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Sex and gender—biological and social constructs—significantly impact the prevalence of protective and risk factors, influencing the burden of Alzheimer's disease (AD; amyloid beta and tau) and other pathologies (e.g., cerebrovascular disease) which ultimately shape cognitive trajectories. Understanding the interplay of these factors is central to understanding resilience and resistance mechanisms explaining maintained cognitive function and reduced pathology accumulation in aging and AD. In this narrative review, the ADDRESS! Special Interest Group (Alzheimer's Association) adopted a multidisciplinary approach to provide the foundations and recommendations for future research into sex‐ and gender‐specific drivers of resilience, including a sex/gender‐oriented review of risk factors, genetics, AD and non‐AD pathologies, brain structure and function, and animal research. We urge the field to adopt a sex/gender‐aware approach to resilience to advance our understanding of the intricate interplay of biological and social determinants and consider sex/gender‐specific resilience throughout disease stages. Highlights Sex differences in resilience to cognitive decline vary by age and cognitive status. Initial evidence supports sex‐specific distinctions in brain pathology. Findings suggest sex differences in the impact of pathology on cognition. There is a sex‐specific change in resilience in the transition to clinical stages. Gender and sex factors warrant study: modifiable, immune, inflammatory, and vascular.

More educated elders are less susceptible to age-related or pathological cognitive changes. We aimed at providing a comprehensive contribution to the neural mechanism underlying this effect thanks to a multimodal approach. Thirty-six healthy elders were selected based on neuropsychological assessments and cerebral amyloid imaging, i.e. as presenting normal cognition and a negative florbetapir-PET scan. All subjects underwent structural MRI, FDG-PET and resting-state functional MRI scans. We assessed the relationships between years of education and i) gray matter volume, ii) gray matter metabolism and iii) functional connectivity in the brain areas showing associations with both volume and metabolism. Higher years of education were related to greater volume in the superior temporal gyrus, insula and anterior cingulate cortex and to greater metabolism in the anterior cingulate cortex. The latter thus showed both volume and metabolism increases with education. Seed connectivity analyses based on this region showed that education was positively related to the functional connectivity between the anterior cingulate cortex and the hippocampus as well as the inferior frontal lobe, posterior cingulate cortex and angular gyrus. Increased connectivity was in turn related with improved cognitive performances. Reinforcement of the connectivity of the anterior cingulate cortex with distant cortical areas of the frontal, temporal and parietal lobes appears as one of the mechanisms underlying education-related reserve in healthy elders. •We relate education to gray matter volume, metabolism and functional connectivity.•Volume and metabolism increases with education predominate in the anterior cingulate.•Anterior cingulate connectivity is also reinforced with education.•This increased connectivity relates to improved cognitive performances.

Aging is accompanied by a decline in memory and other brain functions. Physical exercise may mitigate this decline through the modulation of factors participating in the crosstalk between skeletal muscle and the brain, such as neurotrophins and oxidative stress parameters. We aimed to determine whether long term exercise training (35 ± 15 years) promotes memory maintenance in middle-aged men, and to characterize the changes in neurotrophic factors and lipid oxidation markers in peripheral blood samples in both middle-aged and young men. The neuropsychological analysis showed significant improvements in memory through the Free and Cued Immediate Recall tests, in the middle-aged trained individuals when compared to the sedentary ones. We found a significant decrease in the resting serum BDNF and plasma Cathepsin B (CTSB) levels in the trained groups at both middle and young ages. BDNF and CTSB levels were inversely correlated with weekly hours of exercise. We also found a significant decrease in plasma malondialdehyde, an index of lipid peroxidation, in middle-aged and young trained subjects. The positive impact of long-term exercise training by delaying the onset of physiological memory loss and the associated neurotrophic and redox peripheral modulation, suggests the effectiveness of exercise as preventive strategy against age-related memory loss and neurodegeneration.

Introduction We aimed to define prodromal Alzheimer's disease (AD) and AD dementia using normative neuropsychological data in a large population‐based cohort of adults with Down syndrome (DS). Methods Cross‐sectional study. DS participants were classified into asymptomatic, prodromal AD and AD dementia, based on neurologist's judgment blinded to neuropsychological data (Cambridge Cognitive Examination for Older Adults with Down's syndrome [CAMCOG‐DS] and modified Cued Recall Test [mCRT]). We compared the cutoffs derived from the normative data in young adults with DS to those from receiver‐operating characteristic curve (ROC) analysis. Results Diagnostic performance of the CAMCOG‐DS and modified Cued Recall Test (mCRT) in subjects with mild and moderate levels of intellectual disability (ID) was high, both for diagnosing prodromal AD and AD dementia (area under the curve [AUC] 0.73–0.83 and 0.90–1, respectively). The cutoffs derived from the normative data were similar to those derived from the ROC analyses. Discussion Diagnosing prodromal AD and AD dementia in DS with mild and moderate ID using population norms for neuropsychological tests is possible with high diagnostic accuracy.

Introduction Stakeholder engagement remains scarce in basic brain research. However, it can greatly improve the relevance of investigations and accelerate the translation of study findings to policy. The Lifebrain consortium investigated risk and protective factors influencing brain health using cognition, lifestyle and imaging data from European cohorts. Stakeholder activities of Lifebrain—organized in a separate work package—included organizing stakeholder events, investigating public perceptions of brain health and dissemination. Here, we describe the experiences of researchers and stakeholders regarding stakeholder engagement in the Lifebrain project. Methods Stakeholder engagement in Lifebrain was evaluated through surveys among researchers and stakeholders and stakeholders' feedback at stakeholder events through evaluation forms. Survey data were analysed using a simple content analysis approach, and results from evaluation forms were summarized after reviewing the frequency of responses. Results Consortium researchers and stakeholders experienced the engagement activities as meaningful and relevant. Researchers highlighted that it made the research and research processes more visible and contributed to new networks, optimized data collection on brain health perceptions and the production of papers and provided insights into stakeholder views. Stakeholders found research activities conducted in the stakeholder engagement work package to be within their field of interest and research results relevant to their work. Researchers identified barriers to stakeholder engagement, including lack of time, difficulties in identifying relevant stakeholders, and challenges in communicating complex scientific issues in lay language and maintaining relationships with stakeholders over time. Stakeholders identified barriers such as lack of budget, limited resources in their organization, time constraints and insufficient communication between researchers and stakeholders. Conclusion Stakeholder engagement in basic brain research can greatly benefit researchers and stakeholders alike. Its success is conditional on dedicated human and financial resources, clear communication, transparent mutual expectations and clear roles and responsibilities. Public Contribution Patient organizations, research networks, policymakers and members of the general public were involved in engagement and research activities throughout the project duration.

Introduction The apolipoprotein E (APOE) ε4 allele is the main genetic risk factor for Alzheimer's disease (AD), accelerated cognitive aging, and hippocampal atrophy, but its influence on the association between hippocampus atrophy and episodic‐memory decline in non‐demented individuals remains unclear. Methods We analyzed longitudinal (two to six observations) magnetic resonance imaging (MRI)–derived hippocampal volumes and episodic memory from 748 individuals (55 to 90 years at baseline, 50% female) from the European Lifebrain consortium. Results The change‐change association for hippocampal volume and memory was significant only in ε4 carriers (N = 173, r = 0.21, P = .007; non‐carriers: N = 467, r = 0.073, P = .117). The linear relationship was significantly steeper for the carriers [t(629) = 2.4, P = .013]. A similar trend toward a stronger change‐change relation for carriers was seen in a subsample with more than two assessments. Discussion These findings provide evidence for a difference in hippocampus‐memory association between ε4 carriers and non‐carriers, thus highlighting how genetic factors modulate the translation of the AD‐related pathophysiological cascade into cognitive deficits.

·Healthy aging is associated to increased risk of cognitive decline.·Resting state DMN functional connectivity is considerably affected by aging.·We used computational modeling to investigate DMN effective connectivity.·Effective connectivity in temporal and posterior DMN hubs was reduced.·Lifetime attained education reversed these changes, indicating cognitive reserve. Aging is a major risk factor for neurodegenerative diseases like dementia and Alzheimer's disease. Even in non-pathological aging, decline in cognitive functioning is observed in the majority of the elderly population, necessitating the importance of studying the processes involved in healthy aging in order to identify brain biomarkers that promote the conservation of functioning. The default mode network (DMN) has been of special interest to aging research due to its vulnerability to atrophy and functional decline over the course of aging. Prior work has focused almost exclusively on functional (i.e. undirected) connectivity, yet converging findings are scarce. Therefore, we set out to use spectral dynamic causal modeling to investigate changes in the effective (i.e. directed) connectivity within the DMN and to discover changes in information flow in a sample of cognitively normal adults spanning from 48 to 89 years (n = 63). Age was associated to reduced verbal memory performance. Modeling of effective connectivity revealed a pattern of age-related downregulation of posterior DMN regions driven by inhibitory connections from the hippocampus and middle temporal gyrus. Additionally, there was an observed decline in the hippocampus’ susceptibility to network inputs with age, effectively disconnecting itself from other regions. The estimated effective connectivity parameters were robust and able to predict the age in out of sample estimates in a leave-one-out cross-validation. Attained education moderated the effects of aging, largely reversing the observed pattern of inhibitory connectivity. Thus, medial prefrontal cortex, hippocampus and posterior DMN regions formed an excitatory cycle of extrinsic connections related to the interaction of age and education. This suggests a compensatory role of years of education in effective connectivity, stressing a possible target for interventions. Our findings suggest a connection to the concept of cognitive reserve, which attributes a protective effect of educational level on cognitive decline in aging (Stern, 2009).

Evidence from neuroimaging and electrophysiological studies indicates that the left dorsolateral prefrontal cortex (DLPFC) is a core region in emotional processing, particularly during down-regulation of negative emotional conditions. However, emotional regulation is a process subject to major inter-individual differences, some of which may be explained by personality traits. In the present study we used transcranial direct current stimulation (tDCS) over the left DLPFC to investigate whether transiently increasing the activity of this region resulted in changes in the ratings of positive, neutral and negative emotional pictures. Results revealed that anodal, but not cathodal, tDCS reduced the perceived degree of emotional valence for negative stimuli, possibly due to an enhancement of cognitive control of emotional expression. We also aimed to determine whether personality traits (extraversion and neuroticism) might condition the impact of tDCS. We found that individuals with higher scores on the introversion personality dimension were more permeable than extraverts to the modulatory effects of the stimulation. The present study underlines the role of the left DLPFC in emotional regulation, and stresses the importance of considering individual personality characteristics as a relevant variable, although replication is needed given the limited sample size of our study.

Transcranial direct and alternating current stimulation (tDCS and tACS, respectively) entail capability to modulate human brain dynamics and cognition. However, the comparability of these approaches at the level of large-scale functional networks has not been thoroughly investigated. In this study, 44 subjects were randomly assigned to receive sham ( = 15), tDCS ( = 15), or tACS ( = 14). The first electrode (anode in tDCS) was positioned over the left dorsolateral prefrontal cortex, the target area, and the second electrode (cathode in tDCS) was placed over the right supraorbital region. tDCS was delivered with a constant current of 2 mA. tACS was fixed to 2 mA peak-to-peak with 6 Hz frequency. Stimulation was applied concurrently with functional magnetic resonance imaging (fMRI) acquisitions, both at rest and during the performance of a verbal working memory (WM) task. After stimulation, subjects repeated the fMRI WM task. Our results indicated that at rest, tDCS increased functional connectivity particularly within the default-mode network (DMN), while tACS decreased it. When comparing both fMRI WM tasks, it was observed that tDCS displayed decreased brain activity post-stimulation as compared to online. Conversely, tACS effects were driven by neural increases online as compared to post-stimulation. Interestingly, both effects primarily occurred within DMN-related areas. Regarding the differences in each fMRI WM task, during the online fMRI WM task, tACS engaged distributed neural resources which did not overlap with the WM-dependent activity pattern, but with some posterior DMN regions. In contrast, during the post-stimulation fMRI WM task, tDCS strengthened prefrontal DMN deactivations, being these activity reductions associated with faster responses. Furthermore, it was observed that tDCS neural responses presented certain consistency across distinct fMRI modalities, while tACS did not. In sum, tDCS and tACS modulate fMRI-derived network dynamics differently. However, both effects seem to focus on DMN regions and the WM network-DMN shift, which are highly affected in aging and disease. Thus, albeit exploratory and needing further replication with larger samples, our results might provide a refined understanding of how the DMN functioning can be externally modulated through commonly used non-invasive brain stimulation techniques, which may be of eventual clinical relevance.

The Barcelona Brain Health Initiative is a longitudinal cohort study that began in 2017 and aims to understand and characterize the determinants of brain health maintenance in middle aged adults. A cohort of 4686 individuals between the ages of 40 and 65 years free from any neurological or psychiatric diseases was established, and we collected extensive demographic, socio-economic information along with measures of self-perceived health and lifestyles (general health, physical activity, cognitive activity, socialization, sleep, nutrition and vital plan). Here we report on the baseline characteristics of the participants, and the results of the one-year follow-up evaluation. Participants were mainly women, highly educated, and with better lifestyles compared with the general population. After one year 60% of participants completed the one-year follow-up, and these were older, with higher educational level and with better lifestyles in some domains. In the absence of any specific interventions to-date, these participants showed small improvements in physical activity and sleep, but decreased adherence to a Mediterranean diet. These changes were negatively associated with baseline scores, and poorer habits at baseline were predictive of an improvement in lifestyle domains. Of the 2353 participants who completed the one-year follow-up, 73 had been diagnosed with new neurological and neuropsychiatric diseases. Changes in vital plan at follow-up, as well as gender, sleep quality and sense of coherence at baseline were shown to be significant risk factors for the onset of these diagnoses. Notably, gender risk factor decreased in importance as we adjusted by sleep habits, suggesting its potential mediator effects. These findings stress the importance of healthy lifestyles in sustaining brain health, and illustrate the individual benefit that can be derived from participation in longitudinal observational studies. Modifiable lifestyles, specifically quality of sleep, may partially mediate the effect of other risk factors in the development of some neuropsychiatric conditions.