Apolipoprotein E Ε4 Carrier Status Research Articles

APOE ε4 carrier status modifies plasma p-tau181 concentrations in cognitively healthy super-seniors.

This study investigates the effect of apolipoprotein E (APOE) genotype on neurology plasma biomarkers in cognitively healthy Super-Seniors. Three hundred seventy plasma specimens from Super-Senior participants ≥ 85 years old, who have never been diagnosed with dementia, cancer, diabetes, cardiovascular, or major pulmonary disease, were analyzed on the Quanterix Simoa HD-X analyzer using commercial Neurology 4-plex E and phosphorylated tau (p-tau)181 assays. Eighty (22%) participants were APOE ε4 carriers and 290 (73%) were non-carriers. No significant differences were found between APOE ε4 carriers and non-carriers regarding age, sex, or Mini-Mental State Examination scores. In APOE ε4 carriers, plasma amyloid beta 42/40 was lower and p-tau181 and glial fibrillary acidic protein were higher compared to non-APOE ε4 carriers. After adjusting for demographic variables, p-tau181 was the only biomarker to remain significantly associated with APOE ε4 carrier status. APOE ε4 genotype modifies plasma p-tau181 concentration in seniors resilient to age-related clinical disease, suggesting that some Super-Seniors may have Alzheimer's disease pathology without progressing to cognitive decline. Healthy seniors enable identification of associations that may be masked by disease. Plasma phosphorylated tau (p-tau)181 concentrations associate with apolipoprotein E (APOE) ε4 carriership in healthy seniors. APOE should be accounted for when interpreting p-tau181, regardless of disease.

Dose-response effects of exercise on mental health in community-dwelling older adults: Exploration of genetic moderators

Background/Objective(1) Examine the role of exercise intensity on mental health symptoms in a community-based sample of older adults. (2) Explore the moderating role of genetic variation in brain-derived neurotrophic factor (BDNF) and apolipoprotein E (APOE) on the effects of exercise on mental health symptoms. MethodThis study is a secondary analysis of a three-arm randomized controlled trial, comparing the effects of 6 months of high-intensity aerobic training vs. moderate-intensity aerobic training vs. a no-contact control group on mental health symptoms assessed using the Depression, Anxiety, and Stress Scale (DASS). The BDNF Val66Met polymorphism and APOE ε4 carrier status were explored as genetic moderators of exercise effects on mental health symptoms. ResultsThe exercise intervention did not influence mental health symptoms. The BDNF Val66Met polymorphism did not moderate intervention effects on mental health symptoms. APOE ε4 carrier status moderated the effect of intervention group on perceived stress over 6 months, such that APOE ε4 carriers, but not non-carriers, in the high-intensity aerobic training group showed a decline in perceived stress over 6 months. ConclusionsAPOE ε4 carrier status may modify the benefits of high-intensity exercise on perceived stress such that APOE ε4 carriers show a greater decline in stress as a result of exercise relative to non-APOE ε4 carriers.

Risk of Mild Behavioral Impairment: the role of gender and APOE allele carrier status

AbstractBackgroundGender differences in dementia and dementia‐related neuropsychiatric symptoms are well described. Similarly, the Apolipoprotein E (APOE) ε4 allele is a well‐known predictor of Alzheimer’s disease. However, their impact on the clinical manifestation of Mild Behavioral Impairment (MBI) remains unclear. Using data from the Australian population‐based PATH Through Life Study we explored the associations between gender and APOE ε4 carrier status with MBI. We hypothesized that MBI likelihood would be greater in males and ε4 carriers.Method1316 dementia‐free participants (48% female; aged 72‐79) were included. Gender was self‐reported (female/male). Participants were classified as APOE ε4+ if they carried at least one ε4 allele (APOE ε4/ε4, ε2/ε4, ε3/ε4). MBI was approximated using a previously published transformation algorithm, which utilizes items from the Neuropsychiatric Inventory assessed at a single study visit. Binomial logistic regression was used to examine the role of gender and APOE ε4 carrier status, and their interaction, on predicting MBI status, while controlling for self‐reported years of education.ResultOf the 1316 participants, 339 (25.8%) were APOE ε4+ and 445 (34%) had MBI symptoms. A higher proportion of APOE ε4+ carriers (χ2 (1) = 5.99, p = .014) and men (χ2 (1) = 4.59, p = .032) were in the MBI group compared to the non‐MBI group. Binomial logistic regression showed APOE ε4 carrier status (OR = 1.58, 95% CI: 1.063‐2.344) and male gender (OR = 1.45, 95% CI: 1.093‐1.925) were associated with a greater likelihood of MBI. Male gender was also associated with a 2‐fold greater likelihood of having symptoms of the Decreased Motivation (OR = 2.08, 95% CI: 1.13‐3.86) and Impulse Dyscontrol (OR = 2.16, 95% CI: 1.54‐3.03) domains. No interaction effects were found between gender and APOE ε4 carrier status for MBI or any of its domains.ConclusionThe current study found that in dementia‐free older adults both male gender and APOE ε4+ status increased the risk of having MBI. However, no cumulative/interaction effect between gender and APOE ε4 carrier status was found, suggesting that being both male and APOE ε4+ does not further increase the risk of MBI. These results provide novel and valuable insight into the connection between gender, APOE ε4 carrier status and MBI.

Effect of APOE ε4 and its modification by sociodemographic characteristics on cognitive measures in South Asians from LASI‐DAD

AbstractBackgroundThe ε4 allele of the apolipoprotein E (APOE) gene is the most significant genetic risk factor for dementia in nearly all human populations. However, the effects of APOE ε4 on late‐life cognitive function and its potential modification by sociodemographic factors have not been extensively studied in South Asians. We investigated the effects of APOE ε4 and its interaction with sociodemographic characteristics on cognitive measures in 2,607 South Asians from the Diagnostic Assessment of Dementia for the Longitudinal Aging Study of India (LASI‐DAD).MethodWe determined APOE ε4 carrier status from rs429358 and rs7412 genotypes in whole genome sequencing data. We first examined the main effects of APOE ε4 on seven cognitive measures, including five broad cognitive domain scores, a general cognitive function summary score, and the Hindi Mental State Examination (HMSE) score using linear regression models. Model 1 adjusted for age, sex, state of residence, and the first 10 genetic principal components (PCs). Model 2 additionally adjusted for education level, literacy, and urban/rural residence. We then tested for interaction between APOE ε4 and sociodemographic factors (age, sex, and education) through cross‐product terms, and further evaluated significant interactions (p<0.05) using stratified analysis.ResultAPOE ε4 was inversely associated with all cognitive measures except visuospatial function in the full sample in Model 1 after Bonferroni correction (p<0.007), all of which remained nominally significant in Model 2 (p<0.05). For example, APOE ε4 carrier status was associated with a decrease in the HMSE score of 0.77 points (p = 1.6×10−4) and a decrease in general cognitive function score of 0.09 standard deviations (p = 0.001) in Model 2. Furthermore, interaction tests showed that the effect of APOE ε4 was stronger in females than males for memory (ßAPOE ε4_male = ‐0.121, βAPOE ε4_female = ‐0.177) and language/fluency (βAPOE ε4_male = 0.075, βAPOE ε4_female = ‐0.125), and stratified analysis indicated that the APOE ε4 effects were significant only in females (p<0.05).ConclusionAPOE ε4 is associated with lower cognitive function in older South Asians from India. For memory and language/fluency, this association is stronger in females than males.

Habitual dietary nitrate intake and cognition in the Australian Imaging, Biomarkers and Lifestyle Study of ageing: A prospective cohort study

Dietary nitrate improves cardiovascular health via a nitric oxide (NO) pathway. NO is key to both cardiovascular and brain health. There is also a strong association between vascular risk factors and brain health. Dietary nitrate intake could therefore be associated with better cognitive function and reduced risk of cognitive decline. This is yet to be investigated. The aim of this study was to investigate the association between habitual intake of dietary nitrate from sources where nitrate is naturally present, and cognitive function, and cognitive decline, in the presence or absence of the apolipoprotein E (APOE) ε4 allele. The study included 1254 older adult participants of the Australian Imaging, Biomarkers and Lifestyle Study of Ageing who were cognitively normal at baseline. Plant-derived, vegetable-derived, animal derived nitrate (not including meat where nitrate is an allowed additive), and total nitrate intakes were calculated from baseline food frequency questionnaires using comprehensive nitrate databases. Cognition was assessed at baseline and every 18 months over a follow-up period of 126 months using a comprehensive neuropsychological test battery. Multivariable-adjusted linear mixed effect models were used to examine the association between baseline nitrate intake and cognition over the 126 months (median [IQR] follow-up time of 36 [18-72] months), stratified by APOE ε4 carrier status. In non APOE ε4 carriers, for every 60mg/day higher intake of plant-derived nitrate at baseline there was an associated higher language score [β (95% CI): 0.10 (0.01, 0.19)] over 126 months, after multivariable adjustments. In APOE ε4 carriers, there was an associated better episodic recall memory [0.24 (0.08, 0.41)] and recognition memory [0.15 (0.01, 0.30)] scores. Similar associations were seen for the intakes of vegetable-derived and total nitrate. Additionally, in APOE ε4 carriers, for every 6mg/day higher intake of animal-derived nitrate (excluding meat with nitrate as an allowed additive) at baseline there was an associated higher executive function score [β (95% CI): 1.41 (0.42, 2.39)]. We did not find any evidence of an association between dietary nitrate intake and rate of cognitive decline. Our results suggest that habitual intake of dietary nitrate from sources where nitrate is naturally present impacts cognitive performance in an APOE genotype contingent manner. Further work is needed to validate our findings and understand potential mechanisms underlying the observed effects.

Sleep apnea and cognition in older APOE4 carriers and non‐carriers

AbstractBackgroundSleep apnea (SA) is common in late life and has received much attention as a possible risk factor for Alzheimer’s disease (AD). However, cross‐sectional findings suggest little, if any, relationship between SA and impaired cognition in Apolipoprotein E ε4 (APOE4) allele carriers and non‐carriers. Preclinical AD detection is essential, and the relationship between SA, APOE4, and cognitive impairment merits further analysis in a large sample. Therefore, we investigated whether SA and APOE4 carrier status were related to neuropsychological functioning using the National Alzheimer’s Coordinating Center (NACC) database. We predicted an interaction between SA and APOE4 carrier status, such that APOE4 carriers with SA would show the most significant impairment in cognition.MethodParticipants were at least 65 years of age with normal cognitive status. Sample sizes ranged from 1902 to 1945, depending on available neuropsychological data. SA presence or absence was clinician‐determined. Participants completed nine cognitive measures, including semantic memory (verbal category fluency), executive functioning (verbal letter fluency), visual scanning and executive functioning (Trails A and Trails B), global cognitive functioning (total Montreal Cognitive Assessment [MoCA]), and memory (MoCA–delayed recall and Benson Complex Figure Copy – delayed). We compared non‐carriers (ε3/ε3) and heterozygous carriers (ε3/ε4) using three‐way ANOVAs and ANCOVAs, while considering sex and age.ResultThere were no main or interaction effects of SA, carrier status, or sex on participant age (p>.05). Therefore, age was used as a covariate in three‐way ANCOVAs to enhance the power to detect a significant effect if present. Contrary to our hypotheses, there were no main or interaction effects involving SA (p>.05) with sex or carrier status. An APOE4 main effect was observed only for MoCA total and delayed recall scores.ConclusionPast cross‐sectional studies report a weak or null relationship between SA and cognitive performance. We found no main or interaction effects involving SA with sex or APOE4 carrier status on neuropsychological functioning in a large sample of older adults. Our large sample size helps provide more evidence for these null relationships and is consistent with other large‐sample studies.

Neuropathology-based APOE genetic risk score better quantifies Alzheimer's risk.

Apolipoprotein E (APOE) ε4-carrier status or ε4 allele count are included in analyses to account for the APOE genetic effect on Alzheimer's disease (AD); however, this does not account for protective effects of APOE ε2 or heterogeneous effect of ε2, ε3, and ε4 haplotypes. We leveraged results from an autopsy-confirmed AD study to generate a weighted risk score for APOE (APOE-npscore). We regressed cerebrospinal fluid (CSF) amyloid and tau biomarkers on APOE variables from the Wisconsin Registry for Alzheimer's Prevention (WRAP), Wisconsin Alzheimer's Disease Research Center (WADRC), and Alzheimer's Disease Neuroimaging Initiative (ADNI). The APOE-npscore explained more variance and provided a better model fit for all three CSF measures than APOE ε4-carrier status and ε4 allele count. These findings were replicated in ADNI and observed in subsets of cognitively unimpaired (CU) participants. The APOE-npscore reflects the genetic effect on neuropathology and provides an improved method to account for APOE in AD-related analyses.

APOE ε4 carrier status and sex differentiate rates of cognitive decline in early- and late-onset Alzheimer's disease.

We studied the effect of apolipoprotein E (APOE) ε4 status and sex on rates of cognitive decline in early- (EO) and late- (LO) onset Alzheimer's disease (AD). We ran mixed-effects models with longitudinal cognitive measures as dependent variables, and sex, APOE ε4 carrier status, and interaction terms as predictor variables in 998 EOAD and 2562 LOAD participants from the National Alzheimer's Coordinating Center. APOE ε4 carriers showed accelerated cognitive decline relative to non-carriers in both EOAD and LOAD, although the patterns of specific cognitive domains that were affected differed. Female participants showed accelerated cognitive decline relative to male participants in EOAD only. The effect of APOE ε4 was greater in EOAD for executive functioning (p<0.0001) and greater in LOAD for language (p<0.0001). We found APOE ε4 effects on cognitive decline in both EOAD and LOAD and female sex in EOAD only. The specific patterns and magnitude of decline are distinct between the two disease variants. Apolipoprotein E (APOE) ε4 carrier status and sex differentiate rates of cognitive decline in early-onset (EO) and late-onset (LO) Alzheimer's disease (AD). APOE ε4 in EOAD accelerated decline in memory, executive, and processing speed domains. Female sex in EOAD accelerated decline in language, memory, and global cognition. The effect of APOE ε4 was stronger for language in LOAD and for executive function in EOAD. Sex effects on language and executive function decline differed between EOAD and LOAD.

Resting heart rate is associated with novel plasma atherosclerosis biomarkers.

Resting heart rate (RHR) is a strong predictor of adverse cardiovascular outcomes. Both soluble low-density lipoprotein receptor-related protein-1 (sLRP1) and soluble receptor for advanced glycation end products (sRAGE) are novel plasma biomarkers for atherosclerosis. In this study, we examined the potential associations between RHR and plasma sLRP1 and sRAGE levels and whether any associations might be modified by apolipoprotein E (APOE) ε4 carrier status. This cross-sectional study included 941 apparently healthy adults aged 40 years or older. Plasma sLRP1 and sRAGE levels were measured by a commercial enzyme-linked immunosorbent assay. APOE gene polymorphisms were analyzed by a polymerase chain reaction and Sanger sequencing. RHR was a significant determinant of log-transformed sLRP1 (β = 0.004; 95% confidence interval [CI], 0.002-0.007; P = 0.001) and log-transformed sRAGE (β = 0.005; 95% CI, 0.002-0.007; P <0.001) independently of age, sex, body mass index, blood pressure, blood glucose, blood lipids, lifestyle, and medical history. Additionally, APOE ε4 carrier status was inversely associated with log-transformed plasma sLRP1 level (β = -0.072; 95% CI, -0.130 to -0.015; P = 0.01) and did not modify the relationship between RHR and plasma sLRP1 level. An elevated RHR was associated with increased sLRP1 and sRAGE values, which was not modified by APOE genotype. The underlying mechanism of this effect may be relevant to the progression of atherosclerosis.

Apolipoprotein E (APOE) ε4 Status Moderates the Relationship Between Close-Range Blast Exposure and Cognitive Functioning.

Recent studies suggest that close-range blast exposure (CBE), regardless of acute concussive symptoms, may have negative long-term effects on brain health and cognition; however, these effects are highly variable across individuals. One potential genetic risk factor that may impact recovery and explain the heterogeneity of blast injury's long-term cognitive outcomes is the inheritance of an apolipoprotein (APOE) ε4 allele, a well-known genetic risk factor for Alzheimer's disease. We hypothesized that APOE ε4 carrier status would moderate the impact of CBE on long-term cognitive outcomes. To test this hypothesis, we examined 488 post-9/11 veterans who completed assessments of neuropsychological functioning, psychiatric diagnoses, history of blast exposure, military and non-military mild traumatic brain injuries (mTBIs), and available APOE genotypes. We separately examined the effects of CBE on attention, memory, and executive functioning in individuals with and without the APOE ε4 allele. As predicted, we observed a differential impact of CBE status on cognition as a function of APOE ε4 status, in which CBE ε4 carriers displayed significantly worse neuropsychological performance, specifically in the domain of memory. These results persisted after adjusting for clinical, demographic, and genetic factors and were not observed when examining other neurotrauma variables (i.e., lifetime or military mTBI, distant blast exposure), though these variables displayed similar trends. These results suggest APOE ε4 carriers are more vulnerable to the impact of CBE on cognition and highlight the importance of considering genetic risk when studying cognitive effects of neurotrauma.

APOE interacts with tau PET to influence memory independently of amyloid PET in older adults without dementia.

Apolipoprotein E (APOE) interacts with Alzheimer's disease pathology to promote disease progression. We investigated the moderating effect of APOE on independent associations of amyloid and tau positron emission tomography (PET) with cognition. For 297 nondemented older adults from the Alzheimer's Disease Neuroimaging Initiative, regression equations modeled associations between cognition and (1) cortical amyloid beta (Aβ) PET levels adjusting for tau and (2) medial temporal lobe (MTL) tau PET levels adjusting for Aβ, including interactions with APOE ε4-carrier status. Adjusting for tau PET, Aβ was not associated with cognition and did not interact with APOE. In contrast, adjusting for Aβ PET, MTL tau was associated with all cognitive domains. Further, there was a stronger moderating effect of APOE on MTL tau and memory associations in ε4-carriers, even among Aβ-negative individuals. Findings suggest that APOE may interact with tau independently of Aβ and that elevated MTL tau confers negative cognitive consequences in Aβ-negative ε4 carriers.

Age and the association between apolipoprotein E genotype and Alzheimer disease: A cerebrospinal fluid biomarker-based case-control study.

The ε4 allele of apolipoprotein E (APOE) gene and increasing age are two of the most important known risk factors for developing Alzheimer disease (AD). The diagnosis of AD based on clinical symptoms alone is known to have poor specificity; recently developed diagnostic criteria based on biomarkers that reflect underlying AD neuropathology allow better assessment of the strength of the associations of risk factors with AD. Accordingly, we examined the global and age-specific association between APOE genotype and AD by using the A/T/N classification, relying on the cerebrospinal fluid (CSF) levels of β-amyloid peptide (A, β-amyloid deposition), phosphorylated tau (T, pathologic tau), and total tau (N, neurodegeneration) to identify patients with AD. This case-control study included 1,593 white AD cases (55.4% women; mean age 72.8 [range = 44-96] years) with abnormal values of CSF biomarkers from nine European memory clinics and the American Alzheimer's Disease Neuroimaging Initiative (ADNI) study. A total of 11,723 dementia-free controls (47.1% women; mean age 65.6 [range = 44-94] years) were drawn from two longitudinal cohort studies (Whitehall II and Three-City), in which incident cases of dementia over the follow-up were excluded from the control population. Odds ratio (OR) and population attributable fraction (PAF) for AD associated with APOE genotypes were determined, overall and by 5-year age categories. In total, 63.4% of patients with AD and 22.6% of population controls carried at least one APOE ε4 allele. Compared with non-ε4 carriers, heterozygous ε4 carriers had a 4.6 (95% confidence interval 4.1-5.2; p < 0.001) and ε4/ε4 homozygotes a 25.4 (20.4-31.2; p < 0.001) higher OR of AD in unadjusted analysis. This association was modified by age (p for interaction < 0.001). The PAF associated with carrying at least one ε4 allele was greatest in the 65-70 age group (69.7%) and weaker before 55 years (14.2%) and after 85 years (22.6%). The protective effect of APOE ε2 allele for AD was unaffected by age. Main study limitations are that analyses were based on white individuals and AD cases were drawn from memory centers, which may not be representative of the general population of patients with AD. In this study, we found that AD diagnosis based on biomarkers was associated with APOE ε4 carrier status, with a higher OR than previously reported from studies based on only clinical AD criteria. This association differs according to age, with the strongest effect at 65-70 years. These findings highlight the need for early interventions for dementia prevention to mitigate the effect of APOE ε4 at the population level.

The Aging Slopes of Brain Structures Vary by Ethnicity and Sex: Evidence From a Large Magnetic Resonance Imaging Dataset From a Single Scanner of Cognitively Healthy Elderly People in Korea.

The aging of the brain is a well-investigated topic, but existing analyses have mainly focused on Caucasian samples. To investigate brain aging in East Asians, we measured cortical and subcortical volumes from magnetic resonance imaging (MRI) scans of 1,008 cognitively normal elderly Koreans from the Gwangju Alzheimer’s and Related Dementia cohort and 342 Caucasians from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) database. To determine whether the aging effect varies with ethnicity and sex, beta coefficients of age and confidence intervals (CIs) were estimated in each ethnicity–sex group using a bootstrap method and a regression analysis using the relative volume to intracranial volume as predicted. The betas or aging slopes largely were not significantly different between ethnicity and sex groups in most types of brain structures. However, ethnic differences between the two female groups were found in the brain, most cortical regions, and a few subcortical regions. Ethnic differences in brain aging are likely due in large part to genetic factors; thus, we compared carriers and non-carriers of a gene relevant to longevity and neurodegenerative diseases, such as apolipoprotein E (APOE) ε4. The regions with ethnic differences in women also showed significant differences between Korean APOE ε4 non-carriers and Caucasian APOE ε4 carriers. Furthermore, Caucasian women showed significant APOE ε4 effects in the largest number of regions. These results illustrate that much of the ethnic differences in females may be explained by synergistic effects of ethnic background and APOE ε4 carrier status. Our results suggest that sex-dependent differences of aging between ethnic backgrounds may be due to ethnicity-dependent effects of genetic risk factors, such as APOE ε4. We also presented the normative information on volume estimates of the brain structures of the elderly Korean people in the subdivided age groups. This normative information of the aging brain stratified by ethnicity provides the age-related reference ranges quantified to replace visual judgment and facilitate precise clinical decision-making.

Apolipoprotein E ε4 and cognitive function after surgery in middle-aged and elderly Danish twins.

Transient cognitive impairment is common in adult patients of all ages following anaesthesia and surgery. Apolipoprotein E (APOE) ε4 carriers may have a larger deterioration in short-term cognitive function after major surgery compared with APOE ε4 noncarriers. The aim was to examine the effect of APOE ε4 on the association between exposure to surgery and anaesthesia, and subsequent cognitive functioning. A more pronounced deterioration in cognitive function in APOE ε4 carriers was hypothesised. An observational cross-sectional and a 6 to 10 years longitudinal twin cohort design. Survey and register study of 2936 Danish twins aged 45 to 92 years. Cognitive function was assessed using five age-sensitive cognitive tests. In the cross-sectional study, we compared twins exposed to surgery with a reference group (unexposed). Linear regression models were used adjusting for sex and age and stratified by APOE ε4 carrier status. In the longitudinal cognitive follow-up study 1671 twins participated. Intrapair analyses were also performed using 70 same-sexed twin pairs concordant for APOE ε4 carrier status, but discordant for major surgery. APOE ε4 carriers had lower cognitive scores compared with noncarriers, and this was statistically significant in elderly twins 70+ years of age (mean difference, -0.67; 95% CI, -1.14 to -0.17). There was no significant impact on cognitive function after surgery according to APOE ε4 carrier status in the cross-sectional study. Similarly, there was no APOE ε4 modification in the longitudinal study. Also, in the intrapair analyses no evidence was found of lower cognitive score after major surgery compared with the nonexposed cotwins among APOE ε4 carriers. No evidence was found of more pronounced long-term deterioration in cognitive function after surgery among APOE ε4 carriers, but elderly APOE ε4 carriers in general performed worse on the cognitive tests than noncarriers.

Plasma Lipidomic Analyses in Cohorts With mTBI and/or PTSD Reveal Lipids Differentially Associated With Diagnosis and APOE ε4 Carrier Status.

The differential diagnosis between mild Traumatic Brain Injury (mTBI) sequelae and Post-Traumatic Stress Disorder (PTSD) is challenging due to their symptomatic overlap and co-morbidity. As such, there is a need to develop biomarkers which can help with differential diagnosis of these two conditions. Studies from our group and others suggest that blood and brain lipids are chronically altered in both mTBI and PTSD. Therefore, examining blood lipids presents a minimally invasive and cost-effective approach to identify promising biomarkers of these conditions. Using liquid chromatography-mass spectrometry (LC-MS) we examined hundreds of lipid species in the blood of healthy active duty soldiers (n = 52) and soldiers with mTBI (n = 21), PTSD (n = 34) as well as co-morbid mTBI and PTSD (n = 13) to test whether lipid levels were differentially altered with each. We also examined if the apolipoprotein E (APOE) ε4 allele can affect the association between diagnosis and peripheral lipid levels in this cohort. We show that several lipid classes are altered with diagnosis and that there is an interaction between diagnosis and the ε4 carrier status on these lipids. Indeed, total lipid levels as well as both the degree of unsaturation and chain lengths are differentially altered with diagnosis and ε4 status, specifically long chain unsaturated triglycerides (TG) and both saturated and mono-unsaturated diglycerides (DG). Additionally, an examination of lipid species reveals distinct profiles in each diagnostic group stratified by ε4 status, mainly in TG, saturated DG species and polyunsaturated phosphatidylserines. In summary, we show that peripheral lipids are promising biomarker candidates to assist with the differential diagnosis of mTBI and PTSD. Further, ε4 carrier status alone and in interaction with diagnosis has a strong influence on peripheral lipid levels. Therefore, examining ε4 status along with peripheral lipid levels could help with differential diagnosis of mTBI and PTSD.

APOE4 moderates effects of cortical iron on synchronized default mode network activity in cognitively healthy old-aged adults.

IntroductionApolipoprotein E ε4 (APOE4)–related genetic risk for sporadic Alzheimer's disease is associated with an early impairment of cognitive brain networks. The current study determines relationships between APOE4 carrier status, cortical iron, and cortical network‐functionality.MethodsSixty‐nine cognitively healthy old‐aged individuals (mean age [SD] 66.1 [± 7.2] years; Mini‐Mental State Exam [MMSE] 29.3 ± 1.1) were genotyped for APOE4 carrier‐status and received 3 Tesla magnetic resonance imaging (MRI) for blood oxygen level–dependent functional magnetic resonance imaging (MRI) at rest, three‐dimensional (3D)–gradient echo (six echoes) for cortical gray‐matter, non‐heme iron by quantitative susceptibility mapping, and 18F‐flutemetamol positron emission tomography for amyloid‐βResultsA spatial pattern consistent with the default mode network (DMN) could be identified by independent component analysis. DMN activity was enhanced in APOE4 carriers and related to cortical iron burden. APOE4 and cortical iron synergistically interacted with DMN activity. Secondary analysis revealed a positive, APOE4 associated, relationship between cortical iron and DMN connectivity.DiscussionOur findings suggest that APOE4 moderates effects of iron on brain functionality prior to manifestation of cognitive impairment.

DNA methylation in the APOE genomic region is associated with cognitive function in African Americans

BackgroundGenetic variations in apolipoprotein E (APOE) and proximal genes (PVRL2, TOMM40, and APOC1) are associated with cognitive function and dementia, particularly Alzheimer’s disease. Epigenetic mechanisms such as DNA methylation play a central role in the regulation of gene expression. Recent studies have found evidence that DNA methylation may contribute to the pathogenesis of dementia, but its association with cognitive function in populations without dementia remains unclear.MethodsWe assessed DNA methylation levels of 48 CpG sites in the APOE genomic region in peripheral blood leukocytes collected from 289 African Americans (mean age = 67 years) from the Genetic Epidemiology Network of Arteriopathy (GENOA) study. Using linear regression, we examined the relationship between methylation in the APOE genomic region and multiple cognitive measures including learning, memory, processing speed, concentration, language and global cognitive function.ResultsWe identified eight CpG sites in three genes (PVRL2, TOMM40, and APOE) that showed an inverse association between methylation level and delayed recall, a measure of memory, after adjusting for age and sex (False Discovery Rate q-value < 0.1). All eight CpGs are located in either CpG islands (CGIs) or CGI shelves, and six of them are in promoter regions. Education and APOE ε4 carrier status significantly modified the effect of methylation in cg08583001 (PVRL2) and cg22024783 (TOMM40), respectively. Together, methylation of the eight CpGs explained an additional 8.7% of the variance in delayed recall, after adjustment for age, sex, education, and APOE ε4 carrier status. Methylation was not significantly associated with any other cognitive measures.ConclusionsOur results suggest that methylation levels at multiple CpGs in the APOE genomic region are inversely associated with delayed recall during normal cognitive aging, even after accounting for known genetic predictors for cognition. Our findings highlight the important role of epigenetic mechanisms in influencing cognitive performance, and suggest that changes in blood methylation may be an early indicator of individuals at risk for dementia as well as potential targets for intervention in asymptomatic populations.

Clinical Application of APOE in Alzheimer's Prevention: A Precision Medicine Approach.

Population-attributable risk models estimate that up to one-third of Alzheimer's disease (AD) cases may be preventable through risk factor modification. The field of AD prevention has largely focused on addressing these factors through universal risk reduction strategies for the general population. However, targeting these strategies in a clinical precision medicine fashion, including the use of genetic risk factors, allows for potentially greater impact on AD risk reduction. Apolipoprotein E (APOE), and specifically the APOE ε4 variant, is one of the most well-established genetic influencers on late-onset AD risk. In this review, we evaluate the impact of APOE ε4 carrier status on AD prevention interventions, including lifestyle, nutrigenomic, pharmacogenomic, AD comorbidities, and other biological and behavioral considerations. Using a clinical precision medicine strategy that incorporates APOE ε4 carrier status may provide a highly targeted and distinct approach to AD prevention with greater potential for success.

Apolipoprotein E gene polymorphism, trauma burden, and posttraumatic stress symptoms in U.S. military veterans: Results from the National Health and Resilience in Veterans Study.

Previous research examining the association between apolipoprotein E (APOE) gene polymorphism and risk for posttraumatic stress disorder (PTSD) has been inconsistent due to the use of small and select samples. This study examined the relation between APOE genotype and PTSD symptoms in two nationally representative samples of U.S. military veterans. The potential effect of cumulative trauma burden and social support in moderating this association was also evaluated. The main sample consisted of 1,386 trauma-exposed European American (EA) veterans (mean age: 62-63 years) who participated in the National Health and Resilience in Veterans Study (NHRVS) in 2011. The independent replication sample consisted of 509 trauma-exposed EA veterans from the 2013 NHRVS. APOE ε4 allele carriers reported significantly greater severity of PTSD symptoms than noncarriers in the main, but not the replication, sample. In both samples, the interaction of APOE ε4 carrier status and cumulative trauma burden was associated with greater severity of PTSD symptoms (F range = 2.53-8.09, all P's < .01), particularly re-experiencing/intrusion symptoms (F range = 3.59-4.24, P's < .001). Greater social support was associated with lower severity of PTSD symptoms among APOE ε4 allele carriers with greater cumulative trauma burden (β range -.27 to -.60, P's < .05). U.S. military veterans who are APOE ε4 allele carriers and exposed to a high number of traumas may be at increased risk for developing PTSD symptoms than ε4 noncarriers. Greater social support may moderate this association, thereby highlighting the potential importance of social support promoting interventions in mitigating the effect of ε4 × cumulative trauma burden on PTSD risk.

Association Between Mentally Stimulating Activities in Late Life and the Outcome of Incident Mild Cognitive Impairment, With an Analysis of the APOE ε4 Genotype

Cross-sectional associations between engagement in mentally stimulating activities and decreased odds of having mild cognitive impairment (MCI) or Alzheimer disease have been reported. However, little is known about the longitudinal outcome of incident MCI as predicted by late-life (aged ≥70 years) mentally stimulating activities. To test the hypothesis of an association between mentally stimulating activities in late life and the risk of incident MCI and to evaluate the influence of the apolipoprotein E (APOE) ε4 genotype. This investigation was a prospective, population-based cohort study of participants in the Mayo Clinic Study of Aging in Olmsted County, Minnesota. Participants 70 years or older who were cognitively normal at baseline were followed up to the outcome of incident MCI. The study dates were April 2006 to June 2016. At baseline, participants provided information about mentally stimulating activities within 1 year before enrollment into the study. Neurocognitive assessment was conducted at baseline, with evaluations at 15-month intervals. Cognitive diagnosis was made by an expert consensus panel based on published criteria. Hazard ratios (HRs) and 95% CIs were calculated using Cox proportional hazards regression models after adjusting for sex, age, and educational level. The final cohort consisted of 1929 cognitively normal persons (median age at baseline, 77 years [interquartile range, 74-82 years]; 50.4% [n = 973] female) who were followed up to the outcome of incident MCI. During a median follow-up period of 4.0 years, it was observed that playing games (HR, 0.78; 95% CI, 0.65-0.95) and engaging in craft activities (HR, 0.72; 95% CI, 0.57-0.90), computer use (HR, 0.70; 95% CI, 0.57-0.85), and social activities (HR, 0.77; 95% CI, 0.63-0.94) were associated with a decreased risk of incident MCI. In a stratified analysis by APOE ε4 carrier status, the data point toward the lowest risk of incident MCI for APOE ɛ4 noncarriers who engage in mentally stimulating activities (eg, computer use: HR, 0.73; 95% CI, 0.58-0.92) and toward the highest risk of incident MCI for APOE ɛ4 carriers who do not engage in mentally stimulating activities (eg, no computer use: HR, 1.74; 95% CI, 1.33-2.27). Cognitively normal elderly individuals who engage in specific mentally stimulating activities even in late life have a decreased risk of incident MCI. The associations may vary by APOE ε4 carrier status.