Single-cell atlas reveals correlates of high cognitive function, dementia, and resilience to Alzheimer's disease pathology.

Alzheimer's disease (AD) is the most common cause of dementia worldwide, but the molecular and cellular mechanisms underlying cognitive impairment remain poorly understood. To address this, we generated a single-cell transcriptomic atlas of the aged human prefrontal cortex covering 2.3 million cells from postmortem human brain samples of 427 individuals with varying degrees of AD pathology and cognitive impairment. Our analyses identified AD-pathology-associated alterations shared between excitatory neuron subtypes, revealed a coordinated increase of the cohesin complex and DNA damage response factors in excitatory neurons and in oligodendrocytes, and uncovered genes and pathways associated with high cognitive function, dementia, and resilience to AD pathology. Furthermore, we identified selectively vulnerable somatostatin inhibitory neuron subtypes depleted in AD, discovered two distinct groups of inhibitory neurons that were more abundant in individuals with preserved high cognitive function late in life, and uncovered a link between inhibitory neurons and resilience to AD pathology.

Glucose-oxygen coupling can serve as a biomarker for neuroinflammation-related genetic variants.

The single-nucleotide polymorphism rs3197999 in the macrophage-stimulating protein 1 gene is a missense variant. Studies have indicated that macrophage-stimulating protein 1 mediates neuronal loss and synaptic plasticity damage, and overexpression of the macrophage-stimulating protein 1 gene leads to the excessive activation of microglial cells, thereby resulting in an elevation of cerebral glucose metabolism. Traditional diagnostic models may be disrupted by neuroinflammation, making it difficult to predict the pathological status of patients solely based on single-modal images. We hypothesize that the macrophage-stimulating protein 1 rs3197999 single-nucleotide polymorphism may lead to imbalances in glucose and oxygen metabolism, thereby influencing cognitive resilience and the progression of Alzheimer's disease. In this study, we found that among 121 patients with mild cognitive impairment, carriers of the macrophage-stimulating protein 1 rs3197999 risk allele showed a significant reduction in the coupling of glucose and oxygen metabolism in the dorsolateral prefrontal cortex region. However, the rs3197999 variant did not induce significant differences in glucose metabolism and neuronal activity signals. Furthermore, the rs3197999 risk allele correlated with a higher rate of increase in clinical dementia score, mediated by the coupling of glucose and oxygen metabolism.

TMEM106B coding variant is protective and deletion detrimental in a mouse model of tauopathy.

TMEM106B is a risk modifier of multiple neurological conditions, where a single coding variant and multiple non-coding SNPs influence the balance between susceptibility and resilience. Two key questions that emerge from past work are whether the lone T185S coding variant contributes to protection, and if the presence of TMEM106B is helpful or harmful in the context of disease. Here, we address both questions while expanding the scope of TMEM106B study from TDP-43 to models of tauopathy. We generated knockout mice with constitutive deletion of TMEM106B, alongside knock-in mice encoding the T186S knock-in mutation (equivalent to the human T185S variant), and crossed both with a P301S transgenic tau model to study how these manipulations impacted disease phenotypes. We found that TMEM106B deletion accelerated cognitive decline, hind limb paralysis, tau pathology, and neurodegeneration. TMEM106B deletion also increased transcriptional correlation with human AD and the functional pathways enriched in KO:tau mice aligned with those of AD. In contrast, the coding variant protected against tau-associated cognitive decline, synaptic impairment, neurodegeneration, and paralysis without affecting tau pathology. Our findings reveal that TMEM106B is a critical safeguard against tau aggregation, and that loss of this protein has a profound effect on sequelae of tauopathy. Our study further demonstrates that the coding variant is functionally relevant and contributes to neuroprotection downstream of tau pathology to preserve cognitive function.

Ketone monoester attenuates declines in cognitive performance and oxygen saturation during acute severe hypoxic exposure under resting conditions.

Exogenous ketone supplements are a potential augmentation strategy for cognitive resilience during acute hypoxic exposure due to their capacity to attenuate the decline in oxygen (O2) availability, and by providing an alternative substrate for cerebral metabolism. Utilizing a single-blind randomized crossover design, 16 male military personnel (age, 25.3 ± 2.4 year, body mass, 86.2 ± 9.3 kg) performed tests of cognitive performance at rest in three environments: room air (baseline), normoxia (20 min; 0 m; 20.9% O2) and hypoxia (20 min; 6096 m, 9.7% O2) using a reduced O2 breathing device (ROBD). (R)-3-Hydroxybutyl (R)-3-hydroxybutyrate (R-BD R-ßHB) ketone monoester (KME; 650 mg/kg, split dose given at 30 min prior to each exposure) or taste-matched placebo (PLA) was ingested prior to normoxia and hypoxic exposure. Blood R-ßHB and glucose concentrations, cognitive performance and O2 saturation ( S p O 2 ${{S}_{{\mathrm{p}}{{{\mathrm{O}}}_{\mathrm{2}}}}}$ ) were collected throughout. KME ingestion increased blood R-ßHB concentration, which was rapid and sustained (>4 mM 30 min post; P < 0.001) and accompanied by lower blood glucose concentration (∼20 mg/dL; P < 0.01) compared to PLA. Declines in cognitive performance during hypoxic exposure, assessed as cognitive efficiency during a Defense Automated Neurobehavioral Assessment (DANA) code substitution task, were attenuated with KME leading to 6.8 (95% CL: 1.0, 12.6) more correct responses per minute compared to PLA (P = 0.018). The decline in S p O 2 ${{S}_{{\mathrm{p}}{{{\mathrm{O}}}_{\mathrm{2}}}}}$ during hypoxic exposure was attenuated (6.40% S p O 2 ${{S}_{{\mathrm{p}}{{{\mathrm{O}}}_{\mathrm{2}}}}}$ ; 95% CL: 0.04, 12.75; P = 0.049) in KME compared to PLA (KME, 76.8 ± 6.4% S p O 2 ${{S}_{{\mathrm{p}}{{{\mathrm{O}}}_{\mathrm{2}}}}}$ ; PLA, 70.4 ± 7.4% S p O 2 ${{S}_{{\mathrm{p}}{{{\mathrm{O}}}_{\mathrm{2}}}}}$ ). Acute ingestion of KME attenuated the decline in cognitive performance during acute severe hypoxic exposure, which coincided with attenuation of declines in O2 saturation. HIGHLIGHTS: What is the central question of this study? Can exogenous ketosis act as a countermeasure to declines in blood oxygen saturation and cognitive performance during acute severe hypoxic exposure at rest? What is the main finding and its importance? Acute exogenous ketosis via ingestion of a drink containing the (R)-3-hydroxybutyl (R)-3-hydroxybutyrate ketone monoester prior to acute severe hypoxic exposure attenuated hypoxia-induced declines in blood oxygen saturation and cognitive performance at rest.

A First Exploration: Can Eye Movement Desensitization and Reprocessing Improve Cognition in Older Adults With Posttraumatic Stress Disorder?

OBJECTIVES: In older adults, PTSD is associated with decreased verbal learning and executive dysfunction. Therefore, feasibility of EMDR-treatment to improve cognitive performance in older adults with PTSD was examined. Additionally, we investigated pre-treatment correlation with often co-occurring risk factors for cognitive decline (sleep problems, depressive disorder, physical inactivity, childhood traumatic events). DESIGN: Multicenter design with pre-post measurements. SETTING: Psychiatric Dutch hospitals Mondriaan Mental Health Center and Altrecht. PARTICIPANTS: 22 treatment-seeking PTSD-outpatients (60-84 years). INTERVENTION: Weekly one-hour EMDR session during 3, 6, or 9 months. MEASUREMENTS: PTSD was assessed with Clinician-Administered PTSD-scale for DSM-5 (CAPS-5). Verbal learning memory was measured with Auditory Verbal Learning Test (RAVLT), interference with Stroop Colour-Word Test (SCWT) and working memory with Wechsler Adult Intelligence Scale-Digit Span (WAIS-IV-DS). RESULTS: A Linear mixed-model showed significant improvement on RAVLT immediate-recall (F (1, 21) = 15.928, P = .001, 95% CI -6.98-2.20), delayed-recall (F (1, 21) = 7.095, P = .015, 95% CI -2.43-.30), recognition (F (21) = 8.885, P = .007, 95% CI -1.70- -.30), and SCWT (F (1 ,21) = 5.504, P = .029, 95% CI 4.38-72.78) but not on WAIS-IV-DS (F (20) = -1.237, P = .230, 95% CI -3.07-.78). There was no significant influence of therapy duration and CAPS-5 pre-treatment scores. There were small-medium nonsignificant correlations between CAPS-5 and cognitive performance pre-post differences, and between most cognitive measures and sleep problems, depressive disorder, and physical inactivity. CONCLUSIONS: Cognitive functioning on memory and attention possible increased in older adults with PTSD after EMDR treatment. Further research is needed with a larger sample and a control condition to corroborate these findings and to identify the possible mediating role of modifiable risk factors.

Estimating Gender Differences in the Association between Cognitive Resilience and Mild Cognitive Impairment Incidence.

INTRODUCTION: Recent evidence suggests that the influence of verbal intelligence and education on the onset of subjective cognitive decline may be modulated by gender, where education contributes less to cognitive resilience (CR) in women than in men. This study aimed to examine gender differences in the association between CR and mild cognitive impairment (MCI) incidence in an Australian population-based cohort. METHODS: We included 1,806 participants who had completed at least the first two waves and up to four waves of assessments in the Personality and Total Health (PATH) Through Life study (baseline: 49% female, male = 62.5, SD = 1.5, age range = 60-66 years). CR proxies included measures of educational attainment, occupation skill, verbal intelligence, and leisure activity. Discrete-time survival analyses were conducted to examine gender differences in the association between CR proxies and MCI risk, adjusting for age and apolipoprotein E4 status. RESULTS: Gender differences were only found in the association between occupation and MCI risk, where lower occupation skill was more strongly associated with higher risk in men than in women (odds ratio [OR] = 1.30, 95% confidence interval [CI] [1.07, 1.57]). In both genders, after adjusting for education and occupation, one SD increase in leisure activity was associated with lower MCI risk by 32% (OR = 0.76, 95% CI [0.65, 0.89]). Higher scores in verbal intelligence assessment were associated with reduced risk of MCI by 28% (OR = 0.78, 95% CI [0.69, 0.89]). CONCLUSION: Occupational experience may contribute to CR differently between genders. Life course cognitive engagement and verbal intelligence may be more protective against MCI than education and occupation for both men and women.

Structural white matter properties and cognitive resilience to tau pathology.

INTRODUCTION: We assessed whether macro- and/or micro-structural white matter properties are associated with cognitive resilience to Alzheimer's disease pathology years prior to clinical onset. METHODS: We examined whether global efficiency, an indicator of communication efficiency in brain networks, and diffusion measurements within the limbic network and default mode network moderate the association between amyloid-ß/tau pathology and cognitive decline. We also investigated whether demographic and health/risk factors are associated with white matter properties. RESULTS: Higher global efficiency of the limbic network, as well as free-water corrected diffusion measures within the tracts of both networks, attenuated the impact of tau pathology on memory decline. Education, age, sex, white matter hyperintensities, and vascular risk factors were associated with white matter properties of both networks. DISCUSSION: White matter can influence cognitive resilience against tau pathology, and promoting education and vascular health may enhance optimal white matter properties. HIGHLIGHTS: Aß and tau were associated with longitudinal memory change over ∼7.5 years. White matter properties attenuated the impact of tau pathology on memory change. Health/risk factors were associated with white matter properties.

Cognitive resilience/reserve: Myth or reality? A review of definitions and measurement methods.

INTRODUCTION: This review examines the concept of cognitive reserve (CR) in relation to brain aging, particularly in the context of dementia and its early stages. CR refers to an individual's ability to maintain or regain cognitive function despite brain aging, damage, or disease. Various factors, including education, occupation complexity, leisure activities, and genetics are believed to influence CR. METHODS: We revised the literature in the context of CR. A total of 842 articles were identified, then we rigorously assessed the relevance of articles based on titles and abstracts, employing a systematic approach to eliminate studies that did not align with our research objectives. RESULTS: We evaluate-also in a critical way-the methods commonly used to define and measure CR, including sociobehavioral proxies, neuroimaging, and electrophysiological and genetic measures. The challenges and limitations of these measures are discussed, emphasizing the need for more targeted research to improve the understanding, definition, and measurement of CR. CONCLUSIONS: The review underscores the significance of comprehending CR in the context of both normal and pathological brain aging and emphasizes the importance of further research to identify and enhance this protective factor for cognitive preservation in both healthy and neurologically impaired older individuals. HIGHLIGHTS: This review examines the concept of cognitive reserve in brain aging, in the context of dementia and its early stages. We have evaluated the methods commonly used to define and measure cognitive reserve. Sociobehavioral proxies, neuroimaging, and electrophysiological and genetic measures are discussed. The review emphasizes the importance of further research to identify and enhance this protective factor for cognitive preservation.

Cognitive integrity in Non-Demented Individuals with Alzheimer's Neuropathology is associated with preservation and remodeling of dendritic spines.

INTRODUCTION: Individuals referred to as Non-Demented with Alzheimer's Neuropathology (NDAN) exhibit cognitive resilience despite presenting Alzheimer's disease (AD) histopathological signs. Investigating the mechanisms behind this resilience may unveil crucial insights into AD resistance. METHODS: DiI labeling technique was used to analyze dendritic spine morphology in control (CTRL), AD, and NDAN post mortem frontal cortex, particularly focusing on spine types near and far from amyloid beta (Aß) plaques. RESULTS: NDAN subjects displayed a higher spine density in regions distant from Aß plaques versus AD patients. In distal areas from the plaques, NDAN individuals exhibited more immature spines, while AD patients had a prevalence of mature spines. Additionally, our examination of levels of Peptidyl-prolyl cis-trans isomerase NIMA-interacting 1 (Pin1), a protein associated with synaptic plasticity and AD, showed significantly lower expression in AD versus NDAN and CTRL. DISCUSSION: These results suggest that NDAN individuals undergo synaptic remodeling, potentially facilitated by Pin1, serving as a compensatory mechanism to preserve cognitive function despite AD pathology. HIGHLIGHTS: Spine density is reduced near Aß plaques compared to the distal area in CTRL, AD, and NDAN dendrites. NDAN shows higher spine density than AD in areas far from Aß plaques. Far from Aß plaques, NDAN has a higher density of immature spines, AD a higher density of mature spines. AD individuals show significantly lower levels of Pin1 compared to NDAN and CTRL.

Well-Being and Cognitive Resilience to Dementia-Related Neuropathology.

Not all older adults with dementia-related neuropathology in their brains experience cognitive decline or impairment. Instead, some people maintain relatively normal cognitive functioning despite neuropathologic burden, a phenomenon called cognitive resilience. Using a longitudinal, epidemiological, clinical-pathologic cohort study of older adults in the United States (N = 348), the present research investigated associations between well-being and cognitive resilience. Consistent with preregistered hypotheses, results showed that higher eudaimonic well-being (measured via the Ryff Psychological Well-Being Scale) and higher hedonic well-being (measured via the Satisfaction with Life Scale) were associated with better-than-expected cognitive functioning relative to one's neuropathological burden (i.e., beta-amyloid, neurofibrillary tangles, Lewy bodies, vascular pathologies, hippocampal sclerosis, and TDP-43). The association of eudaimonic well-being in particular was present above and beyond known cognitive resilience factors (i.e., socioeconomic status, education, cognitive activity, low neuroticism, low depression) and dementia risk factors (i.e., apolipoprotein E [ApoE] genotype, medical comorbidities). This research highlights the importance of considering eudaimonic well-being in efforts to prevent dementia.

The association of MIND diet with cognitive resilience to neuropathologies.

INTRODUCTION: Cognitive resilience (CR) can be defined as the continuum of better through worse than expected cognition, given the degree of neuropathology. The relation of healthy diet patterns to CR remains to be elucidated. METHODS: Using longitudinal cognitive data and post mortem neuropathology from 578 deceased older adults, we examined associations between the Mediterranean-DASH Intervention for Neurodegenerative Delay (MIND) diet at baseline and two standardized CR measures reflecting higher cognitive levels over time (CR Level ¯ $_{\overline {{\rm{Level}}}} $ ), and slower decline (CRSlope ), than expected given neuropathology. RESULTS: Compared to individuals in the lowest tertile of MIND score, those in the top tertile had higher CR Level ¯ $_{\overline {{\rm{Level}}}} $ (mean difference [MD] = 0.34; 95% confidence interval [CI] = 0.14, 0.55) and CRSlope (MD = 0.27; 95% CI = 0.05, 0.48), after multivariable adjustment. Overall MIND score was more strongly related to CR than the individual food components. DISCUSSION: The MIND diet is associated with both higher cognition and slower rates of cognitive decline, after controlling for neuropathology, indicating the MIND diet may be important to cognitive resilience.

Late-life physical activity relates to brain tissue synaptic integrity markers in older adults.

INTRODUCTION: Physical activity (PA) is widely recommended for age-related brain health, yet its neurobiology is not well understood. Animal models indicate PA is synaptogenic. We examined the relationship between PA and synaptic integrity markers in older adults. METHODS: Four hundred four decedents from the Rush Memory and Aging Project completed annual actigraphy monitoring (Mean visits = 3.5±2.4) and post mortem evaluation. Brain tissue was analyzed for presynaptic proteins (synaptophysin, synaptotagmin-1, vesicle-associated membrane proteins, syntaxin, complexin-I, and complexin-II), and neuropathology. Models examined relationships between late-life PA (averaged across visits), and timing-specific PA (time to autopsy) with synaptic proteins. RESULTS: Greater late-life PA associated with higher presynaptic protein levels (0.14 < ß < 0.20), except complexin-II (ß = 0.08). Relationships were independent of pathology but timing specific; participants who completed actigraphy within 2 years of brain tissue measurements showed largest PA-to-synaptic protein associations (0.32 < ß < 0.38). Relationships between PA and presynaptic proteins were comparable across brain regions sampled. DISCUSSION: PA associates with synaptic integrity in a regionally global, but time-linked nature in older adults.

Quantifying longitudinal cognitive resilience to Alzheimer's disease and other neuropathologies.

INTRODUCTION: Cognitive resilience (CR) has been defined as the continuum of better (or worse) than expected cognition, given the degree of neuropathology. To quantify this concept, existing approaches focus on either cognitive level at a single time point or slopes of cognitive decline. METHODS: In a prospective study of 1215 participants, we created a continuous measure of CR defined as the mean of differences between estimated person-specific and marginal cognitive levels over time, after accounting for neuropathologies. RESULTS: Neuroticism and depressive symptoms were associated with all CR measures (P-values < .012); as expected, cognitive activity and education were only associated with the cognitive-level approaches (P-values < .0002). However, compared with the existing CR measures focusing on a single measure or slopes of cognition, our new measure yielded stronger relations with risk factors. DISCUSSION: Defining CR based on the longitudinal differences between person-specific and marginal cognitive levels is a novel and complementary way to quantify CR.

Identifying the Main Functional Pathways Associated with Cognitive Resilience to Alzheimer's Disease.

Understanding the mechanisms involved in cognitive resilience in Alzheimer's disease (AD) represents a promising strategy to identify novel treatments for dementia in AD. Previous findings from our group revealed that the study of aged-Tg2576 cognitive resilient individuals is a suitable tool for this purpose. In the present study, we performed a transcriptomic analysis using the prefrontal cortex of demented and resilient Tg2576 transgenic AD mice. We have been able to hypothesize that pathways involved in inflammation, amyloid degradation, memory function, and neurotransmission may be playing a role on cognitive resilience in AD. Intriguingly, the results obtained in this study are suggestive of a reduction of the influx of peripheral immune cells into the brain on cognitive resilient subjects. Indeed, CD4 mRNA expression is significantly reduced on Tg2576 mice with cognitive resilience. For further validation of this result, we analyzed CD4 expression in human AD samples, including temporal cortex and peripheral blood mononuclear cells (PBMC). Interestingly, we have found a negative correlation between CD4 mRNA levels in the periphery and the score in the Mini-Mental State Exam of AD patients. These findings highlight the importance of understanding the role of the immune system on the development of neurodegenerative diseases and points out to the infiltration of CD4+ cells in the brain as a key player of cognitive dysfunction in AD.

Specifying and Mitigating Thermal Stress Effects on Cognition During Personal Protective Equipment Use.

OBJECTIVE: To report present understanding concerning selected task and environmental factors influencing the changing performance capacity associated with use of personal protective equipment (PPE). BACKGROUND: Much knowledge is available concerning change in complex cognitive capacities under the effects of thermal stress. Our science can inform critical care facilities as to remediation strategies such as work-rest schedules to minimize performance error in highly cognitively demanding circumstances such as intensive care units. METHOD: The present exposition draws from the state-of-the-art understanding concerning thermal stress effects on cognition and workload in complex and demanding tasks. RESULTS: The summation and synthesis of HF/E findings provides important insights into combinatorial effects of forms of stress, typically dealt with only as discrete sources in traditional standards and regulations. The identified interaction between ascending thermal stress and cognitive task demand provides an instance of the plurality of ways HF/E can specify performance limitations in safety-critical circumstances, as witnessed in the current pandemic. CONCLUSION: Accumulated HF/E insights provide systematic ways in which to address and ameliorate the combined forces of physical and cognitive stress on medical personnel constrained to use varying forms of PPE. These principles extend beyond this specific domain to all who are required to work in differential and isolated microclimates. APPLICATION: To minimize the possibility of critical and life-threatening error in intensive care facilities which necessitate PPE use, we need principled work-rest ratio and heat stress mitigation guidance. To promote health, we need to champion healthy work practices in our health workers. HF/E insights can help achieve this important goal.

Cognitive resilience among APOE ε4 carriers in the oldest old.

OBJECTIVES: Relatively few APOE ε4+ carriers survive to old age (age 80+) without cognitive impairment (CI); thus, little is known about distinguishing characteristics of resilient APOE ε4+ carriers. Herein, we describe the sociodemographic characteristics of a large sample of resilient APOE ε4+ women from the Women's Health Initiative Memory Study (WHIMS) and compare them to noncarriers and APOE ε4+ women who developed CI before age 80. METHODS: Women were recruited for clinical trials evaluating postmenopausal hormone therapy and incidence of dementia. During posttrial follow-up, cognitive status was adjudicated annually. Among 5716 women, we compared groups by APOE ε4 status using logistic regression, covarying for treatment, demographics, lifestyle, cardiovascular and physical function, well-being, and self-rated general health. RESULTS: Among 557 APOE ε4+ women, those who survived to age 80+ without CI had higher baseline self-rated general health (odds ratio [OR]: 1.02; 95% confidence interval [CI], 1.01-1.04) and cognitive scores (OR: 1.18; 95% CI, 1.12-1.25) than those who did not reach age 80 without CI. Baseline high total cholesterol and low-density lipoprotein (LDL) levels were similar across APOE ε4+ groups but were higher compared with APOE ε4- women. Among women who survived to 80+ without CI, more APOE ε4+ women had a history of high total cholesterol (P = .003) and LDL cholesterol (OR: 1.01; 95% CI, 1.00-1.01). There were no differences in hypertension, diabetes, or other vascular risk factors in APOE ε4+ women compared with noncarriers. CONCLUSIONS: Results highlight the importance of baseline cognitive function and general health for late-life cognition among ε4+ women.

A mathematical model of embodied consciousness.

We introduce a mathematical model of embodied consciousness, the Projective Consciousness Model (PCM), which is based on the hypothesis that the spatial field of consciousness (FoC) is structured by a projective geometry and under the control of a process of active inference. The FoC in the PCM combines multisensory evidence with prior beliefs in memory and frames them by selecting points of view and perspectives according to preferences. The choice of projective frames governs how expectations are transformed by consciousness. Violations of expectation are encoded as free energy. Free energy minimization drives perspective taking, and controls the switch between perception, imagination and action. In the PCM, consciousness functions as an algorithm for the maximization of resilience, using projective perspective taking and imagination in order to escape local minima of free energy. The PCM can account for a variety of psychological phenomena: the characteristic spatial phenomenology of subjective experience, the distinctions and integral relationships between perception, imagination and action, the role of affective processes in intentionality, but also perceptual phenomena such as the dynamics of bistable figures and body swap illusions in virtual reality. It relates phenomenology to function, showing the computational advantages of consciousness. It suggests that changes of brain states from unconscious to conscious reflect the action of projective transformations and suggests specific neurophenomenological hypotheses about the brain, guidelines for designing artificial systems, and formal principles for psychology.

Aging and cognitive resilience: Molecular mechanisms as new potential therapeutic targets.

As the global population ages, the need to prolong lifespan and healthspan becomes increasingly imperative. Understanding the molecular determinants underlying cognitive resilience, together with changes during aging and the (epi)genetic factors that predispose an individual to decreased cognitive resilience, open avenues for researching novel therapies. This review provides a critical and timely appraisal of the molecular mechanisms underlying cognitive resilience, framed within a critical analysis of emerging therapeutic strategies to mitigate age-related cognitive decline. Significant insights from both animals and human subjects are discussed herein, directed either toward active pharmaceutical ingredients (drug repositioning or macromolecules), or, alternatively, advanced cellular therapies.

The Mediating Role of Cortical Atrophy on the Relationship between the Resilience Index and Cognitive Function: Findings from the Healthy Brain Initiative.

Background: Lifestyle factors are linked to differences in brain aging and risk for Alzheimer's disease, underscored by concepts like 'cognitive reserve' and 'brain maintenance'. The Resilience Index (RI), a composite of 6 factors (cognitive reserve, physical and cognitive activities, social engagement, diet, and mindfulness) provides such a holistic measure. Objective: This study aims to examine the association of RI scores with cognitive function and assess the mediating role of cortical atrophy. Methods: Baseline data from 113 participants (aged 45+, 68% female) from the Healthy Brain Initiative were included. Life course resilience was estimated with the RI, cognitive performance with Cognivue®, and brain health using a machine learning derived Cortical Atrophy Score (CAS). Mediation analysis probed the relationship between RI, cognitive outcomes, and cortical atrophy. Results: In age and sex adjusted models, the RI was significantly associated with CAS (ß= -0.25, p = 0.006) and Cognivue® scores (ß= 0.32, p < 0.001). The RI-Cognivue® association was partially mediated by CAS (ß= 0.07; 95% CI [0.02, 0.14]). Conclusions: Findings revealed that the collective effect of early and late-life lifestyle resilience factors on cognition are partially explained by their association with less brain atrophy. These findings underscore the value of comprehensive lifestyle assessments in understanding the risk and progression of cognitive decline and Alzheimer's disease in an aging population.

Left Frontoparietal Control Network Connectivity Moderates the Effect of Amyloid on Cognitive Decline in Preclinical Alzheimer's Disease: The A4 Study.

BACKGROUND: Stronger resting-state functional connectivity of the default mode and frontoparietal control networks has been associated with cognitive resilience to Alzheimer's disease related pathology and neurodegeneration in smaller cohort studies. OBJECTIVES: We investigated whether these networks are associated with longitudinal CR to AD biomarkers of beta-amyloid (Aß). DESIGN: Longitudinal mixed. SETTING: The Anti-Amyloid Treatment in Asymptomatic Alzheimer's Disease (A4) study and its natural history observation arm, the Longitudinal Evaluation of Amyloid Risk and Neurodegeneration (LEARN) study. PARTICIPANTS: A sample of 1,021 cognitively unimpaired older adults (mean age = 71.2 years [SD = 4.7 years], 61% women, 42% APOEε4 carriers, 52% Aß positive). MEASUREMENTS: Global cognitive performance (Preclinical Alzheimer's Cognitive Composite) was assessed over an average 5.4 year follow-up period (SD = 2 years). Cortical Aß and functional connectivity (left and right frontoparietal control and default mode networks) were estimated from fMRI and PET, respectively, at baseline. Covariates included baseline age, APOEε4 carrier status, years of education, adjusted gray matter volume, head motion, study group, cumulative treatment exposure, and cognitive test version. RESULTS: Mixed effects models revealed that functional connectivity of the left frontoparietal control network moderated the negative effect of Aß on cognitive change (p = .025) such that stronger connectivity was associated with reduced Aß-related cognitive decline. CONCLUSIONS: Our results demonstrate a potential protective effect of functional connectivity in preclinical AD, such that stronger connectivity in this network is associated with slower Aß-related cognitive decline.