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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.

•Identified successful agers using baseline and longitudinal cognitive performance.•Successful agers featured functional preservation exhibiting youth-like activation.•Successful agers also recruited additional prefrontal regions, compared to young.•Brain maintenance and frontal recruitment may be complementary in successful aging. Much neuroimaging research has explored the neural mechanisms underlying successful cognitive aging. Two different patterns of functional activation, maintenance of youth-like activity and compensatory novel recruitment, have been proposed to represent different brain functional features underlying individual differences in cognitive aging. In this study, we investigated the functional features in individuals across the adult lifespan who appeared to resist age-related cognitive decline, in comparison to those with typical age-related declines, over the course of four years. We first implemented latent mixture modeling, a data-driven approach, to classify participants as successful and average agers in middle-aged, young-old, and very old groups, based on their baseline and longitudinal cognitive performance. Then, using fMRI with a subsequent memory paradigm at the follow-up visit, brain activation specifically related to successful encoding (i.e., subsequent memory effect: subsequently remembered with high confidence > subsequently forgotten) was compared between people who established successful cognitive aging versus average aging in the three age groups. Several differences in the subsequent memory effect were revealed. First, across core task-related regions commonly used during successful encoding, successful agers exhibited high subsequent memory effect, at a level comparable to the young control group, until very old age; in contrast, average agers showed reduced subsequent memory effect, compared to successful agers, beginning in young-old age when memory performance also reduced in average agers, compared to successful agers. Second, additional recruitment in prefrontal clusters, distant from the core task-related regions, were identified in the left superior frontal and right orbitofrontal cortices in successful agers of young-old age, possibly reflecting functional compensation in successful aging. In summary, successful agers demonstrate a pattern of youth-like activation spanning from middle age to young-old age, as well as novel frontal recruitment in young-old age. Overall, our study demonstrated evidence of two neural patterns related to successful cognitive aging, offering an integrated view of functional features underlying successful aging, and suggests the importance of studying individuals across the lifespan to understand brain changes occurring in mid and early-late life.

The goal of this paper is to review my current understanding of the concepts of cognitive reserve (CR), brain reserve and brain maintenance, and to describe our group’s approach to using imaging to study their neural basis. I present a working model for utilizing data regarding brain integrity, clinical status, cognitive activation and CR proxies to develop analyses that can explore the neural basis of cognitive reserve and brain maintenance. The basic model assumes that the effect of brain changes on cognition is mediated by task-related activation. We treat CR as a moderator to understand how task-related activation might vary as a function of CR, or how CR might operate independently of these differences in task-related activation. My hope is that this presentation will spark discussion across groups that study these concepts, allowing us to come to some common agreement on definitions, methodology and approaches.

•We investigated the optimal patterns of prefrontal lateralization with age via fMRI.•The relationship of lateralization to cognition differed as a function of age.•In middle age, youthlike left-lateralization predicted higher fluid ability.•But old adults who were high in bilateral activation evidenced higher fluid ability.•The roles of brain maintenance and compensation likely change across the lifespan. There is considerable debate about whether additional fMRI-measured activity in the right prefrontal cortex readily observed in older adults represents compensatory activation that enhances cognition or whether maintenance of youthful brain activity best supports cognitive function in late adulthood. To investigate this issue, we tested a large lifespan sample of 461 adults (aged 20–89) and treated degree of left-lateralization in ventrolateral and dorsolateral prefrontal cortex during a semantic judgment fMRI task as an individual differences variable to predict cognition. We found that younger adults were highly left-lateralized, but lateralization did not predict better cognition, whereas higher left-lateralization of prefrontal cortex predicted better cognitive performance in middle-aged adults, providing evidence that left-lateralized, youth-like patterns are optimal in middle age. This relationship was reversed in older adults, with lower laterality scores associated with better cognition. The findings suggest that bilaterality in older adults facilitates cognition, but early manifestation of this pattern during middle age is characteristic of low performers. Implications of these findings for current theories of neurocognitive aging are discussed.

Age-related cognitive decline is a global phenomenon that affects individuals worldwide. The course and extent of this decline are influenced by numerous factors, such as genetics, lifestyle, education, and cognitive engagement. The theory of brain and cognitive reserve/maintenance posits that these factors have a significant impact on the degree of cognitive decline and overall brain health. However, the absence of standardized definitions and measurements for these terms creates ambiguity in research. To address this issue, we utilized a robust and systematic experimental paradigm, employing a considerably large subject pool comprising 17,030 participants from the UK Biobank. Utilizing advanced machine learning methodologies, we were able to accurately quantify both brain maintenance (BM) and cognitive maintenance (CM), making use of six distinct MRI modalities and nine distinct cognitive capabilities. Our study successfully identified several significant features that were meaningfully associated with both BM and CM outcomes. The results of our study demonstrate that lifestyle factors play a significant role in influencing both BM and CM through unique and independent mechanisms. Specifically, our study found that health status is a critical determinant of BM, while diabetes was found to be moderately associated with CM. Furthermore, our study revealed a positive correlation between BM/CM and cognitive reserve. By carefully considering the unique and independent mechanisms that govern both BM and CM, as well as their correlation with cognitive reserve, our study has provided valuable insight into the various strategies that may be leveraged to promote sustainable interventions to enhance cognitive and brain health across the lifespan.

The concept of resilience can be used to explain why there are differences in the degree to which the brain functions of different individuals are impaired due to aging and pathological factors associated with neurodegenerative diseases. It encompasses cognitive reserve, brain reserve, and brain maintenance. Long-term research has identified a default mode network (DMN) related to cognitive reserve. This mode can modulate the negative impact of Alzheimer’s disease (AD) pathological burden on cognitive performance. Meanwhile, the association between neurons and glial cells plays a crucial role in the strength of neural network connections. Glial cells are widely distributed in the brain and interact closely with neurons. Among them, astrocytes are essential for maintaining the normal functions of the central nervous system. In both healthy and diseased states, astrocytes perform a variety of functions, including participating in the regulation of synaptic plasticity, synaptogenesis, maintaining glutamate and ion homeostasis, participating in cholesterol and sphingolipid metabolism, and being able to respond to environmental factors. All of these functions are associated with Alzheimer’s disease. In this review, first, we provided an overview of Cognitive Reserve, Brain Maintenance, and Brain Reserve. Then, we expounded on the possible mechanisms of action related to glial cells. Finally, we described their roles in Alzheimer’s disease and therapeutic development. This review may provide information and relevant therapeutic strategies for future research as well as the design of diagnostic and therapeutic interventions.

The goal of this review article is to provide a resource for longitudinal studies, using animal models, directed at understanding and modifying the relationship between cognition and brain structure and function throughout life. We propose that forthcoming longitudinal studies will build upon a wealth of knowledge gleaned from prior cross-sectional designs to identify early predictors of variability in cognitive function during aging, and characterize fundamental neurobiological mechanisms that underlie the vulnerability to, and the trajectory of, cognitive decline. Finally, we present examples of biological measures that may differentiate mechanisms of the cognitive reserve at the molecular, cellular, and network level.

ObjectiveCognitively engaging lifestyles have been associated with reduced risk of conversion to dementia. Multiple mechanisms have been advocated, including increased brain volumes (ie, brain reserve) and reduced disease progression (ie, brain maintenance). In cross-sectional studies of presymptomatic frontotemporal dementia (FTD), higher education has been related to increased grey matter volume. Here, we examine the effect of education on grey matter loss over time.MethodsTwo-hundred twenty-nine subjects at-risk of carrying a pathogenic mutation leading to FTD underwent longitudinal cognitive assessment and T1-weighted MRI at baseline and at 1 year follow-up. The first principal component score of the graph-Laplacian Principal Component Analysis on 112 grey matter region-of-interest volumes was used to summarise the grey matter volume (GMV). The effects of education on cognitive performances and GMV at baseline and on the change between 1 year follow-up and baseline (slope) were tested by Structural Equation Modelling.ResultsHighly educated at-risk subjects had better cognition and higher grey matter volume at baseline; moreover, higher educational attainment was associated with slower loss of grey matter over time in mutation carriers.ConclusionsThis longitudinal study demonstrates that even in presence of ongoing pathological processes, education may facilitate both brain reserve and brain maintenance in the presymptomatic phase of genetic FTD.

We examined brain and cognitive reserve related to bilingualism in older adults with, or at-risk for, Alzheimer's disease (AD) from the Canadian Consortium on Neurodegeneration in Aging and the Quebec Consortium for the Early Identification of Alzheimer's Disease. We used surface-based morphometry methods to measure cortical thickness and volume of language-related and AD-related brain regions. We did not observe evidence of brain reserve in language-related regions. However, reduced hippocampal volume was observed for monolingual, but not bilingual, older adults with AD. Thus, bilingualism is hypothesized to contribute to reserve in the form of brain maintenance in the context of AD.

Due to the high prevalence of Alzheimer's disease (AD) in adults with Down syndrome (DS), trisomy 21 is now considered a genetic form of AD (DSAD). A better understanding of factors that can prevent or delay AD is vital to improve outcomes for adults with DS. In this narrative review, we apply AD and cognitive aging research frameworks to study resistance and resilience in DSAD. Given the variability in the timing of pathology and symptoms, we discuss the evidence supporting the role of genetic, biological, socio‐behavioral, lifestyle, and environmental factors in resistance and resilience to DSAD. We also consider how co‐occurring health conditions in DS may influence resistance and resilience, and how methods from AD research can be applied to DSAD. Ultimately, this framework aims to guide future research and translate findings into clinical interventions to improve outcomes in DSAD. Highlights Definitions of resistance and resilience in the genetic form of Alzheimer's disease (DSAD) are proposed for guiding the field. Variability in the timing of AD pathology and symptoms suggests the potential for resistance and resilience mechanisms in DSAD. Genetic, biological, socio‐behavioral, lifestyle, and environmental factors have the potential to build resistance or resilience in DSAD. Future research will require longitudinal and experimental designs, life course approaches, and large cohort studies.