Erratum to: Association between Modifiable Risk Factors and Levels of Blood-Based Biomarkers of Alzheimer's and Related Dementias in the Look AHEAD Cohort.

[This corrects the article DOI: 10.14283/jarlife.2024.1.].

Association between Modifiable Risk Factors and Levels of Blood-Based Biomarkers of Alzheimer's and Related Dementias in the Look AHEAD Cohort.

Background: Emerging evidence suggests that a number of factors can influence blood-based biomarker levels for Alzheimer's disease (AD) and Alzheimer's related dementias (ADRD). We examined the associations that demographic and clinical characteristics have with AD/ADRD blood-based biomarker levels in an observational continuation of a clinical trial cohort of older individuals with type 2 diabetes and overweight or obesity. Methods: Participants aged 45-76 years were randomized to a 10-year Intensive Lifestyle Intervention (ILI) or a diabetes support and education (DSE) condition. Stored baseline and end of intervention (8-13 years later) plasma samples were analyzed with the Quanterix Simoa HD-X Analyzer. Changes in Aß42, Aß40, Aß42/Aß40, ptau181, neurofilament light chain (NfL), and glial fibrillary acidic protein (GFAP) were evaluated in relation to randomization status, demographic, and clinical characteristics. Results: In a sample of 779 participants from the Look AHEAD cohort, we found significant associations between blood-based biomarkers for AD/ADRD and 15 of 18 demographic (age, gender, race and ethnicity, education) and clinical characteristics (APOE, depression, alcohol use, smoking, body mass index, HbA1c, diabetes duration, diabetes treatment, estimated glomerular filtration rate, hypertension, and history of cardiovascular disease) . Conclusions: Blood-based biomarkers of AD/ADRD are influenced by common demographic and clinical characteristics. These factors should be considered carefully when interpreting these AD/ADRD blood biomarker values for clinical or research purposes.

Obesity, diabetes and their metabolic correlates in middle-aged adults with Down syndrome.

BACKGROUND: Obesity in adults without Down syndrome is associated with an adverse metabolic profile including high prevalence of pre-diabetes and diabetes, high levels of insulin, non-high-density lipoprotein (HDL) cholesterol, leptin and high-sensitivity C-reactive protein (hsCRP) and low levels of HDL and adiponectin. We examined whether obesity in middle-aged adults with Down syndrome is also related to an adverse metabolic profile. METHODS: This cross-sectional study included 143 adults with Down syndrome, with a mean age of 55.7 ± 5.7 years and 52.5% women. Body mass index (BMI) was classified as underweight (BMI < 18.5 kg/m2 ), normal (BMI 18.5-24.9 kg/m2 ), overweight (BMI 25-29.9 kg/m2 ) and obese (BMI ≥ 30 kg/m2 ). Diabetes was ascertained by history or by haemoglobin A1c (HbA1c) as normal glucose tolerance (HbA1c < 5.7%), pre-diabetes (HbA1c 5.7-6.4%) and diabetes (HbA1c ≥ 6.5%). We measured non-fasting lipids, hsCRP, insulin, adiponectin and leptin. RESULTS: The majority of the sample had an overweight (46.9%) or obesity (27.3%) status. However, there was a relatively low prevalence of pre-diabetes (9.8%) and diabetes (6.9%). Overweight and obesity status were not associated with lower HDL and adiponectin and higher insulin, non-HDL cholesterol and hsCRP as expected in adults without Down syndrome. However, overweight and obesity were strongly associated with higher leptin (P < 0.001). CONCLUSIONS: The only metabolic correlate of obesity in middle-aged adults with Down syndrome was high leptin levels. Our findings are limited by non-fasting laboratory tests but suggest that middle-aged adults with Down syndrome do not have the adverse metabolic profile related to obesity found in adults without Down syndrome.

Metformin in the Prevention of Alzheimer's Disease and Alzheimer's Disease Related Dementias.

Metformin is a safe and effective medication for Type 2 diabetes (T2D) that has been proposed to decrease the risk of aging related disorders including Alzheimer's Disease (AD) and AD related disorders (ADRD). This review seeks to summarize findings from human and non-human studies examining the association of metformin with AD/ADRD related outcomes. Studies in animal models suggest that metformin could decrease the risk of AD/ADRD through multiple mechanisms including neuroprotective effects, decreasing neuroinflammation, and decreasing AD pathology. However, there are non-human studies that suggest that metformin could increase the risk of AD/ADRD. Observational human studies are also conflicting, but those with better study designs suggest that metformin use in persons with T2D is associated with a lower risk of dementia. However, these observational studies are limited by the use of administrative data to ascertain metformin use and/or cognitive outcomes. There are few clinical trials in persons without T2D that have small sample sizes and short durations but suggest that metformin could prevent AD/ADRD. There are ongoing studies including large clinical trials with long duration that are testing the effect of metformin on AD/ADRD outcomes in persons without T2D at risk for dementia.

Nutrient intake and plasma ß-amyloid.

OBJECTIVE: The widely reported associations between various nutrients and cognition may occur through many biologic pathways including those of ß-amyloid (Aß). However, little is known about the possible associations of dietary factors with plasma Aß40 or Aß42. The aim of the current study was to evaluate the association between nutrient intake and plasma Aß levels. METHODS: In this cross-sectional study, plasma Aß40 and Aß42 and dietary data were obtained from 1,219 cognitively healthy elderly (age >65 years), who were participants in a community-based multiethnic cohort. Information on dietary intake was obtained 1.2 years, on average, before Aß assay. The associations of plasma Aß40 and Aß42 levels and dietary intake of 10 nutrients were examined using linear regression models, adjusted for age, gender, ethnicity, education, caloric intake, apolipoprotein E genotype, and recruitment wave. Nutrients examined included saturated fatty acid, monounsaturated fatty acid, ω-3 polyunsaturated fatty acid (PUFA), ω-6 PUFA, vitamin E, vitamin C, ß-carotene, vitamin B(12), folate, and vitamin D. RESULTS: In unadjusted models that simultaneously included all nutrients, higher intake of ω-3 PUFA was associated with lower levels of Aß40 (ß = -24.7, p < 0.001) and lower levels of Aß42 (ß = -12.3, p < 0.001). In adjusted models, ω-3 PUFA remained a strong predictor of Aß42 (ß = -7.31, p = 0.02), whereas its association with Aß40 was attenuated (ß = -11.96, p = 0.06). Other nutrients were not associated with plasma Aß levels. CONCLUSIONS: Our data suggest that higher dietary intake of ω-3 PUFA is associated with lower plasma levels of Aß42, a profile linked with reduced risk of incident AD and slower cognitive decline in our cohort.

Memory after silent stroke: hippocampus and infarcts both matter.

OBJECTIVE: Memory decline commonly occurs among elderly individuals. This observation is often attributed to early neurodegenerative changes in the hippocampus and related brain regions. However, the contribution of vascular lesions, such as brain infarcts, to hippocampal integrity and age-associated memory decline remains unclear. METHODS: We studied 658 elderly participants without dementia from a prospective, community-based study on aging and dementia who received high-resolution structural MRI. Cortical and subcortical infarcts were identified, and hippocampal and relative brain volumes were calculated following standard protocols. Summary scores reflecting performance on tasks of memory, language, processing speed, and visuospatial function were derived from a comprehensive neuropsychological battery. We used multiple regression analyses to relate cortical and subcortical infarcts, hippocampal and relative brain volume, to measures of cognitive performance in domains of memory, language, processing speed, and visuospatial ability. RESULTS: Presence of brain infarcts was associated with a smaller hippocampus. Smaller hippocampus volume was associated with poorer memory specifically. Brain infarcts were associated with poorer memory and cognitive performance in all other domains, which was independent of hippocampus volume. CONCLUSIONS: Both hippocampal volume and brain infarcts independently contribute to memory performance in elderly individuals without dementia. Given that age-associated neurodegenerative conditions, such as Alzheimer disease, are defined primarily by impairment in memory, these findings have clinical implications for prevention and for identification of pathogenic factors associated with disease symptomatology.

Type 2 diabetes and late-onset Alzheimer's disease.

BACKGROUND/AIMS: To confirm in a cohort recruited in 1999-2001 our finding in a cohort recruited in 1992-1994 relating type 2 diabetes (T2D) to late-onset Alzheimer's disease (LOAD). METHODS: Participants were 1,488 persons aged 65 years and older without dementia at baseline from New York City. T2D was ascertained by self-report. Dementia and LOAD were ascertained by standard research procedures. Proportional hazard regression was used for analyses relating T2D and LOAD. RESULTS: The prevalence of T2D was 17%. There were 161 cases of dementia and 149 cases of LOAD. T2D was related to dementia (hazard ratio = 1.7; 95% confidence interval = 1.4-2.9) and LOAD (1.6; 1.0-2.6) after adjustment for age, sex, education, ethnic group and apolipoprotein E ε4. This association was weaker when only AD - excluding cases of mixed dementia - was considered (hazard ratio = 1.3; 95% confidence interval = 0.8-2.2). CONCLUSION: T2D is associated with LOAD. Cerebrovascular disease may be an important mediator.

Improved diabetes control in the elderly delays global cognitive decline.

OBJECTIVES: To examine whether improved diabetes control is related to better cognitive outcomes. DESIGN: Randomized control trial. SETTING: A randomized trial of telemedicine vs. usual care in elderly persons with type 2 diabetes. PARTICIPANTS: Participants were 2169 persons 55 years and older with type 2 diabetes from New York City and Upstate New York. INTERVENTION: The diabetes case management intervention was implemented by a diabetes nurse, via a telemedicine unit in the participant's home, and in coordination with the primary care physician. MEASUREMENTS: Hemoglobin A1c (HbA1c), systolic blood pressure (SBP), and low density lipoprotein cholesterol (LDL), were measured at a baseline visit and at up to 5 annual follow-up visits. Global cognition was measured at those visits with the Comprehensive Assessment and Referral Evaluation (CARE). RESULT: In mixed models the intervention was related to slower global cognitive decline in the intervention group (p = 0.01). Improvements in HbA1c (p = 0.03), but not SBP or LDL, mediated the effect of the intervention on cognitive decline. CONCLUSION: Improved diabetes control in the elderly following existing guidelines through a telemedicine intervention was associated with less global cognitive decline. The main mediator of this effect seemed to be improvements in HbA1c.

Subclinical cerebrovascular disease in mild cognitive impairment.

BACKGROUND: Cerebrovascular disease (CVD) may contribute to mild cognitive impairment (MCI). We sought to determine the relation of white matter hyperintensity (WMH) volume and infarcts in brain MRI to MCI in a community-based sample. METHODS: A total of 679 elderly persons without dementia underwent brain MRI. WMH and infarcts were quantified using research methods. WMH was adjusted for total cranial volume. The Petersen criteria were used to define MCI. MCI was further subclassified into amnestic and non-amnestic. We used logistic regression to relate WMH and infarcts to prevalent MCI. RESULTS: WMH were associated with amnestic MCI (odds ratio [OR] = 1.9; 95% confidence interval [CI] 1.1, 3.4) but not non-amnestic MCI (OR = 1.2; 95% CI 0.4, 1.6) after adjusting for age, gender, ethnic group, education, and APOE-epsilon4. Infarcts were more strongly associated with non-amnestic MCI (OR = 2.7; 95% CI 1.5, 4.8) than amnestic MCI (OR = 1.4; 95% CI 0.9, 2.3). In secondary analyses using continuous cognitive scores as outcomes, WMH, but not infarcts, were related to memory, while infarcts were more strongly related with non-amnestic domains. CONCLUSION: White matter hyperintensity (WMH) is more strongly related to amnestic mild cognitive impairment (MCI). Infarcts are more strongly related to non-amnestic MCI. The nature of WMH in amnestic MCI requires further study.

Body mass index, dementia, and mortality in the elderly.

OBJECTIVES: To explore the association between body mass index and mortality in the elderly taking the diagnosis of dementia into account. DESIGN: Cohort study. SETTING: cohort study of aging in Medicare recipients in New York City. PARTICIPANTS: 1,452 elderly individuals 65 years and older of both genders. MEASUREMENTS: We used proportional hazards regression for longitudinal multivariate analyses relating body mass index (BMI) and weight change to all-cause mortality. RESULTS: There were 479 deaths during 9,974 person-years of follow-up. There were 210 cases of prevalent dementia at baseline, and 209 cases of incident dementia during follow-up. Among 1,372 persons with BMI information, the lowest quartile of BMI was associated with a higher mortality risk compared to the second quartile (HR=1.5; 95% CI: 1.1,2.0) after adjustment for age, gender, education, ethnic group, smoking, cancer, and dementia. When persons with dementia were excluded, both the lowest (HR=1.9; 95% CI=.3,2.6) and highest (HR=1.6; 95% CI: 1.1,2.3) quartiles of BMI were related to higher mortality. Weight loss was related to a higher mortality risk (HR=1.5; 95% CI: 1.2,1.9) but this association was attenuated when persons with short follow-up or persons with dementia were excluded. CONCLUSION: The presence of dementia does not explain the association between low BMI and higher mortality in the elderly. However, dementia may explain the association between weight loss and higher mortality.

Glycemic load and risk of Alzheimer's disease.

OBJECTIVE: to explore the relation of glycemic load (GL) with Alzheimer's disease (AD) risk. DESIGN: Cohort study. SETTING: Cohort of elderly subjects in New York City. PARTICIPANTS: 939 persons 65 years and older without dementia followed for an average of 6.3 years. MEASUREMENTS: Glycemic index, carbohydrate and calorie intake were measured using a semi-quantitative food frequency questionnaire (SFFQ). GL was calculated as the product of carbohydrate intake and glycemic index and adjusted for energy intake. AD was ascertained with standard research criteria. RESULTS: Cox regression was used to relate GL quartiles to AD using time from SFFQ to AD as the time-to-event variable. There was no association between GL and AD after adjustment for age, gender, education, ethnic group, and presence of diabetes. There was no evidence of modification by age, gender, APOE-e4, and presence of diabetes. The only dietary variable associated with a higher risk of AD was total calories (HR of AD for a one-log unit increase =2.2; 95% CI: 1.4,3.5) after adjustment for age, gender, ethnic group, education, diabetes, and APOE-e4. CONCLUSION: GL is not associated with a higher risk of AD in the elderly. Our data does not support the popular practice of low carbohydrate diets for the prevention of AD in the elderly.

Aggregation of vascular risk factors and risk of incident Alzheimer disease.

BACKGROUND: The prevalence of Alzheimer disease (AD) is increasing in the elderly, and vascular risk factors may increase its risk. OBJECTIVE: To explore the association of the aggregation of vascular risk factors with AD. METHODS: The authors followed 1,138 individuals without dementia at baseline (mean age 76.2) for a mean of 5.5 years. The presence of vascular risk factors was related to incident possible and probable AD. RESULTS: Four risk factors (diabetes, hypertension, heart disease, and current smoking) were associated with a higher risk of AD (p < 0.10) when analyzed individually. The risk of AD increased with the number of risk factors (diabetes + hypertension + heart disease + current smoking). The adjusted hazards ratio of probable AD for the presence of three or more risk factors was 3.4 (95% CI: 1.8, 6.3; p for trend < 0.0001) compared with no risk factors. Diabetes and current smoking were the strongest risk factors in isolation or in clusters, but hypertension and heart disease were also related to a higher risk of AD when clustered with diabetes, smoking, or each other. CONCLUSIONS: The risk of Alzheimer disease (AD) increased with the number of vascular risk factors. Diabetes and current smoking were the strongest risk factors, but clusters including hypertension and heart disease also increased the risk of AD. These associations are unlikely to be explained by misclassification of the outcome, given strong associations when only probable AD is considered.

Plasma homocysteine levels and risk of Alzheimer disease.

OBJECTIVE: To explore the association between high homocysteine levels and risk of Alzheimer disease (AD) in the Washington Heights-Inwood Columbia Aging Project (WHICAP). METHODS: The authors obtained fasting plasma samples in 909 elderly subjects chosen at random from a cohort of Medicare recipients; there was longitudinal data in 679 subjects without dementia at baseline who were followed for 3,206 person-years. Prevalent and incident dementia and its subtypes were diagnosed using standard methods. RESULTS: There were 128 persons with prevalent AD and 109 with incident AD in 3,206 person-years of follow-up. The adjusted OR of prevalent AD for the highest quartile of homocysteine compared to the lowest was 1.3 (95% CI = 0.7, 2.3; p for trend = 0.25). In longitudinal analyses, the authors found that the adjusted hazard ratio of AD for the highest quartile of homocysteine was 1.4 (95% CI = 0.8, 2.4; p for trend = 0.31). The authors also found that high homocysteine levels were not related to a decline in memory scores over time. Age was a significant confounder in all the analyses. The study had 80% power to detect a hazard ratio of 1.3 in the longitudinal analyses. CONCLUSION: High homocysteine levels were not associated with AD and were not related to a decrease in memory scores over time.

Antibiotic use and risk of ischemic stroke in the elderly.

PURPOSE: To determine whether treating infections with antibiotics that have antichlamydial activity decreases the risk of ischemic stroke in the elderly. SUBJECTS: We analyzed data from 199 553 subjects 65 years and older in a health care claims database who had continuous health and pharmacy coverage for at least 2 years between January 1, 1991, and September 30, 1997. Using proportional hazards models with time-dependent covariates for prior antibiotic prescription and adjusting for cardiovascular risk factors, we determined the associations between antibiotic use and first claim for ischemic stroke (n = 7,335) during the observation period. RESULTS: Rates of stroke (per 1,000 person-years) were 6.64 for macrolides, 9.27 for quinolones, 7.49 for tetracyclines, 6.88 for penicillins, 7.97 for cephalosporins, 8.58 for trimethoprim-sulfamethoxazole, and 7.29 for subjects with no antibiotic claims. The adjusted hazard ratios (HR) were 0.94 (95% confidence interval [CI]: 0.87 to 1.01) for macrolides, 1.04 (95% CI: 0.91 to 1.18) for tetracyclines, 1.02 (95% CI: 0.95 to 1.08) for penicillins, and 1.00 (95% CI: 0.82 to 1.22) for trimethoprim-sulfamethoxazole. Subjects with claims for quinolone antibiotics (HR = 1.17; 95% CI: 1.09 to 1.26) and cephalosporins (HR = 1.09; 95% CI: 1.02 to 1.16) had a slightly higher risk of stroke. CONCLUSION: Exposures to short courses of antibiotics are not associated with lower risk of ischemic stroke in patients aged 65 years and older.

Diabetes mellitus and risk of Alzheimer's disease and dementia with stroke in a multiethnic cohort.

Research on the relation between diabetes mellitus and dementia has produced conflicting results, and the relation has not been investigated among Blacks and Hispanics. In this study, Cox proportional hazards models were used to analyze longitudinal data from 1,262 elderly subjects without dementia at baseline (1991-1996) who were followed for an average of 4.3 years between 1992 and 1997. Outcomes were incident Alzheimer's disease and dementia associated with stroke. The prevalence of diabetes was 20% at baseline. The adjusted relative risk of Alzheimer's disease among persons with diabetes as compared with those without diabetes was 1.3 (95% confidence interval (CI): 0.8, 1.9). The adjusted relative risk for the composite outcome of Alzheimer's disease and cognitive impairment without dementia (without stroke) in subjects with diabetes was 1.6 (95% CI: 1.2, 2.1). The adjusted relative risk of stroke-associated dementia in persons with diabetes was 3.4 (95% CI: 1.7, 6.9). Among Blacks and Hispanics, approximately one third of the risk of stroke-associated dementia was attributable to diabetes (33% (95% CI: 31, 36) and 36% (95% CI: 33, 37), respectively), as compared with 17% (95% CI: 13, 22) among Whites. The finding of an association between diabetes and the composite outcome of Alzheimer's disease and cognitive impairment without dementia (without stroke) is consistent with prior reports of a modest relation between diabetes and Alzheimer's disease.

Resolution of cardiomyopathy after ablation of atrial flutter.

OBJECTIVES: We sought to serially assess left ventricular (LV) function before and after catheter ablation of atrial flutter (AFI). BACKGROUND: The relation of tachycardia-induced cardiomyopathy to AFI and its response to direct catheter ablation are unknown. METHODS: LV function was assessed in a series of 59 consecutive patients with successful radiofrequency ablation (RFA) of AFI before and after the procedure. Eleven patients had dilated cardiomyopathy (LV ejection fraction [LVEF] <50%) and congestive heart failure (CHF) symptoms and are the subject of this report. LV function was assessed by LVEF on two-dimensional echocardiography and functional status by New York Heart Association (NYHA) CHF classification. RESULTS: Patients were 59 +/- 8 years old, and were all male. Five patients had a preablation diagnosis of idiopathic cardiomyopathy. The preablation LVEF was 30.9 +/- 11.0% and improved to 41.3 +/- 16% (p = 0.005) when measured 7 months after successful ablation. NYHA CHF class improved from 2.6 +/- 0.5 to 1.6 +/- 0.9 (p = 0.002). Six (55%) of 11 patients had normalization of the LVEF, with complete resolution of CHF symptoms. A lower preablation LVEF and functional class predicted nonresolution of dilated cardiomyopathy (p = 0.002 and 0.001, respectively). CONCLUSIONS: Restoration of normal sinus rhythm by RFA in patients with chronic AFI and cardiomyopathy substantially improved LV function. Resolution of dilated cardiomyopathy occurred in the majority of patients. Tachycardia-induced cardiomyopathy may be a more common mechanism of LV dysfunction in patients with AFI than expected, and aggressive treatment of this arrhythmia should be considered.