Lifestyle and incident dementia: A COSMIC individual participant data meta­analysis.

INTRODUCTION: The LIfestyle for BRAin Health (LIBRA) index yields a dementia risk score based on modifiable lifestyle factors and is validated in Western samples. We investigated whether the association between LIBRA scores and incident dementia is moderated by geographical location or sociodemographic characteristics. METHODS: We combined data from 21 prospective cohorts across six continents (N = 31,680) and conducted cohort-specific Cox proportional hazard regression analyses in a two-step individual participant data meta-analysis. RESULTS: A one-standard-deviation increase in LIBRA score was associated with a 21% higher risk for dementia. The association was stronger for Asian cohorts compared to European cohorts, and for individuals aged ≤75 years (vs older), though only within the first 5 years of follow-up. No interactions with sex, education, or socioeconomic position were observed. DISCUSSION: Modifiable risk and protective factors appear relevant for dementia risk reduction across diverse geographical and sociodemographic groups. HIGHLIGHTS: A two-step individual participant data meta-analysis was conducted. This was done at a global scale using data from 21 ethno-regionally diverse cohorts. The association between a modifiable dementia risk score and dementia was examined. The association was modified by geographical region and age at baseline. Yet, modifiable dementia risk and protective factors appear relevant in all investigated groups and regions.

Remote testing in Abbiategrasso (RTA): results from a counterbalanced cross-over study on direct-to-home neuropsychology with older adults.

BACKGROUND: The SARS-CoV-2 pandemic forced to rethink teleneuropsychology, since neuropsychological assessments started to be performed by phone or videoconference, with personal devices and without direct assistance from the clinician, a practice called "Direct-To-Home NeuroPsychology" (DTH-NP). AIMS: The present study, employing a counterbalanced cross-over design, was aimed at evaluating (1) the feasibility and (2) the acceptability of DTH-NP in Italian older adults without previously diagnosed neurocognitive disorder, (3) the comparability between remote and face-to-face administration of selected neuropsychological tests. METHODS: Fifty-eight community-dwelling older adults (65-85 years) were randomly assigned to one of two groups performing a complete neuropsychological assessment remotely (via phone call and videoconference) and face-to-face, in a counterbalance order, 8 weeks apart. The study recruitment rate was calculated, and the number of uncompleted tests and acceptability questionnaire responses were compared between the two administration modalities. Comparability was defined as good reliability of DTH-NP (intraclass correlation coefficient) and agreement between remote and face-to-face scores (Bland-Altman plots). RESULTS: Recruitment rate was 81%, with a preference for telephonic contact (79%). The acceptability analysis did not reveal any issues related to the DTH-NP assessment, even if most participants would rather repeat it face-to-face. Tests assessing short-term memory, language, and reasoning showed good comparability. DISCUSSION AND CONCLUSION: Our results point out to a good recruitment rate in a DTH-NP study in an Italian population of older adults (mean age = 80), satisfying acceptability of DTH-NP and remote-face-to-face comparability of certain verbally mediated tests. Further studies including larger samples in videoconference modality, and outpatients, could better clarify its strengths and limits.

Parental history of dementia and the risk of dementia: A cross-sectional analysis of a global collaborative study.

BACKGROUND: Parental history of dementia appears to increase the risk of dementia, but there have been inconsistent results. We aimed to investigate whether the association between parental history of dementia and the risk of dementia are different by dementia subtypes and sex of parent and offspring. METHODS: For this cross-sectional study, we harmonized and pooled data for 17,194 older adults from nine population-based cohorts of eight countries. These studies conducted face-to-face diagnostic interviews, physical and neurological examinations, and neuropsychological assessments to diagnose dementia. We investigated the associations of maternal and paternal history of dementia with the risk of dementia and its subtypes in offspring. RESULTS: The mean age of the participants was 72.8 ± 7.9 years and 59.2% were female. Parental history of dementia was associated with higher risk of dementia (odds ratio [OR] = 1.47, 95% confidence interval [CI] = 1.15-1.86) and Alzheimer's disease (AD) (OR = 1.72, 95% CI = 1.31-2.26), but not with the risk of non-AD. This was largely driven by maternal history of dementia, which was associated with the risk of dementia (OR = 1.51, 95% CI = 1.15-1.97) and AD (OR = 1.80, 95% CI = 1.33-2.43) whereas paternal history of dementia was not. These results remained significant when males and females were analyzed separately (OR = 2.14, 95% CI = 1.28-3.55 in males; OR = 1.68, 95% CI = 1.16-2.44 for females). CONCLUSIONS: Maternal history of dementia was associated with the risk of dementia and AD in both males and females. Maternal history of dementia may be a useful marker for identifying individuals at higher risk of AD and stratifying the risk for AD in clinical trials.

Sex differences in dementia risk and risk factors: Individual-participant data analysis using 21 cohorts across six continents from the COSMIC consortium.

INTRODUCTION: Sex differences in dementia risk, and risk factor (RF) associations with dementia, remain uncertain across diverse ethno-regional groups. METHODS: A total of 29,850 participants (58% women) from 21 cohorts across six continents were included in an individual participant data meta-analysis. Sex-specific hazard ratios (HRs), and women-to-men ratio of hazard ratios (RHRs) for associations between RFs and all-cause dementia were derived from mixed-effect Cox models. RESULTS: Incident dementia occurred in 2089 (66% women) participants over 4.6 years (median). Women had higher dementia risk (HR, 1.12 [1.02, 1.23]) than men, particularly in low- and lower-middle-income economies. Associations between longer education and former alcohol use with dementia risk (RHR, 1.01 [1.00, 1.03] per year, and 0.55 [0.38, 0.79], respectively) were stronger for men than women; otherwise, there were no discernible sex differences in other RFs. DISCUSSION: Dementia risk was higher in women than men, with possible variations by country-level income settings, but most RFs appear to work similarly in women and men.

The clinical heterogeneity of subjective cognitive decline: a data-driven approach on a population-based sample.

BACKGROUND: subjective cognitive decline (SCD) refers to the subjective experience of cognitive decline in the absence of detectable cognitive impairment. SCD has been largely studied as a risk condition for cognitive decline. Empirical observations suggest that persons with SCD are heterogeneous, including individuals with early Alzheimer's disease and others with psychological vulnerabilities and/or physical comorbidity. The semiology of SCD is still in its infancy, and the features predicting cognitive decline are poorly defined. The present study aims to identify subgroups of SCD using a data-driven approach and study their clinical evolution across 8 years. METHODS: the study population is the InveCe.Ab population-based cohort, including cognitively unimpaired people aged 70-74 years and followed for 8 years. Hierarchical cluster analysis (HCA) was carried out to identify distinct SCD subgroups based on nine clinical and cognitive features. Longitudinal changes by baseline SCD status were estimated using linear mixed models for cognitive decline and Cox proportional-hazard model for all-cause dementia risk. RESULTS: out of 956 individuals, 513 were female (54%); and the mean age was 72.1 (SD = 1.3), education was 7.2 (3.3), and 370 (39%) reported cognitive complaints (SCD). The HCA resulted in two clusters (SCD1 and SCD2). SCD2 were less educated and had more comorbidities, cardiovascular risk and depressive symptoms than SCD1 and controls. SCD2 presented steeper cognitive decline (Mini-Mental State Examination; ß = -0.31) and increased all-cause dementia risk (hazard-ratio = 3.4). CONCLUSIONS: at the population level, basic clinical information can differentiate individuals with SCD at higher risk of developing dementia, underlining the heterogeneous nature of this population even in a sample selected for a narrow age range, in a specific geographic area.

Life during COVID-19 lockdown in Italy: the influence of cognitive state on psychosocial, behavioral and lifestyle profiles of older adults.

OBJECTIVE: Few studies have examined lockdown effects on the way of living and well-being of older adults stratified by cognitive state. Since cognitive deficits are common in this population, we investigated how cognition influenced their understanding of the pandemic, socio-behavioral responses and lifestyle adaptations during lockdown, and how these factors affected their mood or memory. METHOD: Telephone-based survey involving 204 older adults ≥65 y/o (median: 82) with previous assessments of cognitive state: 164 normal-old (NOLD), 24 mild-neurocognitive disorder (mild-NCD), 18 mild-moderate dementia. A structured questionnaire was developed to assess psychological and socio-behavioral variables. Logistic regression was used to ascertain their effects on mood and memory. RESULTS: With increasing cognitive deficits, understanding of the pandemic and the ability to follow lockdown policies, adapt to lifestyle changes, and maintain remote interactions decreased. Participants with dementia were more depressed; NOLDs remained physically and mentally active but were more bored and anxious. Sleeping and health problems independently increased the likelihood of depression (OR: 2.29; CI: 1.06-4.93; p = 0.034 and OR: 2.45; CI: 1.16-5.16; p = 0.018, respectively); Regular exercise was protective (OR: 0.30; CI: 0.12-0.72; p = 0.007). Worsening subjective memory complaints were associated with dementia (p = 0.006) and depression (p = 0.004); New-onset sleeping problems raised their odds (OR: 10.26; CI: 1.13-93.41; p = 0.039). Finally, >40% with health problems avoided healthcare mainly due to fear of contagion. DISCUSSION: NOLD and mild-NCD groups showed similar mood-behavioral profiles suggesting better tolerance of lockdown. Those with dementia were unable to adapt and suffered from depression and cognitive complaints. To counteract lockdown effects, physical and mental activities and digital literacy should be encouraged.

Effect of a Social Networking Site Training on Cognitive Performance in Healthy Older People and Role of Personality Traits. Results from the Randomized Controlled Trial Ageing in a Networked Society-Social Experiment (ANS-SE) Study.

OBJECTIVES: The study aimed to evaluate the short-term efficacy of social network sites (SNSs) training on cognitive performance in cognitively healthy older individuals, and to explore the influence of personality traits on cognitive benefits of SNSs training. METHODS: The Aging in a Networked Society-Social Experiment study was a randomized controlled trial with three arms: intervention group (course on SNSs use), active control group (lifestyle education) and waiting list. Among the 180 eligible participants, 144 participated, 115 completed the study. The assessment comprised: Stroop Color and Word Test, Wechsler tests (Digit span, Symbol search, Coding), and Eysenck Personality Questionnaire- Revised- Short Form. RESULTS: There was no significant cognitive improvement for treatment group versus the control groups. Time interference significantly worsened in lifestyle education group compared to the waiting list, after controlling for baseline test scores and personality traits. CONCLUSION: The present study does not support the usefulness of SNSs training with healthy older adults. The educational content of lifestyle education is not an inert condition among individuals with high levels of neuroticism and socially desirable responding. There is a need to design experimental conditions in the control groups which do not influence participant's outcomes.

The Effect of Information and Communication Technology and Social Networking Site Use on Older People's Well-Being in Relation to Loneliness: Review of Experimental Studies.

BACKGROUND: In the last decades, the relationship between social networking sites (SNSs) and older people's loneliness is gaining specific relevance. Studies in this field are often based on qualitative methods to study in-depth self-perceived issues, including loneliness and well-being, or quantitative surveys to report the links between information and communication technologies (ICTs) and older people's well-being or loneliness. However, these nonexperimental methods are unable to deeply analyze the causal relationship. Moreover, the research on older people's SNS use is still scant, especially regarding its impact on health and well-being. In recent years, the existing review studies have separately focused their attention on loneliness and social isolation of older people or on the use of ICTs and SNSs in elderly populations without addressing the relationship between the former and the latter. This thorough qualitative review provides an analysis of research performed using an experimental or quasi-experimental design that investigates the causal effect of ICT and SNS use on elderly people's well-being related to loneliness. OBJECTIVE: The aims of this review are to contrast and compare research designs (sampling and recruitment, evaluation tools, interventions) and the findings of these studies and highlight their limitations. METHODS: Using an approach that integrates the methodological framework for scoping studies and the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines for systematic reviews, we identified 11 articles that met our inclusion criteria. A thematic and content analysis was performed based on the ex post categorization of the data on the selected studies, and the data were summarized in tables. RESULTS: The analysis of the selected articles showed that: (1) ICT use is positively but weakly related to the different measures of older people's well-being and loneliness, (2) overall, the studies under review lack a sound experimental design, (3) the main limitations of these studies lie in the lack of rigor in the sampling method and in the recruitment strategy. CONCLUSIONS: The analysis of the reviewed studies confirms the existence of a beneficial effect of ICT use on the well-being of older people in terms of reduced loneliness. However, the causal relationship is often found to be weak. This review highlights the need to study these issues further with adequate methodological rigor.

Randomized controlled trial on the efficacy of a multilevel non-pharmacologic intervention in older adults with subjective memory decline: design and baseline findings of the E.Mu.N.I. study.

BACKGROUND: Alzheimer's Disease (AD) is a multifactorial disorder driven by genetic and modifiable lifestyle risk factors. Lifestyle primary prevention initiatives may reduce the prevalence and incidence of dementia in older adults. OBJECTIVES: The E.Mu.N.I study is a randomized controlled trial investigating the effect of multilevel non-pharmacologic interventions on cognitive performances (primary outcome) and structural and vascular brain MRI markers (secondary outcome), as well as markers of brain functional connectivity change (exploratory outcome), in older adults with subjective memory decline (SMD). Here, we present the study design and the baseline features of the sample. METHODS: Cognitively intact older adults with SMD, enrolled between February 2016 and June 2017, were randomly assigned to one of the 3 interventions for 1 year: Active Control Intervention (ACI), i.e., educational lessons; Partial Intervention (PI), i.e., homotaurine administration (100 mg/die) and lessons on the Mediterranean diet; Multilevel Intervention (MI), i.e., PI plus computerized cognitive training and physical exercise training. RESULTS: One-hundred and twenty-eight eligible participants were enrolled (66% female; age: 68 ± 5 years). Eighty-two percent of the sample was composed of volunteers with SMD from the community. Participants were randomly allocated to the interventions as follows: ACI (N = 40), PI (N = 44), MI (N = 44). No significant differences among groups emerged on socio-demographic, clinical-neuropsychological variables and MRI markers at baseline. CONCLUSIONS: The outcomes obtained from the E.Mu.N.I. study will clarify the efficacy of multilevel non-pharmacologic interventions on cognitive and neuroimaging markers in SMD individuals. This is a crucial step forward for the development of cost-effective non-pharmacologic primary prevention initiatives for AD.

Functional brain effects of hand disuse in patients with trapeziometacarpal joint osteoarthritis: executed and imagined movements.

The human trapeziometacarpal (TMC) joint has a crucial evolutionary importance as it permits rotation and opposition of the thumb to the other fingers. In chronic TMC joint osteoarthritis (i.e., rhizarthrosis), this motor ability, essential for pinching, grasping, and manipulating objects, may become difficult or impossible due to intolerable pain. Here, we assess whether patients with rhizarthrosis show signs of abnormal brain representation of hand movements. To this end, we studied 35 patients with rhizarthrosis, affecting predominantly one of the two hands, and 35 healthy subjects who underwent both behavioural and fMRI measures of brain activity during overtly executed or imagined thumb-to-finger-opposition movements. The patients with rhizarthrosis were slower than controls both in motor execution and imagination. In the patients, correlation between the motor execution and imagination times was preserved, even though such correlation was less strong than in normal controls. The fMRI measures showed reduced activation in the hand primary motor and dorsal premotor cortex for the patients only during explicit movements. This was true for both hands, yet more so for the most affected hand. No significant differences were seen for the motor imagery task. These results show that an orthopaedic disorder that reduces patients' motoric repertoire in the absence of any neurological impairment is sufficient to induce neurofunctional changes in the cortical representation of hand movements. The substantial preservation of motor imagery with its neural counterparts distinguishes the neurological patterns of rhizarthrosis from those of complete immobilization or amputation suggesting that motor imagery may be used to boost motor recovery in rhizarthrosis after surgical treatment.

The Complexity of Reading Revealed by a Study with Healthy Older Adults.

Aging, even when healthy, involves changes in cognitive functioning that can gradually affect the everyday activities and well-being of older people. Reading, which requires the integrity of several functions and their integration, is important to maintaining high cognitive and emotional stimulation over time. Our study aimed to investigate whether reading ability declines with aging. To explore also why reading would decline, we explored the changes in the performance of visual and attention tasks. A group of 58 neurologically healthy older people aged from 65 to 75 underwent neuropsychological assessment to investigate their global cognitive functioning, reading skills, crowding, and attention components. We found a decline in reading abilities as a function of aging (ß = 0.34, p < 0.05). We did not find an increase in crowding or difficulties in visual acuity. Furthermore, we found no decline with age in tasks of simple reaction times, visuospatial attention, and other single components of attention. Interestingly, we instead found a worsening with age in the Symbol Digit Modalities Test (ß = -0.26, p < 0.05), involving attention, working memory, and processing speed, which explains part of the reading decline. Our results suggest that task complexity is a fundamental aspect to account for aging changes.

Use of Antihypertensives, Blood Pressure, and Estimated Risk of Dementia in Late Life: An Individual Participant Data Meta-Analysis.

Importance: The utility of antihypertensives and ideal blood pressure (BP) for dementia prevention in late life remains unclear and highly contested. Objectives: To assess the associations of hypertension history, antihypertensive use, and baseline measured BP in late life (age >60 years) with dementia and the moderating factors of age, sex, and racial group. Data Source and Study Selection: Longitudinal, population-based studies of aging participating in the Cohort Studies of Memory in an International Consortium (COSMIC) group were included. Participants were individuals without dementia at baseline aged 60 to 110 years and were based in 15 different countries (US, Brazil, Australia, China, Korea, Singapore, Central African Republic, Republic of Congo, Nigeria, Germany, Spain, Italy, France, Sweden, and Greece). Data Extraction and Synthesis: Participants were grouped in 3 categories based on previous diagnosis of hypertension and baseline antihypertensive use: healthy controls, treated hypertension, and untreated hypertension. Baseline systolic BP (SBP) and diastolic BP (DBP) were treated as continuous variables. Reporting followed the Preferred Reporting Items for Systematic Review and Meta-Analyses of Individual Participant Data reporting guidelines. Main Outcomes and Measures: The key outcome was all-cause dementia. Mixed-effects Cox proportional hazards models were used to assess the associations between the exposures and the key outcome variable. The association between dementia and baseline BP was modeled using nonlinear natural splines. The main analysis was a partially adjusted Cox proportional hazards model controlling for age, age squared, sex, education, racial group, and a random effect for study. Sensitivity analyses included a fully adjusted analysis, a restricted analysis of those individuals with more than 5 years of follow-up data, and models examining the moderating factors of age, sex, and racial group. Results: The analysis included 17 studies with 34 519 community dwelling older adults (20 160 [58.4%] female) with a mean (SD) age of 72.5 (7.5) years and a mean (SD) follow-up of 4.3 (4.3) years. In the main, partially adjusted analysis including 14 studies, individuals with untreated hypertension had a 42% increased risk of dementia compared with healthy controls (hazard ratio [HR], 1.42; 95% CI 1.15-1.76; P = .001) and 26% increased risk compared with individuals with treated hypertension (HR, 1.26; 95% CI, 1.03-1.53; P = .02). Individuals with treated hypertension had no significant increased dementia risk compared with healthy controls (HR, 1.13; 95% CI, 0.99-1.28; P = .07). The association of antihypertensive use or hypertension status with dementia did not vary with baseline BP. There was no significant association of baseline SBP or DBP with dementia risk in any of the analyses. There were no significant interactions with age, sex, or racial group for any of the analyses. Conclusions and Relevance: This individual patient data meta-analysis of longitudinal cohort studies found that antihypertensive use was associated with decreased dementia risk compared with individuals with untreated hypertension through all ages in late life. Individuals with treated hypertension had no increased risk of dementia compared with healthy controls.

Estimating the potential for dementia prevention through modifiable risk factors elimination in the real-world setting: a population-based study.

BACKGROUND: Preventing dementia onset is one of the global public health priorities: around 35% of dementia cases could be attributable to modifiable risk factors. These estimates relied on secondary data and did not consider the concurrent effect of non-modifiable factors and death. Here, we aimed to estimate the potential reduction of dementia incidence due to modifiable risk factors elimination, controlling for non-modifiable risk factors and for the competing risk of death. METHODS: Participants from the InveCe.Ab population-based prospective cohort (Abbiategrasso, Italy) without a baseline dementia diagnosis and attending at least one follow-up visit were included (N = 1100). Participants underwent multidimensional assessment at baseline and after 2, 4, and 8 years, from November 2009 to January 2019. Modifiable risk factors were low education, obesity, hypertension, diabetes, depression, smoking, physical inactivity, hearing loss, loneliness, heart disease, stroke, head injury, and delirium. Non-modifiable risk factors were age, sex, and APOE ε4 genotype. The primary endpoint was dementia diagnosis within the follow-up period (DSM-IV criteria). We performed competing risk regression models to obtain sub-hazard ratio (SHR) for each exposure, with death as competing risk. The exposures associated with dementia were included in a multivariable model to estimate their independent influence on dementia and the corresponding population attributable fraction (PAF). RESULTS: Within the study period (mean follow-up, 82.3 months), 111 participants developed dementia (10.1%). In the multivariable model, APOE ε4 (SHR = 1.89, 95% CI 1.22-2.92, p = 0.005), diabetes (SHR = 1.56, 95% CI 1.00-2.39, p = 0.043), heart disease (SHR = 1.56, 95% CI 1.03-2.36, p = 0.037), stroke (SHR = 2.31, 95% CI 1.35-3.95, p = 0.002), and delirium (SHR = 8.70, 95% CI 3.26-23.24, p <  0.001) were independently associated with increased dementia risk. In the present cohort, around 40% of dementia cases could be attributable to preventable comorbid diseases. CONCLUSIONS: APOE ε4, diabetes, heart disease, stroke, and delirium independently increased the risk of late-life dementia, controlling for the competing risk of death. Preventive intervention addressed to these clinical populations could be an effective approach to reduce dementia incidence. Further studies on different population-based cohort are needed to obtain more generalizable findings of the potential of dementia prevention in the real-world setting. TRIAL REGISTRATION: ClinicalTrials.gov, NCT01345110 .

Loneliness and Social Engagement in Older Adults Based in Lombardy during the COVID-19 Lockdown: The Long-Term Effects of a Course on Social Networking Sites Use.

Older adults are less familiar with communication technology, which became essential to maintain social contacts during the COVID-19 lockdown. The present study aimed at exploring how older adults, previously trained for Social Networking Sites (SNSs) use, experienced the lockdown period. In the first two weeks of May 2020, telephone surveys were conducted with individuals aged 81-85 years and resident in Abbiategrasso (Milan), who previously participated in a study aimed at evaluating the impact of SNSs use on loneliness in old age (ClinicalTrials.gov, NCT04242628). We collected information on SNSs use, self-perceived loneliness, and social engagement with family and friends. Interviewed participants were stratified as trained (N = 60) and untrained (N = 70) for SNSs use, based on their attendance to group courses held the previous year as part of the main experimental study. The groups were comparable for sociodemographics and clinical features. Participants trained for SNSs use reported significantly higher usage of SNSs and reduced feeling of being left out. Compared to pre-lockdown levels, individuals trained for SNSs use showed a lighter reduction in social contacts. These findings support the utility of training older adults for SNSs use in order to improve their social inclusion, even in extreme conditions of self-isolation and perceived vulnerability.

Assessing the impact of Social Networking Site use on older people's loneliness and social isolation. A randomized controlled trial: The Aging in a Networked Society-Social Experiment Study (ANS-SE).

INTRODUCTION: An ageing society poses unprecedented challenges to societies. Information and Communication Technologies (ICTs), including Social Networking Sites (SNSs), may contribute to contrast loneliness and social isolation in old age. Despite of the potentialities of SNSs, there is only a handful of studies assessing the causal relationship of SNS use and older people's well-being. This paper aims to provide further evidence on the design of randomised controlled trials exploring the causal impact of SNS use on loneliness and social isolation in old age. METHODS AND ANALYSIS: The Aging in a Networked Society-Social Experiment Study (ANS-SE) is a randomised controlled trial conducted on people aged 75 and over residing in a town located in the Milan area (Italy) aiming to assess the impact of SNS use on loneliness and social isolation (i.e. the primary outcomes of this study). The study is constituted of two stages, i.e. the baseline and the follow up. The experiment is structured into one treatment group and two control groups; the interventions are the attendance to a course on SNS use (T1) and lifestyle education and brain functioning (C1). The inactive control group (C) is constituted of a waiting list. We will perform bivariate and regression analysis. ETHICS AND DISSEMINATION: The study has been approved by the Ethic Committee of the University of Milano Bicocca (prot. 431/2019) and was registered at Clinical Trials.gov (NCT04242628). Written consent was obtained from all respondents. Results from the study will be discussed with the local community and stakeholders, presented in national and international conferences and published in leading peer-review journals. The consent forms, the anonymised dataset, and the relevant statistical codes will be deposited with the Italian Unidata archive, also in charge of releasing the data to the public, upon a short embargo period.

CSF cutoffs for MCI due to AD depend on APOEε4 carrier status.

Amyloid and tau pathological accumulation should be considered for Alzheimer's disease (AD) definition and before subjects' enrollment in disease-modifying trials. Although age, APOEε4, and sex influence cerebrospinal fluid (CSF) biomarker levels, none of these variables are considered by current normality/abnormality cutoffs. Using baseline CSF data from 2 independent cohorts (PharmaCOG/European Alzheimer's Disease Neuroimaging Initiative and Alzheimer's Disease Neuroimaging Initiative), we investigated the effect of age, APOEε4 status, and sex on CSF Aß42/P-tau distribution and cutoff extraction by applying mixture models with covariates. The Aß42/P-tau distribution revealed the presence of 3 subgroups (AD-like, intermediate, control-like) and 2 cutoffs. The identification of the intermediate subgroup and of the higher cutoff was APOEε4 dependent in both cohorts. APOE-specific classification (higher cutoff for APOEε4+, lower cutoff for APOEε4-) showed higher diagnostic accuracy in identifying MCI due to AD compared to single Aß42 and Aß42/P-tau cutoffs. APOEε4 influences amyloid and tau CSF markers and AD progression in MCI patients supporting i) the use of APOE-specific cutoffs to identify MCI due to AD and ii) the utility of considering APOE genotype for early AD diagnosis.

Association of postoperative delirium with markers of neurodegeneration and brain amyloidosis: a pilot study.

The aim of the study was to investigate the association between postoperative delirium (POD) and in vivo markers of Alzheimer's disease pathology in nondemented hip fracture surgery patients. POD was assessed with the Confusion Assessment Method. Amyloid load was quantified on 18F-Flutemetamol positron emission tomography images as standardized uptake value ratio. Secondary outcome measures were gray matter volumes, white matter integrity, and functional connectivity at rest. All the patients with POD (POD+, N = 5) were amyloid negative (standardized uptake value ratio <0.59), whereas 6 out of 11 patients without POD (POD-) showed brain amyloid positivity. POD+ compared to POD- displayed: lower gray matter volumes in the amygdala (p = 0.003), in the middle temporal gyrus and in the anterior cingulate cortex (p < 0.001), increased diffusivity in the genu of the corpus callosum and in the anterior corona radiata (p < 0.05), and higher functional connectivity within the default mode network (p < 0.001). POD patients showed altered gray and white matter integrity in the fronto-limbic regions in absence of brain amyloidosis. Based on this preliminary investigation, delirium pathophysiology might be independent of Alzheimer's disease. Future studies on larger samples are needed to confirm this hypothesis.

Association between CSF biomarkers, hippocampal volume and cognitive function in patients with amnestic mild cognitive impairment (MCI).

Few studies have examined the relationship between CSF and structural biomarkers, and cognitive function in MCI. We examined the relationship between cognitive function, hippocampal volume and cerebrospinal fluid (CSF) Aß42 and tau in 145 patients with MCI. Patients were assessed on cognitive tasks from the Cambridge Neuropsychological Test Automated Battery (CANTAB), the Geriatric Depression Scale and the Functional Activities Questionnaire. Hippocampal volume was measured using magnetic resonance imaging (MRI), and CSF markers of Aß42, tau and p-tau181 were also measured. Worse performance on a wide range of memory and sustained attention tasks were associated with reduced hippocampal volume, higher CSF tau and p-tau181 and increased tau/Aß42 ratio. Memory tasks were also associated with lower ability to conduct functional activities of daily living, providing a link between AD biomarkers, memory performance and functional outcome. These results suggest that biomarkers of Aß and tau are strongly related to cognitive performance as assessed by the CANTAB, and have implications for the early detection and characterization of incipient AD.

Efficacy of lifestyle interventions on clinical and neuroimaging outcomes in elderly.

The prevalence of Alzheimer's disease (AD) is constantly growing worldwide in absence of any effective treatment. Methodology and technique advancements facilitated the early diagnosis of AD leading to a shift toward preclinical AD stages investigation in order to delay the disease onset in individuals at risk for AD. Recent evidence demonstrating the aging related multifactorial nature of AD supported the hypothesis that modifiable environmental factors can accelerate or delay the disease onset. In particular, healthy dietary habits, constant physical and cognitive activities are associated with reduced brain atrophy, amyloid load and incidence of AD cases. Due to these promising results, an emerging field of studies is currently investigating the efficacy of interventions addressing different lifestyle habits in cognitive intact elderly individuals as a potential preventive strategy against AD onset. We provide a critical overview of the current evidence on nonpharmacologic treatments in elderly individuals, discussing their efficacy on clinical and neuroimaging outcomes and identifying current methodological issues. Future perspectives, relevant for the scientific community and the worldwide public health institutes will be further discussed.