Slow walking speed and cardiovascular death in well functioning older adults: prospective cohort study

Objective To study the relation between low walking speed and the risk of death in older people, both overall and with regard to the main causes of death

Association of big-5 personality traits with cognitive impairment and dementia: a longitudinal study

BACKGROUND: Personality traits have been linked to cognitive outcomes such as dementia, but whether these associations are robust to the effects of third variables remains the subject of debate. We examined the role of socioeconomic status, depression (history and depressive symptoms), health behaviours and chronic conditions in the association of the big-5 personality traits with cognitive performance, cognitive impairment and incidence of dementia. METHODS: Data on 6135 persons (30% women), aged 60-83 years in 2012/13, are drawn from the Whitehall II Study. Participants responded to the 26-item Midlife Development Inventory to assess personality traits (openness, conscientiousness, extraversion, agreeableness and neuroticism), underwent cognitive testing in 2012/13 and 2015/16 and were followed for incidence of dementia (N=231) until 2019. RESULTS: Logistic regression, adjusted for sociodemographic factors, suggested a cross-sectional association with cognitive impairment for four of the five traits but only neuroticism was associated with incident cognitive impairment. All associations were completely attenuated when the analyses were adjusted for depression. Cox regression (mean follow-up: 6.18 years) adjusted for sociodemographic variables showed higher conscientiousness (HR per SD increment=0.72; 95% CI 0.65 to 0.81) and extraversion (HR=0.85; 95% CI 0.75 to 0.97) to be associated with lower dementia risk; higher neuroticism (HR=1.32; 95% CI 1.17 to 1.49) was associated with increased risk. Further adjustment for depression led to only conscientiousness retaining an association with dementia (HR=0.81; 95% CI 0.69 to 0.96), which was robust to adjustment for all covariates (HR=0.84; 95% CI 0.71 to 0.91; P=0.001). CONCLUSION: Our results show that only conscientiousness has an association with incidence of dementia that is not attributable to socioeconomic status or depression. The association of neuroticism with dementia was explained by depression

Motor function in the elderly: evidence for the reserve hypothesis.

International audienceThe reserve hypothesis accounts for the lack of direct relationship between brain pathology and its clinical manifestations. Research has mostly focused on cognition; our objective is to examine whether the reserve hypothesis applies to motor function. We investigated whether education, a marker of reserve, modifies the association between white matter lesions (WMLs), a marker of vascular brain damage, and maximum walking speed (WS), an objective measure of motor function. We also examined the cross-sectional and longitudinal association between education and WS. Data are from 4,010 participants aged 65-85 years in the longitudinal Three-City-Dijon Study with up to 4 WS measures over 10 years. We examined the interaction between education and WMLs for baseline WS. We studied the association between education and repeated WS measures using linear mixed models, and the role of covariates in explaining the education-WS association. Education was strongly associated with baseline WS; the difference in mean WS between the high and low education groups (0.145 m/s, 95% confidence interval = 0.125-0.165) was equivalent to 7.4 years of age. WMLs were associated with slow WS only in the low education group (p interaction = 0.026). WS declined significantly over time (-0.194 m/s/10 years, 95% confidence interval = -0.206, -0.182), but education did not influence rate of decline. Anthropometric characteristics, parental education, general health, and cognition had the strongest role in explaining the baseline education-WS association. Participants with more education were less susceptible to WMLs' effect on motor function. Higher education was associated with better motor performances but not with motor decline. These results are consistent with the passive reserve hypothesis

Association between ATN profiles and mortality in a clinical cohort of patients with cognitive disorders

BACKGROUND: Alzheimer's disease (AD) is the 5th leading cause of death in people 65 years and older. The ATN classification reflects a biological definition of AD pathology with markers of Aβ deposition (A), pathologic tau (T), and neurodegeneration (N). Little is known about the relationship between ATN status and the risk of mortality, leading us to examine this association in a relatively large population of patients seen at a memory clinic for cognitive disorders. METHODS: Data were drawn from the BioCogBank Study, including patients seen for cognitive disorders in Lariboisiere Hospital (Paris, France), followed up to 15 years. All participants underwent a lumbar puncture for an assessment of the levels of CSF tau (tau), phosphorylated tau (p-tau181), and β-amyloid 42 peptide (Aβ42). Vital status on July 1, 2020, was recorded for each participant using the national mortality register. Individuals were categorized according to their ATN profiles based on CSF Aβ42 or Aβ42/40 ratio, p-tau181, and tau. Kaplan-Meier and multivariate Cox analyses were performed with A-T-N - participants as the reference using a short (5 years) and long follow-up (15 years). RESULTS: Of the 1353 patients in the study (mean age: 68 years old, 53% of women, mean MMSE score: 22.6), 262 died during the follow-up. At 5 years of follow-up, A-T-N + individuals had the highest risk of mortality in Kaplan-Meier and adjusted Cox analyses [HR (95% CI) = 2.93 (1.31-6.56)]. At 15 years of follow-up, patients in the AD spectrum had a higher mortality risk with a gradient effect for biomarker positivity: A-T + [HR = 1.63 (1.04-2.55)], A + T - [HR = 2.17 (1.44-3.26)], and A + T + individuals [HR = 2.38 (1.66-3.39)], compared to A-T-N - patients. Adjustments on potential confounders had little impact on these associations. CONCLUSION: This study shows ATN profiles to be associated with mortality in a relatively large patient cohort based on a memory clinic. Patients with isolated evidence of neurodegeneration had a higher mortality rate in the short follow-up, and patients with the AD profile had the highest mortality rate in the long follow-up

The association of APOE ε4 with cognitive function over the adult life course and incidence of dementia: 20 years follow-up of the Whitehall II study

Background: Approximately 25% of the general population carries at least one ε4 allele of the Apolipoprotein E (APOE ε4), the strongest genetic risk factor for late onset Alzheimer’s disease. Beyond its association with late-onset dementia, the association between APOE ε4 and change in cognition over the adult life course remains uncertain. This study aims to examine whether the association between Apolipoprotein E (APOE) ε4 zygosity and cognition function is modified between midlife and old age. Methods: A cohort study of 5561 participants (mean age 55.5 (SD = 5.9) years, 27.1% women) with APOE genotyping and repeated cognitive tests for reasoning, memory, and semantic and phonemic fluency, during a mean (SD) follow-up of 20.2 (2.8) years (the Whitehall II study). We used joint models to examine the association of APOE genotype with cognitive function trajectories between 45 and 85 years taking drop-out, dementia, and death into account and Fine and Gray models to examine associations with dementia. Results: Compared to non-carriers, heterozygote (prevalence 25%) and homozygote (prevalence 2%) APOE ε4 carriers had increased risk of dementia, sub-distribution hazard ratios 2.19 (95% CI 1.73, 2.77) and 5.97 (95% CI 3.85, 9.28) respectively. Using data spanning 45–85 years with non-ε4 carriers as the reference, ε4 homozygotes had poorer global cognitive score starting from 65 years; ε4 heterozygotes had better scores between 45 and 55 years, then no difference until poorer cognitive scores from 75 years onwards. In analysis of individual cognitive tests, better cognitive performance in the younger ε4 heterozygotes was primarily attributable to executive function. Conclusions: Both heterozygous and homozygous ε4 carriers had poorer cognition and greater risk of dementia at older ages. Our findings show some support for a complex antagonist pleiotropic effect of APOE ε4 heterozygosity over the adult life course, characterized by cognitive advantage in midlife

Sex differences and the role of education in cognitive ageing: analysis of two UK-based prospective cohort studies

BACKGROUND: Previous studies have shown an excess risk of Alzheimer's disease and related dementias among women. Education is thought to have a causal association with dementia onset. We aimed to investigate the role of education in influencing sex differences in cognitive ageing. METHODS: We analysed data from two prospective cohort studies in the UK; the English Longitudinal Study of Ageing (ELSA) and the Whitehall II study, to assess sex differences in cognitive performance and cognitive decline by birth cohort (birth year 1930-38, 1939-45, or 1946-55), before and after adjustment for education, and by high and low education level. Memory was assessed using immediate recall, for which data were available from all waves of the ELSA (2002-14) and Whitehall II (1997-2015) studies. Fluency was assessed using a semantic fluency test based on an animal naming task, with data available from all waves of the Whitehall II study and waves one to five (2002-10) and wave seven (2014) of the ELSA study. Cognitive scores were standardised separately in each study based on the mean and SD of the corresponding test among participants aged 50-59 years with secondary education. FINDINGS: 15 924 participants were included from the two studies. In pooled analyses, women had better memory scores than men in all birth cohorts, irrespective of adjustment for education (eg, at age 60 years, birth cohort 1930-38, mean difference between sexes [male scores minus female scores] -0·25 SDs [95% CI -0·32 to -0·19] after adjustment for education), and in both education level groups. Memory decline was faster in men than in women (at age 60 years, birth cohort 1946-55, mean difference in 13-year change -0·15 SDs [-0·20 to -0·09]; after adjustment for education -0·14 SDs [-0·20 to -0·08]). Men had better fluency scores than women in earlier birth cohorts and in the low education group (at age 60 years, birth cohort 1930-38, mean difference 0·20 SDs [95% CI 0·05 to 0·36]); but women had better fluency scores than men in later birth cohorts and in the high education group (at age 60 years, birth cohort 1946-55, mean difference -0·17 SDs [-0·24 to -0·10]). No sex differences were observed for fluency decline. INTERPRETATION: Our findings suggest that decreasing disparities between sexes in education, due to secular increases in educational opportunities, could attenuate sex differences in dementia risk and cognitive decline in the future. FUNDING: National Institute on Aging, National Institutes of Health; UK Medical Research Council; British Heart Foundation; and National Institute for Health Research

Contribution of smoking towards the association between socioeconomic position and dementia : 32-year follow-up of the Whitehall II prospective cohort study

Background There is consistent evidence of social inequalities in dementia but the mechanisms underlying this association remain unclear. We examined the role of smoking in midlife in socioeconomic differences in dementia at older ages.Methods Analyses were based on 9951 (67% men) participants, median age 44.3 [IQR=39.6, 50.3] years at baseline in 1985-1988, from the Whitehall II cohort study. Socioeconomic position (SEP) and smoking (smoking status (cur-rent, ex-, never-smoker), pack years of smoking, and smoking history score (combining status and pack-years)) were measured at baseline. Counterfactual mediation analysis was used to examine the contribution of smoking to the association between SEP and dementia.Findings During a median follow-up of 31.6 (IQR 31.1, 32.6) years, 628 participants were diagnosed with dementia and 2110 died. Analyses adjusted for age, sex, ethnicity, education, and SEP showed smokers (hazard ratio [HR] 1.36 [95% CI 1.10-1.68]) but not ex-smokers (HR 0.95 [95% CI 0.79-1.14]) to have a higher risk of dementia compared to never-smokers; similar results for smoking were obtained for pack-years of smoking and smoking history score. Mediation analysis showed low SEP to be associated with higher risk of dementia (HRs between 1.97 and 2.02, depending on the measure of smoking in the model); estimate for the mediation effect was 16% for smoking status (Indirect Effect HR 1.09 [95% CI 1.03-1.15]), 7% for pack-years of smoking (Indirect Effect HR 1.03 [95% CI 1.01 -1.06]) and 11% for smoking history score (Indirect Effect HR 1.06 [95% CI 1.02-1.10]). Interpretation Our findings suggest that part of the social inequalities in dementia is mediated by smoking.Funding NIHCopyright (c) 2022 The Author(s). Published by Elsevier Ltd. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/) The Health 2022;23: Published https://doi.org/10.1016/j. lanepe.2022.100516Peer reviewe

Dissection of synaptic pathways through the CSF biomarkers for predicting Alzheimer's disease

OBJECTIVE: To assess the ability of a combination of synaptic CSF biomarkers to separate AD and non-AD disorders and to help in the differential diagnosis between neurocognitive diseases. METHODS: Retrospective cross-sectional monocentric study. All participants explored with CSF assessments for neurocognitive decline were invited to participate. After complete clinical and imaging evaluations, 243 patients were included. CSF synaptic (GAP-43, neurogranin, SNAP-25 total, SNAP-25 aa40, synaptotagmin-1) and AD biomarkers were blindly quantified using ELISA or mass spectrometry. Statistical analysis compared CSF levels between various groups AD dementias n=81, MCI-AD n=30, other MCI n=49, other dementias (OD) n=49, neurological controls n=35) as well as their discriminatory powers. RESULTS: All synaptic biomarkers were significantly increased in MCI-AD and AD -dementias patients compared to other groups. All synaptic biomarkers could efficiently discriminate AD dementias from OD (AUC ≥0.80). All but synaptotagmin were also able to discriminate MCI-AD from controls (AUC ≥0.85) and AD dementias from controls (AUC ≥0.80). Overall, CSF SNAP 25aa40 had the highest discriminative power (AUC=0.93) between AD dementias and controls or OD, and AUC=0.90 between MCI-AD and controls. Higher levels were associated with two alleles of apolipoprotein E (APOE) ε4. CONCLUSION: All synaptic biomarkers tested had a good discriminatory power to distinguish patients with AD abnormal CSF from non-AD disorders. SNAP25aa40 demonstrated the highest power to discriminate AD CSF positive patients from non-AD patients and neurological controls in this cohort. CLASSIFICATION OF EVIDENCE: This retrospective study provides Class II evidence that CSF synaptic biomarkers discriminate patients with AD from non-AD patients