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Logo of nihpaAbout Author manuscriptsSubmit a manuscriptHHS Public Access; Author Manuscript; Accepted for publication in peer reviewed journal;
Stroke. Author manuscript; available in PMC 2013 December 1.
Published in final edited form as:
PMCID: PMC3508298

Carotid Atherosclerosis and Prospective Risk of Dementia

Carrington R. Wendell, Ph.D.,1,2 Shari R. Waldstein, Ph.D.,3,4,5 Luigi Ferrucci, M.D., Ph.D.,1 Richard J. O’Brien, M.D., Ph.D.,6 James B. Strait, M.D., Ph.D.,1 and Alan B. Zonderman, Ph.D.1


Background and Purpose

Though vascular risk factors have been implicated in the development of all-cause dementia and Alzheimer’s disease (AD), few studies have examined the association between subclinical atherosclerosis and prospective risk of dementia.


Participants from the Baltimore Longitudinal Study of Aging (n=364, aged 60–95, median age=73, 60% male, 82% white) underwent initial carotid atherosclerosis assessment and were subsequently assessed for dementia and AD annually for up to 14 years (median=7.0). Cox proportional hazards models predicting (a) all-cause dementia and (b) AD were adjusted for age, sex, race, education, blood pressure, cholesterol, cardiovascular disease, diabetes, and smoking.


Sixty participants developed dementia, with 53 diagnosed as Alzheimer’s disease. Raw rates of future dementia and AD among individuals initially (a) in the upper quintile of carotid intimal medial thickness (IMT) or (b) with bilateral carotid plaque were generally double the rates of individuals with IMT in the lower quintiles or no plaque at baseline. Adjusted proportional hazards models revealed a >2.5-fold increased risk of dementia and AD among individuals in the upper quintile of carotid IMT, and a nearly 2.0-fold increased risk of dementia among individuals with bilateral plaque.


Multiple measures of carotid atherosclerosis are associated with prospective risk of dementia. Individuals in the upper quintile of carotid IMT or bilateral carotid plaque were at greatest risk. These findings underscore the possibility that early intervention to reduce atherosclerosis may help delay or prevent onset of dementia and AD.

Keywords: atherosclerosis, intimal medial thickness, dementia, Alzheimer’s disease


The worldwide prevalence of dementia is expected to nearly double by 2030 and triple by 2050,1 and the search for risk and protective factors has consequently intensified. Historically, cardiovascular health was thought to contribute primarily to vascular dementia, though vascular diseases and risk factors are now understood to be related to all-cause dementia and Alzheimer’s disease as well.2 Cerebrovascular disease and/or cerebral hypoperfusion are considered likely mechanisms.3, 4 Despite these new insights, there is relatively limited research investigating associations between subclinical, or presymptomatic, atherosclerosis and dementia.

Subclinical atherosclerosis is most commonly studied in the carotid arteries, using ultrasonography. Cross-sectionally, increased prevalence of carotid atherosclerosis has been noted in several samples of patients with diagnosed dementia and Alzheimer’s disease.5, 6 Multiple indices of carotid atherosclerosis, including intimal medial thickness (IMT), plaque, and stenosis, have also been linked with accelerated cognitive decline among patients with Alzheimer’s disease7, 8 and dementia-free individuals.9 Yet, studies examining the association between carotid atherosclerosis and incident dementia are sparse.

In the Cardiovascular Health Study (CHS), the highest quartile of carotid IMT was associated with a significantly increased risk of dementia and AD over 5-year follow-up.10 Similarly, over a median follow-up of 9 years, the highest quintile of carotid IMT was related to prospective dementia and AD risk among Rotterdam Study participants.11 Over shorter-term follow-up in the same study, carotid IMT risk ratios increased considerably, and carotid plaque was additionally associated with dementia outcomes. More prospective research is needed to replicate and extend findings regarding incident dementia. Prior research has not consistently examined carotid plaque, an important indicator of degree of atherosclerosis progression. Further, the role of mild cognitive impairment (MCI), a frequent precursor to dementia, has been addressed inconsistently. Here, we examined the association between baseline carotid atherosclerosis, as measured by IMT and plaque, and prospective risk for all-cause dementia and AD among older adults enrolled in the Baltimore Longitudinal Study of Aging (BLSA). We conducted analyses with (a) inclusion of MCI cases in the “at risk for dementia” group and (b) exclusion of MCI.



Participants were enrolled in the BLSA, a prospective study of community-dwelling volunteers initiated by the National Institute on Aging in 1958.12 Approximately every 2 years, participants undergo medical, psychological, and cognitive testing. Beginning in 1994, carotid ultrasonography was performed on a BLSA subset as a function of sonographer availability (random with respect to participant scheduling) and participant willingness to participate. No exclusion criteria were applied, and this subsample was representative of the overall BLSA sample. Participants were included in the present analyses if they underwent carotid ultrasonography at or after age 60 (hereafter referred to as baseline visit) and were cognitively normal. A total of 364 participants were available for the present analysis. Participants were followed annually for up to 14 years (mean=6.7; SD=3.5; median=7.0) with comprehensive cognitive evaluations. No participants underwent carotid artery intervention during the study. All participants provided written informed consent. Institutional Review Board approval was obtained from Johns Hopkins Bayview Medical Center before 2002 and MedStar Research Institute afterwards.

Atherosclerosis Assessment

High-resolution B-mode ultrasonography of the common carotid arteries (CCAs) was performed with a linear-array, 5–10-MHz transducer (Ultramark 9 HDI, Advanced Technology Laboratories, Seattle, WA). A region 1.5cm proximal to the carotid bifurcation was identified, and IMT of the far arterial wall was evaluated as the distance between the lumen/intimal interface and medial/adventitial interface. Specific care was taken to measure IMT in areas devoid of plaque. IMT was measured on a frozen-frame image, magnified to achieve higher resolution of detail, at five contiguous sites at 1 mm intervals in both CCAs. The mean of these values, as well as a dichotomy based upon the 80th percentile of the mean (upper quintile), were used in statistical analyses. More precise quantiles were not feasible due to insufficient sample sizes across cells. The upper quintile dichotomy was selected based upon (a) previous literature identifying heightened risk in the highest IMT quintile and (b) comparability with clinically concerning thresholds of IMT (e.g., 0.9mm). Presence of plaque, defined as focal encroachment of the CCA wall(s), was also noted. Plaque was analyzed categorically as none vs. unilateral vs. bilateral, coded as two dummy variables. A single sonographer performed all measurements. Intra-observer correlation between repeated carotid IMT measurements on 10 BLSA participants was 0.96 (p<.001).13

Dementia Assessment

All participants were followed annually and reviewed at a consensus conference according to previously published protocol.14 See for additional details regarding conference procedures. Dementia diagnosis was determined according to the Diagnostic and Statistical Manual of Mental Disorders, 3rd Edition-Revised criteria.15 Mild cognitive impairment (MCI) diagnosis was made when participants had either single domain cognitive impairment (usually memory), or cognitive impairment in multiple domains without significant functional loss in activities of daily living. MCI cases without ultimate conversion to dementia were treated in two ways: a) retained in the “at risk for dementia” group and b) excluded entirely, to limit the possibility of MCI cases biasing the analyses. Diagnoses of dementia type were formulated during multidisciplinary evaluations based on prospectively collected evidence using National Institute of Neurological and Communication Disorders-Alzheimer’s Disease and Related Disorders Association criteria.16 Both all-cause dementia and AD served as outcomes in the present study.


Covariate selection was predicated upon three criteria: (a) previous demonstration of influence on dementia, carotid atherosclerosis, or both, (b) typical use in previous related literature, and (c) availability for a sufficient number of participants to preclude major reductions in sample size. Sociodemographic covariates included baseline age (years), sex (1=male), race (white=1, non-white=0), and education (based on years of schooling). Baseline self-reported smoking history was coded dichotomously (ever=1, never=0). Resting brachial systolic and diastolic blood pressure (SBP, DBP) values were obtained three times bilaterally and defined by Korotkoff phases I and V, respectively. Blood for lipid assay was drawn after overnight fast. Concentrations of total cholesterol were determined enzymatically (ABA-200 ATC Biochromatic Analyzer; Abbott Laboratories, Irving, TX), and high-density lipoprotein (HDL) cholesterol was determined by dextran sulfate-magnesium precipitation procedure. Baseline cardiovascular disease (i.e., coronary artery disease, myocardial infarction, heart failure) and diabetes mellitus were each defined dichotomously (present=1, absent=0). APOE genotype was determined by polymerase chain reaction amplification of leukocyte DNA followed by HhaI digestion and product characterization and by TaqMan assay systems relying on several single nucleotide polymorphisms around the APOE gene. Participants were classified by presence versus absence of at least one APOE ε4 allele.

Statistical Analyses

Statistical analyses were performed using SAS, version 9.2 (Cary, NC). Descriptive statistics and chi-square tests were computed to examine sample characteristics, including rates of dementia across levels of carotid atherosclerosis. Kaplan-Meier survival curves and log-rank tests were generated to compare unadjusted patterns of survival across different levels of carotid IMT and plaque. Cox proportional hazards models were constructed to assess risk of developing dementia associated with carotid IMT and plaque, controlling for age, sex, race, education, SBP, DBP, total and HDL cholesterol, cardiovascular disease, diabetes mellitus, and smoking. APOE genotype was not included in the primary analyses due to insufficient data, though supplementary analyses were conducted in a subset of participants. Mean carotid IMT was examined continuously and dichotomously (≥80th percentile). Carotid plaques were analyzed by category (none, unilateral, bilateral), using no plaques as the reference category. The dependent measure was age at onset of dementia (all-cause or AD) or the last observed (censored) age of non-diagnosed participants. Due to known associations among atherosclerosis, stroke, and dementia,17 analyses were also run excluding all prevalent and incident stroke (assessed by history). Post hoc power analyses were performed using R, version 2.15.0 (Vienna, Austria).


Table 1 shows sample characteristics at first assessment. Participants ranged in age from 60 to 95 (mean=73.6) and were 60.2% male, 81.9% white, 14.3% black, 3.8% Asian, Pacific-Islander, American Indian, or other. The average participant was well-educated, with the equivalent of a Bachelor’s degree (i.e., >16 years of education). There was a wide range of carotid IMT values (0.35–1.25mm), and the majority of the sample had either no (44.0%) or bilateral (41.5%) plaque. Twenty-three participants (6.3%) underwent carotid ultrasound and cognitive evaluation at first visit but did not undergo subsequent cognitive evaluation. During up to 14 years of follow-up, 60 cases of dementia were identified, of whom 53 cases were AD. Of the overall sample (n=364), 47 individuals (12.9%) were diagnosed with MCI, and 35 individuals (9.6%) had either a history of stroke prior to baseline, or incident stroke over the course of follow-up. Sample sizes for analyses involving carotid plaque were slightly smaller (ndementia=357, nAD=349) due to missing data.

Table 1
Baseline Characteristics of Study Sample (n=364)

Table 2 demonstrates increasing incidence rates of dementia and AD with increasing levels of carotid atherosclerosis. Regarding IMT, 14.0% of individuals with baseline carotid IMT <.80 mm developed dementia over follow-up, whereas 28.1% of individuals with carotid IMT ≥.80 mm developed dementia [X2(1, n=364)=7.64, p=.006]. Rates were similar for AD (12.5% and 25.8%, respectively, [X2(1, n=357)=7.13, p=.008]) and after excluding stroke. Rates became more divergent following exclusion of MCI cases: for all-cause dementia, 15.9% vs. 34.0% for low versus high IMT, respectively [X2(1, n=317)=9.37, p=.002], and for AD, 14.3% vs. 31.4% for low versus high IMT, respectively [X2(1, n=310)=8.78, p=.003]. Regarding plaque, individuals with no, unilateral, and bilateral plaque demonstrated increasing rates of dementia (e.g., 10.2%, 13.5%, and 22.3%, respectively for all-cause dementia [X2(2, n=357)=8.67, p=.013]).

Table 2
Dementia Incidence by Level of Atherosclerosis

Figure 1 shows unadjusted Kaplan-Meier survival curves of incident dementia across different levels of (a) carotid IMT and (b) plaque in the total sample. Similar patterns were noted for other subsamples (i.e., AD, MCI excluded, stroke excluded). Log-rank tests did not show significant differences in median probability of dementia for either carotid IMT (p=.779) or plaque, though the latter finding was marginal (p=.059).

Figure 1
Kaplan-Meier survival curves of incident all-cause dementia by level of (A) carotid IMT and (B) carotid plaque. Statistical tests indicated the proportionality assumption was not violated [Figure A: X2(12)=8.92, p=.709; Figure B: X2(13)=6.76, p=.914]. ...

Cox proportional hazards models demonstrated that carotid IMT was associated with an increased risk for dementia and AD (Table 3). Models with IMT coded continuously were uniformly non-significant (all p’s>.05), whereas dichotomous IMT models showed strong patterns of significance. Specifically, individuals with IMT ≥.80 mm had a greater than 2.5-fold increased risk of dementia (HR=2.55; 95% CI: 1.32–4.96, p=.006) and AD (HR=2.78; 95% CI: 1.37–5.63, p=.005), respectively, compared to individuals with IMT<.80 mm. Hazard ratios were also significant following exclusion of MCI cases from the “at risk” group (Table 3). Following exclusion of stroke, hazard ratios became borderline significant for both dementia (HR=2.09; 95% CI: 0.99–4.42, p=.053) and AD (HR=2.23; 95% CI: 0.99–4.98, p=.052), but remained significant after exclusion of MCI (HRdementia=2.21; 95% CI: 1.06–4.64, p=.036; HRAD=2.35; 95% CI: 1.06–5.22, p=.036).

Table 3
Association between Baseline Carotid Atherosclerosis and Prospective Risk of Dementia

In comparison to no plaque, bilateral plaque was associated with a nearly 2-fold increased risk in dementia in the total sample (HR=1.98; 95% CI: 1.06–3.70, p=.032) and with MCI excluded from the “at risk” group (HR=1.91; 95% CI: 1.02–3.61, p=.045). Hazard ratios remained significant for both samples (i.e., total sample and MCI excluded) following exclusion of stroke. Unilateral plaque was not associated with increased risk of dementia or AD. Models also showed no significant associations between plaque and risk of AD incidence.

Post hoc power analyses were undertaken due to concerns regarding final sample sizes in the subsample analyses (i.e., AD only, MCI excluded, stroke excluded). Analyses were conducted with obtained sample sizes, hazard ratios, and alpha=.05 and demonstrated adequate observed power for the majority of analyses (range of 1-β=.65–.83) with two exceptions. First, analyses examining plaque in the AD-only subgroups (both with and without MCI cases, and with and without stroke) were substantially underpowered to detect significant effects (range of 1-β=.29–.36). Second, analyses examining carotid IMT with stroke excluded were underpowered (range of 1-β=.51–.54), though observed hazard ratios were either significant or marginally significant (p=.05), potentially supporting the robustness of obtained findings.

For tabular results of supplementary analyses with APOE included as a covariate, please see Though sample sizes were reduced by 16–18%, results did not meaningfully change. The only differences arose for analysis of dichotomous IMT in relation to dementia and AD following exclusion of stroke, in which both hazard ratios transitioned from non-significance (p’s=.05) to significance (p’s=.03).


Over up to 14 years of follow-up, we identified strong associations between multiple measures of carotid atherosclerosis and prospective risk of dementia among participants in the Baltimore Longitudinal Study of Aging. Raw rates of dementia and AD among individuals (a) in the upper quintile of carotid IMT or (b) with bilateral plaque were generally double the rates of individuals in the lower quintiles of IMT or with no plaque, respectively. Results of Cox proportional hazards models, adjusted for demographic, biomedical, and behavioral risk factors, demonstrated similar patterns. Individuals in the upper quintile of carotid IMT had a more than 2.5-fold increased risk of both dementia and AD over follow-up, regardless of how MCI cases were treated. Results for carotid IMT were relatively unchanged following exclusion of stroke, though select findings became marginally significant. Bilateral carotid plaque was consistently associated with a nearly 2.0-fold increased risk of dementia. We found no association between plaque and risk of AD. Log-rank tests for Kaplan-Meier survival curves showed no significant differences in median probability of dementia, though these curves do not take into account critical covariates, including age.

Taken together with existing literature, the current results suggest a threshold effect for carotid IMT and risk of dementia and AD. Specifically, continuous IMT was not associated with risk of dementia, whereas IMT was significant when defined as a dichotomy (i.e., at the 80th percentile). Two previous studies, in which carotid IMT was coded as quartiles or quintiles, have showed similar threshold effects. In the Rotterdam study, only the highest quintile of carotid IMT was associated with dementia and AD risk.11 Further, CHS data showed only the highest quartile of carotid IMT to be associated with dementia risk.10 This pattern of findings is consistent with the idea that IMT must reach a criterion thickness to become statistically predictive of dementia. Though IMT has been validated as an index of systemic atherosclerosis,18 it is also known that increased IMT may represent non-atherosclerotic age-associated changes in the vessel wall, or an adaptive response to changes in flow, wall tension, or lumen diameter. However, IMT in the upper quintile of the distribution is less likely to reflect these normative, non-atherosclerotic processes,19 and thereby more likely to be reflective of systemic atherosclerosis burden and associated dementia risk.

To our knowledge, only one prior study has examined carotid plaque and prospective dementia risk.11 In that study, there was no significant association between number of plaques and dementia risk over a median 9-year follow-up, though the relation became significant over much shorter follow-up. In the present study, only bilateral plaque was associated with prospective dementia risk, potentially suggesting that bilaterality (i.e., representing greater severity/systemic presence) may be an important indicator of risk. Patterns of dementia incidence by plaque category (see Table 2) are also consistent with this possibility. Though we found no association between plaque and AD-specific risk, poor observed power in this subgroup jeopardizes the validity of this finding, particularly given the magnitude of obtained hazard ratios.

MCI has been inconsistently considered in the literature. It is typically not mentioned (and presumably included in the “at risk” group) or excluded, but these two approaches have never been examined simultaneously. Doing so in the present study demonstrated that remarkably similar patterns arose, regardless of how MCI was treated. On the one hand, inclusion of MCI in the “at risk” group could unnecessarily bias results, such that imminent dementia cases are categorized as cognitively normal. However, complete exclusion of MCI reduces generalizability of results to community-based populations (where imminent dementia is unavoidable) and reduces sample sizes and associated power available for analyses. Findings from the present study suggest that inclusion of MCI cases in the “at risk” group is a reasonable approach.

Several mechanisms may explain the association between atherosclerosis and dementia. A common genetic vulnerability, such as APOE genotype, may contribute to development of both atherosclerosis and dementia. For example, AD patients carrying the APOE ε4 allele have greater IMTs than AD non-carriers or vascular dementia patients.20 However, there is little evidence that an interaction exists between APOE genotype and subclinical atherosclerosis in the prediction of future onset of dementia.10, 11 Other shared cardiovascular risk factors, such as high blood pressure, may also play a role. Nonetheless, findings from the present study, as well as those from the CHS and Rotterdam studies, all withstood adjustment for a multitude of these risk factors. Subclinical cerebrovascular disease, including silent brain infarctions and white matter disease, and/or cerebral hypoperfusion, may also link atherosclerosis and dementia.3, 4, 21 Lastly, neuropathologic evidence has indicated an association between atherosclerosis and severity of neuritic plaques in AD,22 but there is currently no consensus regarding causality.23

Strengths of this investigation included its prospective design, length of follow-up, assessment of both carotid IMT and plaque, consideration of both all-cause dementia and AD, and attention to MCI and stroke in the analytic design. The study was limited by its sample size and compromised power in certain subgroup analyses. Relatedly, frequency of vascular dementia was not high enough for separate examination, and APOE data were not complete. In addition, the study was based on a convenience sample of typically highly educated participants. The homogeneity and nonrepresentative nature of the sample may limit the generalizability of the study, although the sample’s homogeneity may also restrict the influences of confounding demographic variables. Lastly, it is well known that clinical diagnosis of AD is challenging, with true diagnosis of AD occurring only post-mortem. Every precaution was taken to reduce the likelihood of misclassification, but no approach is infallible.


Overall, findings from the present study suggest that multiple measures of carotid atherosclerosis are associated with prospective risk of dementia. Individuals in the upper quintile of carotid IMT or bilateral carotid plaque were at greatest risk. These findings underscore the possibility that early intervention to reduce atherosclerosis may help delay or prevent onset of dementia and AD.


Sources of Funding

This research was supported by the National Institute on Aging Intramural Research Program, National Institutes of Health.





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