Performing exome sequencing in 14 autosomal dominant early-onset Alzheimer disease (ADEOAD) index cases without mutation on known genes (amyloid precursor protein (APP), presenilin1 (PSEN1) and ...presenilin2 (PSEN2)), we found that in five patients, the SORL1 gene harbored unknown nonsense (n=1) or missense (n=4) mutations. These mutations were not retrieved in 1500 controls of same ethnic origin. In a replication sample, including 15 ADEOAD cases, 2 unknown non-synonymous mutations (1 missense, 1 nonsense) were retrieved, thus yielding to a total of 7/29 unknown mutations in the combined sample. Using in silico predictions, we conclude that these seven private mutations are likely to have a pathogenic effect. SORL1 encodes the Sortilin-related receptor LR11/SorLA, a protein involved in the control of amyloid beta peptide production. Our results suggest that besides the involvement of the APP and PSEN genes, further genetic heterogeneity, involving another gene of the same pathway is present in ADEOAD.
Objective
To determine whether premature menopause (≤40 years) can have long‐lasting effects on later‐life cognition and investigate whether this association varies depending on the type of menopause ...and use of hormone treatment (HT).
Design
Population‐based cohort study.
Setting
The French Three‐City Study.
Population
Four thousand eight hundred and sixty‐eight women aged at least 65 years.
Methods
Multivariable‐adjusted logistic regression models were used to determine the association between age at menopause, type of menopause (surgical, natural), and the use of menopausal HT and later‐life cognitive function.
Main outcome measures
Performance on a cognitive test battery (at baseline and over 7 years) and clinical dementia diagnosis.
Results
Menopause at or before the age of 40 years, both premature bilateral ovariectomy and premature ovarian failure (non‐surgical loss of ovarian function), was associated with worse verbal fluency (OR 1.56, 95%CI 1.12–1.87, P = 0.004) and visual memory (OR 1.39, 95%CI 1.09–1.77, P = 0.007) in later life. HT at the time of premature menopause appeared beneficial for later‐life visual memory but increased the risk of poor verbal fluency. Type of menopause was not significantly associated with cognitive function. Premature menopause was associated with a 30% increased risk of decline in psychomotor speed and global cognitive function over 7 years.
Conclusion
Both premature surgical menopause and premature ovarian failure were associated with long‐term negative effects on cognitive function, which are not entirely offset by menopausal HT. In terms of surgical menopause, these results suggest that the potential long‐term effects on cognitive function should form part of the risk/benefit ratio when considering ovariectomy in younger women.
Dietary fatty acids and antioxidants may contribute to decrease dementia risk, but epidemiologic data remain controversial. The aim of our study was to analyze the relationship between dietary ...patterns and risk of dementia or Alzheimer disease (AD), adjusting for sociodemographic and vascular risk factors, and taking into account the ApoE genotype.
A total of 8,085 nondemented participants aged 65 and over were included in the Three-City cohort study in Bordeaux, Dijon, and Montpellier (France) in 1999-2000 and had at least one re-examination over 4 years (rate of follow-up 89.1%). An independent committee of neurologists validated 281 incident cases of dementia (including 183 AD).
Daily consumption of fruits and vegetables was associated with a decreased risk of all cause dementia (hazard ratio HR 0.72, 95% CI 0.53 to 0.97) in fully adjusted models. Weekly consumption of fish was associated with a reduced risk of AD (HR 0.65, 95% CI 0.43 to 0.994) and all cause dementia but only among ApoE epsilon 4 noncarriers (HR 0.60, 95% CI 0.40 to 0.90). Regular use of omega-3 rich oils was associated with a decreased risk of borderline significance for all cause dementia (HR 0.46, 95% CI 0.19 to 1.11). Regular consumption of omega-6 rich oils not compensated by consumption of omega-3 rich oils or fish was associated with an increased risk of dementia (HR 2.12, 95% CI 1.30 to 3.46) among ApoE epsilon 4 noncarriers.
Frequent consumption of fruits and vegetables, fish, and omega-3 rich oils may decrease the risk of dementia and Alzheimer disease, especially among ApoE epsilon 4 noncarriers.
ObjectiveThe objective of this study was to evaluate the association between occupational exposure to solvents and cognitive performance in middle-aged and early-ageing participants, taking into ...account the working environment.MethodsIn the French Cohorte des consultants des Centres d'examens de santé (CONSTANCES) cohort, 41 854 participants aged 45–69 years completed a self-reported, lifetime occupational exposure questionnaire. Exposure to solvents (gasoline for hand washing, trichloroethylene, white spirit, cellulosic thinner) was first considered as a binary variable (exposed/not exposed). We computed number of solvent types to which participants were exposed, solvent exposure time and delay since last exposure. Cognitive performance was assessed and analysed in reference to norms of neuropsychological battery previously established in CONSTANCES according to age, sex and education. Multiple linear and modified Poisson regression were used to estimate the associations between solvent exposure and cognitive performance adjusting for individual and environmental characteristics, and working conditions (night shift, repetitive and noisy work).ResultsMen had a greater risk of global cognitive impairment when they were exposed to gasoline (relative risk (RR)=1.12, 95% CI 1.03 to 1.22), white spirit (RR=1.14, 95% CI 1.05 to 1.25) or cellulosic thinner (RR=1.17, 95% CI 1.06 to 1.31) at the workplace, even after adjusting for confounders. Women exposed to white spirit or exposed for more than 20 years had poorer global cognitive performance.ConclusionThese findings strengthen our understanding of the detrimental effect of solvent exposure on cognitive health not only in men but also in women for the first time, in a large general population middle-aged and early-ageing sample from France, taking into account working conditions.
Background and purpose
Neuropsychological testing plays a key role in various clinical contexts. Even though a substantial number of adults suffer neurological disorders such as early‐onset dementia, ...stroke, traumatic brain injury or multiple sclerosis, most normative data do not include persons below 65. The aim of this study was to produce updated norms for the Mini‐Mental State Examination, the Free and Cued Selective Reminding Test, the Trail Making Test, verbal fluency tasks and the Digit Symbol Substitution Test for middle‐aged and older adults.
Methods
The sample consisted of 51 879 participants aged 45–70 years from the CONSTANCES study. Norms are presented in percentiles stratified on age, education and gender.
Results
The results illustrated the effect of age in all tests considered. For tests involving speed processing, the impact of age was observed including in tight age range categories (5 years). The results also showed the well‐known effect of education and an effect of gender in tests involving verbal memory and speed processing.
Conclusions
The norms provided allow the variability of the cognitive performances of middle‐aged to older populations to be understood, with a high precision in age categories. The tests considered are broadly used in neuropsychological practice and should be helpful in a variety of clinical contexts.
To compare the power of tests assessing different cognitive domains for the identification of prodromal Alzheimer disease (AD) among patients with mild cognitive impairment (MCI).
Given the early ...involvement of the medial temporal lobe, a precocious and specific pattern of memory disorders might be expected for the identification of prodromal AD.
A total of 251 patients with MCI were tested at baseline by a standardized neuropsychological battery, which included the Free and Cued Selective Recall Reminding Test (FCSRT) for verbal episodic memory; the Benton Visual Retention Test for visual memory; the Deno 100 and verbal fluency for language; a serial digit learning test and the double task of Baddeley for working memory; Wechsler Adult Intelligence Scale (WAIS) similarities for conceptual elaboration; and the Stroop test, the Trail Making test, and the WAIS digit symbol test for executive functions. The patients were followed at 6-month intervals for up to 3 years in order to identify those who converted to AD vs those who remained stable over time. Statistical analyses were based on receiver operating characteristic curve and Cox proportional hazards models.
A total of 59 subjects converted to AD dementia. The most sensitive and specific test for diagnosis of prodromal AD was the FCSRT. Significant cutoff for the diagnosis was 17/48 for free recall, 40/48 for total recall, and below 71% for index of sensitivity of cueing (% of efficacy of semantic cues for retrieval).
The amnestic syndrome of the medial temporal type, defined by the Free and Cued Selective Recall Reminding Test, is able to distinguish patients at an early stage of Alzheimer disease from mild cognitive impairment non-converters.
Background and purpose: The objective of this study is to estimate the number of dementia cases expected to occur in France and Europe over the next few decades until 2050.
Methods: Our estimates ...are based on a model using the European incidence data for dementia by age and sex, the relative mortality risks related to dementia stratified by age classes, and the projections of mortality coefficients in the French and European general population.
Results: In France, in 2010, the number of dementia cases should reach 754000, i.e., 1.2% of the general population or 2.8% of the active population. By 2050 this number should be multiplied by 2.4, i.e., 1813000 cases, which will be 2.6% of the total population and 6.2% of the active population. In Europe this number could reach more than 6 millions in 2010 and 14 millions in 2050. The sensitivity analysis performed on French data showed that our projections were robust to the use of alternative data for incidence and relative mortality risk (variation of 5.5% and 6.5%), but very sensitive to hypotheses of evolution of mortality (variation of −22% to 29%).
Conclusions: The approach used in our study, integrating both the dementia incidence and the mortality in the calculations, allowed us to refine the projections and stress the great sensitivity of the demographic hypotheses forecasts on the evolution of life expectancy. The likely increase is particularly important and confirms that French and European health systems must take this into account when making future plans.
There is accumulating evidence that involvement in leisure activities may be related to risk of dementia; however, there is no consensus concerning the underlying mechanism of this association. ...Hypothesizing that leisure activities may contribute to cognitive reserve (CR), we examined the association between leisure activities and risk of incident dementia and its subtypes within a general population sample, categorizing leisure activity as stimulating, passive, physical, and social. The possibility that these associations may be driven by other proxies of CR was also examined.
Analyses were carried out on 5,698 dementia-free participants aged 65 and over included in the Three-City cohort study in Dijon and Montpellier (France) in 1999-2001. Hazard ratios (HR) were calculated for incident dementia and its subtypes (mixed/vascular dementia and Alzheimer disease) in relation to category of leisure activity.
Stimulating leisure activities were found to be significantly associated with a reduced risk of dementia (n = 161, HR = 0.49, 95% confidence interval CI: 0.31; 0.79) and Alzheimer disease (n = 105, HR = 0.39, 95% CI: 0.21; 0.71) over the 4-year follow-up 1) independently of other proxies of CR, 2) after adjusting for vascular risk factors, depressive symptoms, and physical functioning, and 3) independently of other leisure activities. Furthermore, no significant association was found with other leisure activities and dementia after controlling for the potential confounders.
Our findings support the hypothesis that cognitively stimulating leisure activities may delay the onset of dementia in community-dwelling elders.
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