. It is apparent that the active treatment of certain of these cardiovascular disease risk factors is accompanied by a reduced risk for cognitive impairment. Patients with hypertension who are treated experience fewer cardiovascular disease events as well as less cognitive impairment than similar untreated patients. Patients who exercise may present with less cognitive impairment, and obesity may increase the risk for cognitive impairment. Lipid abnormalities and genetic markers are associated with an increased risk for cardiovascular disease and cognitive impairment. Autopsy studies have demonstrated a correlation between elevated levels of cholesterol and amyloid deposition in the brain. Research has demonstrated a relation between atherosclerotic obstruction lesions in the circle of Willis and dementia. Diabetes mellitus is associated with an increased risk for cardiovascular disease and cognitive impairment. A number of nonpharmacologic factors have a role in reducing the risk for cognitive impairment. Antioxidants, fatty acids, and micronutrients may have a role, and diets rich in fruits and vegetables and other dietary approaches may improve the outlook for patients considered at risk for cognitive impairment. © 2006 Elsevier Inc. All rights reserved. (Am J Cardiol 2006;97:1262–1265)
What has not been widely recognized by physicians and their patients is the relation between cardiovascular disease risk factors (CVDRFs), which have been identified and studied since the Framingham program in 1948, in relation to the occurrence of heart disease and the risk for cognitive impairment. The relation between CVDRFs and changes in cognitive functioning in an older population of almost 11,000 subjects in the Atherosclerotic Risk in Communities was studied by repetitive cognitive testing, and the presence of diabetes mellitus or hypertension was associated with greater decreases in cognition.1 There is much uncertainty and heterogeneity among various observers in the diagnosis of mild cognitive impairment, Alzheimer’s disease (AD), and vascular dementia, but there is agreement in publications that they all relate to memory and cognitive impairment and eventually behavioral changes and language difficulties. The ability to measure the loss of cognitive function and its impairment permits the analysis of a variety of risk factors that contribute to its loss. The metabolic syndrome consists of a cluster of 5 commonly occurring disorders: abdominal obesity, hypertriglyceridemia, low levels of high-density lipoprotein cholesterol, hypertension, and insulin resistance. These disorders have
a Upstate Medical University, Syracuse Preventive Cardiology, Syracuse, New York; and bInstitute for Study of Aging, New York, New York. Manuscript received September 21, 2005; revised manuscript received and accepted December 29, 2005. *Corresponding author: Tel: 315-475-9921; fax: 315-472-7103. E-mail address: [email protected] (D.T. Nash).
0002-9149/06/$ – see front matter © 2006 Elsevier Inc. All rights reserved. doi:10.1016/j.amjcard.2005.12.031
been known to increase the risk for cardiovascular disease occurrence and progression and have been hypothesized to play a role in AD as well as in the development of vascular dementia.2 Insulin influences memory, and treating insulin resistance may reduce the risk for or slow down the development of AD.3 High levels of inflammation also increase the risk for developing diabetes mellitus and atherosclerosis. Similarly, studies have shown that during long-term hyperinsulinemia, insulin may exacerbate the inflammatory response.
Role of Obesity A glance at any crowded street or shopping or entertainment venue within the United States will demonstrate the reality that perhaps 50% of older adults are either overweight or obese, and this is true in most Western societies.4 The investigators of this Swedish study analyzed an 18-year follow-up of ⬎1,000 participants selected at random to undergo testing. The subjects were followed with hospital records, death certificates, and outpatient visits, and none was lost to follow-up. Women who developed dementia tended to be overweight, compared with nondemented (ND) women. A greater degree of overweight was observed in patients who developed AD at ages 70, 75, and 79 years compared with ND women. In women, every 1.0 kg/m2 increase in body mass index increased the risk for AD by 36%. In contrast, there were no body mass index differences between men who became demented and those who did not. www.AJConline.org
Reviews/Cardiovascular Risk Factors and Cognitive Impairment
Role of Hypertension Studies of cognitive impairment and the effect of antihypertensive therapy share a certain number of limitations. Some are longitudinal studies and are subject to confounding variables, including survivor and selection bias, differences in the control of hypertension, and the use of different therapeutic regimens. Others are double-blind, placebo-controlled trials using a variety of different types of antihypertensive drugs. A study published in 1996 examined a 15year longitudinal follow-up of high blood pressure (BP) at the age of 70 years that revealed an increased risk for AD over time.5 Other studies have verified a relation between hypertension and the risk for developing AD over a period of years.6 The treatment of hypertension resulted in a reduction in cognitive impairment in several but not all studies.7 The relation between hypertension and cognitive function has been inconsistent. Most long-term prospective population-based studies have provided strong evidence of the relation between high BP and cognitive impairment.8,9 In a longitudinal study, high BP at the age of 70 years was found to increase the risk for AD, the most common cause of dementia, 10 to 15 years later.10 The positive relation between hypertension and a greater risk for AD was confirmed by several population-based studies of mid-life high BP and late-life AD with follow-up periods of ⬎20 years.7 Hypertension in elderly subjects is usually accompanied by the presence of other risk factors. A subset of 2,584 subjects of the 4,396 patients aged 65 to 74 years of the Medical Research Council’s treatment trial of hypertension11 was followed up over 4.5 years to examine change in cognitive function affected by diuretics or  blockers. The study did not provide evidence that antihypertensive treatment benefits patients’ cognitive function. The Vascular Dementia Project, as part of the double-blind, placebocontrolled Systolic Hypertension in Europe trial, demonstrated that the treatment of hypertension could reduce the risk for dementia.12 Other studies have also evaluated the effects of antihypertensive treatment on cognitive impairment and the incidence of dementia. In a community cohort aged ⱖ75 years, 1,301 subjects without dementia at baseline were followed for an average of 3 years.13 A lower prevalence of dementia was observed for subjects taking an antihypertensive medication compared with those not taking the medication. The protective effects of antihypertensive medication against dementia were also reported in the Rotterdam Study.14
Effects of Exercise A cardiovascular risk factor that is increasingly common among aging adults is the lack of adequate amounts of physical activity on a regular, daily basis. There are many reasons for this inactivity: arthritic complaints, excessive obesity that inhibits walking long distances, unsafe neigh-
1263
borhoods, the lack of a companion, or the lack of a program that would reduce the notion of perceived boredom among many sedentary couch potatoes. However, several crosssectional and longitudinal studies have shown that improving cardiovascular fitness helps reduce the damaging effects of age on cognition and brain structure.15 Other studies have examined the effects of exercise, and although each has caveats and limitations, some are highly informative. A total of 5,925 white, community-based women were recruited at 4 clinical centers for a study of osteoporotic fractures.16 Cognitive performance was measured using a modified Mini-Mental State Examination at baseline and 6 to 8 years later. Physical activity was measured by self-reported blocks (160 m) walked per week and by total kilocalories expended in recreation, blocks walked, and stairs climbed. Cognitive impairment was defined as a ⱖ3-point decrease on repeat Mini-Mental State Examination. The results revealed that women with greater physical activity at baseline were less likely to experience cognitive impairment during the 6 to 8 years of follow-up. Cognitive impairment occurred in 17%, 18%, 22%, and 24% of those in the highest, third, second, and lowest quartile of blocks walked (p ⬍0.001). The results were similar for comparisons of total kilocalories expended per week. Baseline walking speed was not associated with risk for cognitive impairment. Among caveats to consider was the lack of diversity in the study group, a confounder of healthy living habits in the study group, and self-reporting of the distances and recreational activities.16
Role of Statin Drugs Studies of the role of statin drug use and cognition have yielded mixed results. Cross-sectional studies have suggested a diminished risk for dementia, and yet they have not revealed a relation. A small pilot study of 63 patients with mild to moderate AD with Mini-Mental State Examination scores of 12 to 28 were examined and followed on either placebo or atorvastatin 80 mg/day. Atorvastatin reduced cholesterol levels as expected, and there were some positive effects on the progression deterioration of cognitive function and behavior, although some of the tests did not achieve statistical significance.17
Effect of Elevated Cholesterol Levels and Amyloid Deposition The investigators of a recent study examined autopsy cases of patients ⬎40 years and correlated cholesterolemia with the presence or absence of amyloid deposition (subjects with vs without amyloid deposition) as well as cholesterolemia and amyloid load. Amyloid load in human brains was measured by immunohistochemistry and image analysis. There was a correlation with the presence of amyloid de-
1264
The American Journal of Cardiology (www.AJConline.org)
position (diffuse-type senile plaques) in those subjects ⬍55 years old.18 Although there is mounting evidence demonstrating a close relation between spontaneous AD and CVDRFs, specific human investigations have only recently begun to provide further quantitative investigations of brain atherosclerotic injury and its relation to sporadic AD. A voluntary brain donation program was the site of a carefully conducted study that removed and preserved the brains of 54 consecutive Caucasian adults. There were 22 ND control cases and 18 AD cases in the study.19 The circle of Willis was dissected intact at the time of the autopsies, and quantitative analysis was performed on brain weight, white-matter score, plaque score, and arterial occlusion score. All arteries were cut into 3-mm lengths and examined with a dissecting microscope. In the AD group, 87 of the 391 examined arteries (22%) were ⬎80% occluded, whereas only 13 of 277 (4.7%) were as extensively blocked in the ND group (p ⬍0.001). In the AD group, there were 14 arteries with 100% occlusion, whereas in the ND group, only 4 (1.1%) were observed. In the ND group, 73% had occlusions of ⬎50%, and none had occlusions of ⬎70%, whereas in the AD group, 97% of the patients had 50% occlusions and 38% had occlusions of ⬎70% occlusions. These observations link circle-of-Willis atherosclerotic lesions with AD lesions and dementia. Female AD subjects appeared to have a higher degree of pathologic severity and higher total cholesterol, low-density lipoprotein cholesterol, and triglycerides than controls (p ⬍0.01). For many years, neurologists believed that cerebral atherosclerosis had no relation to AD and that plaque and neurofibrillary tangles were the only significant pathologic abnormalities, but this position does not agree with the previously mentioned pathologic study.20
Effect of Diabetes Mellitus and Other Risk Factors on Cognitive Impairment Other cardiovascular risk factors, beyond the familiar risks of hypertension and hyperlipidemia, also appear to have a role in cognitive impairment with aging.8 Data from epidemiologic studies suggest a direct link between diabetes and diabetes-associated co-morbidities of hypertension, dyslipidemia, or hyperinsulinemia with AD. Diabetes mellitus is positively associated with cognitive impairment as well as the risk for dementia. The mechanism through which this occurs is uncertain. Certainly, diabetes is associated with macro- and microvascular changes, and there may be an effect of glucose abnormalities on the cerebral vasculature. In addition, many diabetics present with lipid abnormalities, including lower high-density lipoprotein cholesterol, elevated triglycerides, and increases in remnant particles. The formation of advanced glycation end products may play a role because its formation occurs during normal aging and at an accelerated rate in diabetes mellitus and may be a factor in the protein formations of AD, such as neurofibril-
lary tangles and -amyloid plaques and through other mechanisms. The e4 allele of apolipoprotein-E is associated with an increased risk for AD, as well as with increased plasma cholesterol, low-density lipoprotein cholesterol, and cardiovascular disease.21 Elevated homocysteine levels are another CVDRF that increase the risk for cardiovascular disease and stroke, as well as AD and cognitive impairment in ND subjects. Mixed reports have suggested that the treatment of elevated homocysteine levels is not associated with beneficial effects on cognition; a decision on the effects of therapy for homocysteine will require further confirmatory controlled trials.
Nonpharmacologic Approaches to Cognitive Impairment A study of 815 subjects aged 65 to 94 years revealed that subjects who ate fish ⱖ1 time/week had a 60% reduced risk for developing AD.22 The intake of long-chain n-3 polyunsaturated fatty acids and docosahexaenoic acid (omega-3) was associated with a reduced risk for developing AD during the 4-year study. The intake of a-linolenic acid found in vegetable oils and nuts was protective only in subjects with the e4 allele of apolipoprotein-E. Total n-3 fatty acid was protective only in women. The omega-3 fatty acids have a role in reducing blood triglyceride levels, as well as reducing thrombotic events. Moreover, a recent animal study on the intake of omega-3 fatty acids suggests that dietary docosahexaenoic acid may be protective against the production, accumulation, and toxicity of -amyloid, thereby reducing the risk for AD.23 Animal studies by Joseph et al24 have suggested that diets rich in antioxidant foods, such as spinach, strawberries, and blueberries, may be beneficial in age-related cognitive impairment. They used transgenic mice and demonstrated a protective mechanism derived from blueberry-enhanced memory-associated neuronal signaling. In southern Italy, a study demonstrated that monounsaturated fatty acid intake was significantly associated with a reduction in the odds ratio of developing cognitive impairment.25 A recent study examined 815 healthy patients aged 65 years at baseline and followed them for 4 years. Those in the highest quintile of saturated fat, trans fat, had an increased risk for cognitive impairment.26 In contrast, those in the highest quintile of n-6 fats, available in tree nuts, demonstrated reduced risk. A review of the role of diet in cognitive impairment reveals that although there are some exciting suggestions, a great deal of further research is necessary before drawing strong conclusions. Although there are discrepancies in the data, and further prospective trials are warranted, it is clear that cardiovascular risk factors appear to have a role in the development of cognitive decline, and evidence is at least suggestive that the control of these factors may permit a beneficial effect on the risks of dementia.
Reviews/Cardiovascular Risk Factors and Cognitive Impairment
“You are not required to complete the task at hand, neither are you free from making a start.” Babylonian Talmud 250 AD
Acknowledgment: We wish to acknowledge the valued assistance of Lynn Gorczyca and Jeremy Nash in providing technical and research assistance in the completion of this work. 1. 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– 48. 2. Yaffe K, Kanaya A, Lindquist K, Simonsick EM, Harris T, Shorr RI, Tylavsky FA, Newman AB. The metabolic syndrome, inflammation, and risk of cognitive decline. JAMA 2004;292:2237–2242. 3. Craft S, Watson GS. Insulin and neurodegenerative disease: shared and specific mechanisms. Lancet 2004;3:169 –178. 4. Gustafson D, Rothenberg E, Blennow K, Steen B, Skoog I. An 18-year follow-up of overweight and risk of Alzheimer disease. Arch Intern Med 2003;163:1524 –1528. 5. Skoog I, Lernfelt B, Landahl S, Palmertz B, Andreasson LA, Nilsson L, Persson G, Oden A, Svanborg A. 15-year longitudinal study of blood pressure and dementia. Lancet 1996;347:1141–1145. 6. Launer LJ, Ross GW, Petrovitch H, Masaki K, Foley D, White LR, Havlik RJ. Midlife blood pressure and dementia: the Honolulu-Asia Aging Study. Neurobiol Aging 2000;21:49 –55. 7. SHEP Cooperative Research Group. Prevention of stroke by antihypertensive drug treatment in older persons with isolated systolic hypertension. Final results of the Systolic Hypertension in the Elderly Program (SHEP). JAMA 1991;265:3255–3264. 8. Breteler M. Vascular risk factors for Alzheimer’s disease: an epidemiologic perspective. Neurobiol Aging 2000;21:153–160. 9. Birkenhager WH, Forette F, Seux ML, Wang JG, Staessen JA. Blood pressure, cognitive functions, and prevention of dementias in older patients with hypertension. Arch Intern Med 2001;161:152–156. 10. Kivipelto M, Helkala EL, Laakso MP, Hanninen T, Hallikainen M, Alhainen K, Soininen H, Tuomilehto J, Nissinen A. Midlife vascular risk factors and Alzheimer’s disease in later life: longitudinal, population based study. BMJ 2001;322:1447–1451. 11. Prince MJ, Bird AS, Blizard RA, Mann AH. Is the cognitive function of older patients affected by antihypertensive treatment? Results from 54 months of the Medical Research Council’s trial of hypertension in older adults. BMJ 1996;312:801– 805. 12. Forette F, Seux ML, Staessen JA, Thijs L, Birkenhager WH, Babarskiene MR, Babeanu S, Bossini A, Gil-Extremera B, Girerd X, et al. Prevention of dementia in randomised double-blind placebo-controlled
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26.
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Systolic Hypertension in Europe (Syst-Eur) trial. Lancet 1998;352: 1347–1351. Guo Z, Fratiglioni L, Zhu L, Fastbom J, Winblad B, Viitanen M. Occurrence and progression of dementia in a community population aged 75 years and older: relationship of antihypertensive medication use. Arch Neurol 1999;56:991–996. Veld BA, Ruitenberg A, Hofman A, Stricker BH, Breteler MM. Antihypertensive drugs and incidence of dementia: the Rotterdam Study. Neurobiol Aging 2001;22:407– 412. Colcombe SJ, Kramer AF, Erickson KI, Scalf P, McAuley E, Cohen NJ, Webb A, Jerome GJ, Marquez DX, Elavsky S. Cardiovascular fitness, cortical plasticity, and aging. Proc Natl Acad Sci USA 2004; 101:3316 –3321. Yaffe K, Barnes D, Nevitt M, Lui LY, Covinsky K. A prospective study of physical activity and cognitive decline in elderly women: women who walk. Arch Intern Med 2001;161:1703–1708. Sparks DL, Sabbagh MN, Conner DJ, Lopez J, Launer LJ, Browne P, Wasser D, Johnson-Traver S, Lochhead J, Ziolwolski C. Atorvastatin for the treatment of mild to moderate Alzheimer disease: preliminary results. Arch Neurol 2005;62:753–757. Pappolla MA, Bryant-Thomas TK, Herver D, Pacheco J, Fabra GM. Mild hypercholesterolemia is an early risk factor for the development of Alzheimer amyloid pathology. Neurology 2003;61:199 –205. Roher AE, Esh C, Kokjohn TA, Kalback W, Luehrs DC, Seward JD, Sue LI, Beach TG. Circle of Willis atherosclerosis is a risk factor for sporadic Alzheimer’s disease. Arterioscler Thromb Vasc Biol 2003; 23:2055–2062. Beach TG. The history of Alzheimer’s disease: three debates. J Hist Med Allied Sci 1987;42:327–349. Launer LJ. Diabetes and brain aging: epidemiologic evidence. Curr Diab Rep 2005;5:59 – 63. Kalmijn S, Launer LJ, Ott A, Witteman JC, Hofman A, Breteler MM. Dietary fat intake and the risk of incident dementia in the Rotterdam Study. Ann Neurol 1997;42:776 –782. Lim GP, Calon F, Morihara T, Yang F, Teter B, Ubeda O, Salem N Jr, Frautschy SA, Cole GM. A diet enriched with the omega-3 fatty acid docosahexaenoic acid reduces amyloid burden in an aged Alzheimer mouse model. J Neurosci 2005;25:3032–3040. Joseph JA, Denisova NA, Arendash G, Gorden M, Diamond D. Blueberry supplementation enhances signaling and prevents behavioral deficits in an Alzheimer disease model. Nutr Neurosci 2003;6:153– 162. Solfrizzi V, Panza F, Torres F, Mastroianni F. High monosaturated fatty acid intake protects against age-related cognitive decline. Neurology 1999;52:1563–1569. Morris MC. Chicago health and aging project. Arch Neurol 2003;60: 194 –200.
What has not been widely recognized by physicians and their patients is the relation between cardiovascular disease risk factors (CVDRFs), which have been identified and studied since the Framingham program in 1948, in relation to the occurrence of heart disease and the risk for cognitive impairment. The relation between CVDRFs and changes in cognitive functioning in an older population of almost 11,000 subjects in the Atherosclerotic Risk in Communities was studied by repetitive cognitive testing, and the presence of diabetes mellitus or hypertension was associated with greater decreases in cognition.1 There is much uncertainty and heterogeneity among various observers in the diagnosis of mild cognitive impairment, Alzheimer’s disease (AD), and vascular dementia, but there is agreement in publications that they all relate to memory and cognitive impairment and eventually behavioral changes and language difficulties. The ability to measure the loss of cognitive function and its impairment permits the analysis of a variety of risk factors that contribute to its loss. The metabolic syndrome consists of a cluster of 5 commonly occurring disorders: abdominal obesity, hypertriglyceridemia, low levels of high-density lipoprotein cholesterol, hypertension, and insulin resistance. These disorders have
a Upstate Medical University, Syracuse Preventive Cardiology, Syracuse, New York; and bInstitute for Study of Aging, New York, New York. Manuscript received September 21, 2005; revised manuscript received and accepted December 29, 2005. *Corresponding author: Tel: 315-475-9921; fax: 315-472-7103. E-mail address: [email protected] (D.T. Nash).
0002-9149/06/$ – see front matter © 2006 Elsevier Inc. All rights reserved. doi:10.1016/j.amjcard.2005.12.031
been known to increase the risk for cardiovascular disease occurrence and progression and have been hypothesized to play a role in AD as well as in the development of vascular dementia.2 Insulin influences memory, and treating insulin resistance may reduce the risk for or slow down the development of AD.3 High levels of inflammation also increase the risk for developing diabetes mellitus and atherosclerosis. Similarly, studies have shown that during long-term hyperinsulinemia, insulin may exacerbate the inflammatory response.
Role of Obesity A glance at any crowded street or shopping or entertainment venue within the United States will demonstrate the reality that perhaps 50% of older adults are either overweight or obese, and this is true in most Western societies.4 The investigators of this Swedish study analyzed an 18-year follow-up of ⬎1,000 participants selected at random to undergo testing. The subjects were followed with hospital records, death certificates, and outpatient visits, and none was lost to follow-up. Women who developed dementia tended to be overweight, compared with nondemented (ND) women. A greater degree of overweight was observed in patients who developed AD at ages 70, 75, and 79 years compared with ND women. In women, every 1.0 kg/m2 increase in body mass index increased the risk for AD by 36%. In contrast, there were no body mass index differences between men who became demented and those who did not. www.AJConline.org
Reviews/Cardiovascular Risk Factors and Cognitive Impairment
Role of Hypertension Studies of cognitive impairment and the effect of antihypertensive therapy share a certain number of limitations. Some are longitudinal studies and are subject to confounding variables, including survivor and selection bias, differences in the control of hypertension, and the use of different therapeutic regimens. Others are double-blind, placebo-controlled trials using a variety of different types of antihypertensive drugs. A study published in 1996 examined a 15year longitudinal follow-up of high blood pressure (BP) at the age of 70 years that revealed an increased risk for AD over time.5 Other studies have verified a relation between hypertension and the risk for developing AD over a period of years.6 The treatment of hypertension resulted in a reduction in cognitive impairment in several but not all studies.7 The relation between hypertension and cognitive function has been inconsistent. Most long-term prospective population-based studies have provided strong evidence of the relation between high BP and cognitive impairment.8,9 In a longitudinal study, high BP at the age of 70 years was found to increase the risk for AD, the most common cause of dementia, 10 to 15 years later.10 The positive relation between hypertension and a greater risk for AD was confirmed by several population-based studies of mid-life high BP and late-life AD with follow-up periods of ⬎20 years.7 Hypertension in elderly subjects is usually accompanied by the presence of other risk factors. A subset of 2,584 subjects of the 4,396 patients aged 65 to 74 years of the Medical Research Council’s treatment trial of hypertension11 was followed up over 4.5 years to examine change in cognitive function affected by diuretics or  blockers. The study did not provide evidence that antihypertensive treatment benefits patients’ cognitive function. The Vascular Dementia Project, as part of the double-blind, placebocontrolled Systolic Hypertension in Europe trial, demonstrated that the treatment of hypertension could reduce the risk for dementia.12 Other studies have also evaluated the effects of antihypertensive treatment on cognitive impairment and the incidence of dementia. In a community cohort aged ⱖ75 years, 1,301 subjects without dementia at baseline were followed for an average of 3 years.13 A lower prevalence of dementia was observed for subjects taking an antihypertensive medication compared with those not taking the medication. The protective effects of antihypertensive medication against dementia were also reported in the Rotterdam Study.14
Effects of Exercise A cardiovascular risk factor that is increasingly common among aging adults is the lack of adequate amounts of physical activity on a regular, daily basis. There are many reasons for this inactivity: arthritic complaints, excessive obesity that inhibits walking long distances, unsafe neigh-
1263
borhoods, the lack of a companion, or the lack of a program that would reduce the notion of perceived boredom among many sedentary couch potatoes. However, several crosssectional and longitudinal studies have shown that improving cardiovascular fitness helps reduce the damaging effects of age on cognition and brain structure.15 Other studies have examined the effects of exercise, and although each has caveats and limitations, some are highly informative. A total of 5,925 white, community-based women were recruited at 4 clinical centers for a study of osteoporotic fractures.16 Cognitive performance was measured using a modified Mini-Mental State Examination at baseline and 6 to 8 years later. Physical activity was measured by self-reported blocks (160 m) walked per week and by total kilocalories expended in recreation, blocks walked, and stairs climbed. Cognitive impairment was defined as a ⱖ3-point decrease on repeat Mini-Mental State Examination. The results revealed that women with greater physical activity at baseline were less likely to experience cognitive impairment during the 6 to 8 years of follow-up. Cognitive impairment occurred in 17%, 18%, 22%, and 24% of those in the highest, third, second, and lowest quartile of blocks walked (p ⬍0.001). The results were similar for comparisons of total kilocalories expended per week. Baseline walking speed was not associated with risk for cognitive impairment. Among caveats to consider was the lack of diversity in the study group, a confounder of healthy living habits in the study group, and self-reporting of the distances and recreational activities.16
Role of Statin Drugs Studies of the role of statin drug use and cognition have yielded mixed results. Cross-sectional studies have suggested a diminished risk for dementia, and yet they have not revealed a relation. A small pilot study of 63 patients with mild to moderate AD with Mini-Mental State Examination scores of 12 to 28 were examined and followed on either placebo or atorvastatin 80 mg/day. Atorvastatin reduced cholesterol levels as expected, and there were some positive effects on the progression deterioration of cognitive function and behavior, although some of the tests did not achieve statistical significance.17
Effect of Elevated Cholesterol Levels and Amyloid Deposition The investigators of a recent study examined autopsy cases of patients ⬎40 years and correlated cholesterolemia with the presence or absence of amyloid deposition (subjects with vs without amyloid deposition) as well as cholesterolemia and amyloid load. Amyloid load in human brains was measured by immunohistochemistry and image analysis. There was a correlation with the presence of amyloid de-
1264
The American Journal of Cardiology (www.AJConline.org)
position (diffuse-type senile plaques) in those subjects ⬍55 years old.18 Although there is mounting evidence demonstrating a close relation between spontaneous AD and CVDRFs, specific human investigations have only recently begun to provide further quantitative investigations of brain atherosclerotic injury and its relation to sporadic AD. A voluntary brain donation program was the site of a carefully conducted study that removed and preserved the brains of 54 consecutive Caucasian adults. There were 22 ND control cases and 18 AD cases in the study.19 The circle of Willis was dissected intact at the time of the autopsies, and quantitative analysis was performed on brain weight, white-matter score, plaque score, and arterial occlusion score. All arteries were cut into 3-mm lengths and examined with a dissecting microscope. In the AD group, 87 of the 391 examined arteries (22%) were ⬎80% occluded, whereas only 13 of 277 (4.7%) were as extensively blocked in the ND group (p ⬍0.001). In the AD group, there were 14 arteries with 100% occlusion, whereas in the ND group, only 4 (1.1%) were observed. In the ND group, 73% had occlusions of ⬎50%, and none had occlusions of ⬎70%, whereas in the AD group, 97% of the patients had 50% occlusions and 38% had occlusions of ⬎70% occlusions. These observations link circle-of-Willis atherosclerotic lesions with AD lesions and dementia. Female AD subjects appeared to have a higher degree of pathologic severity and higher total cholesterol, low-density lipoprotein cholesterol, and triglycerides than controls (p ⬍0.01). For many years, neurologists believed that cerebral atherosclerosis had no relation to AD and that plaque and neurofibrillary tangles were the only significant pathologic abnormalities, but this position does not agree with the previously mentioned pathologic study.20
Effect of Diabetes Mellitus and Other Risk Factors on Cognitive Impairment Other cardiovascular risk factors, beyond the familiar risks of hypertension and hyperlipidemia, also appear to have a role in cognitive impairment with aging.8 Data from epidemiologic studies suggest a direct link between diabetes and diabetes-associated co-morbidities of hypertension, dyslipidemia, or hyperinsulinemia with AD. Diabetes mellitus is positively associated with cognitive impairment as well as the risk for dementia. The mechanism through which this occurs is uncertain. Certainly, diabetes is associated with macro- and microvascular changes, and there may be an effect of glucose abnormalities on the cerebral vasculature. In addition, many diabetics present with lipid abnormalities, including lower high-density lipoprotein cholesterol, elevated triglycerides, and increases in remnant particles. The formation of advanced glycation end products may play a role because its formation occurs during normal aging and at an accelerated rate in diabetes mellitus and may be a factor in the protein formations of AD, such as neurofibril-
lary tangles and -amyloid plaques and through other mechanisms. The e4 allele of apolipoprotein-E is associated with an increased risk for AD, as well as with increased plasma cholesterol, low-density lipoprotein cholesterol, and cardiovascular disease.21 Elevated homocysteine levels are another CVDRF that increase the risk for cardiovascular disease and stroke, as well as AD and cognitive impairment in ND subjects. Mixed reports have suggested that the treatment of elevated homocysteine levels is not associated with beneficial effects on cognition; a decision on the effects of therapy for homocysteine will require further confirmatory controlled trials.
Nonpharmacologic Approaches to Cognitive Impairment A study of 815 subjects aged 65 to 94 years revealed that subjects who ate fish ⱖ1 time/week had a 60% reduced risk for developing AD.22 The intake of long-chain n-3 polyunsaturated fatty acids and docosahexaenoic acid (omega-3) was associated with a reduced risk for developing AD during the 4-year study. The intake of a-linolenic acid found in vegetable oils and nuts was protective only in subjects with the e4 allele of apolipoprotein-E. Total n-3 fatty acid was protective only in women. The omega-3 fatty acids have a role in reducing blood triglyceride levels, as well as reducing thrombotic events. Moreover, a recent animal study on the intake of omega-3 fatty acids suggests that dietary docosahexaenoic acid may be protective against the production, accumulation, and toxicity of -amyloid, thereby reducing the risk for AD.23 Animal studies by Joseph et al24 have suggested that diets rich in antioxidant foods, such as spinach, strawberries, and blueberries, may be beneficial in age-related cognitive impairment. They used transgenic mice and demonstrated a protective mechanism derived from blueberry-enhanced memory-associated neuronal signaling. In southern Italy, a study demonstrated that monounsaturated fatty acid intake was significantly associated with a reduction in the odds ratio of developing cognitive impairment.25 A recent study examined 815 healthy patients aged 65 years at baseline and followed them for 4 years. Those in the highest quintile of saturated fat, trans fat, had an increased risk for cognitive impairment.26 In contrast, those in the highest quintile of n-6 fats, available in tree nuts, demonstrated reduced risk. A review of the role of diet in cognitive impairment reveals that although there are some exciting suggestions, a great deal of further research is necessary before drawing strong conclusions. Although there are discrepancies in the data, and further prospective trials are warranted, it is clear that cardiovascular risk factors appear to have a role in the development of cognitive decline, and evidence is at least suggestive that the control of these factors may permit a beneficial effect on the risks of dementia.
Reviews/Cardiovascular Risk Factors and Cognitive Impairment
“You are not required to complete the task at hand, neither are you free from making a start.” Babylonian Talmud 250 AD
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