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ObjectiveTo determine changes in the incidence of dementia between 1988 and 2015.MethodsThis analysis was performed in aggregated data from individuals >65 years of age in 7 population-based cohort studies in the United States and Europe from the Alzheimer Cohort Consortium. First, we calculated age- and sex-specific incidence rates for all-cause dementia, and then defined nonoverlapping 5-year epochs within each study to determine trends in incidence. Estimates of change per 10-year interval were pooled and results are presented combined and stratified by sex.ResultsOf 49,202 individuals, 4,253 (8.6%) developed dementia. The incidence rate of dementia increased with age, similarly for women and men, ranging from about 4 per 1,000 person-years in individuals aged 65–69 years to 65 per 1,000 person-years for those aged 85–89 years. The incidence rate of dementia declined by 13% per calendar decade (95% confidence interval [CI], 7%–19%), consistently across studies, and somewhat more pronouncedly in men than in women (24% [95% CI 14%–32%] vs 8% [0%–15%]).ConclusionThe incidence rate of dementia in Europe and North America has declined by 13% per decade over the past 25 years, consistently across studies. Incidence is similar for men and women, although declines were somewhat more profound in men. These observations call for sustained efforts to finding the causes for this decline, as well as determining their validity in geographically and ethnically diverse populations.

Objectives: We examined the cross-sectional association between lipid fractions and 2 MRI markers of cerebral small vessel disease, white matter hyperintensity volume (WMHV) and lacunes, representing powerful predictors of stroke and dementia. Methods: The study sample comprised 2,608 participants from the 3C-Dijon Study (n = 1,842) and the Epidemiology of Vascular Aging Study (EVA) (n = 766), 2 large French population-based cohorts (72.8 ± 4.1 and 68.9 ± 3.0 years; 60.1% and 58.4% women, respectively). Analyses were performed separately in each study and combined using inverse variance meta-analysis. Lipid fractions (triglycerides, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol) were studied as continuous variables. WMHV was studied both in a continuous and dichotomous manner, the latter reflecting the age-specific top quartile of WMHV (EXT-WMHV). Analyses were adjusted for age and sex. Results: Increasing triglycerides were associated with larger WMHV in the 3C-Dijon Study (β ± SE = 0.0882 ± 0.0302, p = 0.0035), in the EVA Study (β ± SE = 0.1062 ± 0.0461, p = 0.021), and in the combined analysis (β ± SE = 0.0936 ± 0.0252, p = 0.0002) and with higher frequency of lacunes in the 3C-Dijon Study (odds ratio [OR] = 1.65 [95% confidence interval 1.10–2.48], p = 0.015), in the EVA Study (OR = 1.58 [95% confidence interval 0.93–2.70], p = 0.09), and in the combined analysis (OR = 1.63 [95% confidence interval 1.18–2.25], p = 0.003). Associations were attenuated but maintained after adjusting for other vascular risk factors or for inflammatory markers. Associations were present and in the same direction both in participants taking and those not taking lipid-lowering drugs but tended to be stronger in the former for EXT-WMHV. Increasing low-density lipoprotein cholesterol tended to be associated with a decreased frequency and severity of all MRI markers of cerebral small vessel disease in both studies. Conclusions: Increasing triglycerides but not other lipid fractions were associated with MRI markers of cerebral small vessel disease in older community persons.

Objective: Longitudinal studies of dementia rely on the assumption that individuals who drop out are comparable to those who remain in the study, adjusting for measured covariates. Existing methods to handle dropouts account for differences based on past health and cognitive measures. We assess whether such adjustments fully account for differences in future dementia risk. Methods: Among Three-City Study participants in Dijon, France, with 1 (n = 1,633) or 2 (n = 1,168) brain MRI scans, we tested whether white matter lesion volume (WMLV), hippocampal volume, or brain CSF volume predicted dropout (“unable to contact” or “refused interview”) in repeated-measures logistic regression with up to 4 follow-ups (average 3.5 waves). Using linear regression, we also estimated differences in MRI volumes and MRI changes by subsequent dropout status and estimated plausible ranges for selective attrition bias based on these associations. Models were adjusted for demographic, health, and cognitive score covariates. Results: Baseline greater WMLV predicted increased odds of dropping out (adjusted odds ratio = 1.71; 95% confidence interval [CI] 1.20−2.43). Among participants with 2 MRI scans, individuals who subsequently dropped out had significantly worse declines in hippocampal volume (−0.30 SD difference; 95% CI −0.43 to −0.17) between the first and second MRI scans. Conclusions: Higher future dementia risk, indicated by worse past brain MRI findings, predicted future study dropout. Adjustment for selective attrition, based on MRI markers when available, may help reduce bias in estimates of dementia incidence and improve research on dementia risk factors. MRI findings may also help prospectively identify cohort members at elevated risk of attrition.

Objective: The relation between inflammation and brain MRI findings in the elderly remains poorly known. We investigated the association of circulating interleukin-6 (IL-6) and C-reactive protein (CRP) levels with baseline and longitudinal white matter hyperintensities (WMH), silent brain infarction, and brain volumes in community-dwelling elderly free of dementia. Methods: We included 1,841 participants aged 65 to 80 years from the Three City-Dijon cohort. Participants followed an MRI examination at baseline and after a 4-year follow-up (n = 1,316). IL-6 and CRP concentrations were measured at baseline from fasting blood samples. WMH were detected with an automatic imaging processing method and gray matter, hippocampal, white matter, and CSF volumes were estimated with voxel-based morphometry. Silent brain infarctions were assessed visually and defined as focal lesions of ≥3 mm in the absence of stroke. We used analysis of covariance and logistic regression to model the associations between inflammatory biomarkers and brain MRI findings adjusting for potential confounders. Results: In cross-sectional analyses, higher IL-6 levels were associated with higher WMH volumes ( p p = 0.001) and hippocampal ( p = 0.01) volumes, and increasing CSF volumes ( p = 0.002) in a dose-relationship pattern. Similar but weaker relations were observed for CRP. We observed no associations between baseline inflammatory biomarker levels and the evolution of MRI findings over 4 years. Conclusions: IL-6, and, to a lesser degree, CRP levels were associated with WMH severity as well as global markers of brain atrophy. These results suggest that an inflammatory process may be involved in both age-associated brain alterations.

Objectives: We examined the relationship between self-rated health and incident dementia, and investigated the impact of cognitive complaints, depressive symptoms, and functional status on this relationship. Methods: Participants of the 3C Study, a prospective cohort study composed of 8,169 community-dwelling persons aged ≥65 years, were asked to rate their health at the baseline examination in 1999–2001. They were followed for a median of 6.7 years during which dementia was screened and diagnosed. Hazard ratios (HR) of dementia according to baseline self-rated health (good, fair, or poor) were estimated with a Cox model adjusted for potential confounders. Results: During the 46,990 person-years of follow-up, 618 participants developed dementia. Risk of dementia was increased in participants with poor (adjusted HR 1.70, 95% confidence interval [CI] 1.22–2.37) or fair (adjusted HR 1.34, 95% CI 1.13–1.59) self-rated health compared to those with good self-rated health. Poor self-rated health was associated with both AD (1.48, 1.00–2.24) and vascular dementia (3.38, 1.25–9.17). Self-rated health was a stronger predictor of dementia in participants without cognitive complaints (risk of dementia in subjects without cognitive complaints rating their health as poor: 1.96 [1.24–3.09], p = 0.004) and in those without functional disability. Conclusions: Participants rating their health as poor or fair at baseline were at increased risk of incident dementia during follow-up. Self-rated health could help raise awareness of medical doctors about a patient9s risk of dementia, especially in those without conditions indicative of potential cognitive impairment.

Objective: To investigate the relationship between baseline hypertension and severity of white matter hyperintensities (WMH) at 4-year follow-up in a sample of subjects aged 59 to 71 years old at entry.Methods: Subjects were participants in the Epidemiology of Vascular Ageing study, a longitudinal study on vascular aging and cognitive decline. At 4-year follow-up, 845 subjects had a cerebral MRI. MRI examinations were read by a single rater to determine the severity of WMH, ranging from absent to severe. Hypertension at each wave of the study was defined as systolic blood pressure ≥160 mm Hg, diastolic blood pressure ≥95 mm Hg, or use of antihypertensive medication.Results: Hypertension at baseline was significantly associated with an increased risk of having severe WMH at 4-year follow-up. When taking into account both blood pressure levels and antihypertensive drug intake, analysis showed that the risk of having severe WMH was significantly reduced in subjects with normal blood pressure taking antihypertensive medication compared with those with high blood pressure taking antihypertensive agents. Cross-sectional relationships between hypertension and WMH at 4-year follow-up showed that the frequency of severe WMH was significantly higher in people who were hypertensive at both baseline and 4-year follow-up than those who were hypertensive only at 4-year follow-up.Conclusions: Hypertension is a major risk factor for severe WMH. Subjects taking antihypertensive drugs and who have controlled blood pressure had a reduced risk of severe WMH. Longitudinal studies are needed to investigate whether reduction of the development of WMH, by treatment and prevention of hypertension, might reduce the subsequent risk of cognitive deterioration or stroke.

Objective: To report the percentile distribution of Mini-Mental State Examination (MMSE) scores in older people by age, sex, and education level, estimated from longitudinal data, after correcting for loss due to dropout. Methods: The Cambridge City over 75 Cohort is a population-based study of a cohort of 2106 subjects age 75 years and older at study entry followed up over 9 years. At each of the four waves, cognitive function was assessed using MMSE. Based on these data, the relationship between age and MMSE score was modeled. Percentile distributions by age, sex, and education level were provided using inverse probability weighting to correct for dropouts. Results: Performance on MMSE was related to age in men and women. In women, at age 75, MMSE score ranged from 21 (10th percentile) to 29 (90th percentile). At age 95, the range was 10 (10th percentile) to 27 (90th percentile). The upper end of MMSE distribution was slightly modified with age, whereas the lower end of the distribution was very sensitive to age effect. A similar pattern was observed in both sexes. Conclusion: These findings provide norms for MMSE scores in subjects age 75 years and older from longitudinal population-based data. Such norms can be used as reference values to determine where an individual’s score lies in relation to his or her age, sex, and education level.

Objective: The frequency and impact of apathy in subcortical ischemic vascular dementia (SIVD) remain undetermined. The frequency, clinical, neuropsychological, and imaging correlates of apathy were assessed in a large cohort of patients with cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy, a genetic model of SIVD. Methods: Apathy was diagnosed based on Neuropsychiatric Inventory assessment. Degree of disability was assessed by modified Rankin scale, cognitive impairment by Mattis Dementia Rating Scale (MDRS) and Mini-Mental State Examination (MMSE), autonomy by the Instrumental Activities of Daily Living (IADL) scale, and quality of life by SEP-59 self-questionnaire. Validated imaging methods were used to determine the total burden of cerebral lesions. Results: Among 132 patients, 54 (41%) were apathetic. Apathetic patients were older than nonapathetic subjects, had a lower MMSE and MDRS score, had more global disability, and were more limited in IADL. Apathetic patients were more frequently depressed compared to nonapathetic patients and more frequently presented additional neuropsychiatric symptoms. Multiple regression modeling showed a significant and independent association between apathy and a lower score of overall quality of life and between apathy and a higher load of white matter and lacunar lesions. Conclusions: The results suggest that apathy is common in cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), appears in association with cognitive impairment, global functional disability, and severe neuropsychiatric symptoms during the course of the disease, and can occur separately from depression. Apathy has an independent impact on the overall quality of life in CADASIL. CADASIL = cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy; DSM-IV = Diagnostic and Statistical Manual of Mental Disorders, 4th edition; IADL = Instrumental Activities of Daily Living; ICC = intracranial cavity; LL = lacunar lesions; MDRS = Mattis Dementia Rating Scale; MMSE = Mini-Mental State Examination; mRS = modified Rankin scale; NA = not applicable because of insufficient observations; nCM = number of cerebral microhemorrhages; nLL = normalized volume of lacunar lesions; NPI = Neuropsychiatric Inventory; nWMH = normalized volume of white matter hyperintensities; QOL = quality of life; SIVD = subcortical ischemic vascular dementia; TIA = transient ischemic attack; WMH = white matter hyperintensities.

International audience; OBJECTIVE: To examine the association of plasma cholesterol levels, lipid-lowering agent (LLA) intake, and APOE genotype with dementia prevalence. METHODS: The Three-City Study is a population-based cohort of 9,294 subjects selected from the electoral rolls of three French cities (Bordeaux, Dijon, Montpellier). Baseline examination included extensive assessment of exposure to vascular risk factors (including cholesterol levels and LLA use [statin or fibrate]) and clinical diagnosis of dementia. RESULTS: Two percent of participants were demented at baseline. Overall 32.4% of participants had hyperlipidemia, and 15.6% were prescribed statins and 13.7% fibrates. After adjusting for age, gender, education level, and study center, the odds ratio (OR) for dementia was observed to be lower among LLA users (OR = 0.61, 95% CI = 0.41 to 0.91) compared with subjects taking no LLAs. There was no differential effect between statin and fibrate users. The odds for dementia were increased in subjects with hyperlipidemia (OR = 1.43, 95% CI = 1.03 to 1.99). Further adjustment for potential confounders did not modify these associations. In addition, the association between LLA intake and dementia was not modified by APOE genotype, whereas hyperlipidemia was significantly associated with increased dementia prevalence only in non-epsilon4 carriers and non-Alzheimer disease cases. Finally, in participants taking LLAs, the odds for dementia were decreased only in those having normal lipid levels. CONCLUSIONS: This observational study provides further evidence that lipid-lowering agents are associated with decreased risk of dementia, whereas hyperlipidemia is associated with increased odds for non-Alzheimer-disease-type dementia. These effects appear to be independent of all major potential confounders.

Objective: To test the hypothesis that education level modulates the effects of cerebral white matter hyperintensities (WMH) on cognition in a large population-based study. Methods: A total of 845 elderly subjects aged 64 to 76 years who enrolled in a longitudinal study on cognitive decline and vascular aging had an MRI examination. Cognitive functions were assessed by Mini-Mental State Examination, Trail Making Test Part B, Digit Symbol Substitution Test of the Wechsler Adult Intelligence Scale–Revised, Finger Tapping Test, Word Fluency Test, and Raven Progressive Matrix. MRI scans were interpreted visually using a standardized scale for rating WMH. Results: Severe WMH were present in 17% of the participants who had lower performances on tests involving attention tasks. In participants with a lower level of education, presence of severe WMH was significantly associated with lower cognitive performances. This was found for all cognitive tests. Conversely, in participants with a high level of education, there was no significant association between severity of WMH and level of cognitive functions. Conclusion: Education modulates the consequences of WMH on cognition. Participants with a high level of education were protected against the cognitive deterioration related to vascular insults of the brain.

Background: Little is known about the role of the prion protein (PrPsen/gene PRNP). PRNP knockout mice studies suggest that PrPsen may be involved in CNS degeneration. This observation prompted us to examine the influence of PRNP genetic variability on cognitive abilities in the elderly.Methods: In a community-based sample of 1,163 subjects aged 59 to 71 years, we characterized the valine (Val) and methionine (Met) allele of the PRNP polymorphism at codon 129. The effect of this polymorphism was estimated on the Mini-Mental State Examination (MMSE) and on a global composite score built from a battery of nine different neuropsychological tests. The results were adjusted for age, gender, education, and apolipoprotein E (apoE) polymorphism.Results: Cognitive impairment (MMSE score < 24) was present in 2.5% of the Met-Met individuals, 2.9% of the Met-Val individuals, and 7.0% of Val-Val subjects (p = 0.02). Subjects homozygous for the PRNP Val allele had a lower MMSE and global score than the two other genotypes (p< 0.003). This effect was of the same magnitude as that of the apoEϵ4 allele on cognitive performances. Both apoE ϵ4 and PRNP Val allelic effects were additive.Conclusion: This observation suggests that variability of the PRNP locus may be associated with cognitive performance in the elderly. This result, if confirmed, offers potential clues for the role of PRNP in the human brain.