Background Type 2 diabetes mellitus is associated with dementia risk, however evidence is limited for possible associations of diabetes and pre-diabetes with cognitive decline. Objective To determine if diabetes in mid-life is associated with 20-year cognitive decline, and to characterize long-term cognitive decline across clinical categories of hemoglobin A1c (HbA1c). Design Prospective cohort. Setting The community-based Atherosclerosis Risk in Communities (ARIC) Study. Participants 13351 black and white adults aged 48-67 years at baseline (1990-1992). Measurements Diabetes was defined by self-report of physician diagnosis or medication use or HbA1c≥6.5%. Undiagnosed diabetes, pre-diabetes, and glucose control in persons with diagnosed diabetes were defined using clinical categories of HbA1c. Delayed Word Recall, Digit Symbol Substitution, and Word Fluency tests were used to assess cognitive performance, and were summarized using a global Z-score. Results Diabetes in midlife was associated with significantly greater cognitive decline over 20 years (adjusted global Z-score difference=-0.15, 95% CI:-0.22,-0.08), representing a 19% greater decline than those without diabetes. Cognitive decline was significantly greater among persons with pre-diabetes (HbA1c 5.7-6.4%) than those without diabetes and HbA1c<5.7%. Participants with poorly controlled diabetes (HbA1c≥7.0%) had a larger decline compared to persons whose diabetes was controlled (adjusted global Z-score difference=-0.16,p-value=0.071). Longer duration of diabetes was also associated with greater late-life cognitive decline (p-value-for-trend=<0.001). No significant differences in the rates of declines were seen in whites compared to blacks (p-value-for-interaction=0.4357). Limitations Single measurement of HbA1c at baseline, only one test to per cognitive domain, potential geographic confounding of race comparisons. Conclusions These findings suggest that diabetes prevention and glucose control in midlife may protect against late-life cognitive decline.

Background The optimal systolic blood pressure (SBP) treatment goal is in question, with the SBP intervention trial (SPRINT) suggesting benefit for 120mmHg. However, achieving SBP this low may reduce diastolic BP (DBP) to levels that could compromise myocardial perfusion. Objectives To examine the association of DBP with prevalent and progressive myocardial damage (using high-sensitivity cardiac Troponin-T, hs-cTnT). We also examined prospective associations between DBP and coronary heart disease (CHD), stroke, or death over 21 years; overall and stratified by subgroups of interest. Methods We studied 11,565 adults from the Atherosclerosis Risk in Communities (ARIC) study. We evaluated cross-sectional DBP and hs-cTnT (dichotomized at 14 ng/L) associations with logistic regression, longitudinal associations between DBP and hs-cTnT change using generalized linear models adjusted for attrition, and prospective associations between DBP and events with Cox regression. Results Mean baseline age was 57 years, 57% were female and 25% were black. Relative to persons with DBP 80–89mmHg, those with DBP 60–69mmHg and <60mmHg had higher prevalence of baseline hs-cTnT ≥14ng/L (OR 1.5 [95%CI 1.0–2.3] and 2.2 [1.2–4.1]). Participants with DBP 60–69mmHg and <60mmHg also had relatively larger increases in hs-cTnT over the initial 6 years of follow-up (β +6 [95%CI 2–10] and +9 [3–14] ng/L). DBP <60mmHg (vs. 80–89mmHg) was associated with incident CHD (HR 1.5 [1.2–1.9]) and mortality (HR 1.3 [1.1–1.6]), but not with stroke. The DBP and incident CHD association was strongest when baseline hs-cTnT ≥14ng/L (p-value-for-interaction <0·001). Associations of low DBP with prevalent hs-cTnT and incident CHD were most pronounced among those with baseline SBP ≥120mmHg. Conclusion Particularly among adults with SBP ≥120mmHg, and thus elevated pulse-pressure, low DBP was associated with subclinical myocardial damage and CHD events. When titrating treatment to SBP <140mmHg, it may be prudent to ensure DBP levels do not fall below 70mmHg, and particularly below 60mmHg.

IMPORTANCE The association between late-life blood pressure (BP) and cognition may depend on the presence and chronicity of past hypertension. Late-life declines in blood pressure following prolonged hypertension may be associated with poor cognitive outcomes. OBJECTIVE To examine the association of midlife to late-life BP patterns with subsequent dementia, mild cognitive impairment, and cognitive decline. DESIGN, SETTING, AND PARTICIPANTS The Atherosclerosis Risk in Communities prospective population-based cohort study enrolled 4761 participants during midlife (visit 1, 1987-1989) and followed-up over 6 visits through 2016-2017 (visit 6). BP was examined over 24 years at 5 in-person visits between visits 1 and 5 (2011-2013). During visits 5 and 6, participants underwent detailed neurocognitive evaluation. The setting was 4 US communities:

IMPORTANCE Hypertension is a treatable potential cause of cognitive decline and dementia, but its greatest influence on cognition may occur in middle age.OBJECTIVE To evaluate the association between midlife (48-67 years of age) hypertension and the 20-year change in cognitive performance.

Background Hemoglobin A1c (HbA1c) is the standard measure to monitor long-term glucose control in diabetes management and is now used for diagnosis. Fructosamine and glycated albumin are markers of short-term glycemic control that may add complementary information to HbA1c. However, the performance of fructosamine and glycated albumin to identify people at risk of complications is unclear. Methods We measured glycated albumin and fructosamine in 11348 adults without diabetes and 958 adults with diagnosed diabetes who attended the second examination of the Atherosclerosis Risk in Communities (ARIC) Study in 1990–1992 (baseline). We evaluated the associations of fructosamine and glycated albumin with retinopathy and risk of incident chronic kidney disease and incident diabetes during two decades of follow-up. We compared these associations to those for HbA1c. Findings Fructosamine and glycated albumin were strongly associated with retinopathy and these associations were very similar to that observed for HbA1c. Fructosamine and glycated albumin were also significantly associated with risk of incident chronic kidney disease and incident diabetes. Compared to persons with no diabetes and fructosamine or glycated albumin levels <75th percentile, the multivariable-adjusted hazard ratios (95%CIs) for chronic kidney disease for persons with fructosamine and glycated albumin levels >95th percentile were 1.50 (1.22, 1.85) and 1.48 (1.20, 1.83), respectively. The HRs for incident diabetes were 4.96 (4.36, 5.64) for fructosamine >95th percentile and 6.17 (5.45, 6.99) for glycated albumin >95th percentile. Associations were attenuated but persisted after adjustment for HbA1c. Prediction of incident chronic kidney disease by fructosamine (C-statistic, 0.717) and glycated albumin (C-statistic, 0.717) were nearly as strong as by HbA1c (C-statistic, 0.726) but HbA1c outperformed fructosamine and glycated albumin for prediction of incident diabetes with C-statistics of 0.760, 0.706, and 0.703, respectively. Interpretation Fructosamine and glycated albumin were strongly associated with diabetes and its microvascular complications and complemented the prognostic utility of HbA1c.

Advanced glycation end products (AGEs) and their receptors are strongly implicated in the development of diabetes complications. When stimulated by AGEs, the receptors for AGEs (RAGEs) induce inflammation and are thought to fuel disease progression. Soluble circulating RAGE (sRAGE) may counteract the detrimental effects of RAGE. We measured sRAGE in stored plasma from a random sample of 1,201 participants in the Atherosclerosis Risk in Communities (ARIC) Study who were aged 47–68 years, had normal kidney function, and had no history of cardiovascular disease. In cross-sectional analyses, black race, male sex, higher BMI, and higher C-reactive protein were independently associated with low sRAGE. The racial difference was striking, with blacks approximately three times more likely to have low sRAGE compared with whites even after adjustment. During ~18 years of follow-up, there were 192 incident coronary heart disease events, 53 ischemic strokes, 213 deaths, and 253 cases of diabetes (among the 1,057 persons without diabetes at baseline). In multivariable Cox models comparing risk in the first quartile with that in the fourth quartile of baseline sRAGE, low levels of sRAGE were significantly associated with risk of diabetes (hazard ratio 1.64 [95% CI 1.10–2.44]), coronary heart disease (1.82 [1.17–2.84]), and mortality (1.72 [1.11–2.64]) but not ischemic stroke (0.78 [0.34–1.79]). In conclusion, we found that low levels of sRAGE were a marker of future chronic disease risk and mortality in the community and may represent an inflammatory state. Racial differences in sRAGE deserve further examination.

The APOL1 high-risk genotype, present in approximately 13% of blacks in the United States, is a risk factor for kidney function decline in populations with CKD. It is unknown whether genetic screening is indicated in the general population. We evaluated the prognosis of APOL1 high-risk status in participants in the population-based Atherosclerosis Risk in Communities (ARIC) study, including associations with eGFR decline, variability in eGFR decline, and related adverse health events (AKI, ESRD, hypertension, diabetes, cardiovascular disease, pre-ESRD and total hospitalization rate, and mortality). Among 15,140 ARIC participants followed from 1987-1989 (baseline) to 2011-2013, 75.3% were white, 21.5% were black/APOL1 low-risk, and 3.2% were black/APOL1 high-risk. In a demographic-adjusted analysis, blacks had a higher risk for all assessed adverse health events; however, in analyses adjusted for comorbid conditions and socioeconomic status, blacks had a higher risk for hypertension, diabetes, and ESRD only. Among blacks, the APOL1 high-risk genotype associated only with higher risk of ESRD in a fully adjusted analysis. Black race and APOL1 high-risk status were associated with faster eGFR decline (P,0.001 for each). However, we detected substantial overlap among the groups: median (10th-90th percentile) unadjusted eGFR decline was 1.5 (1.0-2.2) ml/min per 1.73 m 2 per year for whites, 2.1 (1.4-3.1) ml/min per 1.73 m 2 per year for blacks with APOL1 low-risk status, and 2.3 (1.5-3.5) ml/min per 1.73 m 2 per year for blacks with APOL1 high-risk status. The high variability in eGFR decline among blacks with and without the APOL1 high-risk genotype suggests that population-based screening is not yet justified.

Studies of long-term cognitive change should account for the potential effects of education on the outcome, since some studies have demonstrated an association of education with dementia risk. Evaluating cognitive change is more ideal than evaluating cognitive performance at a single time point, because it should be less susceptible to confounding. In this analysis of 14,020 persons from a US cohort study, the Atherosclerosis Risk in Communities (ARIC) Study, we measured change in performance on 3 cognitive tests over a 20-year period, from ages 48-67 years (1990-1992) through ages 70-89 years (2011-2013). Generalized estimating equations were used to evaluate the association between education and cognitive change in unweighted adjusted models, in models incorporating inverse probability of attrition weighting, and in models using cognitive scores imputed from the Telephone Interview for Cognitive Status for participants not examined in person. Education did not have a strong relationship with change in cognitive test performance, although the rate of decline was somewhat slower among persons with lower levels of education. Methods used to account for selective dropout only marginally changed these observed associations. Future studies of risk factors for cognitive impairment should focus on cognitive change, when possible, to allow for reduction of confounding by social or cultural factors.