Introduction Alzheimer’s disease (AD) is a neurodegenerative disorder that severely hinders quality of life. Hippocampal hyperactivity is recognised as a biological marker of AD pathology and is associated with episodic memory impairments, the hallmark cognitive symptom of AD. What drives this hyperactivity, however, is not well understood. γ-aminobutyric acid (GABA) is the principal inhibitory neurotransmitter in the brain. Animal models show that age-related GABAergic dysregulation drives hippocampal hyperactivity and cognitive impairment. However, whether this same mechanism translates to humans remains untested. Further, the role of biological sex has not been considered despite the fact that oestrogen modulates GABA receptor expression and GABA release in the hippocampus. Here, we introduce the Sex, Age, GABA, Episodic memory (SAGE) study, a protocol aimed to test an age and sex based GABAergic mechanism of memory impairment in humans.Methods and analysis The SAGE study, which will collect multimodal data from 300 healthy adults (100 per decade from age 50 years to 79 years, two-thirds women), aims to test whether age-related GABAergic dysregulation drives hippocampal hyperactivity and episodic memory decline in humans and whether this mechanism is moderated by sex.

IntroductionResearch suggests that older adults have deficits in selective attention, a cognitive process often queried through the Stroop task. To tease apart whether this is due to failures to inhibit distracting information or to upregulate attention towards target information, younger and older adults completed a task called the Shape Stroop.MethodsIn this task, participants had to name the color of a shape that was occluded by another shape. Critically, congruent or incongruent Stroop words were placed in either the target shape, the occluding (distractor) shape or in the background. We first modeled performance as a function of age-group, Stroop word congruency, and location.ResultsThe results indicate that older adults were more accurate but slower than younger adults to choose the correct shape color. For both younger and older adults, incongruent words induced slower reaction times when words were in the target location, indicating age-invariance in the Stroop effect. To further probe how early and/or late attentional processes contribute to performance and to interrogate the decision strategies adopted across different conditions, we also fit the dual-stage two-phase model of selective attention to our data.DiscussionOur results indicate that older adults tend to be more cautious and require more information before choosing a stimulus to attend to or making a decision. Although older adults’ ability to inhibit irrelevant information seems intact, they show signs of slower information processing in the later stages of attentional processing.

Social isolation negatively impacts health, and incorporating multidimensional indicators into its measurement may better capture its complexity. This study examined latent profiles of older adults based on social isolation indicators and explored how various factors are associated with profile membership. Participants included 5,466 older adults aged 65 + (Mage = 75.16) from the 2012 and 2014 waves of the Health and Retirement Study. Social isolation was measured through both structural (contact frequency with children/other family members/friends and social participation) and functional (loneliness and social support) aspects. Furthermore, the study incorporated sociodemographic, psychological, environmental, and health-related factors as covariates. Latent Profile Analysis and logistic regression were conducted using Mplus. Results exhibited five social isolation group profiles: (1) ‘highly socially engaged’ (6%), (2) ‘moderately socially engaged’ (20%), (3) ‘moderately isolated, but not lonely’ (46%), (4) ‘socially active but unsupported’ (12%), and (5) ‘most socially isolated’ (16%). Structural and functional aspects of social isolation were generally aligned. However, the presence of the ‘socially active but unsupported’ group suggests that engagement in social activities does not necessarily equate to strong social support. Lower education levels were consistently associated with less social engagement across groups and men tended to belong to socially isolated groups more than women. Compared to the ‘highly socially engaged’ group, all other groups showed lower levels of extraversion and openness. The ‘moderately isolated, but not lonely’ and ‘most socially isolated’ groups exhibited worse cognition, more chronic conditions, and greater depressive symptoms. The findings reveal distinct typologies of social isolation among older adults.

Objective:To explore symptoms, knowledge levels, perceptions, and use related to menopause and hormone therapy (HT) and to examine the factors associated with HT use and HT perceptions in perimenopausal and postmenopausal women. Materials and Methods:We used a sample of 98 perimenopausal and postmenopausal women who aged 50-79 and participated in the Sex, ApoE-4, γ-aminobutyric acid, and Episodic memory (SAGE) study (M age = 64.24, standard deviation = 7.49). We applied a series of bivariate Firth logistic regressions to examine the associations of each variable of interest with hormone therapy (HT) use and perceptions. Results:Overall, 89.90% reported positive perceptions of menopause, and 85.71% had positive perceptions of HT. One-third (32.65%) of the sample had used HT. Hot flashes (72.4%) were the most reported menopausal symptom. Logistic regression analyses showed that age, race/ethnicity, current drinking status, menopausal knowledge levels, and vasomotor and genitourinary symptoms were significantly associated with HT use, while race/ethnicity, current drinking status, menopausal knowledge levels, and genitourinary symptoms were also linked to positive HT perceptions. Hispanic participants reported lower menopausal knowledge, less positive HT perceptions, and lower HT use. Conclusions:The majority of women in the SAGE cohort reported positive perceptions of both menopause and HT. Race/ethnicity, along with current drinking status, menopausal knowledge levels, and genitourinary symptoms, were consistently associated with both HT use and HT perceptions. Ethnic differences in menopausal knowledge levels, HT perceptions, and HT use are also discussed.

Abstract This study aimed to investigate the associations between loneliness, social isolation, and five cognitive domains by using a comprehensive neuropsychological battery. Participants included 2,884 older adults (mean age = 72.8) in the 2016 Health and Retirement Study Harmonized Cognitive Assessment Protocol. The 11-item UCLA Loneliness Scale was used for loneliness. For social isolation, several indicators were scaled (e.g., marital status, contact frequency with children, other family members, and friends, and participation in social organizations) using the Steptoe’s Social Isolation Index. Based on the confirmatory factor analysis findings from Zahodne et al. (2020)’s article, the average z-scores of the test results corresponding to each cognitive domain (memory, executive function, visuoconstruction, language, and processing speed) were calculated. Multiple regression for each cognitive domain was conducted. The results revealed that there were significant associations between loneliness and the cognitive scores across all five domains, indicating that the lonelier older adults were, the lower their cognitive scores tend to be. Even after controlling for demographics and depression, these associations remained significant for memory, executive function, and language. Social isolation showed a significant association only with processing speed. However, the interaction term between loneliness and social isolation was not significant across all five cognitive domains. This study provides that links between social isolation, loneliness, and cognition differ across domains. Furthermore, loneliness might have an association with memory, executive function, and language independently of depression.

ObjectivesThe Directed Forgetting paradigm has proven to be a powerful tool to explore motivated forgetting in the lab. Past work has shown that older adults are less able to intentionally suppress information from memory relative to younger adults, which is often attributed to deficits in inhibitory abilities. Instructions in traditional Directed Forgetting tasks contain terms that may elicit stereotype threat in older adults, which may negatively impact memory. Here, we tested whether the instructions in a Directed Forgetting task affected older adults’ ability to appropriately control the contents of memory.MethodsIn two experiments that differed in the number of words presented (30 vs. 48 items), younger and older adults were randomized into one of four crossed Conditions of a Directed Forgetting task. At encoding, participants were either instructed to remember/ forget items, or to think about/not think about items. At test, they were either asked whether the memory probe was old or new, or whether they had seen it before (yes/no). Each experiment contained data from 100 younger (18– 40 years) and 98 older (60+ years) adults, with ~25 participants per Condition. All participants were recruited from Prolific and tested online.ResultsIn neither Experiment 1 nor Experiment 2 did we find evidence of a stereotype threat effect, or age-related effects of directed forgetting. We did find that performance for to-be-forgotten items was worse in conditions with encoding instructions that contained words that might trigger stereotype threat relative to conditions that did not contain such words: when explicitly told to forget items, both older and younger adults forgot more items than did participants who were cued to not think about the words and put them out of mind. However, we found no such difference across the two different remember instructions: regardless of whether participants were told to remember or to think about items, recognition memory for to be retained items was high. The pattern of results across the two experiments was similar, except, not surprisingly, participants performed worse in Experiment 2 than Experiment 1. Interestingly, we found that higher accuracy for to be remembered items was associated with a more positive outlook of one’s own memory relative to others.DiscussionThese results suggest that directed forgetting may not always be impaired in older adults.

White matter hyperintensities (WMH) are associated with cortical thinning. Although they are primarily detected in older participants, these lesions can appear in younger and midlife individuals. Here, we tested whether WMH are associated with cortical thinning in relatively younger (26 to 50 years) and relatively older (58 to 84) participants who were free of dementia, and how these associations are moderated by WMH localization. WMH were automatically quantified and categorized according to the localization of three classes of white matter tracts: association, commissural and projection fibers. Mediation analyses were used to infer whether differences in cortical thickness between younger and older participants were explained by WMH. Our results revealed that total WMH explained between 20.6 to 65.5% of the effect of age on cortical thickness in AD-signature regions including the lateral temporal lobes and supramarginal gyrus, among others. This mediation was slightly stronger for projection WMH, although it was still significant for association and commissural WMH. These results suggest that there is an interplay between vascular and AD causes of cognitive impairment that starts at younger ages.

People are generally able to selectively attend and remember high-value over low-value information. Here, we investigated whether young and older adults would display typical value-based memory selectivity effects for to-be-learned item-value associations when goal-directed information about the meaning of associated values was presented before and after encoding. In two experiments, both young and older adults were presented with one (Experiment 1) or multiple (Experiment 2) lists of words that were arbitrarily paired with different numerical values (e.g., "door-8") or font colors (e.g., "door" presented in red), which indicated each word's value. In Experiment 1, participants were told that the numerical value indicated the relative importance of each item either before they studied the list (preencoding), after they studied it (postencoding), or not at all (no value control instructions). Older adults were significantly more selective in the preencoding condition relative to the other conditions, whereas younger adults were not selective in any condition on this single-list (numerical) value task of Experiment 1. In Experiment 2, young and older adults were tested on four additional lists of both pre- and postencoding trials each after studying and recalling four lists of words without any value instructions. Results from Experiment 2 revealed that both young and older adults selectively prioritized high-value words on the preencoding trials, but not on postencoding trials, on this color-based categorical (low-medium-high) value task. The present study highlights a critical role of goal-directed knowledge of value-based instructions prior to encoding to facilitate typically observed value-directed memory selectivity for important information. (PsycInfo Database Record (c) 2023 APA, all rights reserved).

Introduction:Aging negatively impacts the ability to rapidly and successfully switch between two or more tasks that have different rules or objectives. However, previous work has shown that the context impacts the extent of this age-related impairment: while there is relative age-related invariance when participants must rapidly switch back and forth between two simple tasks (often called "switch costs"), age-related differences emerge when the contexts changes from one in which only one task must be performed to one in which multiple tasks must be performed, but a trial-level switch is not required (e.g., task repeat trials within dual task blocks, often called "mixing costs"). Here, we explored these two kinds of costs behaviorally, and also investigated the neural correlates of these effects.Methods:Seventy-one younger adults and 175 older adults completed a task-switching experiment while they underwent fMRI brain imaging. We investigated the impact of age on behavioral performance and neural activity considering two types of potential costs: switch costs (dual-task switch trials minus dual-task non-switch trials), and mixing costs (dual-task non-switch minus single-task trials).Results:We replicated previous behavioral findings, with greater age associated with mixing, but not switch costs. Neurally, we found age-related compensatory activations for switch costs in the dorsal lateral prefrontal cortex, pars opercularis, superior temporal gyrus, and the posterior and anterior cingulate, but age-related under recruitment for mixing costs in fronto-parietal areas including the supramarginal gyrus and pre and supplemental motor areas.Discussion:These results suggest an age-based dissociation between executive components that contribute to task switching.

In 10 experiments, we investigated the relations among curiosity and people's confidence in their answers to general information questions after receiving different kinds of feedback: yes/no feedback, true or false informational feedback under uncertainty, or no feedback. The results showed that when people had given a correct answer, yes/no feedback resulted in a near complete loss of curiosity. Upon learning they had made an error via yes/no feedback, curiosity increased, especially for high-confidence errors. When people were given true feedback under uncertainty (they were given the correct answer but were not told that it was correct), curiosity increased for high-confidence errors but was unchanged for correct responses. In contrast, when people were given false feedback under uncertainty, curiosity increased for high-confidence correct responses but was unchanged for errors. These results, taken as a whole, are consistent with the region of proximal learning model which proposes that while curiosity is minimal when people are completely certain that they know the answer, it is maximal when people believe that they almost know. Manipulations that drew participants toward this region of "almost knowing" resulted in increased curiosity. A serendipitous result was the finding (replicated four times in this study) that when no feedback was given, people were more curious about high-confidence errors than they were about equally high-confidence correct answers. It was as if they had some knowledge, tapped selectively by their feelings of curiosity, that there was something special (and possibly amiss) about high-confidence errors.

Background:Cognitive inhibition is among the executive functions that decline early in the course of normal aging. Failures to be able to inhibit irrelevant information from memory may represent an essential factor of age-associated memory impairment. While a variety of elaborate behavioral tasks have been developed that presumably all index memory inhibition, the extent to which these different tasks measure the same underlying cognitive construct that declines with age has not been well explored. Methods:In the current study, 100 and 75 cognitively healthy younger (n = 71; age = 30.7 ± 5.4 years, 56.7% female) and older (n = 104, age = 69.3 ± 5.9 years, 66.2% female) adults with equivalent educational attainment performed three computer-based memory inhibition tasks: the Retrieval Induced Forgetting task, the Suppress task, and the Directed Forgetting task. We conducted a principal component analysis using scores derived from different components of these tasks to explore whether and how the tasks relate to one another. We further investigated how age, sex and education, along with, in a subsample of the participants, a neuropsychological measure of episodic memory, impacted both the task scores individually, and the principal components derived from the exploratory analysis. Results:We identified 3 distinct sources of variability which represent potentially independent cognitive processes: memory retrieval facilitation, and two memory inhibition processes that distinguished themselves by the degree of volitional initiation of memory suppression. Only the memory retrieval component correlated with a neuropsychologically-derived episodic memory score, and both memory inhibition principal components were age dependent. Conclusion:Our findings provide support for a distinction in memory suppression processes between those 'instructed' to be performed and those which happen without explicit instruction. This distinction adds nuance to the dichotomous classification of controlled vs. automatic inhibitory mechanisms, which have been shown in previous work to vary as a function of the degree of frontal involvement. Our findings further demonstrate that while both of these measures of inhibition were affected by age, the episodic memory component was not, suggesting that inhibitory impairments may precede memory deficits in healthy aging.

Research suggests a larger Stroop interference effect in older than younger adults. However, it is not clear whether this age-related difference is due to a general slowing of information processing, impairment of inhibitory processes involved in selective attention, or cautionary response strategy. To address this limitation, we asked young and old participants to name the color of one of two orthogonally superimposed shapes while ignoring two identical color-names which were either congruent or incongruent to the color of the target shape, and located either in the target shape, in the distractor shape, or in the background. We fit a dual-stage two-phase model of selective attention to each individual’s data. This model assumes that response selection in a Stroop task happens in two stages: an early stage, which is influenced by attentional weight of both the target and distractor, and a late stage, which is derived from the identity of the target. Comparing the estimated parameters across the two age groups indicated that older adults adopted a more conservative response selection boundary and required more perceptual evidence to make a decision. Moreover, at the first stage of response selection, the rate of evidence accumulation for selection of the target was lower in older adults, whereas both groups had a similar evidence accumulation for selection of the distractors. In the second stage of response selection, older adults showed a lower rate of evidence accumulation. However, older adults showed a higher rate of evidence accumulation for the target identification in the later stage of attention selection. These results indicate an impairment of response selection processes in older adults, though they seem to be better at attending the target stimulus at later stages of response selection. In conclusion, these results shed light on the impact of aging on inhibitory processes involved in selective attention.

Abstract Pattern separation studies suggest age-related declines in discriminating between a newly and a previously encountered overlapping mental representations. However, when similar experiences occur contemporaneously, shared features may serve as intrinsic factors that interfere with the ability to encode and retrieve events as distinct memories. If so, successful inhibition of competitors might also be necessary to maintain memory specificity. Here, we investigated the interplay between memory specificity and inhibitory control in younger (20-35;n=34) and older (65+;n=37) adults by testing whether and how presenting a target item with a lure item (varied in its similarity to the target) influenced recognition accuracy, probed using a 3-item (target, lure, and a non-presented control) forced-choice recognition test. Surprisingly, we found no age-related differences, including in target accuracy, which was high in both groups (young=80.25%; older=77.86%). While not age-specific, we did find that the pattern of errors varied as a function of the level of similarity between the items at encoding. When target and lure were highly similar, a greater proportion of control items were falsely-recognized relative to lure items. It is possible that inhibition of the lure spread to the target, leaving both inaccessible at retrieval (e.g., a retrieval-induced forgetting effect). When the target and lure were less similar, participants false alarmed more to lure than control, potentially because the lure provided less competition and thus did not necessitate inhibitory control. These results shed light on how inhibitory processes might be differentially involved, but age-invariant, depending on the similarity of encoded items.

White matter hyperintensities (WMH) are a key hallmark of subclinical cerebrovascular disease and are known to impair cognition. Here, we parcellated WMH using a novel system that segments WMH based on both lobar regions and distance from the ventricles, dividing the brain into a coordinate system composed of 36 distinct parcels ('bullseye' parcellation), and then investigated the effect of distribution on cognition using two different analytic approaches. Data from a well characterized sample of healthy older adults (58 to 84 years) who were free of dementia were included. Cognition was evaluated using 12 computerized tasks, factored onto 4 indices representing episodic memory, speed of processing, fluid reasoning and vocabulary. We first assessed the distribution of WMH according to the bullseye parcellation and tested the relationship between WMH parcellations and performance across the four cognitive domains. Then, we used a data-driven approach to derive latent variables within the WMH distribution, and tested the relation between these latent components and cognitive function. We observed that different, well-defined cognitive constructs mapped to specific WMH distributions. Speed of processing was correlated with WMH in the frontal lobe, while in the case of episodic memory, the relationship was more ubiquitous, involving most of the parcellations. A principal components analysis revealed that the 36 bullseye regions factored onto 3 latent components representing the natural aggrupation of WMH: fronto-parietal periventricular (WMH principally in the frontal and parietal lobes and basal ganglia, especially in the periventricular region); occipital; and temporal and juxtacortical WMH (involving WMH in the temporal lobe, and at the juxtacortical region from frontal and parietal lobes). We found that fronto-parietal periventricular and temporal & juxtacortical WMH were independently associated with speed of processing and episodic memory, respectively. These results indicate that different cognitive impairment phenotypes might present with specific WMH distributions. Additionally, our study encourages future research to consider WMH classifications using parcellations systems other than periventricular and deep localizations.

OBJECTIVES:Declines in the ability to inhibit information, and the consequences to memory of unsuccessful inhibition, have been frequently reported to increase with age. However, few studies have investigated whether sex moderates such effects. Here, we examined whether inhibitory ability may vary as a function of age and sex, and the interaction between these two factors. METHOD:202 older (mean age = 69.40 years) and younger (mean age =30.59 years) participants who had equivalent educational attainment and self-reported health completed 2 tasks that varied only in the time point at which inhibition should occur: either prior to, or after, encoding. RESULTS:While we did not find evidence for age or sex differences in inhibitory processes when information needed to be inhibited prior to encoding, when encoded information being actively held in working memory needed to be suppressed, we found that older women were particularly impaired relative to both younger women and men of either age group. DISCUSSION:These results provide further support for the presence of memorial inhibitory deficits in older age, but add nuance by implicating biological sex as an important mediator in this relationship, with it more difficult for older women to inhibit what was once relevant in memory.

Evidence suggests that older adults have difficulty relative to younger adults in forgetting irrelevant information. Here we sought to understand the physical basis of this deficit by investigating the relationship between cortical thickness and intentional forgetting, using an item-method directed forgetting task. We tested younger (n = 44) and older (n = 54) adults’ memories for words that they were instructed to either remember or to forget, and then extracted cortical thickness values from brain regions previously shown, using functional neuroimaging, to be associated with memory suppression, including the right inferior frontal gyrus, the right postcentral gyrus and the left superior/middle frontal gyrus. Results from a parallel mediation model indicated that variations in cortical thickness in the right inferior frontal gyrus, but not the right postcentral gyrus or left superior/middle frontal gyrus, partially explained age-related differences in directed forgetting: older adults with thinner cortices in this area showed worse forgetting ability. This is the first study to explore how neuromorphological differences affect the ability to intentionally suppress items in memory. The results suggest that age-related differences in directed forgetting may be partly driven by cortical thickness in a brain structure known to be functionally involved in directed forgetting, and inhibitory control more broadly, supporting a contribution of deficient inhibition to this phenomenon.

Background: The current pilot study was designed to examine the association between hippocampal γ-aminobutyric acid (GABA) concentration and episodic memory in older individuals, as well as the impact of two major risk factors for Alzheimer’s disease (AD)—female sex and Apolipoprotein ε4 (ApoE ε4) genotype—on this relationship. Methods: Twenty healthy, community-dwelling individuals aged 50–71 (11 women) took part in the study. Episodic memory was evaluated using a Directed Forgetting task, and GABA+ was measured in the right hippocampus using a Mescher-Garwood point-resolved magnetic resonance spectroscopy (MRS) sequence. Multiple linear regression models were used to quantify the relationship between episodic memory, GABA+, ApoE ɛ4, and sex, controlling for age and education. Results: While GABA+ did not interact with ApoE ɛ4 carrier status to influence episodic memory (p = 0.757), the relationship between GABA+ and episodic memory was moderated by sex: lower GABA+ predicted worse memory in women such that, for each standard deviation decrease in GABA+ concentration, memory scores were reduced by 11% (p = 0.001). Conclusions: This pilot study suggests that sex, but not ApoE ɛ4 genotype, moderates the relationship between hippocampal GABA+ and episodic memory, such that women with lower GABA+ concentration show worse memory performance. These findings, which must be interpreted with caution given the small sample size, may serve as a starting point for larger studies using multimodal neuroimaging to understand the contributions of GABA metabolism to age-related memory decline.

In this review, we focus on the potential role of the γ-aminobutyric acidergic (GABAergic) system in age-related episodic memory impairments in humans, with a particular focus on Alzheimer's disease (AD). Well-established animal models have shown that GABA plays a central role in regulating and synchronizing neuronal signaling in the hippocampus, a brain area critical for episodic memory that undergoes early and significant morphologic and functional changes in the course of AD. Neuroimaging research in humans has documented hyperactivity in the hippocampus and losses of resting state functional connectivity in the Default Mode Network, a network that itself prominently includes the hippocampus-presaging episodic memory decline in individuals at-risk for AD. Apolipoprotein ε4, the highest genetic risk factor for AD, is associated with GABAergic dysfunction in animal models, and episodic memory impairments in humans. In combination, these findings suggest that GABA may be the linchpin in a complex system of factors that eventually leads to the principal clinical hallmark of AD: episodic memory loss. Here, we will review the current state of literature supporting this hypothesis. First, we will focus on the molecular and cellular basis of the GABAergic system and its role in memory and cognition. Next, we report the evidence of GABA dysregulations in AD and normal aging, both in animal models and human studies. Finally, we outline a model of GABAergic dysfunction based on the results of functional neuroimaging studies in humans, which have shown hippocampal hyperactivity to episodic memory tasks concurrent with and even preceding AD diagnosis, along with factors that may modulate this association.

A key challenge in the field of cognitive neuroscience is to identify discriminable cognitive functions, and then map these functions to brain activity. In the current study, we set out to explore the relationships between performance arising from different cognitive tasks thought to tap different domains of cognition, and then to test whether these distinct latent cognitive abilities also are subserved by corresponding “latent” brain substrates. To this end, we tested a large sample of adults under the age of 40 on twelve cognitive tasks as they underwent fMRI scanning. Exploratory factor analysis revealed 4-factor model, dissociating tasks into processes corresponding to episodic memory retrieval, reasoning, speed of processing and vocabulary. An analysis of the topographic covariance patterns of the BOLD-response acquired during each task similarity also converged on four neural networks that corresponded to the 4 latent factors. These results suggest that distinct ontologies of cognition are subserved by corresponding distinct neural networks.

We propose a framework for understanding epistemic curiosity as a metacognitive feeling state that is related to the individual's Region of Proximal Learning (RPL), an adaptive mental space where we feel we are on the verge of knowing or understanding. First, we review several historical views, contrasting the RPL perspective with alternative views of curiosity. Second, we detail the processes, conditions, and outcomes within the RPL framework which are proposed to be related to curiosity. Finally, we review several lines of evidence relevant to the relation between RPL and curiosity. These include (1) differences in the conditions under which experts and novices mind wander, (2) experiments investigating people's choices of whether to study materials for which they have high versus low feelings of knowing, (3) results related to people's engagement with corrections to errors made with high confidence, and (4) curiosity, attention, and learning data related to the tip-of-the-tongue state.