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.
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).
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.
Depression is associated with an increased risk of dementia and AD in older men and women over 17 years of follow-up.
= 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.
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.
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.
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).
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.
= Alzheimer disease;
= body mass index;
= confidence interval;
= diastolic blood pressure;
= Diagnostic and Statistical Manual of Mental Disorders, 3rd edition, revised;
= hazard ratio.
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.
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.
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.
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.
apolipoprotein E; obesity; metabolic traits; stress; epidemiology; gene-environment interaction
Epidemiologic and laboratory studies suggest that non-steroidal anti-inflammatory drugs (NSAIDs) reduce risk of Alzheimer dementia (AD). We therefore investigated the association between use of NSAIDs, aspirin, and the non-NSAID analgesic acetaminophen with incidence of dementia and AD.
Participants in the Cardiovascular Health Cognition Study included 3,229 individuals aged 65 or older, free of dementia at baseline, with information on medication use. We used Cox proportional hazards regression to estimate the association of medication use with incident all-cause dementia, AD, and vascular dementia (VaD). Additional analyses considered the NSAID-AD relationship as a function of age, presence of at least one ε4 allele at APOE, race, and individual NSAIDs' reported ability to reduce production of the amyloid-beta peptide variant Aβ42.
Use of NSAIDs was associated with a lower risk of dementia (adjusted hazard ratio or aHR 0.76, 95% confidence interval or CI 0.60–0.96), and, in particular, AD (aHR 0.63, CI 0.45–0.88), but not VaD (aHR 0.92, CI 0.65–1.28). No similar trends were observed with acetaminophen (aHR 0.99, CI 0.79 - 1.24). Closer examination suggested AD risk reduction with NSAIDs only in participants having an APOE ε4 allele (aHR 0.34, CI 0.18–0.65; aHR for others 0.88, CI 0.59–1.32). There was no advantage in AD risk reduction with NSAIDs reported to selectively reduce Aβ42.
Results were consistent with previous cohort studies showing reduced risk of AD in NSAID users, but this association was found only in those with an APOE ε4 allele, and there was no advantage for Aβ42 lowering NSAIDs.
Previous studies have shown that high serum ceramides are associated with memory impairment and hippocampal volume loss, but have not examined dementia as an outcome. The aim of this study was to examine whether serum ceramides and sphingomyelins (SM) were associated with an increased risk of all-cause dementia and Alzheimer disease (AD).
Participants included 99 women without dementia aged 70–79, with baseline serum SM and ceramides, enrolled in a longitudinal population-based study and followed for up to 6 visits over 9 years. Baseline lipids, in tertiles, were examined in relation to all-cause dementia and AD using discrete time Cox proportional survival analysis. Lipids were analyzed using electrospray ionization tandem mass spectrometry.
Twenty-seven (27.3%) of the 99 women developed incident dementia. Of these, 18 (66.7%) were diagnosed with probable AD. Higher baseline serum ceramides, but not SM, were associated with an increased risk of AD; these relationships were stronger than with all-cause dementia. Compared to the lowest tertile, the middle and highest tertiles of ceramide d18:1–C16:0 were associated with a 10-fold (95% confidence interval [CI] 1.2–85.1) and 7.6-fold increased risk of AD (95% CI 0.9–62.1), respectively. The highest tertiles of ceramide d18:1–C24:0 (hazard ratio [HR] = 5.1, 95% CI 1.1–23.6) and lactosylceramide (HR = 9.8, 95% CI 1.2–80.1) were also associated with risk of AD. Total and high-density lipoprotein cholesterol and triglycerides were not associated with dementia or AD.
Results from this preliminary study suggest that particular species of serum ceramides are associated with incident AD and warrant continued examination in larger studies.
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.
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.
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.
Age-related memory disorders; aging; Alzheimer’s disease; cognition; dementia; hyperinsulinemia; insulin; vascular
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.
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.
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.
Both low and high TSH levels were associated with an increased risk of developing incident AD in women but not in men.
To determine whether malnutrition and inflammation biomarkers predict all-cause, cancer and cardiovascular mortality in healthy elderly subjects.
Population-based study, Sète, French Mediterranean coast.
553 men and 888 women aged 60+ years from the POLA (Pathologies Oculaires Liées à l’Age) cohort, free of known co-morbidities.
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.
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.
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.
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
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.
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.
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.
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.
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.
There is some evidence that mild Parkinsonian signs (MPS) are associated with increased risk of dementia, suggesting that MPS could be an early biomarker for dementia.
In a new cohort, to determine whether (1) baseline MPS are a predictor of incident dementia, (2) there is an interaction between MPS and other baseline risk factors for dementia (i.e., the presence of both together greatly elevates the risk of dementia).
In a prospective, longitudinal study of community-dwelling elders in northern Manhattan, NY, Parkinsonian signs were rated with an abbreviated Unified Parkinson’s Disease Rating Scale. Risk of incident dementia was assessed using Cox proportional hazards models.
There were 1,851 participants (mean follow-up = 3.7 years). Participants with baseline MPS were twice as likely to develop dementia as participants without MPS: 16.3% vs. 7.7%, unadjusted hazards ratio (HR)= 2.24 (p < 0.001), adjusted HR= 1.98 (p <0.001). MPS were divided into three subtypes: adjusted HRaxial dysfunction = 2.45 (p <0.001), adjusted HRtremor = 2.38 (p = 0.006), and adjusted HRrigidity = 1.16 (p = 0.58). When MPS were treated as a continuous variable, the adjusted HR = 1.15 (p = 0.001). There were no interactions between MPS and other baseline risk factors for dementia, including gender, education, race, family history of dementia, stroke, and APOE-e4.
Baseline MPS seem to be a predictor of incident dementia. These motor signs might therefore serve as a useful biomarker for emerging dementia.
mild parkinsonian signs; population; elderly; epidemiology; incident dementia; Alzheimer’s disease
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).
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).
Metabolic dysregulation, especially insulin resistance, was associated with lower brain volumes and executive function in a large, relatively healthy, middle-aged, community-based cohort.
Studies relating adiposity to dementia are conflicting. We explored the associations of body mass index (BMI) waist circumference (WC), and weight change to dementia, probable Alzheimer’s disease (AD), and dementia associated with stroke (DAS).
Persons without dementia were followed for 5 years; 893 persons had BMI, 907 persons had WC, and 709 persons had a second weight measurement. Dementia was ascertained using standard methods. Cox regression was used for analyses using follow-up as time-to-event, adjusting for demographics, and APOE-ɛ4.
Compared to persons in the first quartile of BMI, persons in the third quartile had a lower dementia and AD risk, and persons in the second quartile had a lower DAS risk. The association between BMI and dementia resembled a U-shape in those < 76 years, while dementia risk decreased with higher BMI in those ≥ 76 years. The 4th quartile of WC was related to a higher DAS risk in the whole sample, and to dementia and AD in persons < 76 years. Weight loss was related to a higher dementia and DAS risk, and weight gain was related to a higher DAS risk only.
The prospective association between adiposity and dementia differs depending on the anthropometric measure used and is modified by age. This may explain previous conflicting reports.
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.
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.
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.
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.
C-reactive protein; dementia; nonagenarian; serum; inflammation
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.
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.
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.
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.
oxidative stress; inflammation; biomarkers; cognitive impairment
Higher dietary intake and circulating levels of docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA) have been related to a reduced risk for dementia, but the pathways underlying this association remain unclear. We examined the cross-sectional relation of red blood cell (RBC) fatty acid levels to subclinical imaging and cognitive markers of dementia risk in a middle-aged to elderly community-based cohort.
We related RBC DHA and EPA levels in dementia-free Framingham Study participants (n = 1,575; 854 women, age 67 ± 9 years) to performance on cognitive tests and to volumetric brain MRI, with serial adjustments for age, sex, and education (model A, primary model), additionally for APOE ϵ4 and plasma homocysteine (model B), and also for physical activity and body mass index (model C), or for traditional vascular risk factors (model D).
Participants with RBC DHA levels in the lowest quartile (Q1) when compared to others (Q2–4) had lower total brain and greater white matter hyperintensity volumes (for model A: β ± SE = −0.49 ± 0.19; p = 0.009, and 0.12 ± 0.06; p = 0.049, respectively) with persistence of the association with total brain volume in multivariable analyses. Participants with lower DHA and ω-3 index (RBC DHA+EPA) levels (Q1 vs Q2–4) also had lower scores on tests of visual memory (β ± SE = −0.47 ± 0.18; p = 0.008), executive function (β ± SE = −0.07 ± 0.03; p = 0.004), and abstract thinking (β ± SE = −0.52 ± 0.18; p = 0.004) in model A, the results remaining significant in all models.
Lower RBC DHA levels are associated with smaller brain volumes and a “vascular” pattern of cognitive impairment even in persons free of clinical dementia.
To investigate the relation between retinopathy and the risk of dementia.
We investigated the associations between retinopathy and dementia and its subtypes Alzheimer disease (AD) and vascular dementia both cross-sectionally and prospectively in the Rotterdam Study, a large population-based cohort study. Digitized retinal images were available for 195 participants with prevalent dementia and 6,078 participants without dementia at baseline (1990–1993). Participants were reexamined in 1993–1994, 1997–1999, and 2002–2004 and were continuously monitored for development of dementia until January 1, 2007. Retinopathy was graded on fundus photographs and was defined as the presence of one or more dot/blot hemorrhages, microaneurysms, cotton wool spots, or evidence of laser treatment for retinopathy.
Retinopathy was associated with prevalent dementia (age and sex-adjusted odds ratio 2.04, 95% confidence interval [CI] 1.34–3.09). Results were similar for AD and vascular dementia. During a mean follow-up of 11.4 years, 735 participants developed incident dementia, of whom 583 had AD and 80 had vascular dementia. There was no association of retinopathy at baseline with the risk of incident dementia during follow-up (age- and sex-adjusted hazard ratio 1.15, 95% CI 0.88–1.48) or the risk of incident AD or vascular dementia.
Retinopathy is more prevalent in persons with dementia but is not associated with an increased risk of dementia over time.
Cognitive reserve is invoked to explain the protective effects of education and cognitively-stimulating activities against all-cause dementia and Alzheimer’s disease (AD). For non-native English speakers (n-NES), speaking English may be a cognitive activity associated with lower dementia risk. We hypothesized that n-NES have lower risk of incident dementia/AD and that educational level might modify this relationship. Participants took part in the Einstein Aging Study (Bronx, NY), a longitudinal study of aging and dementia. All (n = 1779) spoke fluent English and self-reported birthplace and whether English was their first language. n-NES additionally reported mother tongue, age of English acquisition, and current percentile-use of a non-English language. Nested Cox proportional hazards models progressively adjusted for gender, race, education, and immigrant and marital status estimated hazard ratios (HR) for incident dementia/AD as a function of n-NES status. 390 (22%) participants were n-NES. 126 incident dementia cases occurred during 4174 person-years of follow-up (median 1.44; range 0–16); 101 individuals met criteria for probable/possible AD. There was no statistically-significant association between n-NES status and incident dementia in the fully-adjusted model (HR 1.26; 95% CI 0.76–2.09; p = 0.36). Results were similar for AD. Stratification of education into three groups revealed increased risk of dementia for n-NES with ≥16 years of education (HR 3.97; 95% CI 1.62–9.75; p = 0.003). We conclude that n-NES status does not appear to have an independent protective effect against incident dementia/AD, and that n-NES status may contribute to risk of dementia in an education-dependent manner.
Cohort studies; dementia; incidence; multilingualism
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.
Geriatric Medicine; Epidemiology
Lipoprotein-associated phospholipase A2 (Lp-PLA2) is a circulating enzyme with pro-inflammatory and oxidative activities associated with cardiovascular disease and ischemic stroke. While high plasma Lp-PLA2 activity was reported as a risk factor for dementia in the Rotterdam study, no association between Lp-PLA2 mass and dementia or Alzheimer's disease (AD) was detected in the Framingham study. The objectives of the current study were to explore the relationship of plasma Lp-PLA2 activity with cognitive diagnoses (AD, amnestic mild cognitive impairment (aMCI), and cognitively healthy subjects), cardiovascular markers, cerebrospinal fluid (CSF) markers of AD, and apolipoprotein E (APOE) genotype.
Subjects with mild AD (n = 78) and aMCI (n = 59) were recruited from the Memory Clinic, University Hospital, Basel, Switzerland; cognitively healthy subjects (n = 66) were recruited from the community. Subjects underwent standardised medical, neurological, neuropsychological, imaging, genetic, blood and CSF evaluation. Differences in Lp-PLA2 activity between the cognitive diagnosis groups were tested with ANOVA and in multiple linear regression models with adjustment for covariates. Associations between Lp-PLA2 and markers of cardiovascular disease and AD were explored with Spearman's correlation coefficients.
There was no significant difference in plasma Lp-PLA2 activity between AD (197.1 (standard deviation, SD 38.4) nmol/min/ml) and controls (195.4 (SD 41.9)). Gender, statin use and low-density lipoprotein cholesterol (LDL) were independently associated with Lp-PLA2 activity in multiple regression models. Lp-PLA2 activity was correlated with LDL and inversely correlated with high-density lipoprotein (HDL). AD subjects with APOE-ε4 had higher Lp-PLA2 activity (207.9 (SD 41.2)) than AD subjects lacking APOE-ε4 (181.6 (SD 26.0), P = 0.003) although this was attenuated by adjustment for LDL (P = 0.09). No strong correlations were detected for Lp-PLA2 activity and CSF markers of AD.
Plasma Lp-PLA2 was not associated with a diagnosis of AD or aMCI in this cross-sectional study. The main clinical correlates of Lp-PLA2 activity in AD, aMCI and cognitively healthy subjects were variables associated with lipid metabolism.
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.
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.
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.
Our findings suggest that insulin metabolism influences the clinical manifestation of AD only within 3 years.
= Alzheimer disease;
= Diagnostic and Statistical Manual of Mental Disorders, 3rd edition, revised;
= high-density lipoprotein;
= homeostasis model assessment.
The APOE ∊4 allele is an established risk factor for Alzheimer's disease, but reports of its association with vascular dementia (VaD) have been inconsistent. We examined the relationship between APOE ∊4 allele and the risk of incident VaD in a large, population-based cohort of elderly adults with up to 10 years of follow-up between 1995 and 2005.
A total of 3,424 elderly men and women free of dementia were genotyped at the baseline assessment. Incident VaD was identified through standardized procedures administered at 3 follow-up assessments. Cox proportional hazards models were used to evaluate the risk of VaD associated with APOE ∊4.
The adjusted hazard ratio was 1.6 for the participants with 1 APOE ∊4 allele (95% CI: 0.9–2.7; p = 0.083) and 4.4 for those with 2 APOE ∊4 alleles (95% CI: 1.6–12.5; p = 0.005). The increased risk did not appear to be mediated by vascular risk factors.
The APOE ∊4 allele is associated with an increased risk of VaD in a dose-dependent fashion and accounts for almost 20% of VaD in the population.
APOE; Vascular dementia
Falls are a major cause of morbidity and mortality in dementia, but there have been no prospective studies of risk factors for falling specific to this patient population, and no successful falls intervention/prevention trials. This prospective study aimed to identify modifiable risk factors for falling in older people with mild to moderate dementia.
Methods and Findings
179 participants aged over 65 years were recruited from outpatient clinics in the UK (38 Alzheimer's disease (AD), 32 Vascular dementia (VAD), 30 Dementia with Lewy bodies (DLB), 40 Parkinson's disease with dementia (PDD), 39 healthy controls). A multifactorial assessment of baseline risk factors was performed and fall diaries were completed prospectively for 12 months. Dementia participants experienced nearly 8 times more incident falls (9118/1000 person-years) than controls (1023/1000 person-years; incidence density ratio: 7.58, 3.11–18.5). In dementia, significant univariate predictors of sustaining at least one fall included diagnosis of Lewy body disorder (proportional hazard ratio (HR) adjusted for age and sex: 3.33, 2.11–5.26), and history of falls in the preceding 12 months (HR: 2.52, 1.52–4.17). In multivariate analyses, significant potentially modifiable predictors were symptomatic orthostatic hypotension (HR: 2.13, 1.19–3.80), autonomic symptom score (HR per point 0–36: 1.055, 1.012–1.099), and Cornell depression score (HR per point 0–40: 1.053, 1.01–1.099). Higher levels of physical activity were protective (HR per point 0–9: 0.827, 0.716–0.956).
The management of symptomatic orthostatic hypotension, autonomic symptoms and depression, and the encouragement of physical activity may provide the core elements for the most fruitful strategy to reduce falls in people with dementia. Randomised controlled trials to assess such a strategy are a priority.