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Background: In Alzheimer's disease (AD), the associations between tau pathology and brain atrophy and cognitive decline are well established, but imperfect. We investigate whether cerebrospinal fluid (CSF) biomarkers of biological processes (vascular, synaptic, and axonal integrity, neuroinflammation, neurotrophic factors) explain the disconnection between tau pathology and brain atrophy (brain resilience), and tau pathology and cognitive decline (cognitive resilience). Methods: We included 428 amyloid positive participants (134 cognitively unimpaired (CU), 128 with mild cognitive impairment (MCI), 166 with AD dementia) from the BioFINDER-2 study. At baseline, participants underwent tau positron emission tomography (tau-PET), magnetic resonance imaging (MRI), cognitive testing, and lumbar puncture. Longitudinal data were available for MRI (mean (standard deviation) follow-up 26.4 (10.7) months) and cognition (25.2 (11.4) months). We analysed 18 pre-selected CSF proteins, reflecting vascular, synaptic, and axonal integrity, neuroinflammation, and neurotrophic factors. Stratifying by cognitive status, we performed linear mixed-effects models with cortical thickness (brain resilience) and global cognition (cognitive resilience) as dependent variables to assess whether the CSF biomarkers interacted with tau-PET levels in its effect on cortical atrophy and cognitive decline. Results: Regarding brain resilience, interaction effects were observed in AD dementia, with vascular integrity biomarkers (VEGF-A (βinteraction = -0.009, pFDR = 0.047) and VEGF-B (βinteraction = -0.010, pFDR = 0.037)) negatively moderating the association between tau-PET signal and atrophy. In MCI, higher NfL levels were associated with more longitudinal cortical atrophy (β = -0.109, pFDR = 0.033) and lower baseline cortical thickness (β = -0.708, pFDR = 0.033) controlling for tau-PET signal. Cognitive resilience analyses in CU revealed interactions with tau-PET signal for inflammatory (GFAP, IL-15; βinteraction -0.073–-0.069, pFDR 0.001–0.045), vascular (VEGF-A, VEGF-D, PGF; βinteraction -0.099–-0.063, pFDR < 0.001–0.046), synaptic (14–3-3ζ/δ; βinteraction = -0.092, pFDR = 0.041), axonal (NfL; βinteraction = -0.079, pFDR < 0.001), and neurotrophic (NGF; βinteraction = 0.091, pFDR < 0.001) biomarkers. In MCI higher NfL levels (βmain = -0.690, pFDR = 0.025) were associated with faster cognitive decline independent of tau-PET signal. Conclusions: Biomarkers of co-existing pathological processes, in particular vascular pathology and axonal degeneration, interact with levels of tau pathology on its association with the downstream effects of AD pathology (i.e. brain atrophy and cognitive decline). This indicates that vascular pathology and axonal degeneration could impact brain and cognitive resilience. [ABSTRACT FROM AUTHOR]

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‐βHB) 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‐βHB and glucose concentrations, cognitive performance and O2 saturation (SpO2${{S}_{{\mathrm{p}}{{{\mathrm{O}}}_{\mathrm{2}}}}}$) were collected throughout. KME ingestion increased blood R‐βHB 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 SpO2${{S}_{{\mathrm{p}}{{{\mathrm{O}}}_{\mathrm{2}}}}}$ during hypoxic exposure was attenuated (6.40% SpO2${{S}_{{\mathrm{p}}{{{\mathrm{O}}}_{\mathrm{2}}}}}$; 95% CL: 0.04, 12.75; P = 0.049) in KME compared to PLA (KME, 76.8 ± 6.4% SpO2${{S}_{{\mathrm{p}}{{{\mathrm{O}}}_{\mathrm{2}}}}}$; PLA, 70.4 ± 7.4% SpO2${{S}_{{\mathrm{p}}{{{\mathrm{O}}}_{\mathrm{2}}}}}$). Acute ingestion of KME attenuated the decline in cognitive performance during acute severe hypoxic exposure, which coincided with attenuation of declines in O2 saturation. 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. [ABSTRACT FROM AUTHOR]

INTRODUCTION: The molecular basis of cognitive resilience (CR) among pathologically confirmed Alzheimer's disease (AD) cases is not well understood. METHODS: Abundance of 13 cell types and neuronal subtypes in brain bulk RNA‐seq data from the anterior caudate, dorsolateral prefrontal cortex (DLPFC), and posterior cingulate cortex (PCC) obtained from 434 AD cases, 318 cognitively resilient AD cases, and 188 controls in the Religious Orders Study and Rush Memory and Aging Project was estimated by deconvolution. RESULTS: PVALB+ neuron abundance was negatively associated with cognitive status and tau pathology in the DLPFC and PCC (Padj < 0.001) and the most reduced neuronal subtype in AD cases compared to controls in DLPFC (Padj = 8.4 × 10−7) and PCC (Padj = 0.0015). We identified genome‐wide significant association of neuron abundance with TMEM106B single nucleotide polymorphism rs13237518 in PCC (p = 6.08 × 10−12). rs13237518 was also associated with amyloid beta (p = 0.0085) and tangles (p = 0.0073). DISCUSSION: High abundance of PVALB+ neurons may be a marker of CR. TMEM106B variants may influence CR independent of AD pathology. Highlights: Neuron retention and a lack of astrocytosis are highly predictive of Alzheimer's disease (AD) resilience.PVALB+ GABAergic and RORB+ glutamatergic neurons are associated with cognitive status.A TMEM106B single nucleotide polymorphism is related to lower AD risk, higher neuron count, and increased AD pathology. [ABSTRACT FROM AUTHOR]

The aim of this study was to verify whether the level of mental resilience would differentiate reading comprehension performance when using different information carriers. More than 150 people filled out a test regarding the level of resilience. They then participated in a survey using fNIRS. Their task was to read a one-page informational text and answer several questions. The results showed no differences in correct answers between groups of people with different levels of resilience. In the groups of people with high and low levels of resilience, the number of correct answers was not differentiated by the type of carrier. Among those with moderate levels of resilience, better results were obtained by those who read text printed on paper. Analyses of neuronal mechanisms showed that the type of carrier differentiated brain activity in each group. Obtaining the same number of correct answers in the test was the result of different neuronal mechanisms activated in those who used a computer and those who read a printed text. [ABSTRACT FROM AUTHOR]

Background and objectivesThe existing literature highlights the importance of reading books in middle-to-older adulthood for cognitive functioning; very few studies, however, have examined the importance of childhood cognitive resources for cognitive outcomes later in life.Research design and methodsUsing data from 11 countries included in the Survey of Health, Ageing, and Retirement in Europe (SHARE) data set (N = 32,783), multistate survival models (MSMs) were fit to examine the importance of access to reading material in childhood on transitions through cognitive status categories (no cognitive impairment and impaired cognitive functioning) and death. Additionally, using the transition probabilities estimated by the MSMs, we estimated the remaining years of life without cognitive impairment and total longevity. All models were fit individually in each country, as well as within the pooled SHARE sample.ResultsAdjusting for age, sex, education, and childhood socioeconomic status, the overall pooled estimate indicated that access to more books at age 10 was associated with a decreased risk of developing cognitive impairment (adjusted hazard ratio = 0.79, confidence interval: 0.76-0.82). Access to childhood books was not associated with risk of transitioning from normal cognitive functioning to death, or from cognitive impairment to death. Total longevity was similar between participants reporting high (+1 standard deviation [SD]) and low (-1 SD) number of books in the childhood home; however, individuals with more access to childhood books lived a greater proportion of this time without cognitive impairment.Discussion and implicationsFindings suggest that access to cognitive resources in childhood is protective for cognitive aging processes in older adulthood.

Abstract Background In Alzheimer’s disease (AD), the associations between tau pathology and brain atrophy and cognitive decline are well established, but imperfect. We investigate whether cerebrospinal fluid (CSF) biomarkers of biological processes (vascular, synaptic, and axonal integrity, neuroinflammation, neurotrophic factors) explain the disconnection between tau pathology and brain atrophy (brain resilience), and tau pathology and cognitive decline (cognitive resilience). Methods We included 428 amyloid positive participants (134 cognitively unimpaired (CU), 128 with mild cognitive impairment (MCI), 166 with AD dementia) from the BioFINDER-2 study. At baseline, participants underwent tau positron emission tomography (tau-PET), magnetic resonance imaging (MRI), cognitive testing, and lumbar puncture. Longitudinal data were available for MRI (mean (standard deviation) follow-up 26.4 (10.7) months) and cognition (25.2 (11.4) months). We analysed 18 pre-selected CSF proteins, reflecting vascular, synaptic, and axonal integrity, neuroinflammation, and neurotrophic factors. Stratifying by cognitive status, we performed linear mixed-effects models with cortical thickness (brain resilience) and global cognition (cognitive resilience) as dependent variables to assess whether the CSF biomarkers interacted with tau-PET levels in its effect on cortical atrophy and cognitive decline. Results Regarding brain resilience, interaction effects were observed in AD dementia, with vascular integrity biomarkers (VEGF-A (βinteraction = -0.009, pFDR = 0.047) and VEGF-B (βinteraction = -0.010, pFDR = 0.037)) negatively moderating the association between tau-PET signal and atrophy. In MCI, higher NfL levels were associated with more longitudinal cortical atrophy (β = -0.109, pFDR = 0.033) and lower baseline cortical thickness (β = -0.708, pFDR = 0.033) controlling for tau-PET signal. Cognitive resilience analyses in CU revealed interactions with tau-PET signal for inflammatory (GFAP, IL-15; βinteraction -0.073–-0.069, pFDR 0.001–0.045), vascular (VEGF-A, VEGF-D, PGF; βinteraction -0.099–-0.063, pFDR

Abstract 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‐βHB) 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‐βHB and glucose concentrations, cognitive performance and O2 saturation (SpO2) were collected throughout. KME ingestion increased blood R‐βHB concentration, which was rapid and sustained (>4 mM 30 min post; P

Background: Leveraging Alzheimer's disease (AD) imaging biomarkers and longitudinal cognitive data may allow us to establish evidence of cognitive resilience (CR) to AD pathology in-vivo. Here, we applied latent class mixture modeling, adjusting for sex, baseline age, and neuroimaging biomarkers of amyloid, tau and neurodegeneration, to a sample of cognitively unimpaired older adults to identify longitudinal trajectories of CR. Methods: We identified 200 Harvard Aging Brain Study (HABS) participants (mean age = 71.89 years, SD = 9.41 years, 59% women) who were cognitively unimpaired at baseline with 2 or more timepoints of cognitive assessment following a single amyloid-PET, tau-PET and structural MRI. We examined latent class mixture models with longitudinal cognition as the dependent variable and time from baseline, baseline age, sex, neocortical Aβ, entorhinal tau, and adjusted hippocampal volume as independent variables. We then examined group differences in CR-related factors across the identified subgroups from a favored model. Finally, we applied our favored model to a dataset from the Alzheimer's Disease Neuroimaging Initiative (ADNI; n = 160, mean age = 73.9 years, SD = 7.6 years, 60% women). Results: The favored model identified 3 latent subgroups, which we labelled as Normal (71% of HABS sample), Resilient (22.5%) and Declining (6.5%) subgroups. The Resilient subgroup exhibited higher baseline cognitive performance and a stable cognitive slope. They were differentiated from other groups by higher levels of verbal intelligence and past cognitive activity. In ADNI, this model identified a larger Normal subgroup (88.1%), a smaller Resilient subgroup (6.3%) and a Declining group (5.6%) with a lower cognitive baseline. Conclusion: These findings demonstrate the value of data-driven approaches to identify longitudinal CR groups in preclinical AD. With such an approach, we identified a CR subgroup who reflected expected characteristics based on previous literature, higher levels of verbal intelligence and past cognitive activity. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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 (Aβ) plaques. RESULTS: NDAN subjects displayed a higher spine density in regions distant from Aβ 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 Aβ plaques compared to the distal area in CTRL, AD, and NDAN dendrites.NDAN shows higher spine density than AD in areas far from Aβ plaques.Far from Aβ 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. [ABSTRACT FROM AUTHOR]

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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. [ABSTRACT FROM AUTHOR]

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‐β/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: Aβ 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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

The events in Ukraine in 2022 had a devastating effect on its population. The authors of this paper considered whether it would be possible to strengthen both Ukrainian and other young people’s cognitive resilience in the face of different forms of conflict if they were put into contact with students in other countries. One potential means for building this resilience that could be explored in a classroom setting was the provision of a platform through which to compare perspectives with fellow students of other nationalities while gaining exposure to and practical experience with a set of cognitive tools for understanding and addressing challenging situations. The Digital Bridge Project (DPB) was designed to improve these students’ English and critical analysis skills through direct exchange with their counterparts in other parts of the world via five online interviews in which they explored decision-making tools proposed by a variety of authors. The following case study describes how the Project was conducted. Three Ukrainian universities and the University of Europe for Applied Sciences in Iserlohn, Germany participated in this study. The results of the Project indicate that it is a model that can be applied effectively in a variety of subject areas. The authors recommend that schools and universities wishing to emulate the model discussed here should adapt the format to their specific needs. The results of the student surveys from both countries involved indicate that the method can empower students to address a wide range of disruptive forces in business and society with tools that are part of a 21st century skill set for both enhancing managerial decision-making and encouraging participatory democracy.

The Operator 5.0 concept calls for the self-resilience of operators in Industry 5.0, including the cognitive aspect. Despite attempts to develop supporting technologies, achieved results are loosely connected without a comprehensive approach. Looking for novel expectations, this study seeks inspiration from a chaotic environment, where cognitive resilience is a firm standard: military operations. A systematic literature review in Scopus investigated how technology-enabled cognitive resilience is achieved in this context. Extracted details show vast technology support from field operations to control space, against the single or corporate effect of stressors from the work environment, context, content, or users themselves. These technologies generate indirect and direct influence from physical, mental, and cognitive aspects, creating a cognitive resilience effect. The concept of human-machine symbiosis is proposed, with a framework from technology development to resilience training, to inspire developers to define a broader scope, and engineers to facilitate comprehensive adaptation of Operator 5.0 solutions.

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 (β= –0.25, p = 0.006) and Cognivue® scores (β= 0.32, p < 0.001). The RI-Cognivue® association was partially mediated by CAS (β= 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. [ABSTRACT FROM AUTHOR]

Cognitive resilience provides insights into maintaining good cognition despite dementia-related neuropathologic changes. It is of special interest in the oldest-old (age 90+) because age is the strongest risk factor for dementia. We describe the only participant of The 90+ Study, among 367 autopsies, who maintained normal cognition despite intermediate-high levels of 3 dementia-related neuropathologic changes, advanced age, and comorbidities associated with cognitive impairment. This man remained cognitively normal throughout 13 semi-annual study visits, last one being 4 months before his death at 96. His cognitive test scores remained around the 90th percentile for non-timed tests and declined from 90th to 50th percentile (significant for semantic fluency) for timed tests. He remained physically and cognitively active until death, despite extrapyramidal signs in the last year of life. Neuropathological examination revealed intermediate level of Alzheimer's disease neuropathologic change (Thal phase 5, Braak NFT stage IV, CERAD score 3), Lewy bodies and neurites in the olfactory bulb, brainstem and limbic areas (Braak PD stage 4), TDP-43 inclusions in the amygdala and hippocampus (LATE stage 2), and a microvascular lesion in putamen. This case demonstrates that cognitive impairment is not inevitable even in the oldest-old with mutltiple dementia-related neuropathologic changes.

The aim of this study was to verify whether the level of mental resilience would differentiate reading comprehension performance when using different information carriers. More than 150 people filled out a test regarding the level of resilience. They then participated in a survey using fNIRS. Their task was to read a one-page informational text and answer several questions. The results showed no differences in correct answers between groups of people with different levels of resilience. In the groups of people with high and low levels of resilience, the number of correct answers was not differentiated by the type of carrier. Among those with moderate levels of resilience, better results were obtained by those who read text printed on paper. Analyses of neuronal mechanisms showed that the type of carrier differentiated brain activity in each group. Obtaining the same number of correct answers in the test was the result of different neuronal mechanisms activated in those who used a computer and those who read a printed text.

While the concept of cognitive resilience is well-established it has not been defined in a way that can be measured. This has been an impediment to studying its underlying biology and to developing instruments for its clinical assessment. This perspective highlights recent work that has quantified the expression of cortical proteins associated with cognitive resilience, thus facilitating studies of its complex underlying biology and the full range of its clinical effects in aging adults. These initial studies provide empirical support for the conceptualization of resilience as a continuum. Like other conventional risk factors, some individuals manifest higher-than-average cognitive resilience and other individuals manifest lower-than-average cognitive resilience. These novel approaches for advancing studies of cognitive resilience can be generalized to other aging phenotypes and can set the stage for the development of clinical tools that might have the potential to measure other mechanisms of resilience in aging adults. These advances also have the potential to catalyze a complementary therapeutic approach that focuses on augmenting resilience via lifestyle changes or therapies targeting its underlying molecular mechanisms to maintain cognition and brain health even in the presence of untreatable stressors like brain pathologies that accumulate in aging adults. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

In the realm of cognitive science, the phenomenon of "successful cognitive aging" stands as a hallmark of individuals who exhibit cognitive abilities surpassing those of their age-matched counterparts. However, it is paramount to underscore a significant gap in the current research, which is marked by a paucity of comprehensive inquiries that deploy substantial sample sizes to methodically investigate the cerebral biomarkers and contributory elements underpinning this cognitive success. It is within this context that our present study emerges, harnessing data derived from the UK Biobank. In this study, a highly selective cohort of 1060 individuals aged 65 and above was meticulously curated from a larger pool of 17,072 subjects. The selection process was guided by their striking cognitive resilience, ascertained via rigorous evaluation encompassing both generic and specific cognitive assessments, compared to their peers within the same age stratum. Notably, the cognitive abilities of the chosen participants closely aligned with the cognitive acumen commonly observed in middle-aged individuals. Our study leveraged a comprehensive array of neuroimaging-derived metrics, obtained from three Tesla MRI scans (T1-weighted images, dMRI, and resting-state fMRI). The metrics included image-derived phenotypes (IDPs) that addressed grey matter morphology, the strength of brain network connectivity, and the microstructural attributes of white matter. Statistical analyses were performed employing ANOVA, Mann–Whitney U tests, and chi-square tests to evaluate the distinctive aspects of IDPs pertinent to the domain of successful cognitive aging. Furthermore, these analyses aimed to elucidate lifestyle practices that potentially underpin the maintenance of cognitive acumen throughout the aging process. Our findings unveiled a robust and compelling association between heightened cognitive aptitude and the integrity of white matter structures within the brain. Furthermore, individuals who exhibited successful cognitive aging demonstrated markedly enhanced activity in the cerebral regions responsible for auditory perception, voluntary motor control, memory retention, and emotional regulation. These advantageous cognitive attributes were mirrored in the health-related lifestyle choices of the surveyed cohort, characterized by elevated educational attainment, a lower incidence of smoking, and a penchant for moderate alcohol consumption. Moreover, they displayed superior grip strength and enhanced walking speeds. Collectively, these findings furnish valuable insights into the multifaceted determinants of successful cognitive aging, encompassing both neurobiological constituents and lifestyle practices. Such comprehensive comprehension significantly contributes to the broader discourse on aging, thereby establishing a solid foundation for the formulation of targeted interventions aimed at fostering cognitive well-being among aging populations. [ABSTRACT FROM AUTHOR]

BackgroundThe residual approach to measuring cognitive reserve (using the residual reserve index) aims to capture cognitive resilience conferred by cognitive reserve, but may be confounded by factors representing brain resilience. We sought to distinguish between brain and cognitive resilience by comparing interactions between the residual reserve index and amyloid, tau, and neurodegeneration ["AT(N)"] biomarkers when predicting executive function. We hypothesized that the residual reserve index would moderate at least one path from an AT(N) biomarker to executive function (consistent with cognitive resilience), as opposed to moderating a path between two AT(N) biomarkers (suggestive of brain resilience).MethodsParticipants (N = 332) were from the Alzheimer's Disease Neuroimaging Initiative. The residual reserve index represented the difference between observed and predicted memory performance (a positive residual reserve index suggests higher cognitive reserve). AT(N) biomarkers were: CSF β-amyloid1-42/β-amyloid1-40 (A), plasma phosphorylated tau-181 (T), and FDG metabolism in AD-specific regions ([N]). AT(N) biomarkers (measured at consecutive time points) were entered in a sequential mediation model testing the indirect effects from baseline amyloid to executive function intercept (third annual follow-up) and slope (baseline to seventh follow-up), via tau and/or FDG metabolism. The baseline residual reserve index was entered as a moderator of paths between AT(N) biomarkers (e.g., amyloid-tau), and paths between AT(N) biomarkers and executive function.ResultsThe residual reserve index interacted with amyloid pathology when predicting FDG metabolism: the indirect effect of amyloid → FDG metabolism → executive function intercept and slope varied as a function of the residual reserve index. With lower amyloid pathology, executive function performance was comparable at different levels of the residual reserve index, but a higher residual reserve index was associated with lower FDG metabolism. With higher amyloid pathology, a higher residual reserve index predicted better executive function via higher FDG metabolism.ConclusionThe effect of the residual reserve index on executive function performance via FDG metabolism was consistent with cognitive resilience. This suggests the residual reserve index captures variation in cognitive reserve; specifically, neural efficiency, and neural capacity to upregulate metabolism to enhance cognitive resilience in the face of greater amyloid pathology. Implications for future research include the potential bidirectionality between neural efficiency and amyloid accumulation.

Cognitive reserve and related constructs are valuable for aging-related research, but consistency and clarification of terms is needed as there is still no universally agreed upon nomenclature. We propose a new set of definitions for the concepts of reserve, maintenance, and resilience, and we invoke parallel concepts for each that are applicable to cognition and to brain. Our definitions of reserve and resilience correspond reasonably well to dictionary definitions of these terms. We demonstrate logical/methodological problems that arise from incongruence between commonly used conceptual and operational definitions. In our view, cognitive reserve should be defined conceptually as one's total cognitive resources at a given point in time. IQ and education are examples of common operational definitions (often referred to as proxies) of cognitive reserve. Many researchers define cognitive reserve conceptually as a property that allows for performing better than expected cognitively in the face of aging or pathology. Performing better than expected is demonstrated statistically by interactions in which the moderator is typically IQ or education. The result is an irreconcilable situation in which cognitive reserve is both the moderator and the moderation effect itself. Our proposed nomenclature resolves this logical inconsistency by defining performing better than expected as cognitive resilience. Thus, in our usage, we would test the hypothesis that high cognitive reserve confers greater cognitive resilience. Operational definitions (so-called proxies) should not conflate factors that may influence reserve-such as occupational complexity or engagement in cognitive activities-with cognitive reserve itself. Because resources may be depleted with aging or pathology, one's level of cognitive reserve may change over time and will be dependent on when assessment takes place. Therefore, in addition to cognitive reserve and cognitive resilience, we introduce maintenance of cognitive reserve as a parallel to brain maintenance. If, however, education is the measure of reserve in older adults, it precludes assessing change or maintenance of reserve. Finally, we discuss consideration of resistance as a subcategory of resilience, reverse causation, use of residual scores to assess performing better than expected given some adverse factor, and what constitutes high vs. low cognitive reserve across different studies.

While the concept of cognitive resilience is well-established it has not been defined in a way that can be measured. This has been an impediment to studying its underlying biology and to developing instruments for its clinical assessment. This perspective highlights recent work that has quantified the expression of cortical proteins associated with cognitive resilience, thus facilitating studies of its complex underlying biology and the full range of its clinical effects in aging adults. These initial studies provide empirical support for the conceptualization of resilience as a continuum. Like other conventional risk factors, some individuals manifest higher-than-average cognitive resilience and other individuals manifest lower-than-average cognitive resilience. These novel approaches for advancing studies of cognitive resilience can be generalized to other aging phenotypes and can set the stage for the development of clinical tools that might have the potential to measure other mechanisms of resilience in aging adults. These advances also have the potential to catalyze a complementary therapeutic approach that focuses on augmenting resilience via lifestyle changes or therapies targeting its underlying molecular mechanisms to maintain cognition and brain health even in the presence of untreatable stressors like brain pathologies that accumulate in aging adults.

The Quality of Life (QoL), especially of frail and older people, depends on the ability of a person to tolerate stresses and its negative consequences. The toleration is related to the human resilience, reflecting the three basic human functions: cognitive (the thinking process), motor (the movement activity), and autonomous (the internal body processes). The cognitive resilience is acknowledged as one of the main components of human resilience. The cognitive resilience is tightly coupled with the motor resilience. Various motor-cognitive tests are known to assess the reactivity in a custom way and with specialized medical equipment. In this paper, we introduce our concept model of the mobile Health (mHealth) sensorics for digital assistance of the human resilience during person’s daily activity. In reactivity testing, a smartphone becomes a core element, replacing specialized medical equipment and transforming to a daily automatic instrument of human motor-cognitive sensorics. The collected measurements provide the base to monitor person’s mental condition.

It is not yet known which specific qualities of cognitively stimulating activities are most likely to enhance cognitive reserve in older adults. Taking an inductive approach to this problem, we asked 504 older adults with subjective and/or cognitive impairment to complete the Cognitively Stimulating Activities Questionnaire (CSA-Q). Exploratory factor analysis identified a 4-factor structure within a split-half sample, after which confirmatory factor analysis cross-validated the model. Retaining 12 CSA-Q items, the 4 factors were dubbed CSA-Processing, CSA-Challenging, CSA-Connecting and CSA-Socializing. Resulting factor weights were analyzed relative to cognitive reserve proxies and neuropsychological domains. All factors except CSA-Challenging were positively linked to cognitive reserve. Neuropsychologically, CSA-Challenging was modestly and positively correlated with processing speed and executive function, while CSA-Processing was positively correlated with executive function. CSA-Socializing had a small positive correlation with processing speed. Our findings offer new insights into late-life stimulating activities, laying the groundwork for longitudinal and intervention studies. [ABSTRACT FROM AUTHOR]

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 (CRLevel¯$_{\overline {{\rm{Level}}}} $), and slower decline (CRSlope), than expected given neuropathology. Results: Compared to individuals in the lowest tertile of MIND score, those in the top tertile had higher CRLevel¯$_{\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. [ABSTRACT FROM AUTHOR]

Objectives Early-life disadvantage (ELD) relates to lower late-life cognition. However, personality factors, including having an internal locus of control (LOC) or a conscientious personality, relate to resilience and effective stress coping. We explore whether personality factors convey resilience against the negative effects of ELD on cognition, by gender, in Mexico. Methods Using the 2015 Mexican Health and Aging Study, we estimated expected cognition using multiple ELD markers to identify a subsample in the lowest quartile of expected cognition given ELD (n  = 2,086). In this subsample, we estimated cross-sectional associations between personality and having above-median observed cognitive ability (n  = 522) using logistic regression. Results Among those in the lowest quartile of expected cognition, a more internal LOC (β = 0.32 [men] and β = 0.44 [women]) and conscientious personality (β = 0.39 [men] and β = 0.17 [women]) were significantly associated with having above-median cognitive ability in models adjusted for demographic confounders. Larger benefits of conscientiousness were observed for men than women. Associations between personality and having above-median cognitive ability remained statistically significant after further adjustment for health, stress, and cognitive stimulation variables, regardless of gender. Discussion Personality factors may convey resilience among individuals who experienced ELD, potentially breaking the link between ELD and worse late-life cognition. Structural factors and gender roles may affect how much women benefit from personality factors. [ABSTRACT FROM AUTHOR]

ObjectivesRelatively 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.MethodsWomen 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.ResultsAmong 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.ConclusionsResults highlight the importance of baseline cognitive function and general health for late-life cognition among ε4+ women.

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. [ABSTRACT FROM AUTHOR]

In the realm of cognitive science, the phenomenon of “successful cognitive aging” stands as a hallmark of individuals who exhibit cognitive abilities surpassing those of their age-matched counterparts. However, it is paramount to underscore a significant gap in the current research, which is marked by a paucity of comprehensive inquiries that deploy substantial sample sizes to methodically investigate the cerebral biomarkers and contributory elements underpinning this cognitive success. It is within this context that our present study emerges, harnessing data derived from the UK Biobank. In this study, a highly selective cohort of 1060 individuals aged 65 and above was meticulously curated from a larger pool of 17,072 subjects. The selection process was guided by their striking cognitive resilience, ascertained via rigorous evaluation encompassing both generic and specific cognitive assessments, compared to their peers within the same age stratum. Notably, the cognitive abilities of the chosen participants closely aligned with the cognitive acumen commonly observed in middle-aged individuals. Our study leveraged a comprehensive array of neuroimaging-derived metrics, obtained from three Tesla MRI scans (T1-weighted images, dMRI, and resting-state fMRI). The metrics included image-derived phenotypes (IDPs) that addressed grey matter morphology, the strength of brain network connectivity, and the microstructural attributes of white matter. Statistical analyses were performed employing ANOVA, Mann–Whitney U tests, and chi-square tests to evaluate the distinctive aspects of IDPs pertinent to the domain of successful cognitive aging. Furthermore, these analyses aimed to elucidate lifestyle practices that potentially underpin the maintenance of cognitive acumen throughout the aging process. Our findings unveiled a robust and compelling association between heightened cognitive aptitude and the integrity of white matter structures within the brain. Furthermore, individuals who exhibited successful cognitive aging demonstrated markedly enhanced activity in the cerebral regions responsible for auditory perception, voluntary motor control, memory retention, and emotional regulation. These advantageous cognitive attributes were mirrored in the health-related lifestyle choices of the surveyed cohort, characterized by elevated educational attainment, a lower incidence of smoking, and a penchant for moderate alcohol consumption. Moreover, they displayed superior grip strength and enhanced walking speeds. Collectively, these findings furnish valuable insights into the multifaceted determinants of successful cognitive aging, encompassing both neurobiological constituents and lifestyle practices. Such comprehensive comprehension significantly contributes to the broader discourse on aging, thereby establishing a solid foundation for the formulation of targeted interventions aimed at fostering cognitive well-being among aging populations.

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. [ABSTRACT FROM AUTHOR]

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 < β < 0.20), except complexin‐II (β = 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 < β < 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. [ABSTRACT FROM AUTHOR]

This article discusses the transformation of the information environment, which allows an adversary to exploit cyber-enabled psychological and information operations. It presents the options currently available to an adversary to exploit the vulnerability of the information environment, chiefly the cognitive vulnerabilities of target groups. Thus, hostile interests are often pursued through manipulation, using disinformation, propaganda, algorithms and artificial intelligence. In the light of these developments, the article defines a society-centric approach, in which societal and human resilience are emphasised.

• Aging and cognitive resilience depend on genetic and epigenetic factors. • Dendritic spines and microglia are at the forefront of aging and cognitive resilience. • Dendritic spines and microglia improve cognitive resilience. • Outcomes may be boosted if these approaches are combined. 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. [ABSTRACT FROM AUTHOR]

The mechanisms underlying superior cognitive performance in some older adults are poorly understood. We used a multimodal approach to characterize imaging and cognitive features of 26 successful agers (SA; defined by superior episodic memory ability) and 103 typical older adults. Cortical thickness was greater in multiple regions in SA including right anterior cingulate and prefrontal cortex and was related to baseline memory performance. Similarly, hippocampal volume was greater in SA and associated with baseline memory. SA also had lower white matter hypointensity volumes and faster processing speed. While PiB burden did not differ, there was a significant group interaction in the relationship between age and PiB such that older SA individuals were less likely to have high brain β-amyloid. Over time, memory performance in typical older adults declined more rapidly than in SA, although there was limited evidence for different rates of brain atrophy. These findings indicate that superior memory in aging is related to greater cortical and white matter integrity as well as slower decline in memory performance.

Background: Mixed results in the predictive ability of traditional biomarkers to determine cognitive functioning and changes in older adults have led to misdiagnosis and inappropriate treatment plans to address mild cognitive impairment and dementia among older adults. To address this critical gap, the primary goal of the current study is to investigate whether a digital neuro signature (DNS-br) biomarker predicted global cognitive functioning and change over time relative among cognitively impaired and cognitive healthy older adults. The secondary goal is to compare the effect size of the DNS-br biomarker on global cognitive functioning compared to traditional imaging and genomic biomarkers. The tertiary goal is to investigate which demographic and clinical factors predicted DNS-br in cognitively impaired and cognitively healthy older adults. Methods: We conducted two experiments (Study A and Study B) to assess DNS for brain resilience (DNS-br) against the established FDG-PET brain imaging signature for brain resilience, based on a 10min digital cognitive assessment tool. Study A was a semi-naturalistic observational study that included 29 participants, age 65+, withmild tomoderatemild cognitive impairment and AD diagnosis. Study B was also a semi-naturalistic observational multicenter study which included 496 participants (213 mild cognitive impairment (MCI) and 283 cognitively healthy controls (HC), a total of 525 participants--cognitively healthy (n = 283) or diagnosed with MCI (n = 213) or AD (n = 29). Results: DNS-br total score and majority of the 11 DNS-br neurocognitive subdomain scores were significantly associated with FDG-PET resilience signature, PIB ratio, cerebral gray matter and white matter volume after adjusting formultiple testing. DNS-br total score predicts cognitive impairment for the 80+ individuals in the Altoida large cohort study. We identified a significant interaction between the DNS-br total score and time, indicating that participants with higher DNS-br total score or FDG-PET in the resilience signature would show less cognitive decline over time. Conclusion: Our findings highlight that a digital biomarker predicted cognitive functioning and change, which established biomarkers are unable to reliably do. Our findings also offer possible etiologies of MCI and AD, where education did not protect against cognitive decline. [ABSTRACT FROM AUTHOR]

• Cognitive resilience is normal cognition despite dementia-related neuropathologies. • Cognitive resilience in the oldest-old (age 90+) is important due to high dementia risk. • We describe a 96-year-old man resilient to three dementia-related neuropathologies. • Education, activity, low comorbidities, late onset hypertension may be related to resilience. Cognitive resilience provides insights into maintaining good cognition despite dementia-related neuropathologic changes. It is of special interest in the oldest-old (age 90+) because age is the strongest risk factor for dementia. We describe the only participant of The 90+ Study , among 367 autopsies, who maintained normal cognition despite intermediate-high levels of 3 dementia-related neuropathologic changes, advanced age, and comorbidities associated with cognitive impairment. This man remained cognitively normal throughout 13 semi-annual study visits, last one being 4 months before his death at 96. His cognitive test scores remained around the 90th percentile for non–timed tests and declined from 90th to 50th percentile (significant for semantic fluency) for timed tests. He remained physically and cognitively active until death, despite extrapyramidal signs in the last year of life. Neuropathological examination revealed intermediate level of Alzheimer's disease neuropathologic change (Thal phase 5, Braak NFT stage IV, CERAD score 3), Lewy bodies and neurites in the olfactory bulb, brainstem and limbic areas (Braak PD stage 4), TDP-43 inclusions in the amygdala and hippocampus (LATE stage 2), and a microvascular lesion in putamen. This case demonstrates that cognitive impairment is not inevitable even in the oldest-old with mutltiple dementia-related neuropathologic changes. [ABSTRACT FROM AUTHOR]

Introduction: Alzheimer's disease (AD) remains a debilitating condition with limited treatments and additional therapeutic targets needed. Identifying AD protective genetic loci may identify new targets and accelerate identification of therapeutic treatments. We examined a founder population to identify loci associated with cognitive preservation into advanced age., Methods: Genome-wide association and linkage analyses were performed on 946 examined and sampled Amish individuals, aged 76-95, who were either cognitively unimpaired (CU) or impaired (CI)., Results: A total of 12 single nucleotide polymorphisms (SNPs) demonstrated suggestive association (P ≤ 5 × 10 -4 ) with cognitive preservation. Genetic linkage analyses identified > 100 significant (logarithm of the odds [LOD] ≥ 3.3) SNPs, some which overlapped with the association results. Only one locus on chromosome 2 retained significance across multiple analyses., Discussion: A novel significant result for cognitive preservation on chromosome 2 includes the genes LRRTM4 and CTNNA2. Additionally, the lead SNP, rs1402906, impacts the POU3F2 transcription factor binding affinity, which regulates LRRTM4 and CTNNA2., Highlights: GWAS and linkage identified over 100 loci associated with cognitive preservation. One locus on Chromosome 2 retained significance over multiple analyses. Predicted TFBSs near rs1402906 regulate genes associated with neurocognition., (© 2024 The Authors. Alzheimer's & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer's Association.)

Introduction: The molecular basis of cognitive resilience (CR) among pathologically confirmed Alzheimer's disease (AD) cases is not well understood., Methods: Abundance of 13 cell types and neuronal subtypes in brain bulk RNA-seq data from the anterior caudate, dorsolateral prefrontal cortex (DLPFC), and posterior cingulate cortex (PCC) obtained from 434 AD cases, 318 cognitively resilient AD cases, and 188 controls in the Religious Orders Study and Rush Memory and Aging Project was estimated by deconvolution., Results: PVALB+ neuron abundance was negatively associated with cognitive status and tau pathology in the DLPFC and PCC (P adj  < 0.001) and the most reduced neuronal subtype in AD cases compared to controls in DLPFC (P adj  = 8.4 × 10 -7 ) and PCC (P adj  = 0.0015). We identified genome-wide significant association of neuron abundance with TMEM106B single nucleotide polymorphism rs13237518 in PCC (p = 6.08 × 10 -12 ). rs13237518 was also associated with amyloid beta (p = 0.0085) and tangles (p = 0.0073)., Discussion: High abundance of PVALB+ neurons may be a marker of CR. TMEM106B variants may influence CR independent of AD pathology., Highlights: Neuron retention and a lack of astrocytosis are highly predictive of Alzheimer's disease (AD) resilience. PVALB+ GABAergic and RORB+ glutamatergic neurons are associated with cognitive status. A TMEM106B single nucleotide polymorphism is related to lower AD risk, higher neuron count, and increased AD pathology., (© 2024 The Author(s). Alzheimer's & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer's Association.)

Cognitive resilience describes the phenomenon of individuals evading cognitive decline despite prominent Alzheimer's disease neuropathology. Operationalization and measurement of this latent construct is non-trivial as it cannot be directly observed. The residual approach has been widely applied to estimate CR, where the degree of resilience is estimated through a linear model's residuals. We demonstrate that this approach makes specific, uncontrollable assumptions and likely leads to biased and erroneous resilience estimates. We propose an alternative strategy which overcomes the standard approach's limitations using machine learning principles. Our proposed approach makes fewer assumptions about the data and construct to be measured and achieves better estimation accuracy on simulated ground-truth data., Competing Interests: Conflict of interest Paul Maruff is a full-time employee of Cogstate Ltd. Samuel N. Lockhart is a full time employee of Invicro LLC. SCJ has served in the past three years as a consultant to ALZPath and Enigma Biomedical.

BackgroundMixed results in the predictive ability of traditional biomarkers to determine cognitive functioning and changes in older adults have led to misdiagnosis and inappropriate treatment plans to address mild cognitive impairment and dementia among older adults. To address this critical gap, the primary goal of the current study is to investigate whether a digital neuro signature (DNS-br) biomarker predicted global cognitive functioning and change over time relative among cognitively impaired and cognitive healthy older adults. The secondary goal is to compare the effect size of the DNS-br biomarker on global cognitive functioning compared to traditional imaging and genomic biomarkers. The tertiary goal is to investigate which demographic and clinical factors predicted DNS-br in cognitively impaired and cognitively healthy older adults.MethodsWe conducted two experiments (Study A and Study B) to assess DNS for brain resilience (DNS-br) against the established FDG-PET brain imaging signature for brain resilience, based on a 10 min digital cognitive assessment tool. Study A was a semi-naturalistic observational study that included 29 participants, age 65+, with mild to moderate mild cognitive impairment and AD diagnosis. Study B was also a semi-naturalistic observational multicenter study which included 496 participants (213 mild cognitive impairment (MCI) and 283 cognitively healthy controls (HC), a total of 525 participants—cognitively healthy (n = 283) or diagnosed with MCI (n = 213) or AD (n = 29).ResultsDNS-br total score and majority of the 11 DNS-br neurocognitive subdomain scores were significantly associated with FDG-PET resilience signature, PIB ratio, cerebral gray matter and white matter volume after adjusting for multiple testing. DNS-br total score predicts cognitive impairment for the 80+ individuals in the Altoida large cohort study. We identified a significant interaction between the DNS-br total score and time, indicating that participants with higher DNS-br total score or FDG-PET in the resilience signature would show less cognitive decline over time.ConclusionOur findings highlight that a digital biomarker predicted cognitive functioning and change, which established biomarkers are unable to reliably do. Our findings also offer possible etiologies of MCI and AD, where education did not protect against cognitive decline.

BackgroundThe residual approach to measuring cognitive reserve (using the residual reserve index) aims to capture cognitive resilience conferred by cognitive reserve, but may be confounded by factors representing brain resilience. We sought to distinguish between brain and cognitive resilience by comparing interactions between the residual reserve index and amyloid, tau, and neurodegeneration [“AT(N)”] biomarkers when predicting executive function. We hypothesized that the residual reserve index would moderate at least one path from an AT(N) biomarker to executive function (consistent with cognitive resilience), as opposed to moderating a path between two AT(N) biomarkers (suggestive of brain resilience).MethodsParticipants (N = 332) were from the Alzheimer’s Disease Neuroimaging Initiative. The residual reserve index represented the difference between observed and predicted memory performance (a positive residual reserve index suggests higher cognitive reserve). AT(N) biomarkers were: CSF β-amyloid1–42/β-amyloid1–40 (A), plasma phosphorylated tau-181 (T), and FDG metabolism in AD-specific regions ([N]). AT(N) biomarkers (measured at consecutive time points) were entered in a sequential mediation model testing the indirect effects from baseline amyloid to executive function intercept (third annual follow-up) and slope (baseline to seventh follow-up), via tau and/or FDG metabolism. The baseline residual reserve index was entered as a moderator of paths between AT(N) biomarkers (e.g., amyloid-tau), and paths between AT(N) biomarkers and executive function.ResultsThe residual reserve index interacted with amyloid pathology when predicting FDG metabolism: the indirect effect of amyloid → FDG metabolism → executive function intercept and slope varied as a function of the residual reserve index. With lower amyloid pathology, executive function performance was comparable at different levels of the residual reserve index, but a higher residual reserve index was associated with lower FDG metabolism. With higher amyloid pathology, a higher residual reserve index predicted better executive function via higher FDG metabolism.ConclusionThe effect of the residual reserve index on executive function performance via FDG metabolism was consistent with cognitive resilience. This suggests the residual reserve index captures variation in cognitive reserve; specifically, neural efficiency, and neural capacity to upregulate metabolism to enhance cognitive resilience in the face of greater amyloid pathology. Implications for future research include the potential bidirectionality between neural efficiency and amyloid accumulation.

It is not yet known which specific qualities of cognitively stimulating activities are most likely to enhance cognitive reserve in older adults. Taking an inductive approach to this problem, we asked 504 older adults with subjective and/or cognitive impairment to complete the Cognitively Stimulating Activities Questionnaire (CSA-Q). Exploratory factor analysis identified a 4-factor structure within a split-half sample, after which confirmatory factor analysis cross-validated the model. Retaining 12 CSA-Q items, the 4 factors were dubbed CSA-Processing, CSA-Challenging, CSA-Connecting and CSA-Socializing. Resulting factor weights were analyzed relative to cognitive reserve proxies and neuropsychological domains. All factors except CSA-Challenging were positively linked to cognitive reserve. Neuropsychologically, CSA-Challenging was modestly and positively correlated with processing speed and executive function, while CSA-Processing was positively correlated with executive function. CSA-Socializing had a small positive correlation with processing speed. Our findings offer new insights into late-life stimulating activities, laying the groundwork for longitudinal and intervention studies. [ABSTRACT FROM AUTHOR]