APOE Ε4 Noncarriers Research Articles

APOE ε4 status and plasma p-tau181 interact to influence cognitive performance among non-demented older adults

ObjectiveIn this study, we aimed to investigate the relationships among plasma p-tau181, APOE ε4, and cognitive performance in non-demented elderly individuals. MethodsWe used individuals (n = 630) with cognitive normal (CN, n = 182) and mild cognitive impairment (MCI, n = 448). Multiple linear regression models were performed to test the effects of APOE ε4 × plasma p-tau181 interaction on MMSE, CDR-SOB, ADAS-cog13, and RAVLT immediate recall. All models adjusted for age, sex, and education. ResultsIn total, our study comprised 630 samples including 364 APOE ε4 non-carriers and 266 APOE ε4 carriers. In APOE ε4 carriers, plasma p-tau181 was significantly associated with MMSE (B = −0.04, p = 0.003), ADAS-Cog13 (B [unstandardized coefficient] = 0.21, p < 0.001), CDR-SB (B = 0.02, p = 0.003) and RAVLT immediate recall ((B = −0.17, p = 0.035). After correcting for Aβ status and diagnosis, the interaction between APOE ε4 and plasma p-tau181 was significant or marginally significant associations for RAVLT immediate recall (p = 0.076), MMSE (p = 0.011), CDR (p = 0.008), and ADAS-Cog13 (p < 0.001). ConclusionsOur findings suggested that plasma p-tau181 levels predicted cognitive performance among non-demented older adults, but only in the APOE ε4 carriers.

Obesity reduces hippocampal structure and function in older African Americans with the APOE-ε4 Alzheimer's disease risk allele.

Excess body weight and Alzheimer's disease (AD) disproportionately affect older African Americans. While mid-life obesity increases risk for AD, few data exist on the relationship between late-life obesity and AD, or how obesity-based and genetic risk for AD interact. Although the APOE-ε4 allele confers a strong genetic risk for AD, it is unclear if late-life obesity poses a greater risk for APOE-ε4 carriers compared to non-carriers. Here we assessed: (1) the influence of body mass index (BMI) (normal; overweight; class 1 obese; ≥ class 2 obese) on cognitive and structural MRI measures of AD risk; and (2) the interaction between BMI and APOE-ε4 in older African Americans. Seventy cognitively normal older African American participants (Mage = 69.50 years; MBMI = 31.01 kg/m2; 39% APOE-ε4 allele carriers; 86% female) completed anthropometric measurements, physical assessments, saliva collection for APOE-ε4 genotyping, cognitive testing, health and lifestyle questionnaires, and structural neuroimaging [volume/surface area (SA) for medial temporal lobe subregions and hippocampal subfields]. Covariates included age, sex, education, literacy, depressive symptomology, and estimated aerobic fitness. Using ANCOVAs, we observed that individuals who were overweight demonstrated better hippocampal cognitive function (generalization of learning: a sensitive marker of preclinical AD) than individuals with normal BMI, p = 0.016, ηp2 = 0.18. However, individuals in the obese categories who were APOE-ε4 non-carriers had larger hippocampal subfield cornu Ammonis region 1 (CA1) volumes, while those who were APOE-ε4 carriers had smaller CA1 volumes, p = 0.003, ηp2 = 0.23. Thus, being overweight by BMI standards may preserve hippocampal function, but obesity reduces hippocampal structure and function in older African Americans with the APOE-ε4 Alzheimer's disease risk allele.

Ranking the risk factors for Alzheimer's disease; findings from the UK Biobank study.

The cause of the most common form of dementia, sporadic Alzheimer's disease (AD), remains unknown. This may reflect insufficiently powered studies to date for this multi-factorial disorder. The UK Biobank dataset presents a unique opportunity to rank known risk factors and determine novel variables. A custom machine learning approach for high dimensionality data was applied to explore prospectively associations between AD in a sub-cohort of 156,209 UK Biobank participants aged 60-70 including more than 2,090 who were subsequently diagnosed with AD. After the possession of the APOE4 allele, the next highest ranked risk factors were other genetic variants within the TOMM40-APOE-APOC1 locus. When stratified by their apolipoprotein 4 (APOE4) carrier status, the most prominent risk factors in carriers were AST:ALT ratio, the "number of treatments/ medications" taken as well as "time spent in hospital" while protection was conferred by "Sleeplessness/Insomnia". In non-APOE carriers, lower socioeconomic status and fewer years of education were highly ranked but effect sizes were small relative to APOE4 carriers. Possession of the APOE4 allele was confirmed as the most important risk factor in AD. Other TOMM40-APOE-APOC1 locus variants further moderate the risk of AD in APOE4 carriers. Liver pathology is a novel risk factor in APOE4 carriers while "Sleeplessness/Insomnia" is protective in AD irrespective of APOE4 status. Other factors such as "Number of treatments/ medications" suggest that multimorbidity is an important risk factor for AD. Future treatments aimed at co-morbidities, including liver disease, may concomitantly lower the risk of sporadic AD.

Effect of APOE ε4 genotype on amyloid-β, glucose metabolism, and gray matter volume in cognitively normal individuals and amnestic mild cognitive impairment.

The presence of apolipoprotein E ε4 (APOE ε4) is associated with an increased risk of developing Alzheimer disease (AD). The aim of this study was to assess the effects of APOE ε4 on amyloid-β (Aβ) pathology, glucose metabolism, and gray matter (GM) volume and their longitudinal changes in healthy control (HC) and amnestic mild cognitive impairment (aMCI). We included 50 HCs and 109 aMCI patients from the Alzheimer's Disease Neuroimaging Initiative phase 2/GO based on availability of baseline T1-weighted magnetic resonance imaging, 18 F-florbetapir positron emission tomography (PET), and 18 F-fluorodeoxyglucose (FDG) PET. Of these, 35 HCs and 67 aMCI patients who underwent 24-month scans were included for follow-up study. Voxelwise analysis revealed that APOE ε4 carriers exhibited greater baseline Aβ deposition than APOE ε4 noncarriers in both diagnostic groups. However, there was no significant difference between APOE ε4 noncarriers and APOE ε4 carriers in terms of 18 F-FDG PET standardized uptake value ratio and GM volume. Region of interest-based analysis showed statistically significant greater Aβ deposition in APOE ε4 carriers than APOE ε4 noncarriers only in aMCI patients. Furthermore, APOE ε4 carriers generally exhibited a greater magnitude and spatial extent of longitudinal changes in Aβ deposition than APOE ε4 noncarriers in both diagnostic groups. Our findings suggest a differential effect of APOE ε4 on Aβ pathology, glucose metabolism, and GM volume. Studying APOE ε4-related brain changes with neuroimaging biomarkers in preclinical AD offers an opportunity to further our understanding of the pathophysiology of AD at an early stage.

Omega-3 supplementation increases omega-3 fatty acids in lipid compartments that can be taken up by the brain independent of APOE genotype status: A secondary analysis from a randomised controlled trial1

BACKGROUND: Omega-3 fatty acid (OM3) intake is associated with a lower risk of developing Alzheimer’s disease, but individuals carrying the ɛ4 allele of apolipoprotein E (APOE4) might not benefit from this prevention strategy. Indeed, they might have lower OM3 into plasma free fatty acid (FFA) and lysophosphatidylcholine (LPC) compartments, the two forms the brain can take-in. OBJECTIVE: To evaluate the docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA) concentrations in the FFA and LPC pre- and post-OM3 supplementation in APOE4 carriers and non-carriers. DESIGN: Plasma samples from 25 APOE4 carriers and non-carriers before and six months after receiving 2.5 g/d DHA+EPA daily were analyzed. DHA and EPA concentrations in the LPC, and FFA were compared by supplementation and genotype. A secondary analysis investigated the interaction between body mass index (BMI) and APOE genotype status. RESULTS: There was no genotype x supplement interaction nor a genotype effect on LPC and FFA. However, there was a supplement effect where OM3 increased in all lipid compartment by &lt; 1-fold to 4-fold. Individuals with a low BMI had higher OM3 increase concentrations in the LPC than those with a high BMI. CONCLUSIONS: APOE4 carriers and non-carriers can both benefit from taking an OM3 supplement. However, individuals with a high BMI have lower OM3 increases than those with a lower BMI.

The APOE4 effect: structural brain differences in Alzheimer's disease according to the age at symptom onset.

How the APOE genotype can differentially affect cortical and subcortical memory structures in biomarker-confirmed early-onset (EOAD) and late-onset (LOAD) Alzheimer's disease (AD) was assessed. Eighty-seven cerebrospinal fluid (CSF) biomarker-confirmed AD patients were classified according to their APOE genotype and age at onset. 28 were EOAD APOE4 carriers (+EOAD), 21 EOAD APOE4 non-carriers (-EOAD), 23 LOAD APOE4 carriers (+LOAD) and 15 LOAD APOE4 non-carriers (-LOAD). Grey matter (GM) volume differences were analyzed using voxel-based morphometry in Papez circuit regions. Multiple regression analyses were performed to determine the relation between GM volume loss and cognition. Significantly more mammillary body atrophy in +EOAD compared to -EOAD is reported. The medial temporal and posterior cingulate cortex showed less GM in +LOAD compared to -LOAD. Medial temporal GM volume loss was also found in +EOAD compared to -LOAD. With an exception for +EOAD, medial temporal GM was strongly associated with episodic memory in the three groups, whilst posterior cingulate cortex GM volume was more related with visuospatial abilities. Visuospatial abilities and episodic memory were also associated with the anterior thalamic nucleus in -LOAD. Our results show that the APOE genotype has a significant effect on GM integrity as a function of age of disease onset. Specifically, whilst LOAD APOE4 genotype is mostly associated with increased medial temporal and parietal atrophy compared to -LOAD, for EOAD APOE4 might have a more specific effect on subcortical (mammillary body) structures. The findings suggest that APOE genotype needs to be taken into account when classifying patients by age at onset.

THE COMPARISON OF DUAL TASK TIME AMONG APOE CARRIERS AGAINST NON-APOE CARRIERS IN AGING ADULTS

Abstract No single variable has been identified as the sole factor for predicting an individuals’ declining health status. In order to predict mental or physical decline in older adults, researchers have designed tasks that include both a physical and mental or cognitive demand known as dual task (DT). The purpose of implementing dual task is to assess the possible changes in accuracy when a second task gets compounded with a given single task. Our study consists of males and females aged from 45 to 75 years who have risk factors for dementia. Each subject was randomly assigned to either a health coaching (HC), or health education (HE) control group. The HC group received coaching to address the lifestyle areas known to be linked to AD risk, such as diet, exercise, sleep, stress, cognitive training, and social interaction. Blood markers of each individual have been assessed to determine carrier status of Apolipoprotein E 4 (APOE4) due to the correlation between the allele and increased risk of Alzheimer’s. To be included in the study, the participants must have at least 2 positive risk factors for AD as determined by the Australian National University-Alzheimer Disease Risk Index (ANU-ADRI). Among non-APOE carriers, a 2x3 (group x time) mixed ANOVA revealed a significant interaction effect wherein the HC group improved DTC score more than the HE group from time 1 to time 3, F (2, 362) =1.253, P=0.017. No significant interaction was noted for APOE carriers.

Pulse Pressure Is Associated with Rapid Cognitive Decline over 4 Years: A Population-Based Cohort Study.

Aiming to investigate the relationship between pulse pressure (PP) and cognitive decline, cognitively normal subjects from a community-based longitudinal cohort were followed-up for 4 years. The Mini-Mental State Examination (MMSE) was used to evaluate global cognitive function, and a ≥2-point decrease in the MMSE score from baseline was defined as cognitive decline. Restricted cubic spline, multivariable linear regression and logistic regression were used to investigate the relationship between PP and cognitive decline. A total of 1173 participants completed the follow-up, and 205 (17.5%) met the criteria for cognitive decline. Restricted cubic splines showed no nonlinear relationship between PP and ΔMMSE (Poverall = 0.037, Pnon-linear = 0.289) or cognitive decline (Poverall = 0.003, Pnon-linear = 0.845). Multivariable linear regression analysis showed that PP was positively related to ΔMMSE (b = 0.021, p = 0.020). Multivariable logistic regression analysis showed that PP was positively associated with cognitive decline (OR = 1.020, p = 0.023). A stratified analysis found an association between PP and cognitive decline in participants who were aged ≤65 years, male, and APOEε4 noncarriers and who had school education ≤6 years or hypertension. A sensitivity analysis after propensity-score matching did not alter our findings. These findings highlight that elevated PP is associated with rapid cognitive decline, particularly in males, middle-aged, low-educated, hypertensive individuals and APOEε4 noncarriers.

Plasma NfL predicts default mode network functional connectivity in older adults at higher risk for Alzheimer’s disease

AbstractBackgroundNeurofilament light (NfL) is a measure of neuronal damage and has the potential as a monitoring and prognostic biomarker of Alzheimer’s disease (AD) (Mattsson et al., 2019). Likewise, alterations in default mode network (DMN) functional connectivity (FC) may predict AD progression (Jones et al., 2016). Here, we investigated the relationship between plasma NfL levels and DMN FC along the continuum of AD, and explored whether APOE ε4 status influenced this relationship.MethodResting‐state functional MRI data and blood samples were available for 103 older adults (17 with AD dementia, age: 69.2±6.9; m/f: 8/9; CDR: 0.7±0.3; and 86 without dementia (includes amnestic MCI and control), age: 71.7±7.4; m/f: 21/65; CDR: 0.3±0.2). Plasma NfL was measured using a single‐molecule array (Simoa) assay. We calculated DMN FC using 32 high consensus DMN ROIs from Dworetsky et al. (2021). DMN FC was defined as the average correlation between the mean time‐series of three ROIs labeled as posterior cingulate cortex and those of all the other ROIs. Participants’ APOE status was defined as APOE ε4 carriers (ε3/ε4 or ε4/ε4) and noncarriers (ε3/ε3). Multiple regression was run with DMN FC as the outcome variable, plasma NfL as the predictor, and age and sex as covariates.ResultPlasma NfL levels were higher in those with dementia compared to those without dementia (t = 4.4608, p = 0.0002) but did not differ between amnestic MCI and control (t = 1.6116, p = 0.1130). Across all participants, plasma NfL did not predict DMN FC (Β = 0.0045, p = 0.4830). However, higher plasma NfL was marginally associated with higher DMN FC in those with dementia (Β = 0.0045, p = 0.0657) but not in those without dementia (Β = 0.0021, p = 0.3160). Moreover, in those without dementia, higher plasma NfL predicted higher DMN FC in APOE ε4 carriers (Β = 0.0079, p = 0.0312) but not in APOE ε4 noncarriers (Β = 0.0023, p = 0.4871).ConclusionOur results indicate that the increase of DMN FC, seen at early stages of AD (Damoiseaux et al., 2012), is significantly associated with more neuronal damage in APOE ε4 carriers without dementia.

Plasma NfL predicts default mode network functional connectivity in older adults at higher risk for Alzheimer’s disease

AbstractBackgroundNeurofilament light (NfL) is a measure of neuronal damage and has the potential as a monitoring and prognostic biomarker of Alzheimer’s disease (AD) (Mattsson et al., 2019). Likewise, alterations in default mode network (DMN) functional connectivity (FC) may predict AD progression (Jones et al., 2016). Here, we investigated the relationship between plasma NfL levels and DMN FC along the continuum of AD, and explored whether APOE ε4 status influenced this relationship.MethodResting‐state functional MRI data and blood samples were available for 103 older adults (17 with AD dementia, age: 69.2±6.9; m/f: 8/9; CDR: 0.7±0.3; and 86 without dementia (includes amnestic MCI and control), age: 71.7±7.4; m/f: 21/65; CDR: 0.3±0.2). Plasma NfL was measured using a single‐molecule array (Simoa) assay. We calculated DMN FC using 32 high consensus DMN ROIs from Dworetsky et al. (2021). DMN FC was defined as the average correlation between the mean time‐series of three ROIs labeled as posterior cingulate cortex and those of all the other ROIs. Participants’ APOE status was defined as APOE ε4 carriers (ε3/ε4 or ε4/ε4) and noncarriers (ε3/ε3). Multiple regression was run with DMN FC as the outcome variable, plasma NfL as the predictor, and age and sex as covariates.ResultPlasma NfL levels were higher in those with dementia compared to those without dementia (t = 4.4608, p = 0.0002) but did not differ between amnestic MCI and control (t = 1.6116, p = 0.1130). Across all participants, plasma NfL did not predict DMN FC (Β = 0.0045, p = 0.4830). However, higher plasma NfL was marginally associated with higher DMN FC in those with dementia (Β = 0.0045, p = 0.0657) but not in those without dementia (Β = 0.0021, p = 0.3160). Moreover, in those without dementia, higher plasma NfL predicted higher DMN FC in APOE ε4 carriers (Β = 0.0079, p = 0.0312) but not in APOE ε4 noncarriers (Β = 0.0023, p = 0.4871).ConclusionOur results indicate that the increase of DMN FC, seen at early stages of AD (Damoiseaux et al., 2012), is significantly associated with more neuronal damage in APOE ε4 carriers without dementia.

Mid‐to‐Late Life Healthy Lifestyle Modifies Genetic Risk for Longitudinal Cognitive Aging among Asymptomatic Individuals from the Wisconsin Registry for Alzheimer’s Prevention

AbstractBackgroundGenetic and lifestyle factors contribute to an individual’s risk for developing Alzheimer’s disease (AD). A better understanding of interactions between these factors may help design targeted interventions. In this study, we investigated whether number of long‐term healthy lifestyles modified the effect of genetic predisposition to AD on cognitive decline during the preclinical stage of AD.MethodsWe evaluated longitudinal associations of cognitive aging with a healthy lifestyle composite score, which included physical activity, diet, smoking, cognitive activity, and alcohol consumption, and the interaction of the healthy lifestyle composite score with APOE ε4 carrier status and a non‐APOE polygenic risk score (PRS) in a sample of 848 individuals from the Wisconsin Registry for Alzheimer’s Prevention (Table 1). The primary outcome was a multi‐domain cognitive composite (PACC3); secondary outcomes were immediate/delayed memory and executive function composites. We fitted all analyses using a linear mixed effects model and adjusted for within‐individual and within‐family correlation.ResultsFavorable lifestyles can marginally modify the age dependent influence of APOE on PACC3 (p = 0.1) and executive function (p = 0.14), and significantly mitigate the adverse effect of APOE ε4 on delayed recall as people aging (p &lt; 0.01, Figure 1). However, we observed no statistically significant interactions between non‐APOE PRS, combined lifestyle factors, and age for all the assessed cognitive outcomes (Figure 2). When we further stratify the sample by the APOE ε4 carrier status, we found the interaction between non‐APOE PRS, age, and healthy lifestyle is statistically significant for PACC3 (p = 0.02) and delayed recall (p &lt; 0.01) and marginally significant for immediate learning (p = 0.06) among APOE ε4 carriers (Figure 3). Among APOE ε4 noncarriers, combined lifestyle factors can only modify the age‐dependent adverse genetic influence of non‐APOE PRS on PACC3 (p = 0.01), but the protective effect is more evident at a younger age (Figure 4). These results are robust to multiple sensitivity analyses.ConclusionA favorable lifestyle can mitigate the genetic risk caused by both APOE ε4 and non‐APOE PRS, but the protective effect against non‐APOE PRS is more evident among APOE ε4 carriers.

Global and local ancestry modulate APOE association with Alzheimer's neuropathology and cognitive outcomes in an admixed sample

AbstractBackgroundDementia affects more Black individuals, likely due to a combination of environmental and biological factors1,2,3. APOE ε4 allele risk of dementia is different between individuals with European (EUR) and African (AFR) ancestries4,5,6. It is unclear what drives these differences in Alzheimer’s disease (AD) neuropathology among patients with cognitive decline, both outcomes influenced by different sets of biological and environmental factors. We studied the interaction between global and local APOE African ancestry, e4 allele, burden of neuritic plaques (NP) and neurofibrillary tangles (NFT), and cognition in a postmortem sample of admixed individuals with AD pathology.MethodCommunity‐dwelling autopsied brains (n=400) without neuropathological changes or with NP scored using CERAD and NFT scored by Braak stage but lacking others comorbid neuropathologies. Subject’s cognitive function prior to death as assessed using Clinical Dementia Rating sum of boxes (CDR‐SOB). APOE genotypes were assessed with allele‐specific amplification. Global ancestry was inferred using Admixture and local ancestry using RFMix, derived from panels of variants interrogated by microarray.ResultWhen dichotomously ascertained at 2% of AFR, and adjusting for age, sex, educational attainment and APOE ε4 carrier status, the admixed group is significantly protected of neuritic plaques (NP, beta=‐0.21, p=0.04) but not neurofibrillary tangles (NFT, beta=0.137, p=0.39). However, CDR‐SOB was associated with continuously distributed AFR (Table 1) only among individuals with severe levels of NFT (beta=7.04, p&lt;0.001) and NP (beta=3.9, p&lt;0.001). Stratifying the same analysis between APOE status, only APOE ε4 noncarriers presented significant associations between AFR and CDR‐SOB, but APOE ε4 carriers lost significance. APOE local ancestry inference of showed that non‐European admixed APOE ε4 noncarriers had lower NP burden outcomes (Table 2, beta=‐0.28, p=0.032 and beta=‐0.27, p=0.015 with and without adjusting for AFR, respectively), but worst cognitive decline compared to European APOE of the same genotype group when adjusting by NP levels (beta=1.01, p=0.041, without adjusting for AFR). Lastly, APOE ε has a significant effect on neuropathology, but not cognition, only within European local ancestry contexts (Table 3, beta=0.61, p&lt;0.001).ConclusionOur results demonstrate a complex relation between APOE genotypes and local ancestry, AFR global ancestry and AD‐related neuropathology and cognition outcomes.

Effect of APOE4 on Plasma Phospho‐tau 217 and Neurofilament Light in the PSEN1 E280A Autosomal Dominant Alzheimer’s Disease Colombian Kindred

AbstractBackgroundThe Colombian kindred affected by the autosomal dominant AD causative mutation PSEN1 E280A are an invaluable population in determining the utility of blood biomarkers (BB) and how additional risk factors may affect BB years to decades prior to symptom onset. Neurofilament light (NfL) (Quiroz et al., 2020) and phospho‐tau 217 (p‐tau217) (Palmqvist et al., 2020) diverge about 20 years prior to onset of clinical symptoms in carriers compared to non‐carriers. How APOE4 carriage may influence NfL and p‐tau217 in the kindred is unknown. We assessed cross‐sectional effects of APOE4 carriage on plasma NfL and p‐tau217 in the PSEN1 E280A kindred.MethodWe used a single molecule array immunoassay to quantify plasma NfL and a Meso Scale Discovery based plasma immunoassay to quantify p‐tau217. 1428 persons (age 18 to 75, mean 35.8, 23% APOE4 carriers, 54% PSEN1 E280A carriers) had available data for NfL analyses. A total of 612 persons (age 18 to 60, mean 35.9, 25% APOE4 carriers, 62% PSEN1 E280A carriers) had available data for p‐tau217 analyses. Age related trajectories were derived from cross‐sectional log‐transformed p‐tau217 and NfL concentrations modelled using a restricted cubic spline model. Model parameters were estimated using a Hamiltonian Markov chain Monte Carlo method in E280A mutation and APOE4 carriage defined groups. The primary comparison was made between APOE4 carrier and noncarriers within E280A carriers and noncarriers separately.ResultIn PSEN1 E280A mutation carriers, plasma NfL concentrations begin to differentiate those who were APOE4 carriers from non‐carriers at age 47.4 (figure 1). Plasma NfL concentrations did not differentiate APOE4 carriers versus non‐carriers in those without the PSEN1 E280A mutation though concentration of NfL trended higher in APOE4 carriers in the higher age range of the sample. Plasma p‐tau217 concentrations did not differentiate APOE4 carriers from non‐carriers in PSEN1 E280A mutation carriers or non‐carriers.ConclusionAPOE4 carriage results in accelerated NfL plasma increases in PSEN1 E280A mutation carriers starting at about the age of symptom onset. The inability to detect APOE4‐related ptau217 and NfL differences in the other groups may be related to the younger age of participants and limitations in statistical power.

Reduced brain activity during a working memory task in middle-aged apolipoprotein E ε4 carriers with overweight/obesity.

The apolipoprotein E ε4 (APOE ε4) allele and midlife obesity are independent risk factors for Alzheimer's disease (AD). Both of these risk factors are also associated with differences in brain activation, as measured by blood oxygenation level-dependent (BOLD) responses, in the absence of detectable cognitive deficits. Although the presence of these risk factors may influence brain activity during working memory tasks, no study to date has examined whether the presence of the ε4 allele explains variation in working memory brain activity while matching for levels of overweight/obesity. The primary aim of this study was to determine whether the presence of the ε4 allele is associated with differences in task-functional magnetic resonance imaging (fMRI) brain activation in adults with overweight/obesity. We predicted that ε4 carriers would have greater brain activation in regions that support working memory. This ancillary study included 48 (n = 24 APOE ε4 carriers; n = 24 APOE ε4 non-carriers), sedentary middle-aged adults (Mean age = 44.63 ± 8.36 years) with overweight/obesity (Mean BMI = 32.43 ± 4.12 kg/m2) who were matched on demographic characteristics. Participants were a subsample enrolled in 12-month randomized clinical trial examining the impact of energy-restricted diet and exercise on cardiovascular health outcomes. Participants completed a n-back working memory task with fMRI, which were completed within one month of the start of the intervention. Participants also underwent pseudo-continuous arterial spin labeling scans, a MRI measure of cerebral blood flow (CBF). Compared to non-ε4 carriers with overweight/obesity, ε4 carriers with overweight/obesity had lower fMRI brain activity in the middle frontal gyrus, pre and post central gyrus, supramarginal gyrus, superior temporal gyrus, lateral occipital cortex, and angular gyrus (z range = 2.52-3.56) during the n-back working memory task. Differences persisted even when controlling for CBF in these brain regions. These results indicate that presence of the APOE ε4 allele in middle-aged adults with overweight/obesity is related to altered brain activity during a working memory paradigm, which may confer risk for accelerated neurocognitive decline in late adulthood. Future research is needed to clarify the clinical implications of these findings in the context of risk for AD.

Cardiometabolic diseases, polygenic risk score, APOE genotype, and risk of incident dementia: A population-based prospective cohort study

Objective We aimed to prospective investigate the association between cardiometabolic diseases (CMDs) with dementia, and to examine whether genetic factors and CMDs jointly contribute to the incidence of dementia.Methods We used data from the UK biobank of 204,646 adults aged 37-73 free of dementia at baseline. Genetic risk for dementia including APOE ε4 status and polygenic risk score (PRS) categorized as low, intermediate, and high. CMDs including ischemic heart disease (IHD), stroke, and type 2 diabetes (T2D) were confirmed by touchscreen questionnaires, medical examinations, and hospital inpatient records.Results Over the follow-up (median: 12.5 years), 5,750 participants developed dementia. The HRs (95% CI) of those with APOE ε4 carriers and high PRS were 3.16 (3.00-3.33) and 1.50 (1.41-1.60), respectively. The risk of dementia was 70% higher among those with CMDs (HR: 1.70; 95% CI: 1.60-1.82). In joint effect analyses, compared to no CMDs and APOE ε4 non-carriers, the HRs (95% CIs) of dementia were 3.53 (3.31-3.76)/2.06 (1.89-2.23) in participants with only APOE ε4 carriers and CMDs, and 5.06 (4.64-5.53) for those with APOE ε4 carriers plus CMDs. Compared to no CMDs and low PRS, the HRs (95% CIs) of dementia were 1.29 (1.19-1.40)/1.60 (1.48-1.73) in participants with only intermediate and high PRS, and 2.00 (1.79-2.23)/2.63 (2.38-2.92) for those with intermediate, and high PRS plus CMDs. Moreover, there were significant additive and multiplication interactions between CMDs and APOE ε4 carriers of dementia, but only multiplication interaction was observed for PRS.Conclusions CMDs were associated with higher risk of dementia regardless of genetic risk for dementia.

Modifiable and non-modifiable risk factors of dementia on midlife cerebral small vessel disease in cognitively healthy middle-aged adults: the PREVENT-Dementia study

BackgroundConsiderable overlap exists between the risk factors of dementia and cerebral small vessel disease (SVD). However, studies remain limited to older cohorts wherein pathologies of both dementia (e.g. amyloid) and SVD (e.g. white matter hyperintensities) already co-exist. In younger asymptomatic adults, we investigated differential associations and interactions of modifiable and non-modifiable inherited risk factors of (future) late-life dementia to (present-day) mid-life SVD.MethodsCognitively healthy middle-aged adults (aged 40–59; mean 51.2 years) underwent 3T MRI (n = 630) as part of the PREVENT-Dementia study. To assess SVD, we quantified white matter hyperintensities, enlarged perivascular spaces, microbleeds, lacunes, and computed composite scores of SVD burden and subtypes of hypertensive arteriopathy and cerebral amyloid angiopathy (CAA). Non-modifiable (inherited) risk factors were APOE4 status and parental family history of dementia. Modifiable risk factors were derived from the 2020 Lancet Commission on dementia prevention (early/midlife: education, hypertension, obesity, alcohol, hearing impairment, head injuries). Confirmatory factor analysis (CFA) was used to evaluate the latent variables of SVD and risk factors. Structural equation modelling (SEM) of the full structural assessed associations of SVD with risk factors and APOE4*risk interaction.ResultsIn SEM, the latent variable of global SVD related to the latent variable of modifiable midlife risk SVD (β = 0.80, p = .009) but not non-modifiable inherited risk factors of APOE4 or family history of dementia. Interaction analysis demonstrated that the effect of modifiable risk on SVD was amplified in APOE4 non-carriers (β = − 0.31, p = .009), rather than carriers. These associations and interaction effects were observed in relation to the SVD subtype of hypertensive arteriopathy, rather than CAA. Sensitivity analyses using separate general linear models validated SEM results.ConclusionsEstablished modifiable risk factors of future (late-life) dementia related to present-day (mid-life) SVD, suggesting that early lifestyle modifications could potentially reduce rates of vascular cognitive impairment attributed to SVD, a major ‘silent’ contributor to global dementia cases. This association was amplified in APOE4 non-carriers, suggesting that lifestyle modifications could be effective even in those with genetic predisposition to dementia.

Association of Red Blood Cell Omega-3 Fatty Acids With MRI Markers and Cognitive Function in Midlife: The Framingham Heart Study.

Diet may be a key contributor to brain health in midlife. In particular, omega-3 fatty acids have been related to better neurologic outcomes in older adults. However, studies focusing on midlife are lacking. We investigated the cross-sectional association of red blood cell (RBC) omega-3 fatty acid concentrations with MRI and cognitive markers of brain aging in a community-based sample of predominantly middle-aged adults and further explore effect modification by APOE genotype. We included participants from the Third-Generation and Omni 2 cohorts of the Framingham Heart Study attending their second examination. Docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA) concentrations were measured from RBC using gas chromatography, and the Omega-3 index was calculated as EPA + DHA. We used linear regression models to relate omega-3 fatty acid concentrations to brain MRI measures (i.e., total brain, total gray matter, hippocampal, and white matter hyperintensity volumes) and cognitive function (i.e., episodic memory, processing speed, executive function, and abstract reasoning) adjusting for potential confounders. We further tested for interactions between omega-3 fatty acid levels and APOE genotype (e4 carrier vs noncarrier) on MRI and cognitive outcomes. We included 2,183 dementia-free and stroke-free participants (mean age of 46 years, 53% women, 22% APOE-e4 carriers). In multivariable models, higher Omega-3 index was associated with larger hippocampal volumes (standard deviation unit beta ±standard error; 0.003 ± 0.001, p = 0.013) and better abstract reasoning (0.17 ± 0.07, p = 0.013). Similar results were obtained for DHA or EPA concentrations individually. Stratification by APOE-e4 status showed associations between higher DHA concentrations or Omega-3 index and larger hippocampal volumes in APOE-e4 noncarriers, whereas higher EPA concentrations were related to better abstract reasoning in APOE-e4 carriers. Finally, higher levels of all omega-3 predictors were related to lower white matter hyperintensity burden but only in APOE-e4 carriers. Our results, albeit exploratory, suggest that higher omega-3 fatty acid concentrations are related to better brain structure and cognitive function in a predominantly middle-aged cohort free of clinical dementia. These associations differed by APOE genotype, suggesting potentially different metabolic patterns by APOE status. Additional studies in middle-aged populations are warranted to confirm these findings.

Determining Whether Sex and Zygosity Modulates the Association between APOE4 and Psychosis in a Neuropathologically-Confirmed Alzheimer's Disease Cohort.

Background: The APOE4 allele is a genetic risk factor for developing late-onset Alzheimer’s disease (AD). Previous work by our group revealed that female APOE4 homozygotes with Lewy body (LB) pathology were more likely to experience psychosis compared to female APOE4 non-carriers, whereas in males there was no APOE4 dose-dependent significant effect. The objective of this study was to refine our previous findings by adjusting for covariates and determining the probability of an APOE4 sex-mediated effect on psychosis. Methods: Neuropathologically confirmed AD patients with LB pathology (n = 491) and without LB pathology (n = 716) were extracted from the National Alzheimer’s Coordinating Center (NACC). Patients were classified as psychotic if they scored positively for delusions and/or hallucinations on the Neuropsychiatric Inventory. Analysis consisted of a preliminary unadjusted binary logistic regression and a Generalized Additive binary logistic regression Model (GAM) to predict the relationship between APOE4 status and sex on the presence of psychosis in both cohorts, adjusting for age, education and MMSE. Results: In the cohort with LB pathology, female APOE4 homozygotes were significantly more likely to experience psychosis compared to female APOE4 non-carriers (OR = 4.15, 95%CI [1.21, 14.2], p = 0.023). Female heterozygotes were also more likely to experience psychosis compared to female APOE4 non-carriers, but to a lesser extent (OR = 2.37, 95%CI [1.01, 5.59], p = 0.048). There was no significant difference in males with LB pathology or in any sex in the cohort without LB pathology. Conclusions: Sex and zygosity influence the effect of APOE4 on psychosis in neuropathologically confirmed AD patients, with the effect being limited to females with LB pathology.

Global and local ancestry modulate APOE association with Alzheimer’s neuropathology and cognitive outcomes in an admixed sample

Dementia is more prevalent in Blacks than in Whites, likely due to a combination of environmental and biological factors. Paradoxically, clinical studies suggest an attenuation of APOE ε4 risk of dementia in African ancestry (AFR), but a dearth of neuropathological data preclude the interpretation of the biological factors underlying these findings, including the association between APOE ε4 risk and Alzheimer’s disease (AD) pathology, the most frequent cause of dementia. We investigated the interaction between African ancestry, AD-related neuropathology, APOE genotype, and functional cognition in a postmortem sample of 400 individuals with a range of AD pathology severity and lack of comorbid neuropathology from a cohort of community-dwelling, admixed Brazilians. Increasing proportions of African ancestry (AFR) correlated with a lower burden of neuritic plaques (NP). However, for individuals with a severe burden of NP and neurofibrillary tangles (NFT), AFR proportion was associated with worse Clinical Dementia Rating sum of boxes (CDR-SOB). Among APOE ε4 carriers, the association between AFR proportion and CDR-SOB disappeared. APOE local ancestry inference of a subset of 309 individuals revealed that, in APOE ε4 noncarriers, non-European APOE background correlated with lower NP burden and, also, worse cognitive outcomes than European APOE when adjusting by NP burden. Finally, APOE ε4 was associated with worse AD neuropathological burden only in a European APOE background. APOE genotype and its association with AD neuropathology and clinical pattern are highly influenced by ancestry, with AFR associated with lower NP burden and attenuated APOE ε4 risk compared to European ancestry.

Increased plasma and brain immunoglobulin A in Alzheimer’s disease is lost in apolipoprotein E ε4 carriers

BackgroundAlzheimer’s disease (AD) is foremost characterized by β-amyloid (Aβ)-extracellular plaques, tau-intraneuronal fibrillary tangles (NFT), and neuroinflammation, but over the last years it has become evident that peripheral inflammation might also contribute to the disease. AD patients often demonstrate increased levels of circulating proinflammatory mediators and altered antibody levels in the blood. In our study, we investigated the plasma Immunoglobulin A (IgA) levels in association with apolipoprotein E (APOE) ε4 status and Aβ pathology.MethodsIgA levels in antemortem-collected (cohort I) and postmortem-collected (cohort II) plasma samples from AD patients (n = 30 in cohort I and n = 16 in cohort II) and non-demented age-matched controls (NC) (n = 42 in cohort I and n = 7 in cohort II) were measured using ELISA. Hippocampal sections from cohort II were immunostained against IgA, and the IgA area fraction as well as the number of IgA positive (IgA+) cells in the cornu ammonis region were analysed using ImageJ. The relationship between plasma IgA levels and cognition, C-reactive protein (CRP), and cerebrospinal fluid (CSF) AD biomarkers in cohort I as well as neuropathology, IgA+ cell number, and IgA area fraction in cohort II was analysed before and after grouping the cohorts into APOEε4 carriers and APOEε4 non-carriers.ResultsPlasma IgA levels were higher in AD patients compared to NC in both cohorts. Also, AD patients demonstrated higher IgA area fraction and IgA+ cell number compared to NC. When APOEε4 status was considered, higher plasma IgA levels in AD patients were only seen in APOEε4 non-carriers. Finally, plasma IgA levels, exclusively in APOEε4 non-carriers, were associated with cognition, CRP, and CSF Aβ levels in cohort I as well as with IgA area fraction, IgA+ cell number, and Aβ, Lewy body, and NFT neuropathology in cohort II.ConclusionsOur study suggests that AD pathology and cognitive decline are associated with increased plasma IgA levels in an APOE allele-dependent manner, where the associations are lost in APOEε4 carriers.