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1.  Carotid Atherosclerosis and Prospective Risk of Dementia 
Background and Purpose
Though vascular risk factors have been implicated in the development of all-cause dementia and Alzheimer’s disease (AD), few studies have examined the association between subclinical atherosclerosis and prospective risk of dementia.
Methods
Participants from the Baltimore Longitudinal Study of Aging (n=364, aged 60–95, median age=73, 60% male, 82% white) underwent initial carotid atherosclerosis assessment and were subsequently assessed for dementia and AD annually for up to 14 years (median=7.0). Cox proportional hazards models predicting (a) all-cause dementia and (b) AD were adjusted for age, sex, race, education, blood pressure, cholesterol, cardiovascular disease, diabetes, and smoking.
Results
Sixty participants developed dementia, with 53 diagnosed as Alzheimer’s disease. Raw rates of future dementia and AD among individuals initially (a) in the upper quintile of carotid intimal medial thickness (IMT) or (b) with bilateral carotid plaque were generally double the rates of individuals with IMT in the lower quintiles or no plaque at baseline. Adjusted proportional hazards models revealed a >2.5-fold increased risk of dementia and AD among individuals in the upper quintile of carotid IMT, and a nearly 2.0-fold increased risk of dementia among individuals with bilateral plaque.
Conclusions
Multiple measures of carotid atherosclerosis are associated with prospective risk of dementia. Individuals in the upper quintile of carotid IMT or bilateral carotid plaque were at greatest risk. These findings underscore the possibility that early intervention to reduce atherosclerosis may help delay or prevent onset of dementia and AD.
doi:10.1161/STROKEAHA.112.672527
PMCID: PMC3508298  PMID: 23103489
atherosclerosis; intimal medial thickness; dementia; Alzheimer’s disease
2.  Inverse association between cancer and Alzheimer’s disease: results from the Framingham Heart Study  
Objectives To relate cancer since entry into the Framingham Heart Study with the risk of incident Alzheimer’s disease and to estimate the risk of incident cancer among participants with and without Alzheimer’s disease.
Design Community based prospective cohort study; nested age and sex matched case-control study.
Setting Framingham Heart Study, USA.
Participants 1278 participants with and without a history of cancer who were aged 65 or more and free of dementia at baseline (1986-90).
Main outcome measures Hazard ratios and 95% confidence intervals for the risks of Alzheimer’s disease and cancer.
Results Over a mean follow-up of 10 years, 221 cases of probable Alzheimer’s disease were diagnosed. Cancer survivors had a lower risk of probable Alzheimer’s disease (hazard ratio 0.67, 95% confidence interval 0.47 to 0.97), adjusted for age, sex, and smoking. The risk was lower among survivors of smoking related cancers (0.26, 0.08 to 0.82) than among survivors of non-smoking related cancers (0.82, 0.57 to 1.19). In contrast with their decreased risk of Alzheimer’s disease, survivors of smoking related cancer had a substantially increased risk of stroke (2.18, 1.29 to 3.68). In the nested case-control analysis, participants with probable Alzheimer’s disease had a lower risk of subsequent cancer (0.39, 0.26 to 0.58) than reference participants, as did participants with any Alzheimer’s disease (0.38) and any dementia (0.44).
Conclusions Cancer survivors had a lower risk of Alzheimer’s disease than those without cancer, and patients with Alzheimer’s disease had a lower risk of incident cancer. The risk of Alzheimer’s disease was lowest in survivors of smoking related cancers, and was not primarily explained by survival bias. This pattern for cancer is similar to that seen in Parkinson’s disease and suggests an inverse association between cancer and neurodegeneration.
doi:10.1136/bmj.e1442
PMCID: PMC3647385  PMID: 22411920
3.  Use of Framingham risk score and new biomarkers to predict cardiovascular mortality in older people: population based observational cohort study 
Objectives To investigate the performance of classic risk factors, and of some new biomarkers, in predicting cardiovascular mortality in very old people from the general population with no history of cardiovascular disease.
Design The Leiden 85-plus Study (1997-2004) is an observational prospective cohort study with 5 years of follow-up.
Setting General population of the city of Leiden, the Netherlands.
Participants Population based sample of participants aged 85 years (215 women and 87 men) with no history of cardiovascular disease; no other exclusion criteria.
Main measurements Cause specific mortality was registered during follow-up. All classic risk factors included in the Framingham risk score (sex, systolic blood pressure, total and high density lipoprotein cholesterol, diabetes mellitus, smoking and electrocardiogram based left ventricular hypertrophy), as well as plasma concentrations of the new biomarkers homocysteine, folic acid, C reactive protein, and interleukin 6, were assessed at baseline.
Results During follow-up, 108 of the 302 participants died; 32% (35/108) of deaths were from cardiovascular causes. Classic risk factors did not predict cardiovascular mortality when used in the Framingham risk score (area under receiver operating characteristic curve 0.53, 95% confidence interval 0.42 to 0.63) or in a newly calibrated model (0.53, 0.43 to 0.64). Of the new biomarkers studied, homocysteine had most predictive power (0.65, 0.55 to 0.75). Entering any additional risk factor or combination of factors into the homocysteine prediction model did not increase its discriminative power.
Conclusions In very old people from the general population with no history of cardiovascular disease, concentrations of homocysteine alone can accurately identify those at high risk of cardiovascular mortality, whereas classic risk factors included in the Framingham risk score do not. These preliminary findings warrant validation in a separate cohort.
doi:10.1136/bmj.a3083
PMCID: PMC2615548  PMID: 19131384
4.  Glucose Levels and Risk of Dementia 
The New England journal of medicine  2013;369(6):540-548.
BACKGROUND
Diabetes is a risk factor for dementia. It is unknown whether higher glucose levels increase the risk of dementia in people without diabetes.
METHODS
We used 35,264 clinical measurements of glucose levels and 10,208 measurements of glycated hemoglobin levels from 2067 participants without dementia to examine the relationship between glucose levels and the risk of dementia. Participants were from the Adult Changes in Thought study and included 839 men and 1228 women whose mean age at baseline was 76 years; 232 participants had diabetes, and 1835 did not. We fit Cox regression models, stratified according to diabetes status and adjusted for age, sex, study cohort, educational level, level of exercise, blood pressure, and status with respect to coronary and cerebrovascular diseases, atrial fibrillation, smoking, and treatment for hypertension.
RESULTS
During a median follow-up of 6.8 years, dementia developed in 524 participants (74 with diabetes and 450 without). Among participants without diabetes, higher average glucose levels within the preceding 5 years were related to an increased risk of dementia (P = 0.01); with a glucose level of 115 mg per deciliter (6.4 mmol per liter) as compared with 100 mg per deciliter (5.5 mmol per liter), the adjusted hazard ratio for dementia was 1.18 (95% confidence interval [CI], 1.04 to 1.33). Among participants with diabetes, higher average glucose levels were also related to an increased risk of dementia (P = 0.002); with a glucose level of 190 mg per deciliter (10.5 mmol per liter) as compared with 160 mg per deciliter (8.9 mmol per liter), the adjusted hazard ratio was 1.40 (95% CI, 1.12 to 1.76).
CONCLUSIONS
Our results suggest that higher glucose levels may be a risk factor for dementia, even among persons without diabetes. (Funded by the National Institutes of Health.)
doi:10.1056/NEJMoa1215740
PMCID: PMC3955123  PMID: 23924004
5.  Depressive symptoms and risk of dementia 
Neurology  2010;75(1):35-41.
Objectives:
Depression may be associated with an increased risk for dementia, although results from population-based samples have been inconsistent. We examined the association between depressive symptoms and incident dementia over a 17-year follow-up period.
Methods:
In 949 Framingham original cohort participants (63.6% women, mean age = 79), depressive symptoms were assessed at baseline (1990-1994) using the 60-point Center for Epidemiologic Studies Depression Scale (CES-D). A cutpoint of ≥16 was used to define depression, which was present in 13.2% of the sample. Cox proportional hazards models adjusting for age, sex, education, homocysteine, and APOE ε4 examined the association between baseline depressive symptoms and the risk of dementia and Alzheimer disease (AD).
Results:
During the 17-year follow-up period, 164 participants developed dementia; 136 of these cases were AD. A total of 21.6% of participants who were depressed at baseline developed dementia compared with 16.6% of those who were not depressed. Depressed participants (CES-D ≥16) had more than a 50% increased risk for dementia (hazard ratio [HR] 1.72, 95% confidence interval [CI] 1.04-2.84, p = 0.035) and AD (HR 1.76, 95% CI 1.03-3.01, p = 0.039). Results were similar when we included subjects taking antidepressant medications as depressed. For each 10-point increase on the CES-D, there was significant increase in the risk of dementia (HR 1.46, 95% CI 1.18-1.79, p < 0.001) and AD (HR 1.39, 95% CI 1.11-1.75, p = 0.005). Results were similar when we excluded persons with possible mild cognitive impairment.
Conclusions:
Depression is associated with an increased risk of dementia and AD in older men and women over 17 years of follow-up.
GLOSSARY
= Alzheimer disease;
= Clinical Dementia Rating;
= Center for Epidemiologic Studies Depression Scale;
= confidence interval;
= Diagnostic and Statistical Manual of Mental Disorders, 4th edition;
= hazard ratio;
= mild cognitive impairment;
= Mini-Mental State Examination.
doi:10.1212/WNL.0b013e3181e62138
PMCID: PMC2906404  PMID: 20603483
6.  Impact of Psychological Stress on the Associations Between Apolipoprotein E Variants and Metabolic Traits: Findings in an American Sample of Caregivers and Controls 
Psychosomatic medicine  2010;72(5):427-433.
Objective
To examine the association between apolipoprotein E (APOE) gene variants and waist circumference, fasting plasma glucose, serum insulin, serum high-density lipoprotein cholesterol, and serum triglycerides, all metabolic traits known as cardiovascular disease (CVD) endophenotypes, in a population of stressed individuals and controls. Abdominal obesity, insulin resistance, elevated serum lipid concentration, and APOE polymorphisms have been associated with CVD risk. Current evidence supports the hypothesis that gene-environment interactions modulate serum lipid concentrations.
Methods
The association between rs769450, rs405509, rs439401, and metabolic traits were analyzed in a U.S. sample of 126 white caregivers of a relative with Alzheimer's disease or other major dementia and 122 white controls. The associations were analyzed, using multivariate analysis of variance adjusted for age, sex, and medications.
Results
Significant multivariate interactions were found, using both additive (p = .009) and dominant (p = .047) models between rs439401 (C/T) and caregiver stress in relation to a profile of metabolic variables. Univariate analyses found the TT genotype to be associated with more adverse levels of waist circumference (interaction, p = .026), triglycerides (interaction, p = .001) and high-density lipoprotein cholesterol (interaction, p = .001) among caregivers but with a more favorable profile of these endophenotypes among controls. There were no significant associations or interactions involving the other two single nucleotide polymorphisms.
Conclusion
The APOE rs439401 TT genotype is associated with an adverse metabolic profile among chronically stressed individuals compared with individuals not similarly stressed in whom a more favorable profile is expressed. Confirmation of these results in further research would indicate that the TT genotype can be used to identify persons at high risk for CVD when subjected to chronic stress.
doi:10.1097/PSY.0b013e3181de30ad
PMCID: PMC3625667  PMID: 20467002
apolipoprotein E; obesity; metabolic traits; stress; epidemiology; gene-environment interaction
7.  Lipoprotein phospholipase A2 (Lp-PLA2) and cerebral microbleeds (CMBs) in the Framingham Heart Study 
Background and Purpose
Cerebral microbleeds (CMBs) due to cerebral amyloid angiopathy generally occur in lobar regions, while those due to hypertensive vasculopathy are deep. Inflammation may be an underlying mechanism for CMB, with varying associations according to CMB location. Lipoprotein phospholipase-A2 (Lp-PLA2) is a circulating enzyme marker of vascular inflammation associated with risk of ischemic stroke and dementia. We hypothesized that higher Lp-PLA2 levels would be related to higher prevalence of CMBs, with possible regional specificity.
Methods
Framingham Offspring participants aged ≥65 years with available Lp-PLA2 measures and brain MRI were included. Logistic regression models were used to relate Lp-PLA2 activity and mass to presence of CMBs, adjusted for age, sex, medication use (aspirin, anticoagulants, and statins), systolic blood pressure, APOE, current smoking, and diabetes.
Results
819 participants (mean age 73 years; 53% women) were included; 106 (13%) had CMBs; 82 (10%) lobar and 27 (3%) deep. We did not observe significant associations of CMB and LpPLA2 measures in multivariable adjusted analyses. However, there was a significant interaction between APOE genotype and Lp-PLA2 activity in their relation to presence of deep CMBs (p-interaction=0.01). Among persons with APOE ε3/ε3, the OR for deep CMB was 0.95 [0.59–1.53; p=0.83], while among those with at least one ε2 or ε4 allele, OR=3.46 [1.43–8.36; p=0.006].
Conclusions
In our community-based sample of older adults, there was no significant association of Lp-PLA2 with total or lobar CMBs. The association of higher levels of Lp-PLA2 activity with deep CMBs among those with at least one APOE ε2 or ε4 allele merits replication.
doi:10.1161/STROKEAHA.112.656744
PMCID: PMC3544291  PMID: 22961963
8.  Myeloperoxidase Is an Early Biomarker of Inflammation and Cardiovascular Risk in Prepubertal Obese Children 
Diabetes Care  2012;35(11):2373-2376.
OBJECTIVE
Obesity is associated with a state of chronic low-grade inflammation. Myeloperoxidase (MPO) plays an important role in the initiation and progression of acute and chronic inflammatory diseases, such as cardiovascular disease (CVD). The objectives of the current study were to evaluate plasma MPO levels in prepubertal obese children and to determine whether MPO could be an early biomarker of inflammation and CVD risk.
RESEARCH DESIGN AND METHODS
In a prospective multicenter case-control study paired by age and sex of 446 Caucasian prepubertal children ages 6–12 years, 223 normal-weight and 223 obese children were recruited. Blood pressure, waist circumference, weight, and height were measured. In addition to MPO, glucose, insulin, metabolic lipid parameters, oxidized low-density lipoproteins, adiponectin, leptin, resistin, C-reactive protein (CRP), interleukin 6, tumor necrosis factor α, matrix metalloproteinase-9 (MMP-9), and plasminogen activator inhibitor 1 were determined.
RESULTS
We found that MPO was elevated in prepubertal obese children and that this enzyme was associated with such proinflammatory and cardiovascular risk biomarkers as CRP, MMP-9, and resistin. Insulin resistance calculated by the homeostatic assessment model was the best predictor of MPO.
CONCLUSIONS
MPO is an early biomarker of inflammation associated with CVD risk in obese children at the prepubertal age.
doi:10.2337/dc12-0614
PMCID: PMC3476926  PMID: 22912422
9.  The PREVENT study: a prospective cohort study to identify mid-life biomarkers of late-onset Alzheimer's disease 
BMJ Open  2012;2(6):e001893.
Introduction
Epidemiological studies indicate that significant decreases in the incidence of Alzheimer's disease (AD) may be obtained by targeting multiple middle-age risk factors. However, as dementia is unlikely to be diagnosed for decades, short-term outcome measures are required. AD biomarker changes precede clinical symptoms by many years, but their sensitivity to mid-life change remains unknown.
Methods and analysis
PREVENT is a prospective cohort study examining biomarker status at mid-life in at least 150 individuals genetically at high, medium or low risk of late-onset AD. Participants are children of individuals with or without a diagnosed AD allocated to high, medium and low-risk groups according to parental clinical status and ApoE genotype. The biomarkers examined over 2 years are plasma and CSF Aβ42 amyloid, Tau and pTau, proinflammatory cytokines, acute-phase proteins, medial temporal-lobe atrophy, white matter lesion volume, cognitive performance related to transentorhinal and hippocampal functioning and hypothalamic−pituitary−adrenal and sympathetic axes regulation.
Ethics and dissemination
Detected pathologies are communicated to the participant's general practitioner with their permission. Risk status by genotype would not be revealed. The results of the study would be published in peer-reviewed journals and validated biomarkers used to construct a randomised controlled intervention study.
doi:10.1136/bmjopen-2012-001893
PMCID: PMC3533047  PMID: 23166135
Geriatric Medicine; Epidemiology
10.  Insulin metabolism and the risk of Alzheimer disease 
Neurology  2010;75(22):1982-1987.
Objective:
Diabetes mellitus has been associated with an increased risk of Alzheimer disease (AD), but how it exerts its effect remains controversial. Possible pathophysiologic mechanisms are glucose toxicity and a direct effect of insulin on amyloid metabolism. Most studies had short follow-up, and longer-term effects of diabetes on AD risk are unknown. We investigated whether fasting glucose and insulin levels and insulin resistance are associated with the risk of AD and whether this risk is constant over time.
Methods:
The study was based on 3,139 participants of the Rotterdam Study, a population-based cohort study. All subjects were free from dementia, did not have a history of diabetes, and had fasting levels of glucose and insulin measured at baseline. Insulin resistance was estimated with the homeostasis model assessment. We investigated how fasting glucose, insulin, and insulin resistance are related to the risk of AD in 3 different strata according to time-to-event, using Cox proportional hazards models.
Results:
During follow-up, 211 participants developed AD, 71 of them within 3 years of baseline. Levels of insulin and insulin resistance were associated with a higher risk of AD within 3 years of baseline. After 3 years, the risk was no longer increased. Glucose was not associated with a higher risk of AD. There was no interaction of APOE ε4 carriership and insulin metabolism on the risk of AD.
Conclusions:
Our findings suggest that insulin metabolism influences the clinical manifestation of AD only within 3 years.
GLOSSARY
= Alzheimer disease;
= Diagnostic and Statistical Manual of Mental Disorders, 3rd edition, revised;
= high-density lipoprotein;
= homeostasis model assessment.
doi:10.1212/WNL.0b013e3181ffe4f6
PMCID: PMC3014236  PMID: 21115952
11.  Insulin and Sex Interactions in Older Adults with Mild Cognitive Impairment 
Alzheimer’s disease (AD) and other dementias are likely preceded by a protracted preclinical state. Thus, identification of biomarkers that signal potential points of intervention during this prodromal phase (during which patients are largely able to compensate for their cognitive deficits) is of paramount importance. Insulin is a pancreatic hormone with potent central nervous system effects, and insulin dysregulation has been implicated in the pathogenesis of both AD and vascular dementia. The aim of the current study was to determine whether circulating insulin differs as a function of mild cognitive impairment (MCI) diagnosis, and whether this relationship is mediated by sex and apolipoprotein E (APOE) genotype. A sample of 549 nondemented participants aged 65 and over from the Adult Changes in Thought community-based cohort underwent cognitive testing and blood draw to determine fasting levels of plasma insulin. Subjects were categorized as having normal cognitive functioning, amnestic MCI, or nonamnestic MCI. Results showed that the relationship between insulin and diagnostic category is moderated by sex, such that men with nonamnestic or amnestic MCI have higher fasting plasma insulin than cognitively normal men, while women with amnestic MCI have lower fasting plasma insulin than cognitively normal women. Exploratory analyses suggest that APOE ε4 genotype may further influence the relationship between sex and insulin. Future research will help determine whether insulin dysregulation results in differential effects on vascular function and AD pathology as a function of sex and/or APOE genotype.
doi:10.3233/JAD-2012-120202
PMCID: PMC3798013  PMID: 22571978
Age-related memory disorders; aging; Alzheimer’s disease; cognition; dementia; hyperinsulinemia; insulin; vascular
12.  Late-life depression and risk of vascular dementia and Alzheimer’s disease: systematic review and meta-analysis of community-based cohort studies 
The British Journal of Psychiatry  2013;202(5):329-335.
Background
Late-life depression may increase the risk of incident dementia, in particular of Alzheimer’s disease and vascular dementia.
Aims
To conduct a systematic review and meta-analysis to evaluate the risk of incident all-cause dementia, Alzheimer’s disease and vascular dementia in individuals with late-life depression in population-based prospective studies.
Method
A total of 23 studies were included in the meta-analysis. We used the generic inverse variance method with a random-effects model to calculate the pooled risk of dementia, Alzheimer’s disease and vascular dementia in older adults with late-life depression.
Results
Late-life depression was associated with a significant risk of all-cause dementia (1.85, 95% CI 1.67-2.04, P<0.001), Alzheimer’s disease (1.65, 95% CI 1.42-1.92, P<0.001) and vascular dementia (2.52, 95% CI 1.77-3.59, P<0.001). Subgroup analysis, based on five studies, showed that the risk of vascular dementia was significantly higher than for Alzheimer’s disease (P = 0.03).
Conclusions
Late-life depression is associated with an increased risk for all-cause dementia, vascular dementia and Alzheimer’s disease. The present results suggest that it will be valuable to design clinical trials to investigate the effect of late-life depression prevention on risk of dementia, in particular vascular dementia and Alzheimer’s disease.
doi:10.1192/bjp.bp.112.118307
PMCID: PMC3640214  PMID: 23637108
13.  Association of Plasma Leptin Levels with Incident Alzheimer’s Disease and MRI Measures Of Brain Aging: The Framingham Study 
Context
The adipokine leptin facilitates long-term potentiation and synaptic plasticity in the hippocampus, promotes β-amyloid clearance and improves memory function in animal models of aging and Alzheimer’s disease (AD).
Objective
To relate baseline circulating leptin concentrations in a dementia-free community-based sample prospectively to 1) incident dementia and AD during follow-up and 2) to MRI (magnetic resonance imaging) measures of brain aging in survivors.
Design, Setting and Participants
Plasma leptin concentrations were measured in 785 dementia-free persons (mean age 79 [SD, 5 yrs], 62% women) from the Framingham Original cohort at the 22nd examination cycle (1990–1994). A sub-sample of 198 dementia-free survivors underwent volumetric brain MRI between 1999 and 2005, approximately 7.7 years after leptin was assayed. Two measures of brain aging, the total cerebral brain volume (TCBV) and temporal horn volume (THV; inversely related to hippocampal volume) were assessed.
Main outcome measure
Incidence of dementia and AD during follow-up till December 31st, 2007.
Results
During a median follow-up of 8.3 (range 0 to 15.5) years, 111 participants developed incident dementia, 89 had AD. Higher leptin levels were associated with a lower risk of incident dementia and AD in multivariable models (hazard ratios [HR] per one-SD increment in log-leptin were 0.68 [0.54–0.87] for all-cause dementia and 0.60 [0.46–0.79] for AD). This corresponds to an absolute AD risk over a 12 year follow-up of 25% for persons in the lowest quartile (Q1) versus 6% for persons in Q4 of sex-specific leptin levels. In addition, a one SD elevation in plasma leptin was associated with higher TCBV and lower THV, although the association of leptin with THV did not reach statistical significance.
Conclusions
Circulating leptin is directly related to indices of brain health in asymptomatic adults and inversely related to risk of incident dementia and AD. Our findings require confirmation in independent samples.
doi:10.1001/jama.2009.1836
PMCID: PMC2838501  PMID: 20009056
leptin; adipokines; dementia; Alzheimer’s disease
14.  Diabetes and the brain: issues and unmet needs 
Neurological Sciences  2014;35:995-1001.
Diabetes mellitus (DM) is associated with an increased risk of mild cognitive impairment, dementia and stroke. The association between DM and dementia appears to be stronger for vascular cognitive impairment than for Alzheimer’s disease, suggesting cerebrovascular disease may be an important factor in cognitive impairment in DM. Although the exact mechanisms by which DM affects the brain remain unclear, changes to brain vasculature, disturbances of cerebral insulin signaling, insulin resistance, glucose toxicity, oxidative stress, accumulation of advanced glycation end products, hypoglycemic episodes, and alterations in amyloid metabolism may all be involved. Cognitive impairment and dementia associated with DM may also be mediated via vascular risk factors, in particular brain ischemia, the occurrence of which can have an additive or synergistic effect with concomitant neurodegenerative processes. To date, no drug has been approved for the treatment of vascular dementia and there are no specific pharmacological treatments for preventing or reducing cognitive decline in patients with DM. Most focus has been on tighter management of vascular risk factors, although evidence of reduced cognitive decline through reducing blood pressure, lipid-lowering or tighter glycemic control is inconclusive. Tailored, multimodal therapies may be required to reduce the risk of cognitive dysfunction and decline in patients with DM. The use of pleiotropic drugs with multimodal mechanisms of action (e.g., cerebrolysin, Actovegin) may have a role in the treatment of cognitive dysfunction and their use may warrant further investigation in diabetic populations.
doi:10.1007/s10072-014-1797-2
PMCID: PMC4064119  PMID: 24777546
Diabetes; Cognitive impairment; Vascular dementia; Stroke
15.  APOE ε2 is associated with intact cognition but increased Alzheimer pathology in the oldest-old 
Neurology  2009;72(9):829-834.
Background
Many studies have examined the role of Apolipoprotein E (APOE) genotype in the development of dementia, specifically Alzheimer’s disease (AD). The APOE ε4 allele (APOE4) is a risk factor for both clinical and neuropathological AD whereas the APOE ε2 allele (APOE2) seems to be protective. This would predict, even with advanced age, that APOE2 carriers would be less likely to have dementia and less likely to meet pathological criteria for AD.
Methods
The first 85 genotyped participants from The 90+ Study to come to autopsy were included. All-cause dementia (using DSM-IV criteria) and AD (using NINCDS-ADRDA criteria) diagnoses were made by consensus conference using all available information including neuropsychological testing, neurological examination and medical records. Neuropathological examination included Braak and Braak staging for plaques and tangles and diagnosis of neuropathological AD using NIA-Reagan criteria.
Results
Across all genotypes, 58.5% of subjects were diagnosed with clinical dementia (81% of dementia was AD) and 50.0% met neuropathological criteria for AD. Compared to those with an APOE ε3/ε3 genotype (APOE 3/3), APOE4 carriers were more likely to be diagnosed with dementia (OR=12.2,95%CI=1.5–102.0), whereas APOE2 carriers were not (OR=0.3,95%CI=0.1–1.3). Surprisingly, both APOE4 (OR=4.6,95%CI=1.3–16.5) and APOE2 (OR=7.8,95%CI=1.5–40.2) carriers were more likely to meet neuropathological criteria for AD than those with APOE3/3 genotype.
Conclusions
In the oldest-old, the presence of APOE2 was associated with a somewhat reduced risk of dementia, but paradoxically was associated with increased AD neuropathology. Therefore, oldest-old APOE2 carriers may have some mechanism that contributes to the maintenance of cognition independently of the formation of AD pathology.
doi:10.1212/01.wnl.0000343853.00346.a4
PMCID: PMC2667799  PMID: 19255410
16.  APOE ε2 is associated with intact cognition but increased Alzheimer pathology in the oldest old 
Neurology  2009;72(9):829-834.
Background: Many studies have examined the role of APOE genotype in the development of dementia, specifically Alzheimer disease (AD). The APOE ε4 allele (APOE4) is a risk factor for both clinical and neuropathologic AD whereas the APOE ε2 allele (APOE2) seems to be protective. This would predict, even with advanced age, that APOE2 carriers would be less likely to have dementia and less likely to meet pathologic criteria for AD.
Methods: The first 85 genotyped participants from The 90+ Study to come to autopsy were included. All-cause dementia (using DSM-IV criteria) and AD (using National Institute of Neurological and Communicative Disorders and Stroke–Alzheimer's Disease and Related Disorders Association criteria) diagnoses were made by consensus conference using all available information including neuropsychological testing, neurologic examination, and medical records. Neuropathologic examination included Braak and Braak staging for plaques and tangles and diagnosis of neuropathologic AD using National Institute on Aging–Reagan criteria.
Results: Across all genotypes, 58.5% of subjects were diagnosed with clinical dementia (81% of dementia was AD) and 50.0% met neuropathologic criteria for AD. Compared to those with an APOE ε3/ε3 genotype (APOE3/3), APOE4 carriers were more likely to be diagnosed with dementia (odds ratio [OR] = 12.2, 95% confidence interval [CI] = 1.5–102.0), whereas APOE2 carriers were not (OR = 0.3, 95% CI = 0.1–1.3). Surprisingly, both APOE4 (OR = 4.6, 95% CI = 1.3–16.5) and APOE2 (OR = 7.8, 95% CI = 1.5–40.2) carriers were more likely to meet neuropathologic criteria for AD than those with APOE3/3 genotype.
Conclusions: In the oldest old, the presence of the APOE ε2 allele (APOE2) was associated with a somewhat reduced risk of dementia, but paradoxically was associated with increased Alzheimer disease (AD) neuropathology. Therefore, oldest old APOE2 carriers may have some mechanism that contributes to the maintenance of cognition independently of the formation of AD pathology.
doi:10.1212/01.wnl.0000343853.00346.a4
PMCID: PMC2667799  PMID: 19255410
17.  Association of Metabolic Dysregulation With Volumetric Brain Magnetic Resonance Imaging and Cognitive Markers of Subclinical Brain Aging in Middle-Aged Adults 
Diabetes Care  2011;34(8):1766-1770.
OBJECTIVE
Diabetic and prediabtic states, including insulin resistance, fasting hyperglycemia, and hyperinsulinemia, are associated with metabolic dysregulation. These components have been individually linked to increased risks of cognitive decline and Alzheimer’s disease. We aimed to comprehensively relate all of the components of metabolic dysregulation to cognitive function and brain magnetic resonance imaging (MRI) in middle-aged adults.
RESEARCH DESIGN AND METHODS
Framingham Offspring participants who underwent volumetric MRI and detailed cognitive testing and were free of clinical stroke and dementia during examination 7 (1998–2001) constituted our study sample (n = 2,439; 1,311 women; age 61 ± 9 years). We related diabetes, homeostasis model assessment of insulin resistance (HOMA-IR), fasting insulin, and glycohemoglobin levels to cross-sectional MRI measures of total cerebral brain volume (TCBV) and hippocampal volume and to verbal and visuospatial memory and executive function. We serially adjusted for age, sex, and education alone (model A), additionally for other vascular risk factors (model B), and finally, with the inclusion of apolipoprotein E-ε4, plasma homocysteine, C-reactive protein, and interleukin-6 (model C).
RESULTS
We observed an inverse association between all indices of metabolic dysfunction and TCBV in all models (P < 0.030). The observed difference in TCBV between participants with and without diabetes was equivalent to approximately 6 years of chronologic aging. Diabetes and elevated glycohemoglobin, HOMA-IR, and fasting insulin were related to poorer executive function scores (P < 0.038), whereas only HOMA-IR and fasting insulin were inversely related to visuospatial memory (P < 0.007).
CONCLUSIONS
Metabolic dysregulation, especially insulin resistance, was associated with lower brain volumes and executive function in a large, relatively healthy, middle-aged, community-based cohort.
doi:10.2337/dc11-0308
PMCID: PMC3142014  PMID: 21680719
18.  The Role of Peripheral Inflammatory Markers in Dementia and Alzheimer’s Disease: A Meta-Analysis 
Background.
Studies that have investigated the association between markers of inflammation and risk of dementia are conflicting. Therefore, the researchers conducted a systematic review and meta-analysis of observational studies with the hypothesis that an increased level of peripheral proinflammatory markers would be associated with risk of all-cause dementia or Alzheimer’s disease (AD).
Methods.
The researchers conducted a literature search of observational studies indexed in the PubMed and PsycInfo databases. Selected studies included those with at least one peripheral inflammatory biomarker and its association with risk of all-cause dementia or AD. Random effects models were used to generate pooled hazard ratios (HRs) comparing the top versus bottom quantile of inflammatory marker level. Heterogeneity was assessed using the I 2 statistic.
Results.
Seven studies were identified, combining for a total 5,717 participants, 746 cases of all-cause dementia and 565 cases of AD. An increased level of C-reactive protein was associated with a 45% increased risk of all-cause dementia (HR: 1.45; 95% CI: 1.10, 1.91). Similarly, a higher level of interleukin-6 was associated with a 32% increased risk (HR: 1.32; 95% CI: 1.06, 1.64) of all-cause dementia. For AD alone, the association with C-reactive protein was less pronounced (HR: 1.21; 95% CI: 1.03, 1.42) and interleukin-6 was not associated with risk of AD (HR: 1.06; 95% CI: 0.83, 1.35). No significant heterogeneity was found in any of the meta-analyses (I 2 = 0%–40%, p ≥ .16).
Conclusions.
An increased peripheral level of inflammatory markers is associated with a modest increase in risk of all-cause dementia. Evidence for an association with risk of AD alone is limited.
doi:10.1093/gerona/gls187
PMCID: PMC3693673  PMID: 22982688
Dementia; Alzheimer; Cognitive decline; Inflammation; c-reactive protein; Interleukin-6
19.  Dietary antioxidants and long-term risk of dementia 
Archives of neurology  2010;67(7):819-825.
OBJECTIVE
To study consumption of major dietary antioxidants in relation to long-term risk of dementia.
DESIGN AND SETTING
The Rotterdam Study, a population-based, prospective cohort study in the Netherlands.
PARTICIPANTS
A total of 5,395 participants, aged 55+ years, who were free of dementia and provided dietary information at study baseline.
MAIN OUTCOME MEASURES
Incidence of dementia and Alzheimer’s disease (AD), based on internationally accepted criteria, in relation to dietary intake of vitamin E, vitamin C, beta carotene, and flavonoids.
RESULTS
During an average follow-up period of 9.6 years, dementia developed in 465 participants, of whom 365 were diagnosed with AD. In multivariate models adjusted for age, education, APOE ε4 genotype, total energy intake, alcohol intake, smoking habits, body-mass index (BMI), and supplement use, higher intake of vitamin E at baseline was associated with a lower long-term risk of dementia (p-trend=0.02). Compared to participants in the lowest tertile of vitamin E intake, those in the highest tertile were 25% less likely to develop dementia (HR, 0.75; 95% CI, 0.59–0.95 with adjustment for potential confounders). Dietary intakes of vitamin C, beta carotene, and flavonoids were not associated with dementia risk (after multivariate adjustment, p-trend=1.0 for both vitamin C and beta carotene and p-trend=0.6 for flavonoids). Results were similar when AD risk was specifically examined.
CONCLUSION
Higher intake of foods rich in vitamin E may modestly reduce long-term risk of dementia and AD.
doi:10.1001/archneurol.2010.144
PMCID: PMC2923546  PMID: 20625087
20.  Inflammatory biomarkers are associated with total brain volume 
Neurology  2007;68(13):1032-1038.
Background
Systemic inflammation is associated with ischemia and Alzheimer disease (AD). We hypothesized that inflammatory biomarkers would be associated with neuroimaging markers of ischemia (i.e., white matter hyperintensities [WMH]) and AD (i.e., total brain volume [TCB]).
Methods
MRI WMH and TCB were quantified on 1,926 Framingham Offspring participants free from clinical stroke, TIA, or dementia (mean age 60 ± 9 years; range 35 to 85 years; 54% women) who underwent measurement of a circulating inflammatory marker panel, including CD40 ligand, C-reactive protein, interleukin-6 (IL-6), soluble intracellular adhesion molecule-1, monocyte chemoattractant protein-1, myeloperoxidase, osteoprotegerin (OPG), P-selectin, tumor necrosis factor-alpha (TNFα), and tumor necrosis factor receptor II. To account for head size, both TCB (TCBV) and WMH (WMH/TCV) were divided by total cranial volume. We used multivariable linear regression to relate 10 log-transformed inflammatory biomarkers to brain MRI measures.
Results
In multivariable models, inflammatory markers as a group were associated with TCBV (p < 0.0001) but not WMH/TCV (p = 0.28). In stepwise models adjusted for clinical covariates with backwards elimination of markers, IL-6 and OPG were inversely associated with TCBV; TNFα was inversely related to TCBV in a subset of 1,430 participants. Findings were similar in analyses excluding individuals with prevalent cardiovascular disease. The relations between TCBV and inflammatory markers were modified by both sex and age, and generally were more pronounced in men and in older individuals.
Conclusions
Although our observational cross-sectional data cannot establish causality, they are consistent with the hypothesis that higher inflammatory markers are associated with greater atrophy than expected for age.
doi:10.1212/01.wnl.0000257815.20548.df
PMCID: PMC2758770  PMID: 17389308
21.  The 32-year relationship between cholesterol and dementia from midlife to late life(e–Pub ahead of print) 
Neurology  2010;75(21):1888-1895.
Background:
Cellular and animal studies suggest that hypercholesterolemia contributes to Alzheimer disease (AD). However, the relationship between cholesterol and dementia at the population level is less clear and may vary over the lifespan.
Methods:
The Prospective Population Study of Women, consisting of 1,462 women without dementia aged 38–60 years, was initiated in 1968–1969 in Gothenburg, Sweden. Follow-ups were conducted in 1974–1975, 1980–1981, 1992–1993, and 2000–2001. All-cause dementia was diagnosed according to DSM-III-R criteria and AD according to National Institute of Neurological and Communicative Disorders and Stroke–Alzheimer's Disease and Related Disorders Association criteria. Cox proportional hazards regression examined baseline, time-dependent, and change in cholesterol levels in relation to incident dementia and AD among all participants. Analyses were repeated among participants who survived to the age of 70 years or older and participated in the 2000–2001 examination.
Results:
Higher cholesterol level in 1968 was not associated with an increased risk of AD (highest vs lowest quartile: hazard ratio [HR] 2.82, 95% confidence interval [CI] 0.94–8.43) among those who survived to and participated in the 2000–2001 examination. While there was no association between cholesterol level and dementia when considering all participants over 32 years, a time-dependent decrease in cholesterol over the follow-up was associated with an increased risk of dementia (HR 2.35, 95% CI 1.22–4.58).
Conclusion:
These data suggest that midlife cholesterol level is not associated with an increased risk of AD. However, there may be a slight risk among those surviving to an age at risk for dementia. Declining cholesterol levels from midlife to late life may better predict AD risk than levels obtained at one timepoint prior to dementia onset. Analytic strategies examining this and other risk factors across the lifespan may affect interpretation of results.
GLOSSARY
= Alzheimer disease;
= body mass index;
= confidence interval;
= diastolic blood pressure;
= Diagnostic and Statistical Manual of Mental Disorders, 3rd edition, revised;
= hazard ratio.
doi:10.1212/WNL.0b013e3181feb2bf
PMCID: PMC2995387  PMID: 21068429
22.  Elevated c-reactive protein levels are associated with prevalent dementia in the oldest-old 
Background
C-reactive protein (CRP) is a nonspecific marker of inflammation that is increased in the brain and serum of patients with Alzheimer’s disease (AD) and has been associated with increased risk of developing dementia. Inflammation increases with age and the number of people reaching the age of 90 and older is growing, making the association between inflammation and dementia increasingly relevant. Using a cross-sectional design, we examined if high levels of serum CRP are associated with increased odds of prevalent dementia in the oldest-old.
Methods
Serum CRP levels of 305 participants (mean age 94.3 ± 2.9 years) from The 90+ Study, a longitudinal cohort study of people 90 and older, were evaluated with respect to all-cause dementia (DSM-IV criteria). CRP levels were divided into three categories: undetectable (< 0.5 mg/dL), detectable (0.5 – 0.7 mg/dL) and elevated (≥0.8 mg/dL). Odds ratios (OR) were calculated using logistic regression and adjusted for covariates.
Results
Relative to participants with undetectable CRP levels, participants with detectable or elevated CRP levels had increased odds of all-cause dementia (detectable: OR 3.0, 95% CI 1.2 – 7.3; elevated: OR 5.0, 95% CI 1.9 – 12.9). When participants were subdivided by gender, significantly increased odds ratios were seen only in women.
Conclusions
In the oldest-old, high CRP levels are associated with increased odds of all-cause dementia, particularly in women. Prospective studies are necessary to confirm if increased CRP levels are associated with increased risk of developing dementia in this age group.
doi:10.1016/j.jalz.2009.04.1230
PMCID: PMC2740472  PMID: 19560102
C-reactive protein; dementia; nonagenarian; serum; inflammation
23.  Biomarkers of inflammation and malnutrition associated with early death in healthy elderly people 
Objectives
To determine whether malnutrition and inflammation biomarkers predict all-cause, cancer and cardiovascular mortality in healthy elderly subjects.
Design
Prospective cohort.
Setting
Population-based study, Sète, French Mediterranean coast.
Participants
553 men and 888 women aged 60+ years from the POLA (Pathologies Oculaires Liées à l’Age) cohort, free of known co-morbidities.
Measurements
Plasma levels of cholesterol, albumin, transthyretin (TTR), C-reactive protein (CRP) and alpha 1-acid glycoprotein (AAG) were measured at baseline. To investigate the risks of 5-year (early) and 5–9 year (late) mortality hazard ratios (HR) were evaluated using Cox models.
Results
In men, the early death risk was increased for high CRP and AAG and for low albumin and TTR. In women, early death was associated with high AAG, low TTR and cholesterol. For late death, the only significant association was with CRP in men. A synergistic effect was observed between biomarkers of inflammation and malnutrition. The adjusted HR of early death was 4.98(95% Confidence Interval(CI)= 2.25–11.01) for both CRP in the highest quartile and albumin in the lowest in men. This risk was increased for AAG in the highest quartile and TTR in the lowest in men and women with an HR of 6.86(95%CI= 3.20–14.71) and 4.64(95%CI= 1.79–12.05) respectively. Cancer mortality was increased for high CRP and AAG and for low albumin and TTR in men but not in women.
Conclusions
Biomarkers of inflammation and malnutrition together predict early mortality. In healthy elderly subjects TTR and AAG could be helpful in identifying elderly subjects at higher risk of death.
doi:10.1111/j.1532-5415.2008.01677.x
PMCID: PMC2683250  PMID: 18410327
Age Factors; Aged; Aged, 80 and over; C-Reactive Protein; metabolism; Cardiovascular Diseases; immunology; mortality; Cause of Death; Cholesterol; blood; Female; Follow-Up Studies; France; Health Surveys; Humans; Inflammation Mediators; blood; Male; Middle Aged; Neoplasms; immunology; mortality; Orosomucoid; metabolism; Prealbumin; metabolism; Proportional Hazards Models; Prospective Studies; Protein-Energy Malnutrition; diagnosis; immunology; mortality; Reference Values; Risk Assessment; Serum Albumin; metabolism; Sex Factors
24.  Thyroid Function and the Risk of Alzheimer’s Disease: The Framingham Study 
Archives of internal medicine  2008;168(14):1514-1520.
Background
Clinical hypo- and hyperthyroidism are recognized causes of reversible dementia but prior studies relating thyroid stimulating hormone (TSH) levels to cognitive performance in clinically euthyroid persons have yielded inconsistent results.
Methods
We related serum TSH concentrations measured at baseline (1977–79) to the risk of developing AD in 1,864 cognitively intact, clinically euthyroid Framingham Original cohort participants (mean age 71, 59% women). Sex-specific Cox models were constructed using tertiles of TSH (second tertile [T2] as referent) and adjusting for age, APOE ε4 allele status, education, plasma homocysteine, current smoking, body-mass index, prevalent stroke and atrial fibrillation.
Results
Over a follow-up period of 12.7 years (range 1 to 25 years), 209 subjects (142 women) developed AD. Women in the lowest (TSH <1.0 mU/L) and highest (TSH >2.10mU/L) tertiles of serum TSH concentrations were at increased risk of developing AD (multivariable-adjusted hazard Ratio [HR] 2.39, 95% confidence intervals [CI] 1.47–3.87; p<0.001, and 2.15, 95% CI 1.35–3.52; p=0.003, respectively) compared to those in the middle tertile. TSH levels were not related to AD risk in men. Analyses excluding subjects on thyroid supplementation did not significantly alter these relationships. In analyses limited to participants with serum TSH 0.1 – 10 mU/L, the U-shaped relations of TSH and AD risk was maintained in women but not when analyses were limited to those with TSH levels between 0.5 to 5.0 mU/L.
Conclusions
Both low and high TSH levels were associated with an increased risk of developing incident AD in women but not in men.
doi:10.1001/archinte.168.14.1514
PMCID: PMC2694610  PMID: 18663163
25.  Association of Biomarkers for Inflammation, Endothelial Dysfunction and Oxidative Stress with Cognitive Impairment. The Epidemiology of Hearing Loss Study (EHLS) 
Background
Individual biomarkers of inflammation, endothelial dysfunction and oxidative stress have been associated with cognitive impairment. This study explored whether a combination of biomarkers could prospectively identify those who developed cognitive decline.
Methods
Biomarkers were obtained during the baseline examination of the Beaver Dam Eye Study (1988–90), and cognitive status was assessed during the 5-year follow-up examination of the Epidemiology of Hearing Loss Study (1998–2000). Cognitive impairment was defined as a score of < 24 points on the Mini-Mental State Examination or self- or proxy report of Alzheimer Disease or dementia. Among those with cognitive data, interleukin-6, isoprostanes, protein carbonyl, soluble inter-cellular adhesion molecule-1 and vascular cell adhesion molecule-1 were available for 950 participants and 2,336 had high sensitivity C-reactive protein.
Results
Biomarkers of inflammation and endothelial dysfunction were not associated with cognitive impairment. There was a weak inverse association between higher levels of protein carbonyl content and cognitive impairment (OR, 0.8 per quartile of protein carbonyl content, p=0.045 unadjusted for multiple comparisons). This was not significant on multiple testing and may have been a chance finding.
Conclusion
We found that many markers of inflammation and endothelial dysfunction were not associated with cognitive impairment. An inverse association with carbonyl protein, a marker of oxidative stress needs further confirmation.
doi:10.5455/oams.031212.br.004
PMCID: PMC3693393  PMID: 23814681
oxidative stress; inflammation; biomarkers; cognitive impairment

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