Subclinical Cardiovascular Disease and Death, Dementia, and Coronary Heart Disease in Individuals Age 80+

Abstract

Background

The successful prevention and treatment of CHD and stroke has resulted in substantial increase in longevity with a subsequent growth in the population of older individuals at risk for dementia.

Objectives

We evaluated the relationship of coronary and other peripheral atherosclerosis to risk of death, dementia, and CHD in the very elderly. Because of substantial differences in extent of vascular disease between men and women, sex- and race-specific analyses were included with a specific focus for women with low CAC Agatston scores.

Methods

We evaluated the relationship between measures of subclinical measures of CVD (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 1998–99 (mean age 80) to 2012–13 (mean age 93).

Results

Thirty-six percent of participants had CAC scores >400. Women and African-Americans had lower CAC scores. Few men had low amounts of CAC. The extent of CAC scores or the number of coronary calcifications was directly related to age-adjusted total mortality and CHD. Age-specific incidence of dementia was higher than for CHD. Only about 25% of deaths were due to CHD and 16% to dementia. Approximately 64% of all deaths had diagnosis of dementia prior to death. White women with low CAC scores had a significant decreased incidence of dementia.

Conclusions

Incidence of dementia in individuals age 80+ is greater than that for CHD. CAC, as a marker of atherosclerosis, is a determinant of mortality and the risk of CHD and MI. White women with low CAC scores had a significant decreased risk of dementia. A very important unanswered question, especially in the elderly age 80+, is whether prevention of atherosclerosis and its complications is associated with less extent of AD pathology and dementia.

INTRODUCTION

The prevention and treatment of CVD has been a primary determinant of increased longevity of older individuals. Improved therapies for clinical 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 lower incidence of clinical CHD than men even at older ages and less coronary atherosclerosis as measured by CAC.(4,6,7) Women also have first heart attack at older age than men; about 72 in women and mid 60s in men.(8) The extent of subclinical coronary atherosclerosis is a very powerful predictor of risk of clinical coronary artery disease (CAD), CHF, 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 individuals at risk for dementia. The majority of dementia cases in the United States are over the age of 75 at the time of diagnosis. Women live longer than men and therefore are at increased lifetime risk for Alzheimer’s disease (AD), especially age 85+.(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 AD 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 individuals who survived to age 80+ with minimal cerebral, peripheral, or coronary atherosclerosis have a reduced risk of dementia and brain neuropathology as compared to the majority of older individuals 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 over 9 years, attenuated with longer follow up. The extent of calcification in the coronary arteries, aortic arch, extracranial carotid arteries, and intracranial carotid arteries were correlated cross-sectionally with lower cognitive scores.(31–33) Calcification in the intra- and extra-cranial 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 (1992–1998) 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 (ABI).(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 to both mild cognitive impairment (MCI) and prevalent dementia but not after age adjustment.(37,38) Blacks had lower CAC than whites.(39)

In this study, we examined the relationship of subclinical CAD and risk of clinical CVD and dementia age 80+ in 532 participants of the CHS Cognition Study (CHS-CS) in Pittsburgh from 1998–99 to 2014. We specifically tested two hypotheses in participants age 80+ followed for 10+ years: Do CAC and other measures of subclinical vascular disease predict: 1) risk of death; and 2) risk of dementia andCHD. 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 to predominantly prevalent dementia.

METHODS

The CHS-Cognition Study (CHS-CS) dementia follow up study was a continuation of the original CHS limited to the Pittsburgh field center of the CHS from 1998–99 to 2014. In 1992–94, 924 participants had an MRI of the brain. In 1998–99, 532 of the 924 (58%) participants were included in the Pittsburgh CHS-CS (1998–99 through 2014) if alive and not demented in 1998–99 and having either a second MRI in 1998–99 and/or a detailed cognitive evaluation in 1998–99.(40,41) There were 199 deaths and 116 demented prior to 1998–99 and of the 609 participants eligible for the Pittsburgh CHS-CS, 87.5% (n=532) were included in the study, 449 that 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 1998–99. Also, 14 of the 532 participants refused further evaluations and have been excluded from most of the analysis. (Appendix 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 Tesla scanner as previously described.(42,43) White matter lesions and ventricular size were determined using a linear scale from 0 to 9 based on a referenced standard.

Cognitive and Neurological evaluations

All participants had a neuropsychological battery in 1998–99, 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 visit (41) or using the telephone interview for cognitive 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 1998–99 and annually from 2002–03 through 2013.

Diagnostic Procedure

Diagnosis of dementia was based on a deficit in performance in two or more cognitive domains of sufficient severity to affect instrumental activities of daily living 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 being cognitively normal and then adjudicated to specific type of dementia or MCI based on 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 through phone 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 due to CHD.(45,46)

CAC was measured in 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 ultrasound instrument.(36,37) Analysis was restricted to 311 (72%) of the 433 free of clinical CAD in 1998–99. (Table 1, Appendix Figure 1)

Table 1.

Relationship of Risk Factors in 1998–99 and CAC Agatston Scores in the CHS-CS, n=311 free of CVD in 1998–99^*

	CAC Agatston Score
	≤10 N (%)	11–100 N (%)	101–400 N (%)	>400 N (%)	Age- adjusted p-value
Median age	75	77	76	78	<0.0001
Race and Gender
White women	25 (16)	33 (21)	44 (28)	55 (35)
Black women	18 (40)	10 (22)	12 (27)	5 (11)
White men	5 (6)	12 (16)	18 (23)	42 (55)
Black men	10 (34)	5 (17)	5 (17)	9 (32)	<.0001
Smoking
Never	25 (45)	27 (44)	42 (55)	41 (38)
Past	24 (44)	31 (51)	27 (36)	56 (52)
Current	6 (11)	3 (5)	7 (9)	10 (9)	0.291
Hypertension
No	35 (61)	34 (57)	41 (54)	62 (57)
Yes	22 (39)	26 (43)	35 (46)	47 (43)	0.863
SBP, mmHg
≤120	22 (39)	21 (35)	21 (28)	41 (38)
121–140	22 (39)	25 (42)	32 (43)	38 (35)
>140	12 (21)	14 (23)	21 (28)	30 (28)	0.780
DBP, mmHg
≤65	19 (34)	27 (45)	23 (31)	52 (48)
66–74	24 (43)	20 (33)	27 (36)	36 (33)
≥74	13 (23)	13 (22)	24 (32)	21 (19)	0.208
HDL-C, mg/dL
≤45	13 (26)	7 (13)	19 (28)	34 (35)
46–56	13 (26)	23 (42)	27 (39)	28 (29)
>56	24 (48)	25 (45)	23 (33)	35 (36)	0.059
LDL-C, mg/dL
≤112	20 (40)	21 (38)	28 (41)	33 (35)
113–133	15 (30)	19 (35)	17 (25)	30 (32)
>133	15 (30)	15 (27)	23 (34)	32 (34)	0.909
Triglycerides, mg/dL
≤93	2 (42)	24 (44)	20 (29)	33 (34)
94–140	16 (32)	23 (42)	22 (32)	36 (37)
>140	13 (26)	8 (15)	27 (39)	28 (29)	0.116
Diabetes
No	49 (88)	53 (88)	67 (91)	100 (92)
Yes	7 (13)	7 (12)	7 (9)	9 (8)	0.810
Wall max-common, mm
≤0.95	24 (45)	20 (33)	20 (26)	23 (22)
0.96–1.06	13 (25)	15 (25)	19 (25)	23 (22)
1.07–1.24	11 (21)	16 (27)	22 (29)	28 (27)
>1.24	5 (9)	9 (15)	15 (20)	30 (29)	0.074
Wall max-internal, mm
≤1.01	26 (49)	20 (34)	21 (28)	17 (17)
1.02–1.45	15 (28)	17 (29)	18 (24)	19 (18)
1.46–2.15	10 (19)	12 (20)	17 (23)	30 (29)
>2.15	2 (4)	10 (17)	18 (24)	37 (36)	<.0001
ABI
<0.9	4 (7)	11 (18)	15 (20)	25 (24)
≥0.9	51 (93)	49 (82)	60 (80)	78 (76)	0.075

^*Comparison of level of risk factor and CAC Agatston score

ABI = ankle brachial index; CHS-CS = Cardiovascular Health Study Cognition Study; DBP = diastolic blood pressure; HDL-C = high density lipoprotein cholesterol; LDL-C = low density lipoprotein cholesterol; SBP = systolic blood pressure

Statistical analysis

Descriptive statistics characterized the study population. Categorical variables were presented as frequency and percentage and continuous variables as mean ± standard deviation or median and inter-quartiles if the distribution was skewed. Age-adjusted rates and their 95% CIs were calculated using 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, NC). 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 (PYs) of follow-up for most analyses began at the time of entry to the Pittsburgh CHS-CS in 1998–99 because participants had to be alive and free of dementia based on 1998–99 evaluations. Participants were censored for PYs at either the time of incident diagnosis of dementia or death. Competing risk survival models were used to quantify the hazard ratios for dementia and CHD where those who died but without dementia or CHD were treated as have 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.

RESULTS

The analysis was restricted to 311 (72%) of the 433 free of clinical CAD in 1998–99. (Table 1) There were 157 white women, 45 African-American (AA) women, 77 white men, 29 AA men, and 3 other. African-Americans (AA) 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.

Total Mortality

Median age of death for 73 cognitively normal individuals prior to death was 86 years, for 67 MCI, 89 years, and for 269 with diagnosis of dementia prior to death, 90 years of age. Median year of death was approximately 9 years after beginning of study and CAC measurements in 1998–99.

Only 106 of 422 deaths (25%) were adjudicated by CHS as due to CHD and 24 (6%) to stroke. (Table 2) Dementia was the cause of death in 67 (16%). Approximately 64% of deaths (n=271) had a prior diagnosis of dementia based on adjudication in the CHS-CS.

Table 2.

Causes of Death by Dementia Status to 2015 in the CHS-CS, n=422 Deaths of 532 (79%)

Cause of death	Deceased – Normal* N (col %)	Deceased – MCI* N (col %)	Deceased – Demented* N (col %)	Total
No cause of death	0 (0)	1 (1.4)	1 (0.4)	2
Atherosclerotic CHD	22 (28.2)	19 (26.0)	65 (24.0)	106
Cerebrovascular disease	3 (3.9)	4 (5.5)	17 (6.3)	24
Other atherosclerotic disease	2 (2.6)	2 (2.7)	6 (1.9)	9
Other CVD	3 (3.9)	4 (5.5)	6 (2.2)	13
Non-cardiovascular	48 (61.5)	43 (58.9)	177 (65.3)	268
Dementia	0 (0)	1 (1.4)	66 (24.4)	67
Parkinson’s disease	0 (0)	0 (0)	13 (4.8)	13
Pneumonia	2 (2.6)	2 (2.7)	11 (4.1)	15
Sepsis	0 (0)	1 (1.4)	12 (4.4)	13
Cancer	34 (43.6)	22 (30.1)	38 (14.0)	94
Other	12 (15.4)	17 (23.3)	36 (13.3)	66
Total	78 (18)	73 (17)	271 (64)	422

^*Status prior to death

MCI = mild cognitive impairment, other abbreviations as in Table 1.

CAC scores were significantly related to total mortality for white men and black women, and a non-significant trend (p=.11 for white women). (Table 3, Appendix Table 1)

Table 3.

Death And Dementia Rates* to 2011 and CAC Agatston Score among CHS-CS Participants, White Participants Only, Alive, Not Demented and No CVD at 1998–99 by Sex

	Death						Dementia
	Women (N=148)			Men (N=74)			Women (N=121)			Men (N=67)
	N Pop.	N Death	Age-Adjusted Rate/1000 PY†	N Pop.	N Death	Age-Adjusted Rate/1000 PY†	N Pop.	N Dementia	Age-Adjusted Rate/1000 PY†	N Pop.	N Dementia	Age-Adjusted Rate/1000 PY†
CAC Agatston Score
0	14	7	49 (24–103)	4	0	0	14	4	31 (12–83)	4	3	77 (25–239)
1 – 10	11	5	40 (17–96)	1	0	0	9	4	52 (20–138)	1	0	0
11 – 100	32	19	56 (25–134)	11	8	78 (39–157)	28	16	74 (31–193)	10	7	111 (53–233)
101 – 400	41	29	76 (41–142)	18	8	70 (20–280)	33	18	84 (37–194)	17	6	28 (13–63)
>400	50	33	67 (37–121)	40	30	82 (44–157)	37	23	102 (51–205)	35	18	81 (38–188)
Trend p=0.110				Trend p=0.01			Trend p=0.044			Trend p=0.432

^*Dementia rates restricted to participants without incident dementia before 1998–99

^†95% Confidence limits

PY = person-years, other abbreviations as in Table 1.

In a Cox regression model, CAC >400 versus <10 was an independent significant predictor of total mortality for the entire sample, HR 1.73 (1.18–2.54). 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. (Appendix Table 2) Smoking, lower cognitive scores, diabetes, and higher interleukin-6 were also predictors with wide confidence limits. (Appendix Table 2)

Dementia

The age-specific incidence of dementia was similar for men and women.(41) Among white women, the incidence of dementia with 0 CAC was approximately 1/3 of the rate for women with >400 CAC scores (p=.04). (Table 3, Figure 1) There were no significant trends of CAC and risk of dementia for white men (Table 3) or AA men and women. (Appendix Table 1) The analysis was limited by the small numbers and especially for individuals with low CAC scores.

Figure 1. Central Illustration. Cumulative Incidence of Dementia, 1998-99 to 2013 for White Women and Men by CAC 0-10 and 400+.

Incidence of dementia is similar in men and women. Men with low CAC 0-10 have low cumulative incidence of dementia.

CAC, coronary artery calcium; CHD, coronary heart disease

Time to dementia from the initial CAC measurement was 7.1 years for those with 0 CAC(SD 1.6) versus 5.2 years for those >400 (SD 3.3). Mean age at dementia onset (83 years) was unrelated to CAC levels. (Figure 1)

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 ABI 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.

Table 4.

Age-Adjusted Incidence of CHD (Excluding Participants with CVD [CHD, CHF, Stroke, MI] at 1998–99) and Dementia by Carotid Artery Measures and ABI by Sex Among CHS-CS Participants, White Participants Only

	CHD at 2014				Dementia at 2012*
	Women (N=170)		Men (N=87)		Women (N=137)		Men (N=76)
1998–99 Variables	N Population	Age-Adjusted Rate/1000 PY†	N Population	Age-Adjusted Rate/1000 PY†	N Population	Age-Adjusted Rate/1000 PY†	N Population	Age-Adjusted Rate/1000 PY†
Wall max-common, mm
<0.95	55	25 (10–59)	20	30 (10–86)	44	73 (36–149)	18	132 (41–453)
0.951–1.06	44	26 (11–70)	20	62 (22–181)	36	85 (39–184)	20	85 (30–252)
1.061–1.24	43	46 (21–103)	22	95 (26–457)	34	99 (47–209)	19	44 (19–124)
>1.24	26	32 (14–76)	25	71 (29–217)	23	81 (36–180)	19	71 (29–173)
P for trend	0.074		0.190		0.747		0.998
Wall max-internal, mm	(N=166)		(N=87)		(N=136)		(N=76)
<1.01	37	26 (9–78)	24	40 (15–129)	31	68 (29–165)	21	93 (38–246)
1.011–1.45	42	25 (10–67)	22	75 (26–218)	32	81 (35–188)	21	83 (33–231)
1.451–2.15	54	37 (17–82)	18	55 (20–155)	46	84 (44–165)	16	67 (20–286)
>2.15	33	53 (23–125)	23	85 (34–218)	27	116 (54–254)	18	51 (15–198)
P for trend	0.028		0.290		0.221		0.214
Max % Stenosis	(N=167)		(N=86)		(N=137)		(N=75)
Normal	42	23 (8–67)	26	34 (12–115)	34	67 (29–155)	24	120 (57–278)
1–24%	77	36 (19–67)	36	63 (27–150)	60	80 (45–144)	30	55 (21–156)
25–49%	40	38 (16–95)	20	88 (34–239)	35	105 (51–221)	17	56 (19–168)
>50%	8	34 (11–106)	4	59 (15–235)	8	88 (37–211)	4	80 (20–320)
P for trend	0.290		0.073		0.355		0.047
ABI	(N=		(N=89)		(N=137)		(N=78)
<0.9	33	34 (12–98)	12	70 (31–155)	28	125 (58–274)	9	43 (14–135)
>0.9	135	31 (19–53)	77	57 (32–102)	109	74 (46–119)	69	75 (43–136)
P for trend	0.621		0.834		0.020		0.487

^*Restricted to participants without incident dementia before 1998–99 95% Confidence limits

Abbreviations as in Table 1 and Table 3.

CHD, CVD Incidence

There were 146 incident CHD, mean age 85±5.3. 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 1998–99 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+ in 1998–99 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 Appendix Table 3 and have been previous published in the CHS.(37)

Table 5.

Comparison of Incidence of Dementia and CHD by Age, Race, and Sex in 1998–99 Among CHS-CS Participants With CAC Measurement Only

		Dementia at 2011–12			CHD at 2013–14
	Age in 1998–99	N	N Demented	Age-specific rate/1000 PYs	N	N CHD	Age-specific rate/1000 PYs
Women
White	≤75	49	27	67 (46–98)	45	12	22 (13–40)
	76–80	79	45	78 (58–104)	77	22	24 (16–37)
	81–85	30	19	126 (80–197)	30	12	52 (30–92)
Black	≤75	24	10	48 (26–90)	24	6	19 (8–42)
	76–80	14	10	98 (53–182)	16	7	43 (21–91)
	81–85	4	4	129 (48–344)	4	1	18 (3–129)
Men
White	≤75	20	7	41 (19–85)	16	7	44 (21–93)
	76–80	69	36	76 (55–106)	48	24	56 (38–84)
	81–85	15	9	92 (48–177)	11	6	85 (38–188)
Black	≤75	10	4	57 (21–152)	11	4	32 (12–85)
	76–80	9	6	90 (40–199)	13	6	44 (20–98)
	81–85	7	4	129 (48–344)	4	1	33 (5–237)

Abbreviations as in Table 3.

CHD incidence was directly related to extent of CAC for both white men and white and black women. (Figure 2, 3) Results were similar when restricted to only MI. Among 14 white women with 0 CAC there were no MIs as compared to 11 of 58 (19%) with CAC >400, age-adjusted incidence rate of 17/1,000 PYs. Among black women, there was only 1 of 11 MI with 0 CAC as compared to 2 of 5 (40%) among the small number with CAC >400. In a Cox competing risk model (Appendix Table 2) comparing <10 CAC score to >400, the HR for CHD was 1.54 (0.83–2.86) Diabetes mellitus and subclinical CVD were significant predictors of CHD.(47)

Figure 2. CAC Scores in 1998–99 in Relationship to Age-Adjusted Incident CHD Through 2014 By Race and Sex.

CHD incidence, even in the very old, is higher in men than women and positively related to CAC score, especially low rates (0 CAC).

CAC, coronary artery calcium; CHD, coronary heart disease

Figure 3. Cumulative Incidence of Dementia, 1998–99 to 2013 for White Women and Men by CAC 0–10 and 400+.

Cumulative incidence of CHD is higher in men than women. Both white men and women with lower CAC scores have reduced risk of CHD.

CAC, coronary artery calcium; CHD, coronary heart disease

We also evaluated the relationship between the number of coronary artery calcifications and risk of dementia and CHD for white men and women. (Appendix Table 4) The CAC Agatston score and number calcifications was highly correlated, 0.817 (p=0.0001). Incidence of CHD was significantly related to number of calcifications for both white men and women. P was 0.003 for whites, for white women 0.215, and for white men 0.041.

Age-adjusted incidence of dementia was very low for white women with very few calcifications, e.g. 0,1,2, (p=0.19). (Appendix Table 4) There was an approximate 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 non-significant 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 1998–99, 90 (22%) had a prior to 1998–99 clinical diagnosis of CHD: 73 white, 15 AA, and 2 other. By 2014, 56% had become demented as compared to 55% of those without CHD in 1998–99. Risk of dementia increased from 6%/year age 65–74 in 1998–99 to 15%/year age 80+ in 1998–99. Among white women, history of CHD was associated with greater risk of dementia than no history of CHD age 65–74, 66/1000 person-years versus 146/1000 person-years; age 75–80, 72/1000 versus 130/1000; and age >80, 113/000 versus 146/000. (Appendix Table 5) Results were in the same direction for white men limited by small sample size.

At the end of the study in 2013, there were only 47 (9%) survivors free of dementia, e.g. normal (n=19) and MCI (n=28), mean age 92 among 517 participants in 1998–99, including 33 survivors free of dementia that had CAC measured in 1998–2000. (Appendix Table 6) CAC and ABI 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. (Appendix Table 6) Results were similar when CAC analysis was restricted to participants without CVD at 1998–99.

DISCUSSION

The incidence of dementia in individuals age 80+ is greater than for CHD, especially for women. Only about ¼ of the deaths in this older age population 80+ years of age were attributed to CAD and 16% due to dementia. Almost 2/3 of the deaths had been diagnosed with dementia on the average of 5 years prior to death. The incidence of dementia in older age groups is underestimated in previous studies because of the use of insensitive instruments and infrequent cognitive evaluations.(20)

Zero or very low CAC among white women was associated with a very low risk of dementia, CHDMI, and total mortality based on a small number of white women with zero or very low CAC. These results are consistent with other studies. (48) A recent abstract from the Multi-Ethnic Study of Atherosclerosis noted much lower rates of many diseases, including dementia, for participants age 45–84 with low CAC scores followed for 8 years based only on hospital records.(49)

We previously reported in the Healthy Women Study, premenopausal risk factors measured at age ~48 were predictors of postmenopausal CAC even to approximately age 80+. Approximately 57% of women had 0 CAC at age 62, 12 years postmenopausal.(50) Women converted from 0 CAC to some CAC at about 6%/year over the next 12 years, e.g. 27% at 0 CAC at age 72, and only 13% of the women at age 80+ having 0 CAC in the CHS. Low CAC Agatston scores are a measure of risk factors many years prior to 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 that either prevent or delay 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. However, the sample size is small because few women and practically no men have 0 CAC in this older age group. The results, based on small sample size, need replication in other studies of the elderly with frequent sensitive measures of dementia and CAC.

Third, cardiovascular risk factors, such as elevated BP, 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 CV 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 the majority of dementia in very old ages, e.g. 80+. 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 individuals.

CONCLUSIONS

In summary, a very important unanswered question is whether 0 or very low CAC 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 decrease 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 individuals.

Supplementary Material

Online Appendix

Appendix Figure 1: Selection of Participants of the CHS-CS

Diagram of recruitment of participants for the CHS-CS and for CAC study.

CVD, cardiovascular disease; CHS-CS, Cardiovascular Health Study Cognition Study; CAC, coronary artery calcium; MRI, magnetic resonance imaging

Appendix Figure 2: CVD Incidence 1998–99 to 2012 by Age, Men Only

CHD incidence rates continue to increase with increasing age, even in the very old, for men.

CVD, cardiovascular disease, coronary heart disease; CHF, congestive heart failure; MI, myocardial infarction

Appendix Figure 3: CVD Incidence 1998–99 to 2012 by Age, Women Only

CHD incidence rates continue to increase with age in older women.

CVD, cardiovascular disease, coronary heart disease; CHF, congestive heart failure; MI, myocardial infarction

Perspectives.

Competency in Medical Knowledge

The successes in preventing and treating cardiovascular disease (CVD) have resulted in an increased population of older individuals at very high risk of dementia. The pathology of dementia in the elderly includes Alzheimer’s disease (AD), e.g. amyloid plaques, phosphorylated tau, neurofibrillary tangles, neurodegeneration, and vascular disease. Dementia is diagnosed by both a change in cognition and disability associated with cognitive decline.

Translational Outlook 1

The incidence of dementia in the 80+ age group is greater than for coronary heart disease, myocardial infarction, and stroke. Lesser extent of coronary atherosclerosis, e.g. coronary artery calcium, and other peripheral atherosclerosis or arteriosclerosis may be associated with a reduced incidence of dementia in the very old.

Translational Outlook 2

There is at present no consistent clinical trial evidence for any efficacious therapies to reduce incidence of dementia. Prevention of the progression of atherosclerosis or arteriosclerosis by both modification of known risk factors for vascular disease and variables related to “aging” could have an important role in reducing incidence of dementia and AD.

Abbreviations

AA

African American

AD

Alzheimer’s disease

ABI

ankle brachial index

CAD

coronary artery disease

CHS-CS

Cardiovascular Health Study Cognition Study

HR

hazards ratio

IMT

intimal medial thickness

MCI

mild cognitive impairment

MRI

magnetic resonance imaging