Risk Factor For Cognitive Decline Research Articles

Lower 25-hydroxyvitamin D is associated with severer white matter hyperintensity and cognitive function in patients with non-disabling ischemic cerebrovascular events

ObjectivesThis study aimed to investigate the potential correlations among serum 25-hydroxyvitamin D [25(OH)D] levels, white matter hyperintensity (WMH) and cognitive function in patients with non-disabling ischemic cerebrovascular events (NICE). MethodsThis was a prospective investigation of 160 NICE patients with age of 40 years or older. Cognitive function was evaluated by the Montreal Cognitive Assessment (MoCA). White matter lesions were evaluated by WMH using Fazekas scores. Spearman correlation analysis and linear regression models were used to identify the associations between serum 25(OH)D levels and cognitive function. Binary logistic regression analysis models were used to evaluate the predictable value of serum 25(OH)D levels and WMH for cognitive impairment. ResultsPatients with inadequate 25(OH)D levels had lower MoCA score (P=0.008), and a higher proportion of severe WMH (P=0.043). Spearman correlation analysis demonstrated that serum 25(OH)D concentrations were positively associated with MoCA score (rs=0.185, P=0.019) while negatively related to the proportion of severe WMH (sWMH) (rs=-0.166, P=0.036).The association between 25(OH)D concentrations and MoCA score remained significant in linear regression (adjusted β=0.012, 95%CI:0.001-0.203).Adjusted binary logistic regression analysis showed that the odds ratio of cognitive impairment with insufficient 25(OH)D concentration was 5.038 (95%CI:1.154-21.988) compared with the sufficient group and the sWMH (OR=2.728, 95%CI:1.230-6.051) was identified as an independent risk factor for cognitive decline in NICE patients. ConclusionSerum 25(OH)D levels and white matter lesions were independently and significantly associated with cognitive impairment in NICE patients.

Association of metabolic dysfunction with cognitive decline and Alzheimer's disease: A review of metabolomic evidence

The discovery of new biomarkers that can distinguish Alzheimer's disease (AD) from mild cognitive impairment (MCI) in the early stages will help to provide new diagnostic and therapeutic strategies and slow the transition from MCI to AD. Patients with AD may present with a concomitant metabolic disorder, such as diabetes, obesity, and dyslipidemia, as a risk factor for AD that may be involved in the onset of both AD pathology and cognitive impairment. Therefore, metabolite profiling, or metabolomics, can be very useful in diagnosing AD, developing new therapeutic targets, and evaluating both the course of treatment and the clinical course of the disease. In addition, studying the relationship between nutritional behavior and AD requires investigation of the role of conditions such as obesity, hypertension, dyslipidemia, and elevated glucose level. Based on this literature review, nutritional recommendations, including weight loss by reducing calorie and cholesterol intake and omega-3 fatty acid supplementation can prevent cognitive decline and dementia in the elderly. The underlying metabolic causes of the pathology and cognitive decline caused by AD and MCI are not well understood. In this review article, metabolomics biomarkers for diagnosis of AD and MCI and metabolic risk factors for cognitive decline in AD were evaluated.

A Cluster Analysis of Oral and Cognitive Health Indicators in the CLSA: An Exploratory Study on Cholinergic Activity as the Link.

Poor oral health has been suggested as a risk factor for cognitive decline. Yet, biologically plausible mechanisms explaining this relationship remain unknown. We aimed (1) to identify oral and cognitive health clustering patterns among middle-aged to elderly Canadians and (2) to investigate the extent to which these patterns could be explained by bone mineral density (BMD), a proxy measure of the cholinergic neurons' activity. This cross-sectional study used baseline data from the Comprehensive cohort of the Canadian Longitudinal Study of Aging (CLSA). Oral health was assessed by a self-report questionnaire, and 7 task-based instruments measured cognitive health. We identified oral and cognitive health clusters, our outcome variables, using latent class analysis. Two sets of multivariate logistic regression and 95% confidence intervals were used to investigate whether BMD explains the odds of membership in a certain oral and cognitive health group. The final models were adjusted for socioeconomic, health, and lifestyle factors. Our study sample (N = 25,444: 13,035 males, 12,409 females) was grouped into 5 and 4 clusters based on the oral health status and performance on the cognitive tasks, respectively. After adjusting for all potential covariates, increase in BMD was not associated with higher odds of membership in classes with better oral health (odds ratio [OR] = 1.58 [95% confidence interval {CI}: 0.85-2.92]) and cognitive health (OR = 1.61 [95% CI: 1-2.6]) compared with the groups with the least favorable oral and cognitive health status, respectively. Middle-aged and elderly Canadians show different oral and cognitive health profiles, based on their denture-wearing status and performance on cognitive tests. No evidence could be found to support BMD in place of cholinergic neurons' activity as the common explanatory factor behind the association between oral health and cognitive health. This study is probably the first of its kind to shed light on the cholinergic system as a potential pathway influencing oral and cognitive health. Our findings may support the notion that any potential association between poor oral health and cognitive health might be explained by common contributors, helping clinicians to find the common risk factors for both conditions.

Atlas of the aging mouse brain reveals white matter as vulnerable foci

Aging is the key risk factor for cognitive decline, yet the molecular changes underlying brain aging remain poorly understood. Here, we conducted spatiotemporal RNA sequencing of the mouse brain, profiling 1,076 samples from 15 regions across 7 ages and 2 rejuvenation interventions. Our analysis identified a brain-wide gene signature of aging in glial cells, which exhibited spatially defined changes in magnitude. By integrating spatial and single-nucleus transcriptomics, we found that glial aging was particularly accelerated in white matter compared with cortical regions, whereas specialized neuronal populations showed region-specific expression changes. Rejuvenation interventions, including young plasma injection and dietary restriction, exhibited distinct effects on gene expression in specific brain regions. Furthermore, we discovered differential gene expression patterns associated with three human neurodegenerative diseases, highlighting the importance of regional aging as a potential modulator of disease. Our findings identify molecular foci of brain aging, providing a foundation to target age-related cognitive decline.

Methyl donor supplementation reduces phospho-Tau, Fyn and demethylated protein phosphatase 2A levels and mitigates learning and motor deficits in a mouse model of tauopathy.

Reduced folate status and elevated levels of circulating homocysteine are modifiable risk factors for cognitive decline and dementia. Disturbances in one-carbon metabolism are associated with the pathological accumulation of phosphorylated tau, a hallmark feature of prevalent dementia, including Alzheimer's disease and subgroups of frontotemporal dementia. Here, using transgenic TAU58/2 mouse models of human tauopathy, we tested whether dietary supplementation with L-methylfolate (the active folate form), choline and betaine can reduce tau phosphorylation and associated behavioural phenotypes. TAU58/2 mice fed with the methyl donor-enriched diet showed reduced phosphorylation of tau at the pathological S202 (CP13) and S396/S404 (PHF-1) epitopes and alleviation of associated motor and learning deficits. Compared with mice on the control diet, the decrease in cortical phosphorylated tau levels in mice fed with the methyl donor-enriched diet was associated with enhanced methylation of protein phosphatase 2A, the major brain tau Ser/Thr phosphatase. It also correlated with a reduction in protein levels of Fyn, a tau tyrosine kinase that plays a central role in mediating pathological tau-induced neurodegeneration. Conversely, Fyn expression levels were increased in mice with deficiencies in folate metabolism. Our findings provide the first experimental evidence that boosting one-carbon metabolism with L-methylfolate, choline and betaine can mitigate key pathological, learning and motor deficits in a tauopathy mouse model. They give support to using a combination of methyl donors as a preventive or disease-modifying strategy for tauopathies.

Visit-to-Visit Glucose Variability, Cognition, and Global Cognitive Decline: The Multi-Ethnic Study of Atherosclerosis.

Higher visit-to-visit glucose variability (GV) is associated with dysglycemia and type 2 diabetes (T2D), key risk factors for cognitive decline. Evaluate the association of GV with cognitive performance and decline in racially/ethnically diverse older populations with and without T2D. We calculated the standard deviation of glucose (SDG), average real variability (ARV), and variability independent of the mean (VIM) among 4367 Multi-Ethnic Study of Atherosclerosis participants over 6 clinical examinations. Participants completed a cognitive assessment at the fifth examination, and a subset completed a second assessment 6 years later. We used multivariable linear regression to estimate the association of intraindividual GV with cognitive test scores after adjustments for cardiovascular risk factors and mean glucose level over the study period. Two-fold increments in the VIM and SDG were associated with worse Cognitive Abilities Screening Instrument (CASI) performance, while two-fold increments in VIM and ARV were associated with worse Digit Symbol Coding test score. GV measures were not associated with change in CASI performance among 1834 participants with repeat CASI data 6 years later. However, among 229 participants with incident T2D, the SDG and VIM were associated with decline in CASI (-1.7 [95% CI: -3.1, -0.3] and -2.1 [-3.7, -0.5] points, respectively). In contrast, single-timepoint glucose and HbA1c were not associated with CASI decline among participants with or without incident T2D. Higher visit-to-visit GV over 16 to 18 years is associated with worse cognitive performance in the general population, and with modest global cognitive decline in participants with T2D.

Obesity and Postoperative Cognitive Dysfunction: A Curious Association.

Postoperative cognitive dysfunction (POCD) is a medical condition that impacts cognitive function after surgery, particularly major procedures. Patients with POCD may experience physical symptoms, such as depression, anxiety, and fatigue, severely undermining their quality of life. Research establishes the connection between obesity and cognitive dysfunction since patients diagnosed with obesity are more susceptible to cognitive decline. Although obesity poses a significant risk factor for cognitive impairment, the link between obesity and POCD is still inadequately understood. Therefore, this systematic review explores the correlation between obesity and POCD by detailing potential mechanisms underlying this relationship and identifying areas for further research. Following the guidelines for systematic reviews, we conducted a literature search between August 2022 and April 2023, which identified studies with a substantial number of patients with POCD after major surgeries, including coronary artery bypass grafting, gastrointestinal procedures, cholecystectomy, and carotid endarterectomy. Our findings also demonstrated that a significant percentage of these had obesity, which was statistically significant as a risk factor for cognitive decline. Pathological processes, such as changes in vascular endothelium integrity, systemic inflammation induced by obesity, and apolipoprotein E-epsilon-4 expression, have been identified to contribute to POCD after surgery. Despite the promising results, there remains a gap in the literature. Thus, it is crucial to investigate the relationship between obesity and POCD further, uncover more potential underlying pathophysiological processes, and identify therapeutic targets. These measures would enable healthcare practitioners to prevent or reduce cognitive dysfunction associated with obesity in surgical patients.

Analysis of factors related to cognitive impairment in a community-based, complete enumeration survey in Japan: the Nakayama study.

The number of patients with cognitive disorders is rapidly increasing in the world, becoming not only a medical problem, but also a social problem. There have been many reports that various factors are associated with cognitive dysfunction, but the factors have not yet been fully identified. This was a community-based complete enumeration study which aimed to identify risk and protective factors for dementia. The first phase included all residents aged 65 years or older in a town in Japan. They completed many examinations, such as living conditions questionnaires, physical examination, Mini-Mental State Examination, and brain magnetic resonance imaging. The participants with suspected cognitive impairment underwent additional examinations for detailed evaluation in the second phase. Statistical analysis was performed to identify risk and protective factors for dementia after all participants were diagnosed. There were 927 participants in the baseline evaluation; 611 (65.9%) were healthy, 165 (17.8%) had mild cognitive impairment (MCI), and 151 (16.3%) had dementia. The age-standardised prevalence of dementia was 9.5%. Statistical analyses for amnestic MCI and Alzheimer's disease showed that risk factors for cognitive decline were diabetes mellitus, low activities of daily living, and living alone, and that protective factors were history of exercise and drinking habit. The present findings suggest that several lifestyle-related diseases and factors are associated with cognitive decline. These results support similar findings from previous studies and will be helpful for preventing dementia in the future.

In Case You Haven't Heard…

Scientists have known for some time that addressing hearing loss can reduce a person's chances of developing Alzheimer's disease, but a study released on July 18 shows just how much, a news release from UsAgainstAlzheimer's stated. According to the ACHIEVE study, “A landmark study of the effect of hearing intervention on brain health in older adults,” published in The Lancet, treating hearing loss in older adults who had more risk factors for cognitive decline slowed down the loss of thinking and memory abilities by 48% over three years. The study's findings were also presented by its author, Frank Lin, M.D., Ph.D., of the Johns Hopkins University School of Medicine and Bloomberg School of Public Health, at the annual Alzheimer's Association's International Conference. One in three Americans between the ages of 65 and 74 has hearing loss, according to the National Institutes of Health. Worldwide, mid‐ and late‐life hearing loss is identified as the single largest potentially modifiable risk factor for dementia. The ACHIEVE study is the first randomized clinical trial to investigate whether treating hearing loss in older adults reduces the cognitive decline that can occur with aging.

Hearing intervention versus health education control to reduce cognitive decline in older adults with hearing loss in the USA (ACHIEVE): a multicentre, randomised controlled trial

Hearing loss is associated with increased cognitive decline and incident dementia in older adults. We aimed to investigate whether a hearing intervention could reduce cognitive decline in cognitively healthy older adults with hearing loss. The ACHIEVE study is a multicentre, parallel-group, unmasked, randomised controlled trial of adults aged 70-84 years with untreated hearing loss and without substantial cognitive impairment that took place at four community study sites across the USA. Participants were recruited from two study populations at each site: (1) older adults participating in a long-standing observational study of cardiovascular health (Atherosclerosis Risk in Communities [ARIC] study), and (2) healthy de novo community volunteers. Participants were randomly assigned (1:1) to a hearing intervention (audiological counselling and provision of hearing aids) or a control intervention of health education (individual sessions with a health educator covering topics on chronic disease prevention) and followed up every 6 months. The primary endpoint was 3-year change in a global cognition standardised factor score from a comprehensive neurocognitive battery. Analysis was by intention to treat. This trial was registered at ClinicalTrials.gov, NCT03243422. From Nov 9, 2017, to Oct 25, 2019, we screened 3004 participants for eligibility and randomly assigned 977 (32·5%; 238 [24%] from ARIC and 739 [76%] de novo). We randomly assigned 490 (50%) to the hearing intervention and 487 (50%) to the health education control. The cohort had a mean age of 76·8 years (SD 4·0), 523 (54%) were female, 454 (46%) were male, and most were White (n=858 [88%]). Participants from ARIC were older, had more risk factors for cognitive decline, and had lower baseline cognitive scores than those in the de novo cohort. In the primary analysis combining the ARIC and de novo cohorts, 3-year cognitive change (in SD units) was not significantly different between the hearing intervention and health education control groups (-0·200 [95% CI -0·256 to -0·144] in the hearing intervention group and -0·202 [-0·258 to -0·145] in the control group; difference 0·002 [-0·077 to 0·081]; p=0·96). However, a prespecified sensitivity analysis showed a significant difference in the effect of the hearing intervention on 3-year cognitive change between the ARIC and de novo cohorts (pinteraction=0·010). Other prespecified sensitivity analyses that varied analytical parameters used in the total cohort did not change the observed results. No significant adverse events attributed to the study were reported with either the hearing intervention or health education control. The hearing intervention did not reduce 3-year cognitive decline in the primary analysis of the total cohort. However, a prespecified sensitivity analysis showed that the effect differed between the two study populations that comprised the cohort. These findings suggest that a hearing intervention might reduce cognitive change over 3 years in populations of older adults at increased risk for cognitive decline but not in populations at decreased risk for cognitive decline. US National Institutes of Health.

1318-P: Type 2 Diabetes as a Risk Factor for Dementia—An Analysis of Australian National Registries

High dementia prevalence and associated disability have necessitated a focus on the identification of potentially modifiable risk factors. One such example is type 2 diabetes; however, there are not enough large population-based studies that can provide an accurate estimate of the strength of the association. Therefore, we investigated prospective associations between diabetes and dementia using Australian national registries. The study included ~850,000 people with type 2 diabetes (median age=66.2 years, females=45.5%) registered on the National Diabetes Services Scheme (NDSS) during the period 2002-2014 and followed up for at least 1 year (median 7.0 years). Propensity score matching (based on logistic regression with birth year, sex, socio-economic index and medication history as predictors) was then conducted to match (1:1) people with diabetes to a general population control group without diabetes. The latter comprised people with no registration history on NDSS or record of taking glucose lowering drugs on the Pharmaceutical Benefits Scheme (median age=67.3 years, females=43.9%, median follow up=7.5 years). Dementia was defined either by dementia drug use (cholinesterase inhibitors or memantine) or dementia-related death. The association between diabetes and dementia was examined using Cox’s proportional hazard model that treated each individual with diabetes and their matched control as one stratum. Diabetes was associated with an increased risk of dementia-related death (HR 1.19, 95% CI 1.17, 1.22), while no significant association was observed between diabetes and dementia medication use (HR 0.99, 95% CI 0.97, 1.02). When both dementia-related death and dementia drug use were included in the outcome, diabetes was still associated with an increased risk of dementia (HR 1.11, 95% CI 1.09, 1.14). These findings highlight the need for clinicians to be vigilant in identifying and managing diabetes as a potentially modifiable risk factor for cognitive decline and dementia. Disclosure K.Mehta: None. A.Salim: None. J.W.Sacre: None. K.J.Anstey: Speaker's Bureau; Nutricia. D.J.Magliano: None. J.E.Shaw: Advisory Panel; Abbott Diagnostics, Lilly, Zuellig Pharma Holdings Pte. Ltd., Mylan, Research Support; AstraZeneca, Speaker's Bureau; AstraZeneca, Roche Diagnostics, Lilly, Amgen Inc., Sanofi, Zuellig Pharma Holdings Pte. Ltd. Funding Deakin University (to K.M.); Alicia Baker and Eleanor Shaw Gender Equity Fellowship (to D.J.M.); National Health and Medical Research Council (APP1173952 to J.E.S.); Victorian Government’s Operational Infrastructure Support Program

Altered resting-state functional connectivity patterns in late middle-aged and older adults with obstructive sleep apnea.

Obstructive sleep apnea (OSA) is increasingly recognized as a risk factor for cognitive decline, and has been associated with structural brain alterations in regions relevant to memory processes and Alzheimer's disease. However, it is unclear whether OSA is associated with disrupted functional connectivity (FC) patterns between these regions in late middle-aged and older populations. Thus, we characterized the associations between OSA severity and resting-state FC between the default mode network (DMN) and medial temporal lobe (MTL) regions. Second, we explored whether significant FC changes differed depending on cognitive status and were associated with cognitive performance. Ninety-four participants [24 women, 65.7 ± 6.9 years old, 41% with Mild Cognitive Impairment (MCI)] underwent a polysomnography, a comprehensive neuropsychological assessment and a resting-state functional magnetic resonance imaging (MRI). General linear models were conducted between OSA severity markers (i.e., the apnea-hypopnea, oxygen desaturation and microarousal indices) and FC values between DMN and MTL regions using CONN toolbox. Partial correlations were then performed between OSA-related FC patterns and (i) OSA severity markers in subgroups stratified by cognitive status (i.e., cognitively unimpaired versus MCI) and (ii) cognitive scores in the whole sample. All analyzes were controlled for age, sex and education, and considered significant at a p < 0.05 threshold corrected for false discovery rate. In the whole sample, a higher apnea-hypopnea index was significantly associated with lower FC between (i) the medial prefrontal cortex and bilateral hippocampi, and (ii) the left hippocampus and both the posterior cingulate cortex and precuneus. FC patterns were not associated with the oxygen desaturation index, or micro-arousal index. When stratifying the sample according to cognitive status, all associations remained significant in cognitively unimpaired individuals but not in the MCI group. No significant associations were observed between cognition and OSA severity or OSA-related FC patterns. OSA severity was associated with patterns of lower FC in regions relevant to memory processes and Alzheimer's disease. Since no associations were found with cognitive performance, these FC changes could precede detectable cognitive deficits. Whether these FC patterns predict future cognitive decline over the long-term needs to be investigated.

Increase in skeletal muscular adiposity and cognitive decline in a biracial cohort of older men and women.

Obesity and loss of muscle mass are emerging as risk factors for dementia, but the role of adiposity infiltrating skeletal muscles is less clear. Skeletal muscle adiposity increases with older age and especially among Black women, a segment of the US population who is also at higher risk for dementia. In 1634 adults (69-79 years, 48% women, 35% Black), we obtained thigh intermuscular adipose tissue (IMAT) via computerized tomography at Years 1 and 6, and mini-mental state exam (3MS) at Years 1, 3, 5, 8 and 10. Linear mixed effects models tested the hypothesis that increased IMAT (Year 1-6) would be associated with 3MS decline (Year 5-10). Models were adjusted for traditional dementia risk factors at Year 1 (3MS, education, APOe4 allele, diabetes, hypertension, and physical activity), with interactions between IMAT change by race or sex. To assess the influence of other muscle and adiposity characteristics, models accounted for change in muscle strength, muscle area, body weight, abdominal subcutaneous and visceral adiposity, and total body fat mass (all measured in Years 1 and 6). Models were also adjusted for cytokines related to adiposity: leptin, adiponectin, and interleukin-6. Thigh IMAT increased by 4.85 cm2 (Year 1-6) and 3MS declined by 3.20 points (Year 6-10). The association of IMAT increase with 3MS decline was statistically significant: an IMAT increase of 4.85 cm2 corresponded to a 3MS decline of an additional 3.60 points (p < 0.0001), indicating a clinically important change. Interactions by race and sex were not significant. Clinicians should be aware that regional adiposity accumulating in the skeletal muscle may be an important, novel risk factor for cognitive decline in Black and White participants independent of changes to muscle strength, body composition and traditional dementia risk factors.

Risk and protective factors for cognitive decline in lower educated older adults with 15‐year follow‐up

AbstractBackgroundStudies have identified modifiable risk factors for both prevalence and incidence of cognitive impairment in lower educated older adults. However, patterns of cognitive change, and risk and protective factors for declining versus stable cognitive trajectories have rarely been described in this population. Our goal was to explore the long‐term trajectories of cognitive function and identify modifiable risk and protective factors for cognitive decline beyond education.MethodWe applied group‐based trajectory modelling and multinomial logistic regressions to explore possible trajectories and associated baseline factors on data from a population‐based Health, Welfare and Aging (SABE) survey collected in 2000, 2006, 2010, and 2015 in Sao Paulo, Brazil. Cognitive functioning was assessed using the abbreviated Mini‐Mental State Exam. A total of 354 respondents aged 60 + participating in all follow‐ups were included in the statistical analyses.ResultGroup‐based trajectory modelling identified three different cognitive trajectories, specifically groups with stable (37.4%), declining (53.8%), and strongly declining (8.8%) trajectories, with the last one reaching the threshold for cognitive impairment (Figure 1). Socioeconomic status, specifically living in rural areas during childhood and no schooling or primary education, as well as self‐identified race was systematically different between the groups (Table 1). Moreover, respondents in the stable trajectory were more likely to report living in urban areas, more than primary education, to be white, to earn more than four times the minimum wage/month, to practice manual work, craft or artistic activity at least once a week, and less likely to have had stroke or be widowed. On the other hand, those in the strongly declining trajectory were more likely to be black or mixed and smoke at baseline.ConclusionOur findings suggest substantial potential for modification of risk of cognitive decline even in lower educated older individuals at risk for cognitive impairment. Risk factors related to self‐identified race/ethnicity and socioeconomic status suggest systematic inequalities in brain health potential, with risk for later‐life cognitive impairment. Sample attrition suggests conservative estimates of the magnitude of the risk factors for cognitive decline. Health and social policies should address inequalities to improve later‐life cognitive function of at‐risk individuals.

APOE4 and confluent WMH have a synergistic effect on episodic memory impairment in prodromal dementia

AbstractBackgroundWhite matter hyperintensities (WMH) are a known risk factor for cognitive decline (C.Puzo el. al. 2019). While the ε4 allele of apolipoprotein E gene (APOE4) is another risk factor for cognitive decline in concomitance with WMH (D.Tsuang et. al. 2013), it remains unclear how APOE4 affects the relationship between WMH and cognitive decline, specifically in the prodromal stage of dementia. Our objective was thus to determine how APOE4 moderates the relationship between WMH and cognition in prodromal dementia.Method216 participants with prodromal dementia underwent magnetic resonance imaging (MRI), neuropsychological testing (global and domain‐specific), cardiovascular risk factor assessments and APOE genotyping. Visual ratings for WMH as well as total and lobar WMH volumes were quantified. Moderation analysis was performed to determine the influence of APOE4 on the relationship between WMH and performance on global and domain‐specific cognitive measures (executive function, episodic memory, attention, language) in moderation analysis (Figure 1). The role of confluent and non‐confluent WMH subtype on cognition was additionally studied using moderation analysis and logistic regression (Figure 1).ResultAPOE4 carriers (n = 49) had poorer memory and higher global WMH (p = 0.04), temporal WMH (p = 0.01) and occipital WMH (p = 0.02) compared to APOE4 non‐carriers (n = 167). APOE4 strengthened the relationship between higher total WMH burden and worse episodic memory performance (Fig.2a). At the lobar WMH level, APOE4 strengthened associations between frontal, temporal, parietal and occipital WMH and episodic memory performance (Fig.2b, Fig.2c, Fig.2d, and Fig.2e) with large sized effects (β). APOE4 did not interact with either total or lobar WMH to predict worse cognition in other cognitive domains. Moreover, APOE4 strengthened the relationship between frontal WMH with episodic memory in the confluent WMH subgroup (Fig.2f). Logistic regression model showed memory impairment was 4.81 times more likely to develop in patients carrying APOE4 and with confluent WMH compared to APOE4 non‐carriers and those with non‐confluent WMH (OR 4.81, β 1.57, p&lt;0.01).ConclusionThe impact of WMH on memory may be strongest in APOE4 carriers at the prodromal dementia stage. Clinicians targeting WMH would need to consider the APOE4 allele and WMH severity status to strategize cognitive interventions.

Amyloid PET in patients with carotid occlusive disease: Preliminary results of the AMYCODE study

AbstractBackgroundCarotid occlusive disease (COD) is a risk factor for cognitive decline. One of the proposed underlying mechanisms is that cerebral hypoperfusion may result in accelerated accumulation of amyloid‐β in the brain. We hypothesized that patients with longstanding, unilateral COD have an asymmetrical burden of cerebral amyloid‐β, with more amyloid‐β in the hemisphere ipsilateral to the COD than in the contralateral hemisphere.MethodThe AMYCODE study is a cross‐sectional observational study. Inclusion criterion is a unilateral occlusion of the internal carotid artery. Exclusion criteria are: a contralateral stenosis of &gt; 70% and a history of vascular reconstructive surgery. All patients underwent a neuropsychological assessment, MRI‐scan and dynamic 18F Florbetaben positron emission tomography scan (PET). Global relative perfusion (R1) and binding potential (BPND) were determined from the PET‐images using PMOD and a simplified reference tissue model with the cerebellar grey matter as reference region. Distribution Volume ratio (DVR) was calculated as BPND + 1. We performed Wilcoxon signed‐rank tests to examine differences between hemispheres within subjects.ResultTo date, we included eight participants (seven males, age 66.1±7.3 years, MMSE score 28.1±2.0; inclusion ongoing, target n = 20). Mean global DVR was 1.03±0.03 in the ipsilateral hemisphere (i.e. side of the occlusion) and 1.04±0.02 in the contralateral hemisphere (p = 0.064). Mean global R1 was 0.89±0.06 in the ipsilateral hemisphere and 0.91±0.05 in the contralateral hemisphere (p = 0.033).ConclusionPreliminary analyses suggest that patients with unilateral COD had similar amyloid‐β distribution, despite lower cerebral perfusion in the hemisphere ipsilateral to the COD than in the contralateral hemisphere.

Effect of social isolation and loneliness on functional abilities mediated by cognition (E‐cog) in Mexican older adults during the first wave of COVID‐19 pandemic

AbstractBackgroundLoneliness and social isolation are known risk factors for cognitive decline; their effect in older adults (OA) after COVID‐19 lockdown is emerging.ObjectiveTo establish an association between loneliness with functional abilities mediated by cognition in Mexican OA during the first wave of the COVID‐19 pandemic.MethodCross‐sectional study derived from the cohort “The impact of COVID 19 on well‐being, cognition, and discrimination among older adults in the United States and Latin America”, which included 308 older adults recruited between March‐August 2020 whose cognition‐mediated functional abilities were determined with the Everyday Cognition Scale (E‐Cog) questionnaire. The presence of loneliness (The De Jong Gierveld Loneliness Scale) was a binomial variable. Univariate linear regression models were constructed to determine the association between loneliness, and E‐Cog (Ln) scores, which were later adjusted for potentially confounding variables like age and education. In addition, participants were categorized into tertiles of the global E‐Cog score with the following ranges: Tertile 1 (T1): 37.46 ‐46; Tertile 2 (T2): 46.01‐58 and Tertile 3 (T3): 58.01 or more and were compared using ANCOVA. Satistical analyses were conducted using SPSS version 25.0 for MAC (Chicago, IL, USA), figures were made with RStudio (R version 4.1.0, RStudio, Inc., Boston, MA)ResultThe mean age was 65.4 ± 7.9 years and 75.7% were women. The mean E‐Cog was 57.4 (SD: ± 19.1). 84% of participants (n:259) had loneliness. Those with less perception of loneliness had a better performance on E‐Cog by tertiles. The univariate linear model showed a positive and statistically significant association between loneliness and E‐Cog, adjusted by age, sex and education level (β 0.41, 95% CI: 0.22‐0.38, p: &lt;0.01). This model explained 16.1% of the variability of the E‐Cog score.ConclusionOA with self‐reported loneliness had the worst performance in functional abilities mediated by cognition. These data suggest the need for increased vigilance of those who have loneliness due to its potential deleterious effect on cognitive function.

Social isolation, lifestyle and cognitive functioning in midlife and early‐late life: Implications for risk reduction of cognitive decline and dementia

AbstractBackgroundSocial isolation (SI) is considered a modifiable risk factor for cognitive decline and dementia, is associated with unhealthy lifestyle. We investigated independent and combined associations of SI and lifestyle with cognitive functioning (CF) in a midlife to early‐late life population without dementia. This informs developing more targeted preventive strategies against cognitive decline and dementia.MethodThe “LIfestyle for BRAin health” (LIBRA) score was computed for 6,203 baseline participants of the LIFE‐Adult‐Study, a population‐based German cohort. LIBRA is validated for dementia prediction in midlife to early‐late life populations, consisting of 12 modifiable factors (heart disease, kidney disease, diabetes, obesity, hypertension, hypercholesterolemia, alcohol consumption, smoking, physical inactivity, diet, depression, cognitive activity). Higher scores (‐5.9,+12.7) indicate “worse” lifestyle. SI was assessed with the short Lubben Social Network Scale (score &lt; 12). For CF, we calculated a z‐standardized composite score of the Verbal Fluency Test, the Trail Making Test A and B. Associations of SI and LIBRA with CF were investigated using generalized linear modelling. Bootstrapped structural equation modelling (SEM) tested whether LIBRA mediated the association between SI and CF. Sampling weights were applied, variables z‐standardized for SEM.ResultsParticipants were M = 57.7 (SD = 12.0, range: 40‐79) years old; 50.7% were female; 15.8% were socially isolated. SI (β: ‐.17, 95%CI[‐.24,‐.10]; Wald = 21.45, p &lt; .001) and a higher LIBRA score (β: ‐.03, 95%CI[‐.04,‐.02]; Wald = 31.49, p &lt; .001) were independently associated with lower CF; there was no interaction (β: ‐.003, 95%CI[‐.03,.02]; Wald = 0.06, p = .814; Fig.1). Bootstrapped SEM (reps = 10,000; R² = .34) indicated that LIBRA partially mediated the association between SI and CF (IE = ‐.006, 95%CI[‐.008,‐.003], p &lt; .001; proportion mediated = 8.5%; Fig.2).ConclusionCF is lower in socially isolated than socially integrated individuals without dementia. The CF difference can be partially attributed to modifiable health and lifestyle factors; however, only to a small extent. Therefore, public health initiatives aiming at preventing SI might be more effective in promoting good CF than lifestyle interventions in socially isolated individuals in midlife to early‐late life. This would likely benefit risk reduction of cognitive decline and dementia in later life.

The analysis of fMRI complexity as a biomarker of cognitive decline compared to tau‐PET

AbstractBackgroundTau‐PET detects the neurofibrillary tangle pathology and is considered a biomarker of neuronal injury and cognitive decline. However, PET imaging has radiation exposure risks and is costly. Recently, brain entropy mapping based on rs‐fMRI has emerged as a brain functionality biomarker that indicates the complexity of BOLD signals. Various studies have implied that reduced brain entropy values correlate significantly with cognitive decline in Alzheimer’s disease. This study analyzes the effect of fMRI complexity as a biomarker of cognitive decline in AD compared to tau‐PET.MethodWe obtained the dataset for this study from the Alzheimer’s Disease Neuroimaging Initiative (ADNI). The dataset consisted of 147 subjects (age = 72.5±7.5, M/F = 60/87, CN/MCI/AD = 95/45/7) with a tau‐PET (tracer: 18F‐AV1451) and two fMRI scans. FMRI images underwent standard processing to generate Multi‐Scale Entropy (MSE) maps. We calculated parametric SUVR values based on cerebellar reference regions from tau‐PET images. To determine the ability of MSE and PET images as a risk factor of cognitive decline in AD, convolutional neural networks were used to classify individuals into CN or MCI/AD groups. Each classifier was trained separately with fMRI complexity images or SUVR images. These two models had the same network structures and hyperparameters. We performed a 5‐fold cross‐validation to evaluate each model.ResultThe classifier using fMRI‐MSE achieved an accuracy equivalent to that using tau‐PET (0.7823 vs. 0.7687). We also calculated the Area Under the ROC curve (AUC) to evaluate sensitivity and specificity and observed that the model using fMRI‐MSE achieved AUC of 0.7022, and that using tau‐PET resulted in AUC of 0.6889.ConclusionThe classification performance showed that use of fMRI‐MSE could potentially be an AD biomarker alternative to tau‐PET. Further studies with multisite, larger datasets are required to validate our preliminary results and provide more conclusive evidence.

Association of HbA1c trajectory and variability with cognitive function

AbstractBackgroundType 2 diabetes (T2D) is an important modifiable risk factor for cognitive decline, and increasing evidence suggests that worse glucose control, in addition to a diagnosis of T2D, may play a role in cognitive function in later life. Despite this increasing concern, evidence regarding the relative contributions of poor glucose control and higher glucose variability to cognitive dysfunction among individuals with overweight or obesity is limited, mostly due to lack of repeated measures in many studies.MethodLook AHEAD MIND Study participants, aged 45‐76 years at baseline (2001‐04) with T2D and overweight or obesity, were randomized to an intensive lifestyle intervention focused on weight loss or a diabetes support and education condition, which were discontinued after ∼10 years. HbA1c levels were evaluated at years 1‐4, 6, 8, and 10. Cognitive function was evaluated up to four times between years 8‐18 with a cognitive battery that assessed memory, attention, and executive function domains. Cognitive scores were binned into four groups based on relative timing of cognitive assessments (8‐9; 10‐11; 12‐14; and 15‐18 years). We classified HbA1c variability according to: Variability Independent of the Mean (VIM), Average Real Variability (ARV), and data‐driven latent trajectories. Mixed linear regression models for standardized composite cognitive scores were adjusted for: repeated measures, order of cognitive test, years from randomization, randomization arm, age, sex, race/ethnicity, years of education, CVD history, and APOE ε4.ResultFour HbA1c trajectories were identified: increasing, decreasing, stable‐high, and stable‐low. Composite cognitive scores were significantly lower for increasing, decreasing, and stable‐high HbA1c trajectories ‐compared to stable‐low HbA1c (Table). In multivariable analysis, higher baseline HbA1c, ARV, and VIM were associated with lower composite cognitive scores, and differences between groups were similar by years since randomization. Estimates for ARV and VIM were attenuated when adjusted for baseline HbA1c (not shown). Estimates were similar for tests from all cognitive domains, with little heterogeneity by randomization arm.ConclusionAmong individuals with T2D, higher HbA1c at baseline and greater HbA1c variability over 10 years were significantly associated with lower cognitive scores, suggesting that maintaining glucose control may be useful for the prevention of cognitive decline.