Author + information
- Received September 29, 2015
- Revision received November 24, 2015
- Accepted December 14, 2015
- Published online March 8, 2016.
- Lewis H. Kuller, MD, DrPHa,∗ (, )
- Oscar L. Lopez, MDb,c,
- Rachel H. Mackey, PhD, MPHa,
- Caterina Rosano, MD, MPHa,
- Daniel Edmundowicz, MDd,
- James T. Becker, PhDb,c,e and
- Anne B. Newman, MD, MPHa
- aDepartment of Epidemiology, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, Pennsylvania
- bDepartment of Neurology, School of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania
- cDepartment of Psychiatry, School of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania
- dDepartment of Medicine, Section of Cardiology, Temple University School of Medicine, Philadelphia, Pennsylvania
- eDepartment of Psychology, University of Pittsburgh, Pittsburgh, Pennsylvania
- ↵∗Reprint requests and correspondence:
Dr. Lewis H. Kuller, Department of Epidemiology, Graduate School of Public Health, University of Pittsburgh, 130 North Bellefield Avenue, Room 550, Pittsburgh, Pennsylvania 15261.
Background The successful prevention and treatment of coronary heart disease (CHD) and stroke has resulted in a substantial increase in longevity, with subsequent growth in the population of older people at risk for dementia.
Objectives The authors evaluated the relationship of coronary and other peripheral atherosclerosis to risk of death, dementia, and CHD in the very elderly. Because the extent of vascular disease differs substantially between men and women, sex- and race-specific analyses were included, with a specific focus on women with low coronary artery calcium (CAC) Agatston scores.
Methods We evaluated the relationship between measures of subclinical cardiovascular disease (CAC, carotid intimal medial thickness, stenosis, and ankle brachial index) and risk of dementia, CHD, and total mortality in 532 participants of the Cardiovascular Health Study-Cognition Study from 1998/1999 (mean age, 80 years) to 2012/2013 (mean age, 93 years).
Results Thirty-six percent of participants had CAC scores >400. Women and African-Americans had lower CAC scores. Few men had low CAC scores. CAC score and number of coronary calcifications were directly related to age-adjusted total mortality and CHD. The age-specific incidence of dementia was higher than for CHD. Only about 25% of deaths were caused by CHD and 16% by dementia. Approximately 64% of those who died had a prior diagnosis of dementia. White women with low CAC scores had a significantly decreased incidence of dementia.
Conclusions In subjects 80+ years of age, there is a greater incidence of dementia than of CHD. CAC, as a marker of atherosclerosis, is a determinant of mortality, and risk of CHD and myocardial infarction. White women with low CAC scores had a significantly decreased risk of dementia. A very important unanswered question, especially in the very elderly, is whether prevention of atherosclerosis and its complications is associated with less Alzheimer disease pathology and dementia. (Cardiovascular Health Study [CHS]; NCT00005133)
The prevention and treatment of cardiovascular disease (CVD) has been a primary determinant of increased longevity of older individuals. Improved therapies for clinical coronary heart disease (CHD) and reduced risk factor levels have led to older age at first heart attack, and to higher prevalence of clinical and subclinical CHD (1–5). Women have a lower incidence of clinical CHD than men, even at older ages, and less coronary atherosclerosis, as measured by coronary artery calcium (CAC) (4,6,7). Women also have a first heart attack at an older age than men: at about 72 years of age in women and in the mid-60s in men (8). The extent of subclinical coronary atherosclerosis is a very powerful predictor of risk of clinical coronary artery disease (CAD), congestive heart failure, and stroke (6,9–13). A zero CAC Agatston score is associated with very long-term lower risk of CHD and death, even at older ages (14).
The greater longevity has resulted in an increased population of older people at risk for dementia. Most dementia cases in the United States are older than the age of 75 years at the time of diagnosis. Women live longer than men and, therefore, are at increased lifetime risk for Alzheimer disease, especially at 85+ years of age (15–19). The overall incidence rate of all-cause dementia was similar in men and women in the 90+ study (20). The pathology of dementia at this older age included Alzheimer disease pathology, neurodegeneration, and brain vascular disease (21,22). Numerous studies have documented the association between brain and systemic vascular disease, and risk of dementia (23–31). An important unanswered question is whether older subjects who survived to 80+ years of age with minimal cerebral, peripheral, or coronary atherosclerosis have a reduced risk of dementia and brain neuropathology, as compared with most older patients with extensive subclinical vascular disease.
Few longitudinal studies have evaluated the relationship between CAC and risk of dementia (31). In the Rotterdam Study, common carotid artery intimal medial thickness (IMT), carotid plaque, and peripheral arterial disease were associated with increased risk of dementia greater than 9 years, attenuated with longer follow-up. The extent of calcification in the coronary arteries, aortic arch, extracranial carotid arteries, and intracranial carotid arteries was correlated cross-sectionally with lower cognitive scores (31–33). Calcification in the intracranial and extracranial carotid arteries (but not coronary artery calcification) was a risk factor for incident dementia. In the Age, Gene/Environmental Susceptibility Study (34), dementia increased with age and was significantly related to quartiles of CAC, reduced by adjustment for other risk factors.
The incidence of dementia (1992 to 1998) was higher in participants with prevalent CVD in a previous report from the Cardiovascular Health Study (CHS). The risk of dementia was higher with increased common and internal carotid IMT, and lower ankle-brachial index (35). Participants with higher CAC scores or greater carotid IMT measurements had more CVD events over 5 years of follow-up (36). Higher CAC scores were associated with more brain magnetic resonance imaging (MRI) vascular abnormalities, and with both mild cognitive impairment (MCI) and prevalent dementia, but not after age adjustment (37,38). Black persons had lower CAC than white persons (39).
In this study, we examined the relationship of subclinical CAD and risk of clinical CVD and dementia at 80+ years of age in 532 participants of the CHS Cognition Study (CHS-CS) in Pittsburgh from 1998/1999 to 2014. We specifically tested 2 hypotheses in participants aged 80+ years followed for 10+ years: whether CAC and other measures of subclinical vascular disease predict risk of death and risk of dementia and CHD. We further evaluated whether these associations were similar among men and women.
This report differs from previous CHS publications that included CAC by including predominantly older-age participants 80+ years of age, much longer follow-up, more detailed evaluations of dementia status, and incident (as compared with predominantly prevalent) dementia.
The CHS-CS dementia follow-up study was a continuation of the original CHS limited to the Pittsburgh field center of the CHS from 1998/1999 to 2014. In 1992 to 1994, a total of 924 participants had an MRI of the brain. In 1998/1999, 532 of the 924 (58%) participants were included in the Pittsburgh CHS-CS (1998/1999 through 2014) if alive and not demented in 1998/1999, and having either a second MRI and/or a detailed cognitive evaluation in 1998/1999 (40,41). There were 199 deaths and 116 demented before 1998/1999 and, of the 609 participants eligible for the Pittsburgh CHS-CS, 87.5% (n = 532) were included in the study: 449 who had a second MRI and 83 with detailed cognitive evaluation only. The 77 eligible participants not included in the detailed study were followed as part of the CHS, but did not have repeat MRI or detailed cognitive evaluations after 1998/1999. Also, 14 of the 532 participants refused further evaluations and have been excluded from most of the analysis (Online Figure 1).
The detailed methods for the CHS-CS have been published (41). MRI acquisition and measurements have been described. MRI scanning was completed using a 1.5-T scanner, as previously described (42,43). White matter lesions and ventricular size were determined using a linear scale from 0 to 9 on the basis of a referenced standard.
Cognitive and Neurological Evaluations
All participants had a neuropsychological battery in 1998/1999, which was repeated yearly through 2013. For those participants who could not come in to the clinic for cognitive evaluation, information on cognitive status was obtained at home visits (41) or by telephone, using the Telephone Interview for Cognitive Status. Information on cognition was also obtained from proxies using the Dementia Questionnaire. Symptoms of depression were measured annually with the modified Centers for Epidemiological Studies Depression Scale (41,44). Neurological examinations were done in 1998/1999 and annually from 2002/2003 through 2013.
Diagnosis of dementia was on the basis of a deficit in performance of sufficient severity to affect instrumental activities of daily living in 2 or more cognitive domains, with a history of normal intellectual function before the onset of cognitive abnormalities. A memory deficit was not required for the diagnosis of dementia. Dementia was further classified by type of dementia using standard criteria (41). Participants were classified by adjudicators as having dementia, MCI, or as cognitively normal and then adjudicated to specific type of dementia or MCI on the basis of standard criteria (40,41).
Prevalent CHD was determined at entry into the CHS. Methods of evaluating the prevalent CHD diagnosis have been published (35,37). Incident events occurring after the baseline were evaluated every 6 months, by telephone call or clinic visit, followed by review of medical records and informant interviews, and adjudicated by a committee through 2014 (35,37). The definition of CHD included myocardial infarction (MI), angina pectoris, angioplasty, coronary artery bypass graft, silent MI, and death caused by CHD (45,46).
CAC was measured in May 1998 to June 2000 by electron beam tomography scanning. Quantification of CAC was measured in 434 of 532 (82%) participants in the CHS-CS (35,37). Ultrasound measures of the carotid arteries were obtained using a Toshiba SSA 2070A (Toshiba America Medical Systems, Tustin, CA) ultrasound instrument (36,37). Analysis was restricted to 311 (72%) of the 433 subjects free of clinical CAD in 1998/1999 (Table 1, Online Figure 1).
Descriptive statistics characterized the study population. Categorical variables were presented as frequency and percentage, and continuous variables as mean ± standard deviation or median and interquartile ranges if the distribution was skewed. Age-adjusted rates and their 95% confidence intervals (CIs) were calculated using the direct method. To quantify hazard ratios (HRs) and 95% CIs for the outcome, we used Cox proportional hazard models adjusted for potential confounders. Analyses were performed with SAS version 9.4 (SAS Institute, Cary, North Carolina). All models were 2-sided at alpha = 0.05. Cognitive status was adjudicated to 2013, and death to 2011 centrally and locally at Pittsburgh to 2014. The adjudicators of CVD did not have access to CHS-CS dementia evaluations. Person-years (PY) of follow-up for most analyses began at the time of entry to the Pittsburgh CHS-CS in 1998/1999 because participants had to be alive and free of dementia on the basis of 1998/1999 evaluations. Participants were censored for PY at either the time of incident diagnosis of dementia or death. Competing risk survival models were used to quantify HRs for dementia and CHD, where those who died without dementia or CHD were treated as having competing events. The average time between the dementia diagnosis and death was 5 years. All deaths were evaluated for a diagnosis of dementia before death. Because follow-up in the CHS was every 6 months and yearly for dementia evaluation, detailed information about cognitive performance before death was almost always available.
The analysis was restricted to 311 (72%) of the 433 participants free of clinical CAD in 1998/1999 (Table 1). There were 157 white women, 45 African-American (AA) women, 77 white men, 29 AA men, and 3 others. AAs have lower CAC Agatston scores than whites, and men have higher CAC Agatston scores than women (39). The association of CAC and risk factors at baseline is shown in Table 1.
The median age of death for 73 cognitively normal participants before death was 86 years, for 67 subjects with MCI it was 89 years, and for 269 subjects with a diagnosis of dementia before death it was 90 years of age. The median year of death was approximately 9 years after the beginning of study and CAC measurements in 1998/1999.
Only 106 of 422 deaths (25%) were adjudicated by the CHS as caused by CHD and 24 (6%) by stroke (Table 2). Dementia was the cause of death in 67 (16%). Approximately 64% of deaths (n = 271) had a prior diagnosis of dementia on the basis of adjudication in the CHS-CS.
In a Cox regression model, CAC scores >400 versus <10 were an independent significant predictor of total mortality for the entire sample (HR: 1.73; 95% CI: 1.18 to 2.54). Other predictors were age and the extent of white matter grade in the brain. Traditional CVD risk factors and measures of physical activity were not independent predictors of mortality (Online Table 2). Smoking, lower cognitive scores, diabetes, and higher interleukin-6 were also predictors with wide confidence limits (Online Table 2).
The age-specific incidence of dementia was similar for men and women (41). Among white women, the incidence of dementia with a CAC score of 0 was approximately one-third the rate for women with CAC scores >400 (p = 0.04) (Table 3, Central Illustration). There were no significant trends of CAC and risk of dementia for white men (Table 3), or for AA men and women (Online Table 1). The analysis was limited by the small number of participants, especially for subjects with low CAC scores.
Time to dementia from the initial CAC measurement was 7.1 ± 1.6 years for those with CAC scores of 0 ± versus 5.2 ± 3.3 years for those with CAC scores >400. The mean age at dementia onset (83 years) was unrelated to CAC levels (Central Illustration).
Brain MRI abnormalities, including ventricular and white matter grade, markers of brain infarct, were directly related to CAC score, but did not modulate any relationship of CAC and risk of dementia. There was no significant association between hippocampal volume or ApoE4 and CAC for white men or women (not shown).
For white women, lower ankle brachial index was significantly related to an increased incidence of dementia, and for white men, maximal percent stenosis (inversely) was significant related to the risk of dementia (Table 4). Risk of dementia increased with greater carotid artery wall maximal IMT, especially for white women, but not significantly.
CHD, CVD Incidence
There were 146 incident CHD, mean age 85.0 ± 5.3 years (Online Figures 2 and 3). There were 61 CHD events among white women, 44 CHD events among white men, 17 CHD events for AA women, and 11 CHD events for AA men. Median time for the 133 incident CHD events from 1998/1999 was approximately 6 years. There was little difference in the time to clinical incident events by race and sex.
The age-specific incidence of dementia was greater than for CHD at all ages for women and at older ages for men (Table 5). There were too few events among participants age 85+ years in 1998/1999 to be included in the analysis (Table 5). Incidence of CHD, but not dementia, was higher in men than women. Risk factors for CHD are shown in Online Table 3 and were previously published in the CHS (37).
CHD incidence was directly related to extent of CAC for white men and for both white and black women (Figures 1 and 2⇓). Results were similar when restricted to only MI. Among 14 white women with CAC scores of 0, there were no MIs, as compared with 11 of 58 (19%) in subjects with CAC scores >400, an age-adjusted incidence rate of 17 per 1,000 PY. Among black women, only 1 of 11 MIs had a 0 CAC score, as compared with 2 of 5 (40%) among the small number with CAC >400. In a Cox competing risk model (Online Table 2) comparing CAC scores <10 with those >400, the HR for CHD was 1.54 (95% CI: 0.83 to 2.86). Diabetes mellitus and subclinical CVD were significant predictors of CHD (47).
We also evaluated the relationship between the number of coronary artery calcifications and risk of dementia and CHD for white men and women (Online Table 4). The CAC Agatston score and number of calcifications was highly correlated, 0.817 (p = 0.0001). The incidence of CHD was significantly related to the number of calcifications for both white men and women: for whites, p = 0.003; for white women, p = 0.215; and for white men, p = 0.041.
The age-adjusted incidence of dementia was very low for white women with very few calcifications (e.g., 0, 1, or 2 [p = 0.19]) (Online Table 4). There was an approximately 2-fold difference in the dementia rates from the very low to very high number of calcifications for white women, but no association for white men.
Maximum wall thickness in both the internal and common carotid artery was related to the risk of CHD for white women, and maximal stenosis was related to the risk of CHD for white men (Table 4). There was a nonsignificant trend of increased incidence of CHD for both common and internal carotid artery wall thickness for white men (Table 4).
Among 412 participants free of dementia as of 1998/1999, a total of 90 (22%) had a clinical diagnosis of CHD before 1998/1999: 73 white, 15 AA, and 2 other. By 2014, 56% had become demented, as compared with 55% of those without CHD in 1998/1999. The risk of dementia increased from 6% per year in those 65 to 74 years of age in 1998/1999 to 15% per year in those who were 80+ years of age in 1998/1999. Among white women, history of CHD was associated with greater risk of dementia than no history of CHD from 65 to 74 years of age, 66 per 1,000 PY versus 146 per 1,000 PY; from 75 to 80 years of age, 72 per 1,000 versus 130 per 1,000; and >80 years of age, 113 per 1,000 versus 146 per 1,000 (Online Table 5). Results were in the same direction for white men, but limited by the small sample size.
At the end of the study in 2013, only 47 (9%) of survivors were free of dementia, for example normal (n = 19) and MCI (n = 28), mean age 92 years among 517 participants in 1998/1999, including 33 survivors free of dementia who had CAC measured in 1998/2000 (Online Table 6). CAC and ankle brachial index were significantly lower, especially for alive versus dead, but did not differentiate dementia versus no dementia for either alive or dead participants. Cigarette smoking was significantly less for the alive, nondemented participants. There was also a lower prevalence of hypertension and greater number of blocks walked among those who were alive and nondemented (Online Table 6). Results were similar when CAC analysis was restricted to participants without CVD in 1998/1999.
The incidence of dementia in participants 80+ years of age is greater than for CHD, especially for women. Only about one-fourth of the deaths in this older-age population, 80+ years of age, were attributed to CAD and 16% caused by dementia. Almost two-thirds of those who died had been diagnosed with dementia, on an average of 5 years before death. Previous studies underestimated the incidence of dementia in older-age groups because of the use of insensitive instruments and infrequent cognitive evaluations (20).
Zero or very low CAC scores among white women was associated with a very low risk of dementia, CHD, MI, and total mortality on the basis of a small number of white women with 0 or very low CAC scores. These results are consistent with other studies (48). A recent abstract from the Multi-Ethnic Study of Atherosclerosis noted, solely on the basis of hospital records, much lower rates of many diseases, including dementia, for participants 45 to 84 years of age with low CAC scores followed for 8 years (49).
We previously reported in the Healthy Women Study that premenopausal risk factors measured at ∼48 years of age were predictors of post-menopausal CAC, even to approximately 80+ years of age. Approximately 57% of women had CAC scores of 0 at age 62, a total of 12 years post-menopausal (50). Women converted from 0 CAC to some CAC at about 6% per year over the next 12 years; for example, 27% at 0 CAC at age 72, and only 13% of the women at 80+ years of age had CAC scores of 0 in the CHS. Low CAC Agatston scores are a measure of risk factors many years before the CAC measurements.
These results suggest several scenarios. First, the prevalence of dementia in older populations will likely increase with continued improvement in prevention and treatment of CHD and increasing longevity of the population, assuming that no new therapies either prevent or delay the onset of incident dementia. As age at first heart attack continues to rise, dementia will be an important comorbidity and will affect treatment decisions and outcomes.
Second, a 0 or very low CAC Agatston score was associated with lower incidence of dementia among women.
Third, cardiovascular risk factors, such as elevated blood pressure, diabetes, cigarette smoking, physical inactivity, and abnormal lipoprotein metabolism, are determinants of progression of atherosclerosis to CHD, and could also affect progression of brain pathology, such as amyloid, tau, or neurodegeneration and risk of dementia in the elderly (21,22,28,51). Clinical trials that have evaluated treatment of some of these risk factors, such as blood glucose and lipid lowering, antihypertensive therapy, and recently increasing physical activity, have not consistently demonstrated a reduced risk of dementia. A broad-based cardiovascular risk reduction study also showed improved cognitive function (41).
If delay or prevention of peripheral atherosclerosis resulted in the reduction or slowing of progression of brain neuropathology and subsequent incidence of dementia, then there is the potential for a very substantial impact on reducing most dementia in very old ages (e.g., 80+ years of age). There is a need to test such hypotheses by substantially modifying risk factors, slowing the progression of atherosclerosis, and determining whether such an effect will substantially reduce the incidence of dementia and specific neuropathology among older patients.
The sample size is small because few women and practically no men in this older age group have 0 CAC scores. The results, on the basis of a small sample size, need replication in other studies of the elderly, with frequent sensitive measures of dementia and CAC.
A very important unanswered question is whether 0 or very low CAC scores or other measures of lower extent of atherosclerosis or arteriosclerosis are associated with reduced risk of incident dementia. Interventions to modify known risk factors to prevent the progression of atherosclerosis and arteriosclerosis could result in a decreased older-age incidence of CHD, CVD, and dementia. The alternative could be an unfortunate outcome: that successful control of risk factors and treatment of CHD results in an increasing epidemic of dementia among older people.
COMPETENCY IN MEDICAL KNOWLEDGE: In subjects 80 years of age and older, the incidence of dementia exceeds that of coronary heart disease, but coronary artery calcification, a marker of atherosclerosis, is a determinant of mortality and the risk of myocardial infarction in this elderly population.
TRANSLATIONAL OUTLOOK: Despite its multiple etiologies in the elderly, further research is needed to determine whether the incidence of dementia can be reduced through modification of vascular risk factors or other variables associated with aging.
A full list of principal Cardiovascular Health Study investigators and institutions can be found at CHS-NHLBI.org.
For supplemental tables and figures, please see the online version of this article.
This research was supported by contracts HHSN268201200036C, HHSN268200800007C, N01HC55222, N01HC85079, N01HC85080, N01HC85081, N01HC85082, N01HC85083, and N01HC85086; and grant U01HL080295 from the National Heart, Lung, and Blood Institute, with additional contribution from the National Institute of Neurological Disorders and Stroke. Additional support was provided by R01AG023629 from the National Institute on Aging and, in part, by grants AG20098, AG15928, and AG05133 from the National Institute on Aging. The funding sources did not have any role in the study design; collection, analysis, or interpretation of data; preparation of the manuscript; or decision to submit it for publication. All authors have reported that they have no relationships relevant to the contents of this paper to disclose.
- Abbreviations and Acronyms
- African American
- coronary artery calcium
- coronary artery disease
- coronary heart disease
- confidence interval
- cardiovascular disease
- hazard ratio
- intimal medial thickness
- mild cognitive impairment
- myocardial infarction
- magnetic resonance imaging
- Received September 29, 2015.
- Revision received November 24, 2015.
- Accepted December 14, 2015.
- American College of Cardiology Foundation
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