Midlife Vascular Risk Factors Research Articles

Educational Attainment and Dementia: Mediation by Mid-Life Vascular Risk Factors.

Lower education is associated with higher burden of vascular risk factors in mid-life and higher risk of dementia in late life. We aim to understand the causal mechanism through which vascular risk factors potentially mediate the relationship between education and dementia. In a cohort of 13,368 Black and White older adults in the Atherosclerosis Risk in Communities Study, we assessed the relationship between education (grade school, high school without graduation, high school graduate or equivalent, college, graduate/professional school) and dementia among all participants and among those with incident stroke. Cox models were adjusted for age, race-center (a variable stratified by race and field center), sex, apolipoprotein E (APOE) ε4 genotype, and family history of cardiovascular disease. Causal mediation models assessed mediation by mid-life systolic blood pressure, fasting blood glucose, body mass index, and smoking. More education was associated with 8 to 44% lower risk of dementia compared to grade school-level education in a dose-response pattern, while the relationship between education and post-stroke dementia was not statistically significant. Up to 25% of the association between education and dementia was mediated through mid-life vascular risk factors, with a smaller percentage mediated for lower levels of education. A substantial proportion of the relationship between education and dementia was mediated through mid-life vascular risk factors. However, risk factor modification is unlikely to fully address the large educational disparities in dementia risk. Prevention efforts must also address disparities in socioeconomic resources leading to divergent early-life education and other structural determinants of mid-life vascular risk factors. ANN NEUROL 2023;94:13-26.

Associations of Vascular Risk and Amyloid Burden with Subsequent Dementia.

Midlife vascular risk factors (MVRFs) are associated with incident dementia, as are amyloid β (Aβ) deposition and neurodegeneration. Whether vascular and Alzheimer disease-associated factors contribute to dementia independently or interact synergistically to reduce cognition is poorly understood. Participants in the Atherosclerosis Risk in Communities-Positron Emission Tomography study were followed from 1987-1989 (45-64 years old) through 2016-2017 (74-94 years old), with repeat cognitive assessment and dementia adjudication. In 2011-2013, dementia-free participants underwent brain magnetic resonance imaging (with white matter hyperintensity [WMH] and brain volume measurement) and florbetapir (Aβ) positron emission tomography. The relative contributions of vascular risk and injury (MVRFs, WMH volume), elevated Aβ standardized uptake value ratio (SUVR), and neurodegeneration (smaller temporoparietal brain regions) to incident dementia were evaluated with adjusted Cox models. In 298 individuals, 36 developed dementia (median follow-up=4.9 years). Midlife hypertension and Aβ each independently predicted dementia risk (hypertension: hazard ratio [HR] = 2.57, 95% confidence interval [CI] = 1.16-5.67; Aβ SUVR [per standard deviation (SD)]: HR=2.57, 95% CI=1.72-3.84), but did not interact significantly, whereas late life diabetes (HR=2.50, 95% CI=1.18-5.28) and Aβ independently predicted dementia risk. WMHs (per SD: HR=1.51, 95% CI=1.03-2.20) and Aβ SUVR (HR=2.52, 95% CI=1.83-3.47) independently contributed to incident dementia, but WMHs lost significance when MVRFs were included. Smaller temporoparietal brain regions were associated with incident dementia, independent of Aβ and MVRFs (HR=2.18, 95% CI=1.18-4.01). Midlife hypertension and late life Aβ are independently associated with dementia risk, without evidence for synergy on a multiplicative scale. Given the independent contributions of vascular and amyloid mechanisms, multiple pathways should be considered when evaluating interventions to reduce the burden of dementia. ANN NEUROL 2022;92:607-619.

Abstract 065: Educational Attainment And Dementia Risk: Mediation By Vascular Risk Factors At Mid-life In The Atherosclerosis Risk In Communities (ARIC) Study

Background: Dementia prevention largely focuses on the modification of vascular risk factors and is particularly important among stroke survivors, who have the highest burden of vascular risk factors and are at elevated risk of dementia. Low educational attainment is a risk factor not only for worse vascular profiles at midlife but also for incident dementia. It is unclear to what extent the relationship between education and dementia is mediated through these vascular risk factors. Methods: In a cohort of 14,059 Black and White older adults in four U.S. communities, we assessed the relationship between education and dementia among all participants and, separately, among those with incident stroke. We used causal mediation analysis to assess multiple mediation by midlife hypertension, diabetes, BMI and smoking of the relationship between educational attainment and dementia. Results: Participants with less education had higher prevalence of mid-life risk factors. Lower education was associated with 60% higher risk of dementia and 40% higher risk of post-stroke dementia. About half of the association between education and dementia was mediated through vascular risk factors (Table 1). Conclusion: A substantial proportion of the relationship between education and dementia risk is indeed not mediated through mid-life vascular risk factors. The association between education and dementia was weaker in the high-risk participants who have had an incident stroke, indicating that more proximal causes such as vascular disease prior to the stroke superseded the distal cause of differences in educational attainment. As such, any mediated effect of education on dementia is likely through vascular risk factors earlier on in the life-course. Our findings suggest that dementia prevention efforts must also address disparities in socioeconomic resources as well as other mediating pathways.

Disparities in dementia and AD biomarkers in the ARIC study: The important contribution of social determinants of health

AbstractBackgroundDementia disproportionately impacts people of color in the U.S.. Whether these disparities are due to differences in vascular risk factors, cognitive reserve, or AD pathophysiology remains unclear.MethodBlack and White participants from four U.S. communities were recruited into the Atherosclerosis Risk in Communities (ARIC) study at ages 45‐64. Vascular risk factors were evaluated in midlife and at multiple visits over 30+ years, as were markers of cognitive reserve, with expert classification of dementia. In participants with brain MRI, brain volumes were evaluated in association with dementia. In nondemented participants in the ARIC‐PET ancillary study, florbetapir PET scans were used to quantify brain cortical amyloid; differences in levels by race, vascular risk factors, and white matter hyperintensities (WMH) were evaluated.ResultIn 15744 ARIC participants, dementia was more common in Black vs White participants. Although midlife vascular risk factors were related to dementia, the impact of these risk factors on dementia risk and cortical volumes didn’t differ by race. Lower education was nonsignificantly more strongly associated with dementia in Blacks vs Whites, and an APOE e4 allele was more strongly associated with dementia in Whites. In ARIC‐PET (N=322), vascular risk factors from midlife were associated with PET amyloid, without similar associations for late‐life risk factors; these associations did not significantly differ by race. WMH volume was more strongly associated (cross‐sectionally) with PET amyloid in Blacks vs Whites, but differences were not statistically significantly different. Finally, Blacks had an over two‐fold increased odds of elevated florbetapir PET vs Whites, independent of vascular risk factors, demographics, WMH volume, cognitive status, and APOE genotype.ConclusionConsideration of racial disparities in dementia should consider vascular risk, cognitive reserve, and social determinants of health, across the life course. Vascular risk factors do not appear to differentially impact dementia risk or brain amyloid in Blacks vs Whites, but the greater prevalence of these risk factors in Blacks must be considered. Although the A/T/N framework may clarify underlying biology contributing to Alzheimer’s disease, inclusion of these additional factors is needed to understand and reduce racial disparities in dementia rates.

Association of Preeclampsia With Incident Stroke in Later Life Among Women in the Framingham Heart Study

Contemporary research suggests an association between preeclampsia and later-life stroke among women. To our knowledge, no research to date has accounted for the time-varying nature of shared risk factors for preeclampsia and later-life stroke incidence. To assess the relative risk of incident stroke in later life among women with and without a history of preeclampsia after accounting for time-varying covariates. This population-based cohort study was a secondary analysis of data from the Framingham Heart Study, which was conducted from 1948 to 2016. Women were included in the analysis if they were stroke free at enrollment and had a minimum of 3 study visits and 1 pregnancy before menopause, hysterectomy, or age 45 years. Data on vascular risk factors, history of preeclampsia, and stroke incidence were collected biannually. Participants were followed up until incident stroke or censorship from the study. Marginal structural models were used to evaluate the relative risk of incident stroke among participants with and without a history of preeclampsia after accounting for time-varying covariates. Data were analyzed from May 2019 to December 2020. Presence or absence of preeclampsia among women with 1 or more pregnancies. Incident stroke in later life. A total of 1435 women (mean [SD] age, 44.4 [7.7] years at the beginning of the study; 100% White) with 41 422 person-years of follow-up were included in the analytic sample. Of those, 169 women had a history of preeclampsia, and 231 women experienced strokes during follow-up. At baseline, women with preeclampsia were more likely to be younger, to be receiving cholesterol-lowering medications, to have lower cholesterol and higher diastolic blood pressure, and to currently smoke. The association between preeclampsia and stroke in the marginal structural model was only evident when adjustment was made for all vascular risk factors over the life course, which indicated that women with a history of preeclampsia had a higher risk of stroke in later life compared with women without a history of preeclampsia (relative risk, 3.79; 95% CI, 1.24-11.60). The findings of this cohort study suggest that preeclampsia may be a risk factor for later-life stroke among women after adjustment for time-varying vascular and demographic factors. Future research is warranted to fully explore the mediation of this association by midlife vascular risk factors.

Midlife vascular risk factors and risk of incident dementia: Longitudinal cohort and Mendelian randomization analyses in the UK Biobank.

Midlife clustering of vascular risk factors has been associated with late-life dementia, but causal effects of individual biological and lifestyle factors remain largely unknown. Among 229,976 individuals (mean follow-up 9 years), we explored whether midlife cardiovascular health measured by Life's Simple 7 (LS7) is associated with incident all-cause dementia and whether the individual components of the score are causally associated with dementia. Adherence to the biological metrics of LS7 (blood pressure, cholesterol, glycemic status) was associated with lower incident dementia risk (hazard ratio=0.93 per 1-point increase, 95% confidence interval [CI; 0.89-0.96]). In contrast, there was no association between the composite LS7 score and the lifestyle subscore (smoking, body mass index, diet, physical activity) and incident dementia. In Mendelian randomization analyses, genetically elevated blood pressure was associated with higher risk of dementia (odds ratio=1.31 per one-standard deviation increase, 95% CI [1.05-1.60]). These findings underscore the importance of blood pressure control in midlife to mitigate dementia risk.

Peripheral markers of vascular endothelial dysfunction show independent but additive relationships with brain‐based biomarkers in association with functional impairment in Alzheimer’s disease

AbstractBackgroundCurrent epidemiologic evidence suggests that potentially modifiable midlife vascular risk factors specifically influence propensity for later‐life Alzheimer's disease (AD)‐associated cognitive decline. Despite this, a large knowledge gap still exists with respect to characterization of the biological overlap of highly co‐morbid vascular and AD pathologies in clinical AD. Prior studies focusing on contributions of co‐existing imaging‐based white matter disease and amyloid burden have found independent and/or additive rather than interactive associations to risk for cognitive decline, however recent studies utilizing sensitive measures of vascular dysfunction or expanded panels of AD pathology indicate that more nuanced synergistic associations between these pathologies may exist in AD. We hypothesized that elevated plasma cell adhesion molecule (CAM) levels would correlate with severity of diagnosis and functional impairment in AD dementia and be concomitantly lower in mild cognitive impairment (MCI) and normal controls, respectively, and would act synergistically rather than independently with CSF AD biomarkers in this regard.MethodUsing generalized linear regression models, we examined cross‐sectional relationships of plasma vascular cell adhesion molecule‐1 (VCAM‐1), intercellular adhesion molecule‐1 (ICAM‐1), and E‐Selectin to baseline diagnosis and functional impairment staging (clinical dementia rating sum‐of‐boxes, CDR‐SB) in the Alzheimer's Disease Neuroimaging (ADNI) cohort (n=564). We also assessed for modifying effects of AD risk factors including ApoE‐ε4 genotype, and then tested for interactive association by combining CAMs with CSF biomarkers into CDR‐SB models in a subset with available CSF data (n=351).ResultHigher mean VCAM‐1 (p=0.0026) and ICAM‐1 (p=0.0189) levels were found in AD versus MCI groups, however not in MCI versus cognitively normal groups. Only VCAM‐1 was linked with CDR‐SB scores (p=0.0157), and ApoE‐ε4 genotype modified this effect (p < 0.0001). Contrary to our expectation, we observed independent and additive rather than interactive associations of VCAM‐1 and CSF Aβ42, total tau, phosphorylated tau (P‐tau), and P‐tau/Aβ42 (all < p=0.01) in a combined CDR‐SB model (and ICAM‐1 to a lesser extent).ConclusionOur findings indicate independent rather than synergistic associations of plasma‐based biomarkers of vascular endothelial dysfunction and CSF biomarkers of AD pathology and neurodegeneration with AD‐related clinical impairment. Future longitudinal studies will be needed to validate these findings.

Abstract WP479: Associations Between Vascular Risk, Amyloid Burden and Incident Dementia: The ARIC-PET Study

Background: Midlife vascular risk factors (MVRF) are associated with incident dementia. Similarly, amyloid β(Aβ) and neurodegeneration (e.g.brain volumes), as parts of the Alzheimer’s Disease (AD) ATN framework, are associated with cognition. Whether vascular and AD-associated factors contribute to dementia independently or interact synergistically to reduce cognitive ability is not well understood. Methods: Recruited from 3 U.S. communities, ARIC-PET participants were followed from 1987-89 (45-64 yo) through 2016-17 (74-94 yo). Cognition was evaluated in 2011-13 (ages 69-88), and twice more, every 2-3 years. In 2011-13, nondemented ARIC-PET participants had a brain MRI, with measurement of white matter hyperintensities (WMH) and brain volumes, with florbetapir (Aβ) PET scans in 2012-14; global cortical standardized uptake value ratio (SUVR) was log-transformed and standardized. Dementia was classified by expert review, as well as phone and medical record surveillance. The relative contributions of vascular risk (MVRF, WMH volume) and AD pathology (elevated Aβ SUVR, smaller AD signature region volumes) to incident dementia were evaluated with Cox proportional hazards regression. Results: In 298 individuals, 36 developed dementia. In models with key MVRF, demographics, and Aβ SUVR, hypertension and Aβ each independently predicted dementia risk (per SD of Aβ SUVR: HR 2.57, 95% CI 1.72-3.84; hypertension: HR 2.57, 95% CI 1.16-5.67), but didn’t interact on dementia risk. WMH (per SD: HR 1.51, 95% CI 1.03-2.20) and Aβ SUVR (per SD: HR 2.52, 95% CI 1.83-3.47) each contributed to incident dementia but WMH lost significance when MVRF were added to the model. Smaller AD signature regions were associated with incident dementia, independent of Aβ SUVR, and remained significant after adjustment for MVRF (HR per SD 2.18, 95% CI 1.18-4.01). Conclusions: Midlife hypertension and late-life Aβ independently contribute to dementia risk, but don’t synergize on a multiplicative scale. Neurodegeneration (e.g.smaller AD signature region volume) is also associated with incident dementia, independent of Aβ and MVRF. Multiple pathways leading to dementia should be considered when evaluating risk factors and interventions to reduce the burden of dementia.

CAIDE Dementia Risk Score Indicates Cortical Thinning in Low‐Risk, Middle‐Aged Adults

Increased risk for the future development of Alzheimer's disease begins as early as midlife and can be predicted using modifiable cardiovascular and lifestyle‐related risk factors. The Cardiovascular Risk Factors, Aging and Incidence of Dementia (CAIDE) dementia risk score has been used to predict late life risk of dementia based on midlife vascular risk factors. Additionally, in older adults with mild or subjective cognitive impairment, higher CAIDE scores were associated with greater atrophy in the middle temporal and frontal regions of the brain.PurposeWe aimed to determine if CAIDE score is associated with cortical thickness in middle‐aged cognitively intact adults at risk for cardiovascular disease. We hypothesized individuals with higher CAIDE scores would have reduced cortical thickness in a priori regions associated with memory and attention‐executive function.MethodsA total of 155 middle‐age adults (49±6 years, 52.4% female) classified as cognitively normal were studied. CAIDE score was calculated using the original model that excludes ApoE e4 genotype. This includes age, sex, education level, systolic blood pressure, body mass index, total cholesterol, and physical inactivity. Each factor is given a specific weight and the total score ranges from 0 to 14. Cortical thickness was obtained from high resolution magnetization‐prepared rapid acquisition gradient‐echo images. Thickness values for 24 a priori regions of interest associated with memory and executive function were extracted and analyzed.ResultsA majority of the participants (95.5%) in this sample were categorized as low‐risk, having a CAIDE score of 8 or lower. After using a corrected p‐value (p=0.006) for multiple correlations, there were several significant negative associations between CAIDE score and cortical thickness. These include the right parahippocampal (r=−0.251, p=0.002), left pars opercularis (r=−0.244, p=0.002), right superior frontal (r=−0.229, p=0.004) and left superior frontal (r=−0.247, p=0.002) regions.ConclusionsHigher CAIDE scores in midlife are associated with lower cortical thickness in middle‐age adults at risk for cardiovascular disease. This finding supports the notion that cardiovascular risks may contribute to early alteration of brain structure. We propose that the CAIDE dementia risk score may be useful in predicting future risk of dementia even in low‐risk populations who have no indication of clinically significant cognitive impairment.This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Is Alzheimer's Disease Risk Modifiable?

Population-based clinic-pathological studies have established that the most common pathological substrate of dementia in community-dwelling elderly people is mixed, especially Alzheimer's disease (AD) and cerebrovascular ischemic disease (CVID), rather than pure AD. While these could be just two frequent unrelated comorbidities in the elderly, epidemiological research has reinforced the idea that mid-life (age <65 years) vascular risk factors increase the risk of late-onset (age ≥ 65 years) dementia, and specifically AD. By contrast, healthy lifestyle choices such as leisure activities, physical exercise, and Mediterranean diet are considered protective against AD. Remarkably, several large population-based longitudinal epidemiological studies have recently indicated that the incidence and prevalence of dementia might be decreasing in Western countries. Although it remains unclear whether these positive trends are attributable to neuropathologically definite AD versus CVID, based on these epidemiological data it has been estimated that a sizable proportion of AD cases could be preventable. In this review, we discuss the current evidence about modifiable risk factors for AD derived from epidemiological, preclinical, and interventional studies, and analyze the opportunities for therapeutic and preventative interventions.

Seize the Day for a Day With No Seizures: Modifiable Midlife Risk Factors Identified.

Association Between Midlife Risk Factors and Late-Onset Epilepsy: Results From the Atherosclerosis Risk in Communities Study Johnson EL, Krauss GL, Lee AK, Schneider ALC, Dearborn JL, Kucharska-Newton AM, Huang J, Alonso A, Gottesman RF. JAMA Neurol. 2018 Jul 23 [Epub ahead of print]. doi:10.1001/jamaneurol.2018.1935Importance: The incidence of epilepsy is higher in older age than at any other period of life. Stroke, dementia, and hypertension are associated with late-onset epilepsy; however, the role of other vascular and lifestyle factors remains unclear. Objective: To identify midlife vascular and lifestyle risk factors for late-onset epilepsy. Design, Setting, and Participants: The Atherosclerosis Risk in Communities (ARIC) study is a prospective cohort study of 15 792 participants followed up since 1987 to 1989 with in-person visits, telephone calls, and surveillance of hospitalizations (10 974 invited without completing enrollment). The ARIC is a multicenter study with participants selected from 4 US communities. This study included 10 420 black or white participants from ARIC with at least 2 years of Medicare fee-for-service coverage and without missing baseline data. Data were analyzed between April 2017 and May 2018. Exposures: Demographic, vascular, lifestyle, and other possible epilepsy risk factors measured at baseline (age 45-64 years) were evaluated in multivariable survival models including demographics, vascular risk factors, and lifestyle risk factors. Main Outcomes and Measures: Time to development of late-onset epilepsy (2 or more International Classification of Diseases, Ninth Revision codes for epilepsy or seizures starting at 60 years or older in any claim [hospitalization or outpatient Medicare through 2013]), with first code for seizures after at least 2 years without code for seizures. Results: Of the 10 420 total participants (5878 [56.4%] women and 2794 [26.8%] black participants; median age 55 years at first visit), 596 participants developed late-onset epilepsy (3.33 per 1000 person-years). The incidence was higher in black than in white participants (4.71; 95% confidence interval [CI], 4.12-5.40 vs 2.88; 95% CI, 2.60-3.18 per 1000 person-years). In multivariable analysis, baseline hypertension (hazard ratio [HR], 1.30; 95% CI, 1.09-1.55), diabetes (HR, 1.45; 95% CI, 1.17-1.80), smoking (HR, 1.09; 95% CI, 1.01-1.17), apolipoprotein E ε4 (APOE ε4) genotype (1 allele HR, 1.22; 95% CI, 1.02-1.45; 2 alleles HR, 1.95; 95% CI, 1.35-2.81), incident stroke (HR, 3.38; 95% CI, 2.78-4.10), and dementia (HR, 2.56; 95% CI, 2.11-3.12) were associated with an increased risk of late-onset epilepsy, while higher levels of physical activity (HR, 0.90; 95% CI, 0.83-0.98) and moderate alcohol intake (HR, 0.72; 95% CI, 0.57-0.90) were associated with a lower risk. Results were similar after censoring individuals with stroke or dementia. Conclusions and Relevance: Potentially modifiable risk factors in midlife and the APOE ε4 genotype were positively associated with risk of developing late-onset epilepsy. Although stroke and dementia were both associated with late-onset epilepsy, vascular and lifestyle risk factors were significant even in the absence of stroke or dementia.

Association Between Midlife Risk Factors and Late-Onset Epilepsy

The incidence of epilepsy is higher in older age than at any other period of life. Stroke, dementia, and hypertension are associated with late-onset epilepsy; however, the role of other vascular and lifestyle factors remains unclear. To identify midlife vascular and lifestyle risk factors for late-onset epilepsy. The Atherosclerosis Risk in Communities (ARIC) study is a prospective cohort study of 15 792 participants followed up since 1987 to 1989 with in-person visits, telephone calls, and surveillance of hospitalizations (10 974 invited without completing enrollment). The ARIC is a multicenter study with participants selected from 4 US communities. This study included 10 420 black or white participants from ARIC with at least 2 years of Medicare fee-for-service coverage and without missing baseline data. Data were analyzed betweeen April 2017 and May 2018. Demographic, vascular, lifestyle, and other possible epilepsy risk factors measured at baseline (age 45-64 years) were evaluated in multivariable survival models including demographics, vascular risk factors, and lifestyle risk factors. Time to development of late-onset epilepsy (2 or more International Classification of Diseases, Ninth Revision codes for epilepsy or seizures starting at 60 years or older in any claim [hospitalization or outpatient Medicare through 2013]), with first code for seizures after at least 2 years without code for seizures. Of the 10 420 total participants (5878 women [56.4%] and 2794 black participants [26.8%]; median age 55 years at first visit), 596 participants developed late-onset epilepsy (3.33 per 1000 person-years). The incidence was higher in black than in white participants (4.71; 95% CI, 4.12-5.40 vs 2.88; 95% CI, 2.60-3.18 per 1000 person-years). In multivariable analysis, baseline hypertension (hazard ratio [HR], 1.30; 95% CI, 1.09-1.55), diabetes (HR, 1.45; 95% CI, 1.17-1.80), smoking (HR, 1.09; 95% CI, 1.01-1.17), apolipoprotein E ε4 genotype (1 allele HR, 1.22; 95% CI, 1.02-1.45; 2 alleles HR, 1.95; 95% CI, 1.35-2.81), and incident stroke (HR, 3.38; 95% CI, 2.78-4.10) and dementia (HR, 2.56; 95% CI, 2.11-3.12) were associated with an increased risk of late-onset epilepsy, while higher levels of physical activity (HR, 0.90; 95% CI, 0.83-0.98) and moderate alcohol intake (HR, 0.72; 95% CI, 0.57-0.90) were associated with a lower risk. Results were similar after censoring individuals with stroke or dementia. Potentially modifiable risk factors in midlife and the APOE ε4 genotype were positively associated with risk of developing late-onset epilepsy. Although stroke and dementia were both associated with late-onset epilepsy, vascular and lifestyle risk factors were significant even in the absence of stroke or dementia.

Midlife vascular risk factors and midlife cognitive status in relation to prevalence of mild cognitive impairment and dementia in later life: The Atherosclerosis Risk in Communities Study

IntroductionThe interplay between midlife vascular risk factors and midlife cognitive function with later life mild cognitive impairment (MCI) and dementia (DEM) is not well understood. MethodsIn the Atherosclerosis Risk in Communities Study, cardiovascular risk factors and cognition were assessed in midlife, ages 45–64 years. In 2011–2013, 20–25 years later, all consenting Atherosclerosis Risk in Communities participants underwent a cognitive and neurological evaluation and were given adjudicated diagnoses of cognitively normal, MCI, or DEM. ResultsIn 5995 participants with complete covariate data, midlife diabetes, hypertension, obesity, and hypercholesterolemia were associated with late-life MCI and DEM. Low midlife cognition function was also associated with greater likelihood of late-life MCI or DEM. Both midlife vascular risk factors and midlife cognitive function remained associated with later life MCI or DEM when both were in the model. DiscussionLater life MCI and DEM were independently associated with midlife vascular risk factors and midlife cognition.

Associations Between Midlife Vascular Risk Factors and 25-Year Incident Dementia in the Atherosclerosis Risk in Communities (ARIC) Cohort

Vascular risk factors have been associated with cognitive decline. Midlife exposure to these factors may be most important in conferring late-life risk of cognitive impairment. To examine Atherosclerosis Risk in Communities (ARIC) participants in midlife and to explore associations between midlife vascular risk factors and 25-year dementia incidence. This prospective cohort investigation of the Atherosclerosis Risk in Communities (ARIC) Study was conducted from 1987-1989 through 2011-2013. The dates of this analysis were April 2015 through August 2016. The setting was ARIC field centers (Washington County, Maryland; Forsyth County, North Carolina; Jackson, Mississippi; and Minneapolis suburbs, Minnesota). The study comprised 15 744 participants (of whom 27.1% were black and 72.9% white) who were aged 44 to 66 years at baseline. Demographic and vascular risk factors were measured at baseline (obesity, smoking, diabetes, prehypertension, hypertension, and hypercholesterolemia) as well as presence of the APOE ε4 genotype. After the baseline visit, participants had 4 additional in-person visits, for a total of 5 in-person visits, hospitalization surveillance, telephone calls, and repeated cognitive evaluations. Most recently, in 2011-2013, through the ARIC Neurocognitive Study (ARIC-NCS), participants underwent a detailed neurocognitive battery, informant interviews, and adjudicated review to define dementia cases. Additional cases were identified through the Telephone Interview for Cognitive Status-Modified or informant interview, for participants not attending the ARIC-NCS visit, or by an International Classification of Diseases, Ninth Revision dementia code during a hospitalization. Fully adjusted Cox proportional hazards regression was used to evaluate associations of baseline vascular and demographic risk factors with dementia. In total, 1516 cases of dementia (57.0% female and 34.9% black, with a mean [SD] age at visit 1 of 57.4 [5.2] years) were identified among 15 744 participants. Black race (hazard ratio [HR], 1.36; 95% CI, 1.21-1.54), older age (HR, 8.06; 95% CI, 6.69-9.72 for participants aged 60-66 years), lower educational attainment (HR, 1.61; 95% CI, 1.28-2.03 for less than a high school education), and APOE ε4 genotype (HR, 1.98; 95% CI, 1.78-2.21) were associated with increased risk of dementia, as were midlife smoking (HR, 1.41; 95% CI, 1.23-1.61), diabetes (HR, 1.77; 95% CI, 1.53-2.04), prehypertension (HR, 1.31; 95% CI, 1.14-1.51), and hypertension (HR, 1.39; 95% CI, 1.22-1.59). The HR for dementia for diabetes was almost as high as that for APOE ε4 genotype. Midlife vascular risk factors are associated with increased risk of dementia in black and white ARIC Study participants. Further studies are needed to evaluate the mechanism of and opportunities for prevention of the cognitive sequelae of these risk factors in midlife.

Association Between Birth in a High Stroke Mortality State, Race, and Risk of Dementia

Birth in a group of predominantly southern US states is robustly linked to increased stroke risk. Given the role of cerebrovascular disease in dementia risk, geographic patterning may also occur for dementia incidence. To determine whether birth in 9 high stroke mortality states (HSMSs) is associated with dementia in a diverse cohort of individuals living in Northern California. An observational cohort study included 7423 members of Kaiser Permanente Northern California (KPNC), an integrated health care delivery system, with health survey and clinical examination data available. Data were collected between 1964 and 1973 when the individuals were middle-aged and 1996 and 2015 when participants were in later life. Self-reported state of birth in an HSMS (top quintile of states for stroke mortality). Dementia diagnoses obtained from electronic health records from January 1, 1996, to October 15, 2015. Place of birth, race, educational level, and midlife vascular risk factors data were collected between 1964 and 1973. Of the 7423 persons included in the analysis, 4049 (54.5%) were women; 1354 (18.2%) were black. The mean (SD) age of study participants at their first visit between 1963 and 1974 was 42.94 (1.73) years and mean (SD) age at the beginning of follow-up for dementia in 1996 was 71.14 (2.72) years. Dementia was diagnosed in 2254 (30.4%) of the participants and was more common among those born in an HSMS than those born outside of one (455 [39.0%] vs 1799 [28.8%]). Birth in an HSMS was 9.6 times more common for black participants (795 [58.7%]) than nonblack participants (371 [6.1%]). Overall, birth in an HSMS was associated with a 28% higher risk of dementia (adjusted hazard ratio [aHR], 1.28; 95% CI, 1.13-1.46) adjusted for age, sex, and race. Compared with nonblack persons born outside of an HSMS, black individuals born in an HSMS had the highest dementia risk (aHR, 1.67; 95% CI, 1.48-1.88), followed by black individuals not born in an HSMS (aHR, 1.48; 95% CI, 1.28-1.72), and nonblack persons born in an HSMS had a 46% increased risk (aHR, 1.46; 95% CI, 1.23-1.74). Cumulative 20-year dementia risks at age 65 years were 30.13% (95% CI, 26.87%-32.93%) and 21.80% (95% CI, 20.51%-22.91%) for individuals born in and outside an HSMS, respectively. To our knowledge, this is the first study to date of place of birth and incident dementia and shows increased risk for individuals born in an HSMS, even though all participants subsequently resided in California. Birth in an HSMS was common among black participants. Place of birth has enduring consequences for dementia risk and may be a major contributor to racial disparities in dementia.

Vaskuläres Risiko korreliert mit Alzheimer-Risiko

Gottesman RF et al. Association between midlife vascular risk factors and estimated brain amyloid deposition. JAMA 2017; 317: 1443 – 1450

Midlife Vascular Risk Factors and Late-Life Amyloid Deposition

Vascular risk factors have been associated with Alzheimer disease (AD). Extracellular amyloid plaques are one of the pathologic features of AD. To

Association Between Midlife Vascular Risk Factors and Estimated Brain Amyloid Deposition

Midlife vascular risk factors have been associated with late-life dementia. Whether these risk factors directly contribute to brain amyloid deposition is less well understood. To determine if midlife vascular risk factors are associated with late-life brain amyloid deposition, measured using florbetapir positron emission tomography (PET). The Atherosclerosis Risk in Communities (ARIC)-PET Amyloid Imaging Study, a prospective cohort study among 346 participants without dementia in 3 US communities (Washington County, Maryland; Forsyth County, North Carolina; and Jackson, Mississippi) who have been evaluated for vascular risk factors and markers since 1987-1989 with florbetapir PET scans in 2011-2013. Positron emission tomography image analysis was completed in 2015. Vascular risk factors at ARIC baseline (age 45-64 years; risk factors included body mass index ≥30, current smoking, hypertension, diabetes, and total cholesterol ≥200 mg/dL) were evaluated in multivariable models including age, sex, race, APOE genotype, and educational level. Standardized uptake value ratios (SUVRs) were calculated from PET scans and a mean global cortical SUVR was calculated. Elevated florbetapir (defined as a SUVR >1.2) was the dependent variable. Among 322 participants without dementia and with nonmissing midlife vascular risk factors at baseline (mean age, 52 years; 58% female; 43% black), the SUVR (elevated in 164 [50.9%] participants) was measured more than 20 years later (median follow-up, 23.5 years; interquartile range, 23.0-24.3 years) when participants were between 67 and 88 (mean, 76) years old. Elevated body mass index in midlife was associated with elevated SUVR (odds ratio [OR], 2.06; 95% CI, 1.16-3.65). At baseline, 65 participants had no vascular risk factors, 123 had 1, and 134 had 2 or more; a higher number of midlife risk factors was associated with elevated amyloid SUVR at follow-up (30.8% [n = 20], 50.4% [n = 62], and 61.2% [n = 82], respectively). In adjusted models, compared with 0 midlife vascular risk factors, the OR for elevated SUVR associated with 1 vascular risk factor was 1.88 (95% CI, 0.95-3.72) and for 2 or more vascular risk factors was 2.88 (95% CI, 1.46-5.69). No significant race × risk factor interactions were found. Late-life vascular risk factors were not associated with late-life brain amyloid deposition (for ≥2 late-life vascular risk factors vs 0: OR, 1.66; 95% CI, 0.75-3.69). An increasing number of midlife vascular risk factors was significantly associated with elevated amyloid SUVR; this association was not significant for late-life risk factors. These findings are consistent with a role of vascular disease in the development of Alzheimer disease.

Cardiovascular risk factors and glucose tolerance in midlife and risk of cognitive disorders in old age up to a 49-year follow-up of the Helsinki businessmen study

Purpose: The purpose of this study is to compare midlife predictors of old age dementia with or without concomitant atherosclerotic cardiovascular disease (ASCVD).Design: In the Helsinki Businessmen Study (men born in 1919–1934, n = 3309), death certificates (n = 1885) during up to 49-year follow-up (through 31 December 2013) were screened for dementia (n = 365) and ASCVD, and categorized as (1) AD without ASCVD (“pure” AD, n = 93), (2) AD + ASCVD (n = 126), (3) vascular dementia (VD, n = 82), (4) other or undefined etiology (n = 64). Using Cox analyses, death without dementia and dementia types were compared for the prediction by midlife ASCVD risk factors. Men without diagnosed dementia during follow-up were used as reference.Results: ASCVD risk factors predicted death without dementia during follow-up. Midlife cholesterol was higher in AD + ASCVD and VD as compared with men surviving to old age without known dementia. None of the midlife factors including cholesterol and glucose tolerance predicted pure AD, but midlife cholesterol predicted AD + ASCVD, both as a continuous (hazard ratio [HR] per SD 1.24, 95% CI, 1.04–1.47), and dichotomous variable (cutpoint 6.5 mmol/L; HR 1.67, 95% CI, 1.16–2.40).Conclusion: Midlife cholesterol predicted dementia with vascular features, but midlife vascular risk factors and glucose intolerance were not related to pure Alzheimer disease without concomitant atherosclerotic cardiovascular disease.Key messagesHeterogenous etiology of dementia, which in old age is usually a clinical diagnosis, may confound the role of long-term risk factors.In a longitudinal study with autopsy records, midlife cholesterol predicted dementia with features of atherosclerotic cardiovascular disease but not “pure“ Alzheimer diseaseGlucose tolerance in midlife was not associated with pure Alzheimer’s disease.

Abstract 11917: Midlife Cardiovascular Risk Factors and Late-Life Unrecognized and Recognized Myocardial Infarction Detected by Cardiac Magnetic Resonance (ICELAND-MI, the AGES-Reykjavik Study)

Introduction: The association of midlife atherosclerosis risk factors (RF) with later unrecognized myocardial infarction (UMI) is unclear. We investigated associations of midlife RF with UMI and recognized MI (RMI) detected 31 years later by cardiac magnetic resonance (CMR). Methods: The Reykjavik Study (1967-91) collected serial measures of RF in subjects born 1907-35, mean (SD) age 48 ± 7 years. In ICELAND-MI (2004-07), 936 randomly selected survivors (76 ± 5 years) were evaluated by CMR. Analysis included logistic regression and random effects modeling adjusted for age, sex, and covariates. All comparisons are relative to the no MI group. Results: At baseline midlife evaluation, atherosclerotic risk assessed by a modified Framingham risk score was significantly higher in RMI and UMI than in no MI (7.4 ± 6.3%; 7.1 ± 6.2% vs 5.4 ± 5.8% respectively, p&lt;0.001). RMI and UMI were more common in men (65%, 64% vs 43%; p&lt;0.0001). Compared with no MI, baseline systolic BP was significantly higher in UMI (138 ± 17 mm Hg vs 133 ± 17 mm Hg; p=0.006), and trended higher in RMI (p=0.06). Likewise, baseline diastolic BP was significantly elevated in both RMI and UMI (88 ± 10 mm Hg and 87 ± 10 mm Hg vs 84 ± 10 mm Hg; p&lt;0.02). Serum cholesterol was significantly higher in RMI (6.7 ± 1.1 mmol/L vs 6.2 ± 1.1 mmol/L; p=0.005), as were serum triglycerides (1.4 ± 0.7 mmol/L vs 1.3 ± 0.7 mmol/L; p&lt;0.03). Serum cholesterol trended higher in UMI (p=0.08). Compared to no MI, serial midlife systolic and diastolic BP were significantly higher in RMI [beta=4.03 ± 1.64 (SE) mm Hg, p=0.014 and 2.05 ± 0.94 mm Hg, p=0.025, respectively] as were cholesterol and triglycerides [0.43 ± 0.11 mmol/L, p=0.001 and 0.31 ± 0.07 mmol/L, p&lt;0.0001, respectively]. Systolic BP was significantly higher in UMI [beta=2.76 ±1.31 mm Hg, p=0.036, figure]. Conclusions: Midlife vascular risk factors are associated with UMI and RMI detected by CMR 31 years later. Systolic BP was the most important individual risk factor associated with later UMI.