APOE Ε4 Carrier Status Research Articles

Day‐to‐day sleep and circadian variability in association with Alzheimer’s Disease biomarkers

AbstractBackgroundIncreasing evidence shows that Alzheimer’s Disease (AD) pathology, i.e., the Aß peptide, tau tangles and the APOEε4 allele, have all been associated with disrupted sleep and change in circadian rhythms. However, objective sleep measurements are often assessed over a single night. Measures of day‐to‐day variability might reveal unstable sleep and circadian rhythms that may reflect neurodegenerative processes. We sought to evaluate the association between AD biomarkers and sleep and circadian variability measured over a week of actigraphy.Method203 dementia‐free participants (age: 68.5±5.4 years, 151 women) from the PREVENT‐AD cohort with known APOEε4 carrier status were tested with a week of actigraphy. Overlapping subsamples were tested for determination of cerebrospinal fluid (CSF) Aß1‐42, total t‐tau and p(181)‐tau (n = 100); CSF apoE protein (n = 69); and plasma Aß1‐42 (n = 144). Day‐to‐day variability in actigraphy circadian and sleep measures were assessed using the standard deviation of individual results. Day‐to‐day variability was compared between APOEε4 carriers were compared to non‐carriers using t‐tests. Linear regressions were performed between day‐to‐day variability with CSF and plasma, adjusted for age, sex, and time interval between measurements. An interaction term for APOEε4 carrier status was additionally tested in regression models.ResultAPOEε4 carriers did not differ meaningfully from non‐carriers regarding sleep and circadian variability. Lower CSF Aß1‐42 was associated with higher day‐to‐day variability of time of morning awakening and nighttime sleep duration (ß = ‐0.263, p = 0.009; b = ‐0.206, p = 0.041). Higher plasma Aß1‐42 was also associated with higher day‐to‐day variability for time in bed, activity counts, sleep onset latency, sleep efficiency, and nighttime sleep duration (ß = 0.160 to 0.242; p = 0.010 to 0.002). Lower CSF apoE protein was associated with increased day‐to‐day variability for time of morning awakening, time in bed, activity counts, and nighttime sleep duration (ß = ‐0.243 to ‐0.420; p = 0.042 to <0.001). Higher CSF t‐tau, and a trend for p(181)‐tau were associated with time of morning awakening day‐to‐day variability inε4 carriers only (interaction p<0.001;ß = 0.330, p = 0.047; b = 0.281, p = 0.094).ConclusionSleep and circadian variability are associated with biomarkers of AD pathology and apoE metabolism. These results may suggest that unstable sleep promotes neurodegeneration or, conversely, that AD neuropathology disrupts sleep and circadian function.

Impact of APOE ε4 allele on familial aggregation and cerebrovascular disease in Alzheimer’s Dementia: A cross‐sectional pilot study from India

AbstractBackgroundThe ε4 variant of the apolipoprotein E gene (APOE4) is associated with the risk of Alzheimer’s dementia (AD). Previous studies have reported APOE4 status association with familial loading and vascular changes in AD. With a diverse ethnic population, and high rates of metabolic syndromes, the consequences of being a carrier of the APOE4 polymorphism needs further exploration in Indian context.MethodPatients (N = 452) diagnosed to have AD, including 75 with a family history of AD in first‐degree relatives [‘familial’ AD (FAD)] and others without a significant family history [‘sporadic’ AD (SAD)], under evaluation at a tertiary hospital in India are described. All patients were assessed using Clinical Dementia Rating scale (CDR), Hindi Mental Status Examination (HMSE), Everyday Abilities Scale for India (EASI), Neuropsychiatric Inventory (NPI), and the Hachinski Ischemic Scale (HIS), along with detailed clinical evaluation. Blood samples were collected from AD patients, and 456 matched healthy controls for APOE genotyping using Polymerase Chain Reaction restriction fragment length polymorphism.ResultsThe ε4 allele frequency was 22.57% and 9.65% among AD patients and healthy controls. APOE4 carrier status was noted in 52% of FAD, 38.46% of SAD patients, and was a significant risk factor for FAD with an odd’s ratio (OR) of 1.73 (95% confidence interval (CI):1.04‐2.9, p = 0.03). The presence of APOE4 did not have a significant association with metabolic comorbidities (p = 0.54). Furthermore, APOE4 status was a negative predictor for cerebrovascular disease among all AD patients (OR: 0.32, 95% CI: 0.12‐0.71, p = 0.008).ConclusionAPOE4 allele has a positive association with familial aggregation and a negative association with cerebrovascular adversities in AD. The effect of APOE4 polymorphism on the clinical manifestation of AD in Indian population is unclear and needs further evaluation.

Early Detection of Dementia using Risk Classification in MCI: Outcomes of Shanghai Mild Cognitive Impairment Cohort Study.

The purpose of this study is to identify the risk factors and risk classification associated with the conversion from mild cognitive impairment (MCI) to Alzheimer's disease (AD) dementia to facilitate early intervention and the design of clinical trials for AD. The study comprised a prospective cohort study of 400 subjects with MCI who had annual follow-ups for 3 years. During an average follow-up period of 3.5 years, 109 subjects were diagnosed with all cause of dementia, of whom 104 subjects converted to Alzheimer's dementia and 5 subjects converted to other types of dementia. The cumulative conversion rate was 5.5% (95% CI: 3.4, 8.6), 16.3% (95% CI: 12.9, 21.1), and 31.0% (95% CI: 25.4, 36.5) in each of the first 3 follow-up years, respectively. The factors associated with a greater risk of conversion from MCI to AD included smoking status, ApoE4 carrier status, right hippocampal volume (rt. HV), left temporal lobe volume, and scores on the Revised Chinese version of the Alzheimer's Disease Assessment Scale-Cognitive Subscale 13 (ADAS-Cog-C). The risk classification of the ADAS-Cog-C or Preclinical Alzheimer Cognitive Composite (PACC) score combined with the rt. HV showed a conversion difference among the groups at every annual follow-up. A simple risk classification using the rt. HV and neuropsychological test scores, including those from the ADAS-Cog-C and PACC, could be a practicable and efficient approach to indentify individuals at risk of all-cause dementia.

Neuroimaging biomarkers of the Amyloid, Tau, Neurodegeneration and Vascular framework in association with sleep duration changes over time

AbstractBackgroundBoth short and long sleep duration were previously associated with incident dementia, but underlying mechanisms of this association remains unknown. This project aims to evaluate how self‐reported sleep duration and its change over time associate with (A)myloid, (T)au, (N)eurodegeneration and (V)ascular neuroimaging markers of Alzheimer’s disease (AD).MethodWithin the Framingham Heart Study, two samples were studied: 271 participants (age:53.6±8.0 years; 51%M) who underwent 11C‐PiB amyloid (global, precuneus) and 18F‐Flortaucipir tau (several medial cortical limbic structures) PET imaging; and 2165 participants (age:61.3±11.1 years; 45%M) who underwent an MRI. To estimate neurodegeneration, total brain volume was extracted from MRI. Vascular MRI metrics included white matter hyperintensities (continuous, and dichotomous indicator for extensive for age), covert brain infarcts, and average free‐water. Self‐reported sleep duration was assessed both at the time of neuroimaging testing and around 15 years before, and split by categories (≤6h, 7‐8h, ≥9h). Sleep duration change over time was assessed by change between categories and by continuous delta change (split by negative and positive values for decreased or increased respectively). Logistic and linear regression models were tested between self‐reported sleep duration and neuroimaging metrics, adjusted for age and age2, sex, PET camera, APOE4 carrier status, depression, diabetes, hypertension, and prevalent cardiovascular diseases.ResultsNo association was observed between cross‐sectional self‐reported sleep duration and neuroimaging metrics. Transitioning to longer sleep over time (≤6h to ≥9h and 7‐8h to ≥9h as compared to consistently sleeping 7‐8h) was associated with higher white matter hyperintensities burden (extensive, OR[95%CI]:3.50[0.95‐12.92], p = 0.040;ß[SE]:0.25[0.10], p = 0.015) and higher free‐water (ß[SE]:0.021[0.007], p = 0.003;ß[SE]:0.009[0.002], p = 0.0002). When looking at continuous sleep duration change, increasing sleep duration over time was also associated with higher white matter hyperintensities burden (extensive, OR[95%CI]:1.26[1.02‐1.55], p = 0.032;ß[SE]:0.10[0.04], p = 0.007) and higher free‐water (ß[SE]:0.002[0.001], p = 0.031). Self‐reported sleep duration change was not associated with PET amyloid or tau outcomes.ConclusionVascular pathology in the brain as evidenced by higher white matter hyperintensities burden and free‐water is associated with sleep duration that is getting longer over time, thus potentially explaining its association with dementia risk. In fact, elongation of sleep duration may be an early change in the AD trajectory.

Association of inflammatory proteins with cognitive aging, brain MRI markers, and incident dementia

AbstractBackgroundInflammatory cytokines and chemokines related to the innate and adaptive immune system have been linked to neuroinflammation in Alzheimer’s Disease (AD) dementia. We hypothesized that individual blood‐based inflammatory biomarkers would associate with cognitive function, brain magnetic resonance imaging (MRI) volumes, and risk for dementia in Framingham Heart Study (FHS) participants.MethodProtein biomarkers related to immune cells or associated with inflammatory responses including CD14, CD163, CD5L, CD56, CD40L, CXCL16, SDF1, DPP4, SGP130, sRAGE, and MPO were measured at FHS Offspring exam 7. We identified FHS Offspring participants who underwent neuropsychological (NP) testing (n = 2394) or brain MRI (n = 2135) within five years of the examination; and who were followed up 10 years after age 60 for incident all‐cause dementia (n = 1650). We used linear mixed effect models accounting for family relationships to investigate the associations between the protein biomarkers and NP test performance and brain MRI volumes and Cox proportional hazards models to examine the association with incident dementia. A false discovery rate (FDR) within each outcome set was computed to adjust for multiple testing and FDR ≤ 0.1 indicated significance.ResultParticipants from the NP and MRI samples were on average 61 years old and 54% female. Participants from the incident dementia sample (mean age 68 years) included 126 incident dementia cases within 10 years. In addition to CD14 which has an established association, we observed significant associations between higher CD40L and MPO with poorer NP performance from the executive function domain. Higher CD5L levels were significantly associated with smaller total brain volumes (TCBV), whereas higher sRAGE was associated with larger TCBV. Associations persisted after further adjusting for APOE ϵ4 carrier status and cardiovascular risk factors. None of the protein biomarkers included were significantly associated with risk of incident dementia, with trend towards an association for CD5L.ConclusionSince the proinflammatory factors CD5L, CD40L, sRAGE and MPO are associated with immune cells and are involved in vascular pathology, our study suggests the immune‐vascular axis is associated with cognitive and brain aging. If confirmed in other samples, our findings may provide informative biomarkers of abnormal brain aging.

The Association between Coffee and Tea Consumption at Midlife and Risk of Dementia Later in Life: The HUNT Study.

Studies exploring the possible protective effect of coffee and tea consumption on dementia have shown inconsistent results so far. We aimed to investigate whether consumption of tea and different types of coffee at midlife are associated with dementia later in life and whether sex or ApoE4 influence such association. We included 7381 participants from the Norwegian HUNT Study. Self-reported questionnaires assessed daily consumption of coffee and tea at baseline. After 22 years, individuals 70 years or older were screened for cognitive impairment. General coffee consumption and tea consumption was not associated with dementia risk. Compared to daily consumption of 0-1 cups of coffee, daily consumption of ≥8 cups of boiled coffee was associated with increased dementia risk in women (OR: 1.83, 95% CI: 1.10-3.04, p-value for trend = 0.03) and daily consumption of 4-5 cups of other types of coffee was associated with a decrease in dementia risk in men (OR: 0.48, 95% CI: 0.32-0.72, p-value for trend = 0.05). Furthermore, the association between boiled coffee and increased dementia risk was only found in ApoE4 non-carriers. Differences by sex or ApoE4 carrier status were not supported by strong statistical evidence for interaction. Tea consumption was not associated with dementia risk. type of coffee may play a role in the direction of the association between coffee-drinking habits and dementia later in life.

White matter hyperintensity volume (WMHV) association with APOE e4 carriers and non-carriers (P11-5.005)

<h3>Objective:</h3> Determine whether white matter hyper-intensity volume (WMHV) differs with APOE4 carriage. <h3>Background:</h3> Apolipoprotein E4 (APOE4) allele is associated with an increased risk for both Alzheimer’s Disease (AD) and cardiovascular disease (CVD). APOE4 association with WMHV (a measure of small vessel vasculopathy) is ambiguous. While APOE4 carriage is associated with greater AD pathology, it remains unclear whether cerebrovascular damage is also associated with APOE4 carriage. The aim of this meta-analysis is to determine whether WMHV is associated with APOE carrier status. <h3>Design/Methods:</h3> 12 studies from Pubmed and EMBASE were found where data for sample size, age, WMHV, study setting, and WMHV quantification method were extracted from each article. Random effect models were used to estimate raw and standardized mean differences for WMHV in APOE4 carriers and non-carriers in addition to subgroup analyses (clinic and community). Analyses were carried out using the ‘metacont’ function in the ‘meta’ package in R 4.0.3. <h3>Results:</h3> The 12 studies yielded a total sample size of 16,738 (e4 carrier n=4,721; e4 non-carrier n=12,017) with an average age of 69.72 years. The primary analysis found no significant difference in WMHV between e4 carriers and non-carriers (95% CI (−0.01, 0.15), p = 0.09) with a moderate level between-study heterogeneity (I2 = 64%, 95% CI (33%, 81%). Subgroup analyses showed a small effect size indicating that APOE4 carriers had a greater WMHV (n = 8, 95% CI (0.02, 0.16), p = 0.008) with moderate heterogeneity (I2 = 55%, 95% CI (1%, 80%). No significant difference in WMHV by APOE4 status was noted among clinic-based studies (n = 3, 95% CI (−0.60, 0.41), p = 0.70). <h3>Conclusions:</h3> Our findings show an insignificant difference in WMHV between APOE4 carriers and non-carriers. However, utilized community-based samples showed that WMHV was greater in e4 carriers. This suggests that non-APOE factors have a greater influence on WMHV. <b>Disclosure:</b> Mr. Stipho has nothing to disclose. Mr. Stipho has nothing to disclose. Michael Ahmadi has nothing to disclose.

Interaction between KLOTHO-VS Heterozygosity and APOE ε4 Allele Predicts Rate of Cognitive Decline in Late-Onset Alzheimer's Disease.

KLOTHO-VS heterozygosity (KL-VShet+) promotes longevity and protects against cognitive decline in aging. To determine whether KL-VShet+ mitigates Alzheimer's disease (AD) progression, we used longitudinal linear-mixed models to compare the rate of change in multiple cognitive measures in AD patients stratified by APOE ε4 carrier status. We aggregated data on 665 participants (208 KL-VShet-/ε4-, 307 KL-VShet-/ε4+, 66 KL-VShet+/ε4-, and 84 KL-VShet+/ε4+) from two prospective cohorts, the National Alzheimer's Coordinating Center and the Alzheimer's Disease Neuroimaging Initiative. All participants were initially diagnosed with mild cognitive impairment, later developed AD dementia during the study, and had at least three subsequent visits. KL-VShet+ conferred slower cognitive decline in ε4 non-carriers (+0.287 MMSE points/year, p = 0.001; -0.104 CDR-SB points/year, p = 0.026; -0.042 ADCOMS points/year, p < 0.001) but not in ε4 carriers who generally had faster rates of decline than non-carriers. Stratified analyses showed that the protective effect of KL-VShet+ was particularly prominent in male participants, those who were older than the median baseline age of 76 years, or those who had an education level of at least 16 years. For the first time, our study provides evidence that KL-VShet+ status has a protective effect on AD progression and interacts with the ε4 allele.

Associations of baseline and longitudinal change in cerebellum volume with age-related changes in verbal learning and memory

The cerebellum is involved in higher-order cognitive functions, e.g., learning and memory, and is susceptible to age-related atrophy. Yet, the cerebellum's role in age-related cognitive decline remains largely unknown. We investigated cross-sectional and longitudinal associations between cerebellar volume and verbal learning and memory. Linear mixed effects models and partial correlations were used to examine the relationship between changes in cerebellum volumes (total cerebellum, cerebellum white matter [WM], cerebellum hemisphere gray matter [GM], and cerebellum vermis subregions) and changes in verbal learning and memory performance among 549 Baltimore Longitudinal Study of Aging participants (2,292 visits). All models were adjusted by baseline demographic characteristics (age, sex, race, education), and APOE e4 carrier status. In examining associations between change with change, we tested an additional model that included either hippocampal (HC), cuneus, or postcentral gyrus (PoCG) volumes to assess whether cerebellar volumes were uniquely associated with verbal learning and memory. Cross-sectionally, the association of baseline cerebellum GM and WM with baseline verbal learning and memory was age-dependent, with the oldest individuals showing the strongest association between volume and performance. Baseline volume was not significantly associated with change in learning and memory. However, analysis of associations between change in volumes and changes in verbal learning and memory showed that greater declines in verbal memory were associated with greater volume loss in cerebellum white matter, and preserved GM volume in cerebellum vermis lobules VI-VII. The association between decline in verbal memory and decline in cerebellar WM volume remained after adjustment for HC, cuneus, and PoCG volume. Our findings highlight that associations between cerebellum volume and verbal learning and memory are age-dependent and regionally specific.

Effect of sex on the APOE4-aging interaction in the white matter microstructure of cognitively normal older adults using diffusion-tensor MRI with orthogonal-tensor decomposition (DT-DOME).

The influence of the apolipoprotein E ε4 allele (APOE4) on brain microstructure of cognitively normal older adults remains incompletely understood, in part due to heterogeneity within study populations. In this study, we examined white-matter microstructural integrity in cognitively normal older adults as a function of APOE4 carrier status using conventional diffusion-tensor imaging (DTI) and the novel orthogonal-tensor decomposition (DT-DOME), accounting for the effects of age and sex. Age associations with white-matter microstructure did not significantly depend on APOE4 status, but did differ between sexes, emphasizing the importance of accounting for sex differences in APOE research. Moreover, we found the DT-DOME to be more sensitive than conventional DTI metrics to such age-related and sex effects, especially in crossing WM fiber regions, and suggest their use in further investigation of white matter microstructure across the life span in health and disease.

Mechanisms of Healthy Aging: An Integrated Neurobiological Perspective on Mood and Cognitive Function

Neurobiological approaches to healthy aging can protect against declines in cognitive function and mood disturbances in older adults. This symposium will focus on health-based mechanisms associated with mood and cognition in late life using an integrated micro- and macro-level perspective. Mechanistic pathways and predictors of healthy aging will be discussed across multiple levels of analysis (genetic, molecular, systems-level neurocircuitry, and behavioral). We will discuss these mechanisms of aging and late-life depression cross-sectionally and in the context of non-pharmacological interventions to identify potential pathways for more personalized treatments.This symposium will take a unique approach to classifying the neurobiology of healthy aging. Dr. Swathi Gujral will present a large study of 108 community-dwelling older adults who completed an exercise intervention and discuss differences in stress and emotional health as a function of exercise condition and APOE e4 carrier status. Dr. Julie Dumas will discuss functioning of the nicotinic cholinergic system in older adults and will present effects of nicotinic stimulation and blockade on brain activation and working memory performance in older adults with and without subjective cognitive decline. Dr. Lauren Oberlin will present neuroimaging features of small vessel disease (SVD) in older adults with and without depression and discuss the association between white matter abnormalities and cognitive decline in late life. Dr. Lindsay Victoria will present neural correlates of negative cognitive bias in late-life depression and their impact on treatment response to psychotherapy in depressed older adults.The unifying goal of these presentations is to characterize mechanistic pathways to precisely target cognitive deficits, improve mood, and promote healthy aging. With an emphasis on individual differences, we will examine predictors of change across a range of domains impacted in aging and late-life depression, including stress, working memory, and executive function. This mechanistic approach has important implications for the development of personalized interventions that emphasize health-based approaches to mood and cognitive function in older adults.

White matter hyperintensities in cholinergic pathways are associated with dementia severity in e4 carriers but not in non-carriers.

Among individuals with Alzheimer's disease (AD), APOE e4 carriers with increased white matter hyperintensities (WMHs) may selectively be at increased risk of cognitive impairment. Given that the cholinergic system plays a crucial role in cognitive impairment, this study aimed to identify how APOE status modulates the associations between dementia severity and white matter hyperintensities in cholinergic pathways. From 2018 to 2022, we recruited participants (APOE e4 carriers, n = 49; non-carriers, n = 117) from the memory clinic of Cardinal Tien Hospital, Taipei, Taiwan. Participants underwent brain MRI, neuropsychological testing, and APOE genotyping. In this study, we applied the visual rating scale of the Cholinergic Pathways Hyperintensities Scale (CHIPS) to evaluate WMHs in cholinergic pathways compared with the Fazekas scale. Multiple regression was used to assess the influence of CHIPS score and APOE carrier status on dementia severity based on Clinical Dementia Rating-Sum of Boxes (CDR-SB). After adjusting for age, education and sex, higher CHIPS scores tended to be associated with higher CDR-SB in APOE e4 carriers but not in the non-carrier group. Carriers and non-carriers present distinct associations between dementia severity and WMHs in cholinergic pathways. In APOE e4 carriers, increased white matter in cholinergic pathways are associated with greater dementia severity. In non-carriers, WMHs exhibit less predictive roles for clinical dementia severity. WMHs on the cholinergic pathway may have a different impact on APOE e4 carriers vs. non-carriers.

Abstract 34: Liver Fibrosis, Apolipoprotein E, And Hemorrhagic Stroke Risk: A Cohort Analysis

Introduction: Cirrhosis is associated with an increased risk of hemorrhagic stroke (HS). Liver fibrosis, typically a silent condition, is antecedent to cirrhosis. We hypothesized that liver fibrosis is associated with an increased risk of HS. Further, because apolipoprotein E2 (ApoE2) and E4 (ApoE4) are associated with HS, and because liver-derived peripheral ApoE4 may disrupt endothelial integrity, we evaluated for effect modification by these isoforms. Methods: We performed a cohort analysis using the UK Biobank Study, which prospectively enrolled adults in 2007, with continuous follow-up. We excluded participants with prevalent HS or thrombocytopenia. Liver fibrosis was defined using the validated Fibrosis-4 score. The primary outcome, incident HS (intracerebral or subarachnoid hemorrhage), was captured in UK Biobank based on hospitalization and death registry data. We used Cox proportional hazards models to evaluate the association of liver fibrosis with HS while adjusting for HS risk factors (demographics, systolic blood pressure, hemoglobin A1c, total cholesterol, BMI, tobacco and alcohol use, antithrombotic use). Effect modification by ApoE2 and ApoE4 were evaluated using interaction terms and stratified analyses. Results: Among 453,251 included participants, the mean age was 57 years and 54% were women. Approximately 2% had liver fibrosis, 16% used antithrombotic agents, 29% were ApoE4 carriers, and 15% were ApoE2 carriers. In adjusted Cox models, liver fibrosis was associated with an increased risk of HS (HR, 2.17; 95% CI, 1.51-3.12) (Figure). This relationship appeared stronger in ApoE4 homozygotes (HR, 8.27; 95% CI, 2.30-29.73) than in others (HR, 2.18; 95% CI, 1.47-3.24) (P=0.05, interaction). ApoE4 carrier status, ApoE2 carrier status, and ApoE2 homozygosity did not modify this relationship (P&gt;0.20, interactions). Conclusions: Liver fibrosis was associated with an increased risk of HS, possibly more so in ApoE4 homozygous persons.

The Contribution of Genetic Risk for Alzheimer’s &amp; Cardiovascular Disease to Recovery from Traumatic Brain Injuries

Polygenic risk scores (PRS) represent the genetic likelihood of developing a phenotype and represent an exciting opportunity for the development of personalized medicine. This study used PRS to determine if individuals at high-risk for Alzheimer’s (AD) or cardiovascular disease (CVD) would recover differently after TBI compared to low-risk individuals.&#x0D; GWAS with the Illumina Global Screening Array was performed on DNA available for a subset of the BI-Model Systems cohort (N=189). PRS were chosen from the PGS Catalog (https://www.pgscatalog.org) and calculated using the Michigan Imputation Server. 1-year follow-up data (1Y) for the Functional Independence Measure (FIM) was used to evaluate TBI recovery. FIM represents the subject’s self-care ability after TBI and includes a cognitive and motor component.&#x0D; ANCOVA models were used to elucidate the relationship between PRS risk groups (score in top 20% vs. 80%) and 1Y FIM scores. Covariates included age, education, FIM scores at discharge, injury severity, and genetic ancestry. Post-hoc analysis was conducted using 1Y FIM scores of subjects stratified by AD risk and APOE e4 carrier status, a major risk factor for AD onset. Additional post-hoc analysis evaluated hypertension at 1Y by CVD PRS groups using a cox survival model.&#x0D; Individuals with high AD PRS had lower 1Y FIM scores than those with low risk (p= 0.041). Post-hoc analysis showed a trend for APOE e4 carriers with high AD PRS performing worse on FIM motor testing (p=0.145). There was not significant association between the CVD high-risk group and FIM scores (p=0.389). The cox survival model of hypertension trended towards earlier age of onset in the high-risk subjects (p=0.155).&#x0D; This pilot study shows the potential for PRS to identify individuals at risk for worse TBI recovery, allowing for future research on early interventions and their effects on TBI recovery.

Hormone replacement therapy is associated with improved cognition and larger brain volumes in at-risk APOE4 women: results from the European Prevention of Alzheimer’s Disease (EPAD) cohort

BackgroundThe risk of dementia is higher in women than men. The metabolic consequences of estrogen decline during menopause accelerate neuropathology in women. The use of hormone replacement therapy (HRT) in the prevention of cognitive decline has shown conflicting results. Here we investigate the modulating role of APOE genotype and age at HRT initiation on the heterogeneity in cognitive response to HRT.MethodsThe analysis used baseline data from participants in the European Prevention of Alzheimer’s Dementia (EPAD) cohort (total n= 1906, women= 1178, 61.8%). Analysis of covariate (ANCOVA) models were employed to test the independent and interactive impact of APOE genotype and HRT on select cognitive tests, such as MMSE, RBANS, dot counting, Four Mountain Test (FMT), and the supermarket trolley test (SMT), together with volumes of the medial temporal lobe (MTL) regions by MRI. Multiple linear regression models were used to examine the impact of age of HRT initiation according to APOE4 carrier status on these cognitive and MRI outcomes.ResultsAPOE4 HRT users had the highest RBANS delayed memory index score (P-APOE*HRT interaction = 0.009) compared to APOE4 non-users and to non-APOE4 carriers, with 6–10% larger entorhinal (left) and amygdala (right and left) volumes (P-interaction= 0.002, 0.003, and 0.005 respectively). Earlier introduction of HRT was associated with larger right (standardized β= −0.555, p=0.035) and left hippocampal volumes (standardized β= −0.577, p=0.028) only in APOE4 carriers.ConclusionHRT introduction is associated with improved delayed memory and larger entorhinal and amygdala volumes in APOE4 carriers only. This may represent an effective targeted strategy to mitigate the higher life-time risk of AD in this large at-risk population subgroup. Confirmation of findings in a fit for purpose RCT with prospective recruitment based on APOE genotype is needed to establish causality.

Daytime Sleepiness Is Associated with Lower Cognitive Scores: The Look AHEAD Study.

Daytime sleepiness is common in older adults and may result from poor nighttime sleep due to sleep disordered breathing, fragmented sleep, or other sleep disorders. Daytime sleepiness may be associated with cognition in older adults. We investigated the association between self-reported daytime sleepiness and cognitive function in the Look AHEAD clinical trial. Observational follow-up of a randomized clinical trial of an intensive lifestyle intervention. Clinic. Participants (n=1,778) aged 45-76 years at baseline with type 2 diabetes and overweight or obesity. Participants were randomized to an intensive lifestyle intervention for weight loss or a control condition of diabetes support and education. Participants provided self-reported levels of daytime sleepiness at baseline and years 12-13. Cognitive function was assessed with a neurocognitive battery at years 12-13 and 18-20. Participants who reported having frequent daytime sleepiness (often or always) performed significantly worse than others on the cognitive composite (-0.35; p-value=0.014) after controlling for covariates. When stratified by intervention arm, participants assigned to the intensive lifestyle intervention who reported often/always having daytime sleepiness performed worse on Digit Symbol Coding (-0.63; p-value=0.05) and Trail Making Part-B (-0.56; p-value=0.02) after controlling for covariates. Statistical interactions revealed associations between daytime sleepiness and the following covariates: race and ethnicity, APOE ε4 carrier status, baseline history of cardiovascular disease, and depression. Daytime sleepiness over ~13 years predicted poorer cognitive performance in older individuals who, by virtue of having diabetes and overweight/obesity, are at high risk for sleep disorders and cognitive impairment.

Cortical Iron Accumulation as an Imaging Marker for Neurodegeneration in Clinical Cognitive Impairment Spectrum: A Quantitative Susceptibility Mapping Study.

Cortical iron deposition has recently been shown to occur in Alzheimer's disease (AD). In this study, we aimed to evaluate how cortical gray matter iron, measured using quantitative susceptibility mapping (QSM), differs in the clinical cognitive impairment spectrum. This retrospective study evaluated 73 participants (mean age ± standard deviation, 66.7 ± 7.6 years; 52 females and 21 males) with normal cognition (NC), 158 patients with mild cognitive impairment (MCI), and 48 patients with AD dementia. The participants underwent brain magnetic resonance imaging using a three-dimensional multi-dynamic multi-echo sequence on a 3-T scanner. We employed a deep neural network (QSMnet+) and used automatic segmentation software based on FreeSurfer v6.0 to extract anatomical labels and volumes of interest in the cortex. We used analysis of covariance to investigate the differences in susceptibility among the clinical diagnostic groups in each brain region. Multivariable linear regression analysis was performed to study the association between susceptibility values and cognitive scores including the Mini-Mental State Examination (MMSE). Among the three groups, the frontal (P < 0.001), temporal (P = 0.004), parietal (P = 0.001), occipital (P < 0.001), and cingulate cortices (P < 0.001) showed a higher mean susceptibility in patients with MCI and AD than in NC subjects. In the combined MCI and AD group, the mean susceptibility in the cingulate cortex (β = -216.21, P = 0.019) and insular cortex (β = -276.65, P = 0.001) were significant independent predictors of MMSE scores after correcting for age, sex, education, regional volume, and APOE4 carrier status. Iron deposition in the cortex, as measured by QSMnet+, was higher in patients with AD and MCI than in NC participants. Iron deposition in the cingulate and insular cortices may be an early imaging marker of cognitive impairment related neurodegeneration.

IMPACT OF CALORIE RESTRICTION ON PLASMA ALZHEIMER’S DISEASE BIOMARKERS IN HEALTHY YOUNG AND MIDDLE-AGED ADULTS

Abstract Midlife cardiometabolic risk factors are associated with an increased risk of Alzheimer’s dementia (AD). Moderate calorie restriction (CR) in healthy, non-obese young and middle-aged adults improves cardiometabolic risk factors. Plasma concentrations of amyloid β oligomers (Aβ-42 and Aβ-40) and total tau are emerging biomarkers of AD pathology. Our objective was to determine the impact of two years of CR in healthy young and middle-aged adults on Aβ-42, Aβ-40, and total tau in the Comprehensive Assessment of Long term Effects of Reducing Intake of Energy (CALERIE) Study. Participants were randomized 2:1 to 24 months of CR (prescribed as 25% reduction in baseline calorie requirements) versus an ad libitum (AL) diet. We quantified plasma Aβ-42, Aβ-40, and total tau using the ultrasensitive single molecule array (SIMOA) technology at baseline and two years in a subset of CALERIE (N=133). We used linear regression to evaluate the impact of CR, including age, sex, and presence/absence of the APOE-ε4 risk allele as covariates. We hypothesized that there would be differential CR effects based on APOE-ε4 carrier status; to test this, we included an interaction term. As compared to AL, there was a trend towards decreased Aβ-40, controlling for age, baseline Aβ-40 concentrations, and APOE-ε4 carrier status (β=-12.59, 95% CI[-27.14, 1.96], p=0.093) with 12% (average achieved) CR. The CR*APOE-ε4 carrier status interaction term was significant at a pre-defined threshold of p&amp;lt;0.10 (p=0.062). Stratified by APOE-ε4 carrier status, CR was associated with a decrease in plasma Aβ-40 (β=-33.72, 95% CI[-65.16,-2.09], p=0.041). In conclusion, moderate CR in healthy, non-obese young and middle-aged adults impacts plasma biomarkers of AD risk, primarily in APOE-ε4 carriers.

PATTERNS OF AGING CHANGES IN BODY WEIGHT AND BMI MAY PREDICT CHANCES OF ALZHEIMER'S DISEASE AND LONGEVITY

Abstract Background Lower bodyweight/BMI was previously linked to AD and frailty; however, the role of long-term changes in the bodyweight/BMI in both AD and longevity is not well understood, as is the role of APOE polymorphism in such changes. Methods Using longitudinal data from the Framingham Heart Study (FHS) and the Health and Retirement Study (HRS), we estimated trajectories of the weight and BMI at ages 40 to 75, and compared them between individuals who did and who did not develop AD at ages 75+. We also evaluated associations between APOE4 carrier status and key characteristics of the age-trajectories of weight/BMI, including the age at peak value of the bodyweight/BMI (AgeMax), and slope of the decline in bodyweight/BMI after reaching the maximum. Results Women with late-onset-AD had lower bodyweight/BMI values up to three decades before AD diagnosis. They reached the peak of bodyweight in their 50s, about 10 years earlier than AD-free women. Younger AgeMax was associated with lower survival chances after age 80 in women. APOE4 carriers showed earlier/faster declines in weight and BMI than non-carriers; however, relevance of this to AD was unclear. Conclusion Younger age at peak value of the bodyweight/BMI indicates higher chances of late-onset-AD, while older age can predict better survival later in life and may favor longevity in women. The earlier start of the decline in bodyweight/BMI values could be sign of accelerated aging, which may contribute to AD. Relevance of APOE4 effects on age-trajectories of weight/BMI to AD warrants further investigation.

APOE Allele Frequency in Southern Greece: Exploring the Role of Geographical Gradient in the Greek Population

the apolipoprotein e4 allele (APOE4) constitutes an established genetic risk factor for Alzheimer's Disease Dementia (ADD). We aimed to explore the frequency of the APOE isoforms in the Greek population of Southern Greece. peripheral blood from 175 Greek AD patients, 113 with mild cognitive impairment (MCI), and 75 healthy individuals. DNA isolation was performed with a High Pure PCR Template Kit (Roche), followed by amplification with a real-time qPCR kit (TIB MolBiol) in Roche's Light Cycler PCR platform. APOE4 allele frequency was 20.57% in the ADD group, 17.69% in the MCI group, and 6.67% in the control group. APOE3/3 homozygosity was the most common genotype, while the frequency of APOE4/4 homozygosity was higher in the AD group (8.60%). APOE4 carrier status was associated with higher odds for ADD and MCI (OR: 4.49, 95% CI: [1.90-10.61] and OR: 3.82, 95% CI: [1.59-9.17], respectively). this study examines the APOE isoforms and is the first to report a higher APOE frequency in MCI compared with healthy controls in southern Greece. Importantly, we report the occurrence of the APOE4 allele, related to ADD, as amongst the lowest globally reported, even within the nation, thus enhancing the theory of ethnicity and latitude contribution.