Metabolic syndrome and all-cause mortality in older men and women.

BACKGROUND: Prevalence of metabolic syndrome (MetS) increases with age, but its association with all-cause mortality in older persons remains uncertain. This study investigated the association of all-cause mortality with MetS and its individual components in older men and women. METHODS: A total of 917 men and 1043 women aged 65 years and older from two Italian population-based cohorts were included in the study. MetS was defined according to four different definitions: National Cholesterol Education Program (NCEP), NCEP revised according to the American Heart Association and National Heart Lung Blood Institute (NCEP-R), International Diabetes Organization (IDF) and Joint Interim Statement (JIS). All of these definitions include abdominal obesity, hyperglycaemia, hypertriglyceridaemia, low high-density lipoprotein cholesterol and hypertension. Hazard Ratios (HR) and their corresponding 95% confidence interval (95%CI) estimated from multivariable-adjusted Cox regression models were used to investigate the associations of all-cause mortality with baseline MetS status and individual MetS components. RESULTS: After 6·5 ± 1·8 years of follow-up, there were 179 deaths among women and 193 among men. Mortality risk was increased in women with MetS by any definition, regardless of individual components, but limited to age 70-79 years (NCEP, HR = 2·02, 95%CI, 1·16-3·53; NCEP-R, HR = 2·51, 95%CI, 1·45-4·34; IDF, HR = 2·16, 95%CI, 1·26-3·72; JIS, HR = 2·16, 95%CI, 1·26-3·72). Mortality risk of men was associated with hypertriglyceridaemia below age 70 years (HR = 2·50, 95%CI, 1·19-5·25), but unrelated to MetS status. CONCLUSIONS: Metabolic Syndrome is associated with all-cause mortality in older women but not in men. The association, however, is limited to a narrow age range.

Serum dehydroepiandrosterone sulfate and adverse health outcomes in older men and women.

Low serum dehydroepiandrosterone sulfate (DHEAS) is common in older persons with poor health. The geriatric syndrome of physical frailty is associated with a higher risk of developing fatal and nonfatal health outcomes. However, the association of DHEAS with frailty is uncertain. This study investigated the association of serum DHEAS with frailty and its related adverse outcomes in 416 men and 504 women aged ≥65 years from an Italian prospective population-based cohort study. At baseline, frailty status was defined according to the physical phenotype, and serum DHEAS was measured in a fasting venous blood sample. After 4 years, subjects were reassessed for incident frailty and occurrence of nonfatal frailty-related outcomes (hospital admission, nursing home placement, disability, falls, and fractures). All-cause mortality after 8 years was also recorded. Incident frailty was inversely associated with baseline log-transformed DHEAS in men (odds ratio [OR]=0.35, 95% confidence interval [CI] 0.14-0.88, p=0.026) but not in women. Independent of baseline frailty status, women in the lowest DHEAS quartile compared to the upper three quartiles had a higher risk of hospital admission (OR=0.44, 95% CI 0.21-0.91, p=0.027) and nursing home placement (OR=0.27, 95% CI 0.08-0.95, p=0.041). Baseline log-transformed serum DHEAS was also inversely associated with mortality risk, but limited to women with concurrent frailty (hazard ratio [HR]=0.27, 95% CI 0.11-0.68, p=0.005) or preexisting major diseases (HR=0.57, 95% CI 0.33-0.98, p=0.041). These findings suggest that DHEAS is associated with incident frailty in older men and with fatal and nonfatal frailty-related adverse outcomes in older women.

A comparison of frailty indexes for prediction of adverse health outcomes in an elderly cohort.

This study aimed to compare the predictive accuracy for several frailty-related adverse health outcomes of a cumulative index derived from the Italian population-based elderly cohort of the Conselice Study of Brain Aging (CSBA), which takes into account multiple different domains (demographic, clinical, functional, and nutritional parameters), with that of an index derived from the Study of Osteoporotic Fractures (SOF), modified for application to the CSBA database and henceforth called mSOF, which is exclusively focused on muscular fitness. Data are for 1007 CSBA participants aged ≥ 65 years. Investigated adverse outcomes included 4- and 7-year risk of death and 4-year risk of fractures, falls, disability, hospitalization, and nursing home placement. Accuracy for prediction of these outcomes was investigated using area under the curve (AUC) statistics. CSBA index performed better than mSOF index for prediction of mortality (p<0.001), hospitalization (p=0.002), and nursing home placement (p=0.049). For all outcomes excluding falls, frailty defined by CSBA index had a slightly lower specificity but a much higher sensitivity than frailty defined by mSOF Index. In conclusion, in this elderly cohort, the multidimensional CSBA index is a better predictor of frailty-related adverse health outcomes than the unidimensional mSOF index.

Serum thyroid-stimulating hormone as a predictor of cognitive impairment in an elderly cohort.

BACKGROUND: It is unclear whether in late life serum thyroid-stimulating hormone (TSH) predicts risk of developing cognitive impairment. OBJECTIVE: This study investigated the prospective relationship of serum TSH with the risk of developing mild cognitive impairment (MCI), Alzheimer's disease (AD) and vascular dementia (VaD) in an elderly cohort with a 4-year follow-up. METHODS: Data are for 660 subjects aged 65 years and older from an Italian population-based cohort who were cognitively normal at an extensive assessment in 1999/2000 and underwent follow-up assessment in 2003/2004. Serum TSH was measured at baseline. Multinomial logistic models adjusted for sociodemographic and cardiovascular risk factors were used to investigate the association of serum TSH (both as a tertile and continuous log-transformed variable) with risk of incident MCI, AD and VaD diagnosed according to international criteria. RESULTS: Over 3.8 ± 0.7 years of follow-up, there were 149 incident MCI cases (77 with impairment of memory and 72 with impairment of nonmemory domains) and 86 incident dementia cases (53 with AD, 28 with VaD). No association between baseline TSH and risk of developing any MCI subtype or AD was found. The highest TSH tertile had a threefold higher increased risk of VaD (OR: 3.25, 95% CI: 1.01-10.77, p = 0.048) compared to the lowest tertile. Risk of VaD increased about 60% for each 1 SD increase in log-transformed TSH (OR: 1.61, 95% CI: 1.06-2.44, p = 0.025). CONCLUSIONS: In this elderly cohort, baseline TSH was not related to the risk of developing MCI or AD, but high TSH was associated with an increased risk of VaD. These results suggest further need for research using larger samples to examine the role of TSH as a predictor of VaD and the role of thyroid autoimmunity in vascular cognitive impairment.

Evidence of the association of BIN1 and PICALM with the AD risk in contrasting European populations.

Recent genome-wide association studies have identified 5 loci (BIN1, CLU, CR1, EXOC3L2, and PICALM) as genetic determinants of Alzheimer's disease (AD). We attempted to confirm the association between these genes and the AD risk in 3 contrasting European populations (from Finland, Italy, and Spain). Because CLU and CR1 had already been analyzed in these populations, we restricted our investigation to BIN1, EXO2CL3, and PICALM. In a total of 2816 AD cases and 2706 controls, we unambiguously replicated the association of rs744373 (for BIN1) and rs541458 (for PICALM) polymorphisms with the AD risk (odds ratio [OR] = 1.26, 95% confidence interval [CI] [1.15-1.38], p = 2.9 × 10(-7), and OR = 0.80, 95% CI [0.74-0.88], p = 4.6 × 10(-7), respectively). In a meta-analysis, rs597668 (EXOC3L2) was also associated with the AD risk, albeit to a lesser extent (OR = 1.19, 95% CI [1.06-1.32], p = 2.0 × 10(-3)). However, this signal did not appear to be independent of APOE. In conclusion, we confirmed that BIN1 and PICALM are genetic determinants of AD, whereas the potential involvement of EXOC3L2 requires further investigation.

The conselice study of brain ageing.

Among the age-related diseases, the development of cognitive impairments, in particular dementia, is the most devastating for the individual and has great social and healthcare costs. Accurate information is needed about the prevalence and incidence of cognitive disorders and the physiology of the ageing brain. In particular, only scant data are available about the relationship between ageing, cognitive status and nutritional factors. In order to address these issues we planned the Conselice Study of Brain Ageing, a longitudinal study of physiologic and pathologic brain ageing. The center involved in the study was the municipality of Conselice, Ravenna province, in the Northern Italian region Emilia-Romagna. A total of 1016 subjects aged 65 and over was enrolled at baseline. Information about cognitive status at 4-years of follow-up was collected for 940 of them. These data have been used to estimate prevalence and incidence of dementia in the elderly Italian population and to investigate the possible role of baseline blood homocysteine as risk factors for dementia.

Multi factorial interactions in the pathogenesis pathway of Alzheimer's disease: a new risk charts for prevention of dementia.

BACKGROUND: The population longitudinal study named "The Conselice Study" has been the focus of the present investigation. 65 years old or older participants of this population study on brain aging were followed up for 5 years: 937 subjects completed the follow-up. Relationships of 46 genetic, phenotypic, clinical and nutritional factors on incident cognitive decline and incident dementia cases were investigated. RESULTS: A new statistical approach, called the Auto Contractive Map (AutoCM) was applied to find relationship between variables and a possible hierarchy in the relevance of each variable with incident dementia. This method, based on an artificial adaptive system, was able to define the association strength of each variable with all the others. Moreover, few variables resulted to be aggregation points in the variable connectivity map related to cognitive decline and dementia. Gene variants and cognate phenotypic variables showed differential degrees of relevance to brain aging and dementia. A risk map for age associated cognitive decline and dementia has been constructed and will be presented and discussed. CONCLUSION: This map of variables may be use to identify subjects with increased risk of developing cognitive decline end/or dementia and provide pivotal information for early intervention protocols for prevention of dementia.

The CALHM1 P86L polymorphism is a genetic modifier of age at onset in Alzheimer's disease: a meta-analysis study.

The only established genetic determinant of non-Mendelian forms of Alzheimer's disease (AD) is the ε4 allele of the apolipoprotein E gene (APOE). Recently, it has been reported that the P86L polymorphism of the calcium homeostasis modulator 1 gene (CALHM1) is associated with the risk of developing AD. In order to independently assess this association, we performed a meta-analysis of 7,873 AD cases and 13,274 controls of Caucasian origin (from a total of 24 centers in Belgium, Finland, France, Italy, Spain, Sweden, the UK, and the USA). Our results indicate that the CALHM1 P86L polymorphism is likely not a genetic determinant of AD but may modulate age of onset by interacting with the effect of the ε4 allele of the APOE gene.

Diagnostic performance of an Executive Clock Drawing Task (CLOX) as a screening test for mild cognitive impairment in elderly persons with cognitive complaints.

BACKGROUND: CLOX, a clock drawing test protocol uniquely sensitive to impairment of executive functions, has been proposed as a screening tool for mild cognitive impairment (MCI), but data about its diagnostic efficiency are lacking. METHODS: There are data for 196 subjects, age >or=60 years, referred to a memory clinic for cognitive complaints. After extensive neuropsychological testing, 64 were diagnosed as cognitively normal and 132 with MCI. RESULTS: At standard cutoffs, both CLOX subtests had a fair specificity (CLOX1 72%, CLOX2 92%) but unacceptably low values of sensitivity (CLOX1 54%, CLOX2 28%) and likelihood ratio (CLOX1 1.91, CLOX2 3.59) for MCI. The use of different cutoffs or the combination of CLOX with the Mini-Mental State Examination (MMSE) did not statistically increase diagnostic efficiency. CONCLUSION: CLOX, either alone or in combination with MMSE, is not a useful screening test for MCI in a clinical setting.

Metabolic syndrome and risk of dementia in older adults.

OBJECTIVES: To investigate the association between metabolic syndrome (MetS; a clustering of cardiovascular risk factors including abdominal obesity, hypertension, dyslipidemia, and hyperglycemia, each of which has been individually associated with dementia) and incident dementia, Alzheimer's disease (AD), and vascular dementia (VaD) in older adults before and after the age of 75. DESIGN: Prospective population-based cohort. SETTING: An Italian municipality. PARTICIPANTS: A community-based sample of 749 subjects aged 65 and older who, in 1999/2000, were free of cognitive impairment and, in 2003/04, underwent follow-up for incident dementia. MEASUREMENTS: The relationship between incident overall dementia, AD, and VaD and MetS. Dementia was defined according to the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition. MetS was defined according to the National Cholesterol Education Program criteria. RESULTS: Risk of overall dementia and its subtypes was not associated with MetS or any MetS component in participants younger than 75. In participants aged 75 and older, MetS was associated with a lower risk of AD (hazard ratio (HR)=0.33, 95% confidence interval (CI)=0.12-0.94) but not of VaD, and abdominal obesity was associated with a lower risk of overall dementia (HR=0.53, 95% CI=0.28-0.98). CONCLUSION: MetS measured in late life is not associated with risk of dementia. After age 75, persons with MetS may even be at lower risk for AD.

Blood inflammatory proteins and risk of incident depression in the elderly.

BACKGROUND: It is unclear whether high levels of blood inflammatory proteins are associated with the risk of developing depression in late life. METHODS: Blood C-reactive protein, interleukin (IL)-6, 1 -antichymotrypsin (ACT), intercellular adhesion molecule 1, and tumor necrosis factor were measured in an elderly cohort (n = 968). Major depression diagnosed according to clinical criteria and relevant depressive symptoms measured by the Geriatric Depression Scale (score 6 10) were assessed at baseline and 4 year later. RESULTS: Baseline IL-6 and ACT were increased in both prevalent major depression and relevant depressive symptoms. Baseline ACT was increased in incident major depression. All associations weakened below significance after adjustment for possible confounders and multiple comparisons. CONCLUSIONS: Blood inflammatory proteins do not predict the risk of developing depression in older age.

Blood homocysteine and risk of depression in the elderly.

We studied whether increased blood homocysteine is a predictor for incident depression in a population-based cohort aged >or=65. A total of 240 men and 217 women were identified at baseline and were assessed 4 years later for depression (Geriatric Depression Scale, GDS >or=10 or use of antidepressants). Risk of incident depression was estimated for the highest gender-specific tertile of baseline plasma homocysteine compared to the other tertiles combined in a reference group. As deficiencies of B(12) and folate are the main determinant of increased blood homocysteine in old age, serum concentrations of these vitamins were also measured. In women only, the highest homocysteine tertile was associated with incident depression. However, women with combined serum B(12)/folate deficiency had the highest blood homocysteine but also a lower depression risk than vitamin-replete women. In conclusion, the data only moderately support the hypothesis that blood homocysteine is a predictor of depression.

Multivariable network associated with cognitive decline and dementia.

Data mining of a large data base from the population longitudinal study named "The Conselice Study" has been the focus of the present investigation. Initially, 65 years old or older participants were interviewed, underwent medical and cognitive examination, and were followed up for 5 years: 937 subjects completed the follow-up. Relationships of 35 genetic and/or phenotypic factors with incident cognitive decline and dementia were investigated. The new mathematical approach, called the Auto Contractive Map (AutoCM), was able to show the differential importance of each variables. This new variable processing created a semantic connectivity map that: (a) preserved non-linear associations; (b) showed connection schemes; (c) captured the complex dynamics of adaptive interactions. This method, based on an artificial adaptive system, was able to define the association strength of each variable with all the others. Few variables resulted to be aggregation points and were considered as major biological hubs. Three hubs were identified in the hydroxyl-methyl-gutaryl-CoA reductase (HMGCR) enzyme, plasma cholesterol levels and age. Gene variants and cognate phenotypic variables showed differential degrees of relevance to brain aging and dementia. This data analysis method was compared with another mathematical model called mutual information relevance network and results are presented and discussed.

Prevalent depressive symptoms as a risk factor for conversion to mild cognitive impairment in an elderly Italian cohort.

OBJECTIVE: To examine the association between depressive symptoms and prevalent and incident mild cognitive impairment (MCI) in elderly individuals; to verify whether it is affected by MCI subtype. DESIGN: Prospective, population-based, longitudinal cohort study. SETTING: Adults >or=65 years resident in an Italian municipality. PARTICIPANTS: Baseline data are for 595 subjects with no cognitive impairment (NCI) and 72 subjects with prevalent MCI. NCI subjects underwent a 4-year follow-up for incident MCI. MEASUREMENTS: MCI was diagnosed according to international criteria and classified as with (m + MCI) or without memory impairment (m - MCI). Baseline depressive symptoms were measured using the 30-item Geriatric Depression Scale (GDS). Baseline use of antidepressants was also recorded. RESULTS: Baseline depressive symptoms (GDS >or=10) were more frequent in prevalent MCI cases (44.4%) than in NCI participants (18.3%). The association was independent of MCI subtype, antidepressant use, and sociodemographic and vascular risk factors. In NCI subjects, baseline depressive symptoms were also associated with increased risk of MCI at follow-up, but only for subjects on antidepressant drugs at baseline (incident cases = 72.7%) compared with those without depressive symptoms and not on antidepressant therapy (incident cases = 24.0%). The association was independent of other confounders and stronger for m - MCI (incident cases = 45.4%) with respect to m + MCI (incident cases = 27.3%). CONCLUSIONS: Depressive symptoms are highly prevalent among elderly MCI subjects and, in cognitively normal elderly individuals, are associated with an increased risk of developing MCI. The association is stronger for the MCI subtype without memory impairment.

Plasma tocopherols and risk of cognitive impairment in an elderly Italian cohort.

BACKGROUND: Evidence that vitamin E may preserve cognitive function in elderly subjects is conflicting. The most abundant and most investigated form of vitamin E in humans is alpha-tocopherol, but other antioxidant tocopherols (beta, gamma, and delta) exist in nature. OBJECTIVE: We aimed to investigate plasma concentrations of the natural tocopherols and the tocopherol oxidation markers alpha-tocopherylquinone (alphaTQ) and 5-nitro-gamma-tocopherol (5NGT) in relation to cognitive function in the elderly. DESIGN: Baseline plasma tocopherols and their oxidation markers were measured in 761 elderly Italian subjects from a population-based cohort assessed in 1999-2000 for mild cognitive impairment (MCI) and dementia. In 2003-2004, information about cognitive status was collected for 615 of the 666 subjects without baseline cognitive impairment. Tocopherols and oxidation markers were analyzed as plasma absolute values divided by serum total cholesterol because lipids affect their blood availability. Analyses were adjusted for sociodemographic, genetic, lifestyle, and medical confounders. RESULTS: Compared with the corresponding lowest tertile, the risk of prevalent dementia was higher for the highest tertile of delta-tocopherol/cholesterol [odds ratio (OR): 3.87; 95% CI: 1.46, 10.27] and alphaTQ/cholesterol (4.02; 1.45, 11.14), but the risk of incident dementia was not directly associated with plasma vitamin E metabolites. A U-shaped association, with lower risk for intermediate tertiles, was found for prevalent MCI with 5NGT/cholesterol (0.39; 0.17, 0.91) and for incident dementia with gamma-tocopherol/cholesterol (hazard ratio: 0.42; 95% CI: 0.22, 0.84). CONCLUSIONS: Plasma concentrations of some non-alpha-tocopherol forms of vitamin E are associated with cognitive impairment in elderly people. However, the associations depend on concurrent cholesterol concentration and need further investigation.

Development of an easy prognostic score for frailty outcomes in the aged.

BACKGROUND: identification of frailty is recommended in geriatric practice. However, there is a lack of frailty scores combining easy-to-collect predictors from multiple domains. OBJECTIVE: to develop a frailty score including only self-reported information and easy-to-perform standardised measurements recommended in routine geriatric practice. DESIGN: prospective population-based study. SETTING/PARTICIPANTS: included 1,007 Italian subjects aged 65 and over. MEASUREMENTS: seventeen baseline possible mortality predictors from several domains, 4-year risk of mortality and other adverse health outcomes associated with frailty [fractures, hospitalisation, and new and worsening activities of daily living (ADL) disability]. METHODS: a multivariate Cox model was used to identify the best sub-group of independent predictors and to develop a mortality prognostic score, defined as the number of adverse predictors present. Logistic regression was used to verify whether the score also predicted risk of other frailty outcomes in the cohort survivors. RESULTS: nine independent mortality predictors were identified. Among subjects with score > or =3, each one point increase in the score was associated with a doubling in mortality risk and, among survivors, with an increased risk of all the other adverse health outcomes. CONCLUSIONS: nine easy-to-collect predictors may identify aged people at increased risk of adverse health outcomes associated with frailty.

Mild cognitive impairment: epidemiology and dementia risk in an elderly Italian population.

OBJECTIVES: To investigate prevalence and incidence of mild cognitive impairment (MCI) and its risk of progression to dementia in an elderly Italian population. DESIGN: Longitudinal. SETTING: Population-based cohort aged 65 and older resident in an Italian municipality. PARTICIPANTS: A total of 1,016 subjects underwent baseline evaluation in 1999/2000. In 2003/04, information about cognitive outcome was collected for 745 participants who were free of dementia at baseline. MEASUREMENTS: MCI (classified as with or without impairment of the memory domain), dementia, Alzheimer's dementia (AD), and vascular dementia (VaD) diagnosed according to current international criteria. RESULTS: Overall prevalence of MCI was 7.7% (95% confidence interval (CI)=6.1-9.7 %) and was greater with older age and poor education. During 4 years of follow-up, 155 incident MCI cases were diagnosed, with an incidence rate of 76.8 (95% CI=66.8-88.4) per 1,000 person-years. Approximately half of prevalent and incident MCI cases had memory impairment. Compared with normal cognition, multivariable-adjusted risk for progression from MCI with memory impairment to dementia was 4.78 (95% CI=2.78-8.07) for any dementia, 5.92 (95% CI=3.20-10.91) for AD, and 1.61 (95% CI=0.37-7.00) for VaD. No association with dementia risk was found for MCI without memory impairment. Approximately one-third of MCI cases with memory impairment did not progress to dementia. CONCLUSION: MCI occurs often in this elderly Italian cohort and is associated with greater risk of AD, but only when the impairment involves the memory domain. However, a substantial proportion of MCI cases with memory impairment do not progress to dementia.

Endogenous sex hormones as risk factors for dementia in elderly men and women.

BACKGROUND: The associations of endogenous sex hormones with risk of dementia in the elderly population are not well known. METHODS: The relationship of baseline serum total estradiol (E2) and free testosterone (FT) to 4-year risk of all-cause dementia, Alzheimer's disease (AD), and vascular dementia (VaD) was examined in a dementia-free, population-based cohort of 433 women (mean age 74 years) and 376 men (mean age 73 years). Multivariable proportional hazards regression was used to adjust for sociodemographic and lifestyle variables, body mass index, apolipoprotein E genotype, cardiovascular conditions, and homocysteinemia. RESULTS: Dementia developed in 71 women (46 AD, 21 VaD) and 39 men (23 AD, 12 VaD). In women with high E2 (serum E2 >or= 10 pg/mL), the multivariable-adjusted hazard ratio (HR) for dementia was 1.75 (95% confidence interval [CI], 1.06-2.89). The corresponding multivariable-adjusted HR for AD was 1.94 (95% CI, 1.04-3.61), whereas no association was found for VaD. No association with dementia was found for serum FT in women and for either serum E2 or FT in men. CONCLUSION: High serum E2 is an independent predictor for dementia and AD in elderly women.

Blood inflammatory markers and risk of dementia: The Conselice Study of Brain Aging.

Incidence studies of blood inflammatory markers as predictors of dementia in older age are few and did not take into account hyperhomocysteinemia, although this condition is associated with both inflammation and increased risk of dementia. We investigated the relationships of baseline serum C-reactive protein (CRP), serum interleukin 6 (IL6), plasma alpha-1-antichymotrypsin, and hyperhomocysteinemia (defined as plasma total homocysteine>15 micromol/L) with risk of incident Alzheimer's disease (AD) and vascular dementia (VaD) in a dementia-free Italian population-based elderly cohort (n=804, 53.2% women, mean age 74 years) with 4 years of follow-up. No inflammatory marker, alone or in combination, predicted AD risk whereas the combination of high CRP and high IL6 was associated with risk of VaD (HR, 2.56; 95%CI, 1.21-5.50) independently of socio-demographic confounders, traditional risk factors and hyperhomocysteinemia. By contrast, in the same model, hyperhomocysteinemia was independently associated with AD (HR, 1.91; 95%CI, 1.02-3.56) but not VaD risk. Blood inflammatory markers are associated with increased VaD risk but do not predict AD, which seems selectively associated with hyperhomocysteinemia.

Apolipoprotein E e4 allele affects risk of hyperhomocysteinemia in the elderly.

BACKGROUND: Apolipoprotein E (APOE) plays a central role in VLDL metabolism. Both APOE e4 allele (APOE4) and C-reactive protein (CRP) are associated with greater risk of dementia and vascular disease, but APOE4 carriers have lower blood concentrations of CRP than do noncarriers, possibly through a mechanism favoring the clearance of the CRP VLDL-bound fraction. Homocysteine, another risk factor for vascular disease and dementia, also binds to VLDL in blood. However, the association between APOE4 and hyperhomocysteinemia has never been thoroughly investigated. OBJECTIVE: We investigated in an elderly population whether 1) APOE4 is associated with hyperhomocysteinemia [plasma total homocysteine (tHcy) > 15 micromol/L], 2) hyperhomocysteinemia affects the association between APOE4 and high CRP (serum CRP > 3 mg/L), and 3) B vitamin status affects these associations. DESIGN: APOE4 genotypes were assessed and tHcy, CRP, and serum concentrations of folate and vitamin B-12 were measured in 671 cognitively healthy subjects (52% women; mean age: 73 y) from an Italian population-based prospective cohort study. RESULTS: APOE4 carriers without high CRP [multivariate-adjusted odds ratio (OR): 0.22; 95% CI: 0.08, 0.59] had a lower risk of hyperhomocysteinemia than did noncarriers. The risk of high CRP was lower in APOE4 carriers without hyperhomocysteinemia (multivariate-adjusted OR: 0.51; 95% CI: 0.31, 0.85) than in noncarriers. The associations were not affected by B vitamin status. CONCLUSION: Independently from B vitamin status, APOE4 carriers have a lower risk of hyperhomocysteinemia and of high CRP than do noncarriers, but the presence of one condition attenuates the association of APOE4 with the other condition.