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. Author manuscript; available in PMC: 2020 Jul 1.
Published in final edited form as: Int J Geriatr Psychiatry. 2019 Apr 15;34(7):1050–1057. doi: 10.1002/gps.5108

Type 2 diabetes and later cognitive function in older American Indians: The Strong Heart Study

Brenna Cholerton 1, Adam Omidpanah 2, Steven P Verney 3, Lonnie A Nelson 2, Laura D Baker 4, Astrid Suchy-Dicey 2, William T Longstreth Jr 5,6, Barbara V Howard 7, Jeffrey A Henderson 8, Thomas J Montine 1, Dedra Buchwald 2
PMCID: PMC6579638  NIHMSID: NIHMS1022171  PMID: 30924200

Abstract

Objectives

Insulin resistance is a substantial health issue for American Indians, with type 2 diabetes overrepresented in this population as compared to non-Hispanic whites. Insulin resistance and its related conditions in turn increase risk for dementia and cognitive impairment. The aim of the current study was to determine whether type 2 diabetes and insulin resistance at midlife was associated with later life cognitive testing in a large sample of older American Indians, aged 65 and over.

Methods

American Indian participants who underwent both fasting blood draw as part of the Strong Heart Study and had subsequent cognitive testing as part of the later adjunct Cerebrovascular Disease and its Consequences in American Indians study were included (n=790). Regression models examined type 2 diabetes and impaired fasting glucose and subsequent cognitive test performance as part of a longitudinal study design. The relationship between a continuous measure of insulin resistance and later cognitive test performance was assessed using generalized estimating equations.

Results

Controlling for demographic and clinical factors, verbal fluency and processing speed/working memory were significantly negatively associated with having type 2 diabetes and with insulin resistance, but not with impaired fasting glucose.

Conclusion

In this sample of American Indians, type 2 diabetes at midlife was associated with subsequent lower performance on measures of executive function. These results may have important implications for future implementation of diagnostic and intervention services in this population.

Keywords: American Indians, Cognition, Dementia, Diabetes, Insulin resistance, Strong Heart Study

INTRODUCTION

Type 2 diabetes mellitus, a major chronic health disease, is overrepresented in American Indians by about twofold in comparison to non-Hispanic whites.1,2 In the general population, type 2 diabetes is associated with an elevated risk for cognitive decline and dementia.3 A recent comprehensive meta-analysis demonstrated a 73% increased risk for all-cause dementia among those with type 2 diabetes; this risk increased to 127% when vascular dementia (VaD) was examined independently.4 This finding is unsurprising, as insulin resistance, the disruption of the ability of insulin to perform its normal action in cells, and its related conditions, including type 2 diabetes, hypertension, obesity, and cardiovascular disease, are associated with vascular brain injury, including small- and large-vessel disease, and cognitive impairment.5 Risk for dementia due to Alzheimer’s disease (AD) is also increased substantially among groups with type 2 diabetes.4 Chronic peripheral hyperinsulinemia caused by insulin resistance ultimately lowers brain insulin levels; such reductions may in turn lead to decreased clearance of the beta amyloid (Aβ) peptide and increased hyperphosphorylation of tau,6 the hallmark pathologic features of AD neuropathology. Insulin resistance is also associated with increased levels of inflammation and oxidative stress,7 presenting additional risk for dementia-associated processes independent from Aβ and tau.

Given the increased risk for dementia conferred by type 2 diabetes, a link between insulin resistance syndromes and cognitive impairment in non-demented individuals is expected and has been reported in primarily Caucasian samples. The issue has not been examined in populations of American Indians. Peripheral insulin resistance, measured by the homeostasis model assessment-estimated insulin resistance (HOMA-IR), is associated with decreased executive function, with mixed findings related to episodic memory.8–11 Similarly, frank type 2 diabetes has been primarily associated with reductions in processing speed, executive function, and memory.12,13

The pathologic processes underlying dementia due to AD and vascular brain injury may begin years or even decades prior to clinical manifestation of symptoms,14,15 with midlife identified as a potential critical period of intervention.16,17 Indeed, midlife type 2 diabetes and other cardiovascular risk factors may be particularly associated with increased risk for impaired cognition and dementia.18,19 Thus, for some people, early elevated markers of insulin resistance may represent the beginning of a cascade of negative events in the brain ultimately associated with AD, VaD or both. For example, a recent study of late middle aged participants demonstrated an association with higher insulin resistance and higher Pittsburgh compound B binding in fronto-temporal regions, suggesting higher amyloid deposition in these individuals.20

Despite the increased risk for conditions associated with cognitive decline and dementia, little is known about the risk for cognitive impairment in American Indians as it relates to type 2 diabetes and insulin resistance. In the current study, we describe the relationship between type 2 diabetes and impaired glucose tolerance in midlife (median age =50.6 years) and subsequent cognitive test performance later in life (median age = 72.0 years). We further explore whether a sensitive continuous index of insulin resistance (HOMA-IR) collected during midlife is associated with subsequent cognitive function in the Cerebrovascular Disease and its Consequences in American Indians (CDCAI) study, the largest sample of American Indians with cognitive, neuroimaging, medical data and cultural information collected to date.

METHODS

Participants

The Strong Heart Study (SHS) is a longitudinal study investigating cardiovascular disease in older American Indians, and it remains the largest comprehensive, longitudinal study of American Indian health in the U.S.21 Between 1989 to 1991, the SHS enrolled 4,549 American Indian participants aged 45 and 74 years throughout communities located in the Northern plains, Southern plains, and Southwest.21 Participants were followed longitudinally across three study phases over 15 years. Data collected during each phase included demographic factors, medical history, medication use, personal health habits, a physical examination, and a fasting blood sample.

In 2010–2013, participants from the SHS were recruited for CDCAI, designated as the “Strong Heart Stroke Study” by participating communities and field centers, designed as a follow-up study to evaluate brain injury in the surviving members of the SHS cohort via brain magnetic resonance imaging (MRI), cognitive testing, and medical history. Inclusion and exclusion criteria have been described;22 briefly, participants had to be eligible to undergo MRI and must have been able to speak English fluently in order to complete the cognitive test measures. DNA was extracted from whole plasma during the Strong Heart Family Study, and genotyped for APOE using previously described methods.23,24 A total of 1,033 unrelated participants aged 65 and over were enrolled in CDCAI, with a mean of 21.1 years between the initial and follow up examinations (range 18.3 – 24.3 years). Of these, 215 participants completed study visits but were not included in analyses because their community withdrew consent to us the data, resulting in a preliminary analytic sample of 818 participants. Institutional review boards, local units of the Indian Health Service, and individual tribal councils approved all study procedures, and all participants provided written informed consent.

For the current study, we compared plasma measurements taken during Phase 1 of SHS with cognitive measurements assessed during CDCAI (Figure 1). Individuals with missing fasting labs (n=25), baseline large vessel stroke (n=1), or missing clinical data (n=2) were excluded, leaving a total of 790 participants with cognitive test data and valid measurements of fasting plasma insulin and glucose were available for analyses.

Figure 1.

Figure 1.

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Timeline of plasma measurement and cognitive data collection in the Strong Heart Study and the CDCAI.

Plasma measurements

Plasma samples were taken during Phase I of the SHS study and stored at −70°C, and fasting plasma insulin and glucose were assessed as previously described.21,25 Impaired fasting glucose was defined as fasting glucose between 100–125 mg/dL. Type 2 diabetes was defined as fasting glucose ≥126 mg/dL or self-reported current use of insulin or oral hypoglycemic medications. Insulin resistance was assessed in participants not currently taking antidiabetic medication using the HOMA-IR equation: fasting insulin (μU/mL) × fasting glucose (mmol/L)/22.5.26

Cognitive measurements

Cognitive measures administered during the CDCAI visit included the following:

  1. Modified Mini-Mental Status Examination (3MSE),27 a 100-point global cognitive screening measure designed to provide an overall representation of cognitive status.

  2. California Verbal Learning Test –II, Short Form (CVLT-II SF),28 a measure of verbal learning and declarative memory, consisting of a list of 9 words from semantically-related categories which the subject is asked to recall across four learning trials (total immediate recall), following a brief intrusion task (short delay recall), and after a 10-minute delay (long delay recall).

  3. Coding subtest from the Wechsler Adult Intelligence Scale-IV (WAIS-IV),29 a measure of processing speed and visual working memory requiring the participant to identify and fill in as many missing symbols as possible based on a predetermined code over 2 minutes.

  4. Verbal fluency, a measure of phonemic verbal fluency (using letters F,A,S)30 in which the participant is required to provide as many words as possible beginning with a given letter within a one-minute time frame. This test is primarily considered a measure of executive function.

Statistical analyses

Descriptive data were compiled for demographic, self-report and clinical measures, biomarker, and cognitive measures. Regression models examining cognitive test performance were fit controlling for a three-level exposure derived from fasting plasma glucose and diabetic status during SHS Phase 1 (referred to as “baseline”): normal fasting glucose (<100mg/dL), impaired fasting glucose (100–125 mg/dL), and type 2 diabetes (≥126 mg/dL or undergoing current diabetes treatment) controlling for baseline age, sex, education level, site, native language fluency at home (speaks fluently, not fluently, or not at all), body mass index (BMI), self-report alcohol consumption (current drinker, former drinker, never drank), tobacco smoking (past, current, never), and APOE genotype (є4+, є4-). The relationship between baseline HOMA-IR and subsequent cognitive test performance during CDCAI was measured using generalized estimating equations (GEE) and included the same covariates and cognitive outcomes. The HOMA-IR analyses omitted participants with medically treated type 2 diabetes at baseline due to mediating effects of anti-diabetic medications or fasting insulin (n=88). Secondary HOMA-IR analyses were performed stratifying by type 2 diabetes diagnosis at baseline. Statistical tests were two-tailed; the significance threshold was set at P < 0.05. All statistical analyses were performed in R version 3.1.2.

RESULTS

Demographic, clinical, and cognitive measures of participants with type 2 diabetes, impaired fasting glucose, and normal fasting glucose are detailed in Table 1. Mean age at baseline was 51.7 years and mean age at follow up was 73.0 years. Of those participants with type 2 diabetes at baseline, 52% were not medically treated at baseline. Among participants without type 2 diabetes, the average HOMA-IR measured at baseline was 3.7 (SD=2.9). In contrast, participants with medically untreated type 2 diabetes had an average baseline HOMA-IR of 10.0 (SD=7.7).

Table 1.

Characteristics of Cerebrovascular Disease and Its Consequences in American Indians (CDCAI) participants

Normal glucosea (n = 261) Impaired fasting glucoseb(n = 344) Type 2 diabetesc (n = 185) Total (n = 790)
Baseline demographic and clinical characteristics
Age, years mean (sd) 51.3 (5.5) 51.7 (5.5) 53.0 (5.9) 51.9 (5.6)
Male n (%) 80 (30.7) 128 (37.2) 52 (28.1) 260 (32.9)
Education, years mean (sd) 12.5 (3.0) 12.3 (2.7) 12.0 (2.6) 12.3 (2.8)
Site n (%)
Southwest 16 (6.1) 32 (9.3) 45 (24.3) 93 (11.8)
Southern plains 101 (38.7) 155 (45.1) 74 (40.0) 330 (41.8)
Northern plains 144 (55.2) 157 (45.6) 66 (35.7) 367 (46.5)
Native language fluency n (%)
Fluently 91 (34.9) 104 (30.2) 81 (43.8) 276 (34.9)
Not fluently 71 (27.2) 93 (27.0) 50 (27.0) 214 (27.1)
Not at all 99 (37.9) 14 (42.7) 54 (29.2) 300 (38.0)
Smoking n (%)
Never 71 (27.2) 93 (27.0) 64 (34.6) 228 (28.9)
Ever 65 (24.9) 136 (39.5) 70 (37.8) 271 (34.3)
Current 125 (47.9) 115 (33.4) 51 (27.6) 291 (36.8)
Alcohol use n (%)
Never 23 (8.8) 43 (12.5) 31 (16.8) 97 (12.3)
Ever 105 (40.2) 151 (43.9) 81 (43.8) 337 (42.7)
Current 133 (51.0) 150 (43.6) 73 (39.5) 356 (45.1)
BMI mean (sd) 28.6 (5.8) 30.9 (5.3) 33.2 (5.3) 30.7 (5.7)
HOMA-IR mean (sd) 2.5 (1.6) 4.5 (3.3) 11.7 (8.2) 5.5 (5.8)
HBA1c mean (sd) 4.9 (0.5) 5.2 (0.5) 7.8 (2.4) 5.7 (1.7)
APOE є4 carrier n (%) 68 (26.1) 72 (20.9) 37 (20.0) 177 (22.4)
Cognitive findings at follow-up
3MSE mean (sd) 88.6 (9.7) 88.9 (8.7) 86.9 (9.8) 88.3 (9.3)
CVLT-II SF: total immediate recall mean (sd) 22.4 (5.5) 22.6 (5.2) 22.7 (4.9) 22.6 (5.2)
CVLT-II SF: short delay recall; mean (sd) 5.8 (2.2) 5.9 (2.0) 6.1 (1.9) 5.9 (2.1)
CVLT-II SF: long delay recall; mean (sd) 5.4 (2.4) 5.4 (2.2) 5.5 (2.2) 5.4 (2.3)
WAIS-IV Coding; mean (sd) 45.5 (17.3) 45.2 (15.2) 38.6 (13.8) 43.8 (15.9)
Verbal fluency (FAS); mean (sd) 25.8 (12.1) 24.4 (10.9) 21.5 (10.7) 24.2 (11.3)
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Abbreviations: 3MSE, modified mini mental state exam; APOE, Apolipoprotein E; BMI, body mass index; CVLT-II SF: California Verbal Learning Test-II Short Form; HBA1c, Hemoglobin A1c; WAIS-IV, Wechsler Adult Intelligence Scale—Fourth Edition

a

Normal fasting glucose was defined as fasting glucose <100 mg/dL

b

Impaired fasting glucose was defined as fasting glucose between 100–125 mg/dL

c

Type 2 diabetes was defined as self-reported current use of insulin or oral hypoglycemic medications (n=88) or fasting glucose >126 mg/dL

Baseline type 2 diabetes, impaired fasting glucose, and normal fasting glucose & cognition

Associations between baseline glucose status (normal glucose, impaired fasting glucose, type 2 diabetes) and subsequent cognitive test performance are displayed in Table 2. In comparison with participants who had normal glucose levels at baseline, type 2 diabetes at baseline was associated with significantly worse subsequent performance on measures of processing speed and verbal fluency, translating to a −4.41 difference in Coding score and a −3.58 difference in verbal fluency score. When those with impaired fasting glucose were compared with participants with normal glucose, significant differences in cognitive test performance were lacking. To assess whether control of glucose levels among diabetics influenced the results, HbA1c was included as a covariate in secondary analyses; these analyses did not yield substantially different results.

Table 2.

Associations between baseline fasting glucose and subsequent cognitive outcomes in American Indians

Impaired fasting glucose vs. normal fasting glucose Type 2 diabetes vs. normal fasting glucose
β coefficient 95% CI P-value β coefficient 95% CI P-value
3MSE 0.777 (−0.597, 2.152) 0.268 −0.351 (−2.062, 1.360) 0.688
CVLT-II SF: total immediate recall 0.319 (−0.528, 1.166) 0.460 0.717 (−0.299, 1.732) 0.167
CVLT-II SF: short delay recall 0.126 (−0.210, 0.462) 0.462 0.369 (−0.052, 0.791) 0.086
CVLT-II SF: long delay recall 0.101 (−0.267, 0.469) 0.591 0.241 (−0.229, 0.712) 0.315
WAIS-IV Coding 0.304 (−1.912, 2.521) 0.788 −4.413 (−7.100, −1.725) 0.001
Verbal fluency (FAS) −1.059 (−2.760, 0.642) 0.223 −3.583 (−5.545, −1.621) <0.001
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Model adjusted for 3-level exposure of fasting glucose: normal < 100 mg/Dl, impaired 100–125 mg/dl, and diabetic 126 or higher, baseline age, sex, education, site, fluency of native language, baseline BMI, smoking status, alcohol consumption, and APOE є4 allele presence

Abbreviations: 3MSE, modified mini mental state exam; APOE, Apolipoprotein E; BMI, body mass index; CI: confidence interval; CVLT-II SF: California Verbal Learning Test-II Short Form; WAIS-IV, Wechsler Adult Intelligence Scale—Fourth Edition

HOMA-IR & cognition

To determine whether a more sensitive measure of insulin resistance was associated with later cognitive test performance across the entire sample, excluding 89 participants with medically treated type 2 diabetes, the relationship between HOMA-IR and cognitive test performance was examined. Regression model results are summarized in Table 3. After controlling for all covariates, a unit difference in HOMA-IR was associated with a significant −0.29 difference in Coding score (95% CI −0.58, −0.01). Similarly a unit difference in HOMA-IR was associated with a significant −0.21 difference in verbal fluency score (95% CI −0.40, −0.02). However, when stratified by baseline type 2 diabetes status (type 2 diabetes, no type 2 diabetes), none of the results were significant for either group.

Table 3.

Associations between baseline HOMA-IR and cognitive outcomes in American Indians

N Test mean (sd) β coefficient 95% CI P-value
3MSE 666 88.5 (9.1) −0.100 (−0.309, 0.109) 0.347
CVLT-SF: Total Learning 689 22.5 (5.3) 0.020 (−0.088, 0.128) 0.716
CVLT-SF: Delayed Recall Short 689 5.9 (2.1) 0.026 (−0.020, 0.072) 0.266
CVLT-SF: Delayed Recall Long 689 5.4 (2.3) 0.023 (−0.024, 0.069) 0.337
WAIS-IV Coding 699 44.6 (15.9) −0.293 (−0.578, −0.007) 0.045
Verbal Fluency (FAS) 698 24.5 (11.4) −0.211 (−0.401, −0.021) 0.030
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Model adjusted for baseline age, sex, education, site, fluency of native language, BMI, smoking status, alcohol consumption, and e4 allele presence. Sample comprises untreated diabetic and non-diabetic participants

Abbreviations: 3MSE, modified mini mental state exam; CI: confidence interval; CVLT-II SF: California Verbal Learning Test-II Short Form; WAIS-IV, Wechsler Adult Intelligence Scale—Fourth Edition

DISCUSSION

The link between midlife risk factors and subsequent cognitive decline may be especially problematic for American Indians, who have higher levels of insulin resistance-related syndromes,1 and in whom late life cognitive decline and dementia has been sparsely studied. In the first large-scale study of its kind in American Indians, our results suggest that midlife type 2 diabetes is associated with impairment of specific cognitive functions in later life, namely processing speed/working memory and verbal fluency.

Multiple potential mechanisms exist by which midlife type 2 diabetes may negatively impact cognition later in life. Midlife diabetes may represent a marker of chronic allostatic load affecting multiple systems, especially the cardiovascular system.31 Vascular brain injury, in its many forms, is strongly associated with cognitive impairment and dementia.32 Insulin dysfunction may impact the vasculature via direct effects including modulation of capillary recruitment, vasodilation, and regional blood flow, and indirectly by increasing risk of type 2 diabetes, hyperlipidemia, hypertension, and inflammation.33,34 Type 2 diabetes is a known risk factor for cardiovascular and cerebrovascular disease and associated atherosclerosis and micro- and macrovascular neuropathologic lesions.35,36 Vascular endothelial dysfunction is a characteristic consequence of type 2 diabetes, likely related to a combination of endothelial insulin resistance and inflammation, and may increase susceptibility to hypoxic events, ischemia, and blood brain barrier leakage.37,38 Such dysfunction may be evident prior to white matter changes on imaging and is associated with poorer cognitive function in both demented and nondemented groups.39 These observations are supported by results from prospective community studies, which largely indicate an increased risk for VCI and VaD among those with type 2 diabetes.4,40

We found an association between midlife insulin resistance and type 2 diabetes and later-life cognitive function that falls largely within the executive domain (phonemic verbal fluency and processing speed/working memory); poor performance on these and related measures are frequently associated with cognitive impairment that has a vascular contribution. Indeed, autopsy results from a large community sample indicate that microvascular cortical and subcortical changes were associated with executive functions,41 and a recent meta-analysis indicated that the greatest impairment in those with vascular cognitive impairment compared to normal controls was in processing speed.42 Similarly, a consistent link between executive functions in those with metabolic syndrome and type 2 diabetes has been reported, with reduced processing speed one of the most frequent cognitive deficiencies identified.43,44 Thus, elevated insulin resistance may confer a risk for increased cognitive decline associated with vascular dysfunction in American Indians.

In addition to cognitive impairment and increased dementia risk associated with the effects of insulin resistance on the vasculature, insulin resistance may be a key factor in a hypothesized “metabolic pathway” to the development of AD. However, while autopsy studies have yielded an association between type 2 diabetes and vascular pathology, the relationship between AD pathology and type 2 diabetes is more tenuous.45 In the current study, we did not find an association between insulin resistance and subsequent episodic memory performance, the cognitive domain most commonly associated with underlying AD pathology. This lack of association may indicate that, in this population, the impact of insulin resistance on vascular brain injury may be more prominent than on AD pathologic processes. Of note, vascular risk factors may interact synergistically to amplify the effects of the AD cascade. For example, vascular dysfunction may be associated with progression of amyloid and tau pathology,46 and although whether insulin resistance increases specific AD risk in this population is unknown.

We did not find an association between impaired fasting glucose at baseline and subsequent cognitive function. In addition, although we found an association between a continuous measure of insulin resistance (HOMA-IR) and processing speed and verbal fluency, these results were not maintained when the group was divided according to diabetes status, suggesting either reduce statistical power or attenuation of effect due to the exclusion of medically treated type 2 diabetes, which represents a more advanced stage of disease. These results suggest that in this population, it may be the presence of frank diabetes at midlife that represents particular later cognitive risk. This is supported by a large-scale study of older adults with type 2 diabetes that incorporated retrospective HMO record review that found an increased prevalence of dementia in American Indians in comparison to other groups with type 2 diabetes; these differences persisted after adjustment for other cardiovascular risk factors.47 Consistent with prior reports of increased prevalence of type 2 diabetes in American Indian populations,1,2 23% of the sample met the study definition for type 2 diabetes, a substantially higher prevalence than the recently reported 14.3% in middle-aged adults in the U.S.48 Importantly, in our sample a surprisingly large percentage of those with diabetes at baseline were untreated (53%) at baseline, suggesting a need for increased screening and treatment programs. Indeed, evidence from the original SHS yielded a higher conversion rate from impaired glucose tolerance to frank type 2 diabetes in middle-aged to older adults,49 suggesting an urgent need to identify those most at risk for type 2 diabetes earlier.

This study has limitations that would be useful to address in future study designs as well as in follow-up of the current cohort. First, clinical data that would permit or suggest diagnosis of dementia or mild cognitive impairment were not collected, and important cognition-related covariates, such as education, were based on participant self-report. Future research should focus specifically on effective and reliable cognitive diagnosis among these communities, as well as the impact of the type and extent of educational attainment on cognitive task performance. Second, as this is a retrospective study, we do not have a detailed assessment of diabetic history, cognitive data collection at baseline, or follow up measures of insulin resistance. Thus, given that age of onset of type 2 diabetes was unknown, we were unable to control for disease duration in our analyses. Thus, given that age of onset of type 2 diabetes was unknown, we were unable to control for disease duration in our analyses. The lack of glucose or insulin resistance measurements at follow up substantially tempers our ability to fully understand the impact of changing diabetic status in the years after baseline on subsequent cognitive function. Further, determining whether midlife type 2 diabetes or insulin resistance is associated with faster cognitive decline may be more illuminating in terms of more precisely describing the relationship between insulin resistance and risk for cognitive dysfunction. For example, a recent study suggested that while baseline midlife cognitive scores were lower among those with type 2 diabetes, rate of subsequent cognitive change did not differ among those with and without type 2 diabetes,50 while still others have found a difference in rate of decline.51,52 Elucidating this association in American Indians will be important. Finally, we have limited cognitive testing available with variable sensitivity, and we do not have normative data for cognitive tests in this sample, thus are not able to determine what equals “impairment.”

This study represents a unique contribution to the apparent insulin-dementia interaction, providing evidence in a large and well-characterized cohort of American Indians. Large-scale intervention and education programs targeting vascular risk factors instituted at midlife and beyond may help to reduce risk, not only for dementia but other associated chronic illnesses. Future directions include gathering informative data from imaging studies and other markers of underlying pathology in this population and determining the relative risk of AD and VaD in this group.

Key points:

  1. Midlife type 2 diabetes and insulin resistance are associated with reduced executive function in later life in older American Indian participants.

  2. Although prior research demonstrates a link between type 2 diabetes, insulin resistance, and cognition, this study represents a unique contribution by providing evidence in a large and well-characterized cohort of American Indians.

  3. These results may help to guide future intervention and education programs targeting vascular risk factors instituted at midlife and beyond.

Acknowledgments

This work was supported by National Heart Lung and Blood Institute (HL093086), National Institute on Aging grant (P50AG005135), and National Institute of Neurological Disorders and Stroke (P50 NS062684). The opinions expressed in this paper are those of the authors and do not necessarily reflect the views of the IHS. We wish to sincerely thank all study participants for their important role.

Funding sources: National Heart Lung and Blood Institute (HL093086), National Institute on Aging (P50AG005135), and National Institute of Neurological Disorders and Stroke (P50 NS062684)

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