Apolipoprotein E Ε4 Status Research Articles

Homocysteine, neurodegenerative biomarkers, and APOE ε4 in neurodegenerative diseases.

Elevated plasma homocysteine (Hcy) is associated with an increased risk of developing neurodegenerative diseases; however, its relationship with the apolipoprotein E (APOE) ε4 allele has not been well characterized. Participants clinically diagnosed with Alzheimer's disease or mild cognitive impairment (AD/MCI), frontotemporal dementia, Parkinson's disease, or cerebrovascular disease were stratified by the presence of the APOE ε4 allele. Volumetric magnetic resonance imaging, plasma amyloid/tau/neurodegeneration biomarkers, and cognitive performance were quantified. Across all diagnostic groups, Hcy was associated with lower brain parenchymal fraction and greater neurofilament light chain in APOE ε4 non-carriers only. In AD/MCI, Hcy was associated with phosphorylated tau 217 in APOE ε4 non-carriers, but not in carriers. Exploratory analyses revealed interactions between Hcy and APOE ε4 on memory and visuospatial function. Hcy may contribute to neurodegeneration depending on the presence of the APOE ε4 allele and specific disease processes. Trials on vitamin B12 supplementation may consider stratifying by APOE genotype. Highlights Homocysteine (Hcy) was associated with neurodegenerative biomarkers across disease groups. Relationships with Hcy were predominantly found in apolipoprotein E (APOE) ε4 non-carriers. In Alzheimer's disease, associations between Hcy and phosphorylated tau 217 were found in APOE ε4 non-carriers only. Significant interactions existed between Hcy and APOE ε4 status on cognition.

APOE ε4 carrier status moderates the effect of lifestyle factors on cognitive reserve.

This study examines the role of lifestyle factors in cognitive reserve among older adults, focusing on the moderating effect of apolipoprotein E (APOE) ε4 status. Data from 157 participants aged 45 and older from the Healthy Brain Initiative (HBI) were analyzed. Cognitive reserve was estimated using residual scores from Cognivue Clarity tests after accounting for brain atrophy and white matter hyperintensities (WMHs). Lifestyle factors included education, occupational attainment, physical activity, social engagement, diet, and mindfulness. Structural equation models were conducted to assess interactions. Significant interactions were found between APOE ε4 status and mindfulness and social engagement on cognitive reserve, indicating stronger associations for APOE ε4 carriers. APOE ε4 carriers may benefit more from certain lifestyle factors, potentially through stress reduction and anti-inflammatory pathways. These findings support integrating APOE ε4 genetic screening into personalized prevention strategies to enhance interventions aimed at preserving cognitive function and delaying dementia onset in at-risk populations. Mindfulness and social engagement have increased cognitive reserve in APOE ε4 carriers. Study uses residual scores from Cognivue Clarity tests to estimate cognitive reserve. APOE ε4 carriers show stronger associations with certain lifestyle factors on cognitive reserve. Personalized interventions could enhance cognitive resilience in genetically at-risk populations. Comprehensive assessment of multiple lifestyle factors highlights targeted intervention benefits.

Association Between Traumatic Brain Injury and Cognitive Decline Among Middle-to-Older Aged Men in the Vietnam Era Twin Study of Aging.

Traumatic brain injury (TBI) is associated with increased risk of dementia. However, whether TBI is associated with greater cognitive decline over time in specific cognitive domains among older adults is not well understood. This prospective cohort study used data from 1476 male Vietnam Era Twin Study of Aging participants (average age at study entry = 57.9 years, range = 51-71 years; 97.6% non-Hispanic; 92.5% White) collected from 2003 to 2019, who had complete information on prior TBI. Participants completed a comprehensive neuropsychological assessment at up to three visits over up to a 12-year follow-up period during which they also self-reported their history of TBI. Multivariable, linear mixed-effects models were used to assess associations between TBI and cognitive performance trajectories. Effect measure modification by apolipoprotein E (APOE) epsilon 4 (ε4) genotype status was assessed in a subset of participants. Thirty-one percent of participants reported a history of TBI; 29.4% were APOE ε4 carriers. There were no statistically significant associations of TBI with decline in episodic memory, executive function, or processing speed among participants overall. In models stratified by APOE ε4 carrier status, TBI was associated with a larger magnitude of decline in executive function for APOE ε4 carriers (β = -0.0181; 95% confidence interval [CI] -0.0335, -0.0027) compared to noncarriers (β = -0.0031; 95% CI -0.0128, 0.0067; P Interaction = 0.03). In sensitivity analyses, TBI earlier in life (before military induction, average age = 20 years) was associated with faster declines in executive function compared to no TBI, irrespective of APOE ε4 status. In this sample of middle-to-older aged men, TBI was associated with faster declines in executive function among APOE ε4 carriers and among those who reported TBI in early life. These findings support the importance of a life course perspective when considering factors that may influence cognitive health in aging.

APOE ε4 and Intracerebral Hemorrhage in Patients With Brain Arteriovenous Malformation

Intracerebral hemorrhage (ICH) is a serious complication of brain arteriovenous malformation (AVM). Apolipoprotein E (APOE) ε4 is a well-known genetic risk factor for ICH among persons without AVM, and cerebral amyloid angiopathy is a vasculopathy frequently observed in APOE ε4 carriers that may increase the risk of ICH. To assess whether APOE ε4 is associated with a higher risk of ICH in patients with a known AVM. This cross-sectional study including 412 participants was conducted in 2 stages (discovery and replication) using individual-level data from the UK Biobank (released March 2012 and last updated October 2023) and the All of Us Research Program (commenced on May 6, 2018, with its latest update provided in October 2023). The occurrence of AVM and ICH was ascertained at the time of enrollment using validated International Classification of Diseases, Ninth Revision and Tenth Revision, codes. Genotypic data on the APOE variants rs429358 and rs7412 were used to ascertain the ε status. For each study, the association between APOE ε4 variants and ICH risk was assessed among patients with a known AVM by using multivariable logistic regression. The discovery phase included 253 UK Biobank participants with known AVM (mean [SD] age, 56.6 [8.0] years, 119 [47.0%] female), of whom 63 (24.9%) sustained an ICH. In the multivariable analysis of 240 participants of European ancestry, APOE ε4 was associated with a higher risk of ICH (odds ratio, 4.58; 95% CI, 2.13-10.34; P < .001). The replication phase included 159 participants with known AVM enrolled in All of Us (mean [SD] age, 57.1 [15.9] years; 106 [66.7%] female), of whom 29 (18.2%) sustained an ICH. In multivariable analysis of 101 participants of European ancestry, APOE ε4 was associated with higher risk of ICH (odds ratio, 4.52; 95% CI, 1.18-19.38; P = .03). The results of this cross-sectional study of patients from the UK Biobank and All of Us suggest that information on APOE ε4 status may help identify patients with brain AVM who are at particularly high risk of ICH and that cerebral amyloid angiopathy should be evaluated as a possible mediating mechanism of the observed association.

Correlation between the APOE ε4 genotype, lifestyle habits, and cognitive deficits in Chinese adults over 60: a cross-sectional analysis in China.

Apolipoprotein E (APOE) epsilon 4 is regarded as the most significant genetic contributor linked to mild cognitive impairment (MCI) and Alzheimer's disease (AD). Daily life elements might also influence cognitive abilities to some extent. This research aimed to investigate whether carrying APOE ε4 alters the effects of lifestyle on cognitive ability. The research included 1871 senior community members with APOE gene data, all participating in clinical, neuropsychological, and daily living factor assessments. Based on their APOE ε4 status, they were categorized into two groups: the APOE ε4 group (n = 362) and the non-APOE ε4 group (n = 1,509). Subsequently, a multivariate logistic regression analysis was employed to investigate the link between cognitive deficits and APOE ε4, along with lifestyle patterns. Our research revealed a reduced incidence of MCI (OR = 0.745, 95% CI: 0.587-0.945, p = 0.015) and dementia (OR = 0.422, 95% CI: 0.259-0.688, p = 0.001) in the non-APOE ε4 carriers. Furthermore, the general linear regression analysis revealed a notable interplay between APOE ε4 and sleep disturbances, potentially impacting cognitive deterioration together (F = 6.817, p = 0.001). The research indicates that possessing APOE ε4 alters the impact of everyday life factors on cognitive decline. In addition, there is a significant interaction between APOE ε4 and sleep disorders, which may jointly lead to the appearance of cognitive impairment.

Associations between homocysteine, tau, and neurodegenerative markers in apolipoprotein ε4 non‐carriers with clinical Alzheimer’s disease

AbstractBackgroundHomocysteine (Hcy) is an amino acid generated as a byproduct of methionine metabolism. It is a risk factor for vascular and neurodegenerative diseases. This study investigated relationships between plasma Hcy concentrations and neurodegenerative biomarkers in people clinically diagnosed with Alzheimer’s disease (AD) or mild cognitive impairment (MCI) due to AD.MethodParticipants were identified from the Ontario Neurodegenerative Disease Research Initiative. Brain parenchymal fraction (BPF) was quantified using T1‐ and T2‐weighted structural magnetic resonance imaging with an in‐house Semi‐Automated Brain Region Extraction and Lesion Explorer package. Plasma amyloid beta (Aβ) 42, Aβ40, phosphorylated tau 181 (p‐tau181), and neurofilament light chain (NfL) were measured with Single molecule array (Simoa) assays. Linear regression analyses were used to test associations between Hcy and neuroimaging or plasma biomarkers, controlling for age, sex, hypertension, hyperlipidemia, diabetes, cholesterol, and vitamin B12. Analyses were stratified by apolipoprotein E (APOE) ε4 carrier status (non‐carriers: n = 64, mean age = 70.9 years, 41% female; carriers: n = 62, mean age = 71.2 years, 50% female).ResultIn APOE ε4 non‐carriers, Hcy was associated negatively with BPF (β = ‐0.233, p = 0.047, 95% CI [‐0.460, ‐0.003]), notably in temporal lobe regions in exploratory regional analyses. Hcy was also associated positively with plasma concentrations of NfL (β = 0.403, p = 0.007, 95% CI [0.117, 0.688]) and p‐tau181 (β = 0.357, p = 0.023, 95% CI [0.051, 0.663]) in APOE ε4 non‐carriers. Also, in APOE ε4 non‐carriers, Hcy was associated positively with Aβ40 (β = 0.367, p = 0.015, 95% CI [0.074, 0.660]) and Aβ42 (β = 0.305, p = 0.041, 95% CI [0.012, 0.598]), but not with the Aβ42/40 ratio (β = 0.155, p = 0.339, 95% CI [‐0.166, 0.476]). None of these associations were seen in APOE ε4 carriers.ConclusionIn non‐carriers of the APOE ε4 allele clinically diagnosed with AD or MCI, homocysteine was associated with Amyloid, tau and neurodegeneration. The specificity of these relationships to ε4 non‐carriers identifies a unique risk factor profile for AD that is independent of APOE ε4 status.

Physical activity and brain amyloid beta: A longitudinal analysis of cognitively unimpaired older adults.

The current study evaluated the relationship between habitual physical activity (PA) levels and brain amyloid beta (Aβ) over 15 years in a cohort of cognitively unimpaired older adults. PA and Aβ measures were collected over multiple timepoints from 731 cognitively unimpaired older adults participating in the Australian Imaging, Biomarkers and Lifestyle (AIBL) Study of Aging. Regression modeling examined cross-sectional and longitudinal relationships between PA and brain Aβ. Moderation analyses examined apolipoprotein E (APOE) ε4 carriage impact on the PA-Aβ relationship. PA was not associated with brain Aβ at baseline (β=-0.001, p=0.72) or over time (β=-0.26, p=0.24). APOE ε4 status did not moderate the PA-Aβ relationship over time (β=0.12, p=0.73). Brain Aβ levels did not predict PA trajectory (β=-54.26, p=0.59). Our study did not identify a relationship between habitual PA and brain Aβ levels. Physical activity levels did not predict brain amyloid beta (Aβ) levels over time in cognitively unimpaired older adults (≥60 years of age). Apolipoprotein E (APOE) ε4 carrier status did not moderate the physical activity-brain Aβ relationship over time. Physical activity trajectories were not impacted by brain Aβ levels.

Predicting amyloid PET positivity using plasma p-tau181 and other blood-based biomarkers.

This study aimed to determine the efficacy of combining plasma phosphorylated tau (p-tau)181, amyloid beta (Aβ)42/Aβ40, neurofilament light (NfL), and apolipoprotein E (APOE) genotypes for detecting positive amyloid positron emission tomography (PET), which is little known in the Asian population, in two independent cohorts. Biomarkers were measured using a single-molecule array (Simoa) in a cohort study (Asan). All participants underwent amyloid PET. Significant changes in the area under the curve (AUC) and Akaike Information Criterion values were considered to determine the best model. The generalizability of this model was tested using another cohort (KBASE-V). In the Asan cohort, after adjusting for age and sex, p-tau181 (AUC=0.854) or APOE ε4 status (AUC=0.769) distinguished Aβ status with high accuracy. Combining them or adding NfL and Aβ42/40 improved model fitness. The best-fit model included the plasma p-tau181, APOE ε4, NfL and Aβ42/40. The models established from the Asan cohort were tested in the KBASE-V cohort. Additionally, in the KBASE-V cohort, these three biomarker models had similar AUC in cognitively unimpaired (AUC=0.768) and mild cognitive impairment (MCI) (AUC=0.997) participants. Plasma p-tau181 showed a high performance in determining Aβ-PET positivity. Adding plasma NfL and APOE ε4 status improved the model fit without significant improvement in AUC.

Association of plasma phosphor-tau181 with Aβ levels may vary by APOE ε4 status and sex among non-demented old adults

BackgroundTo evaluate the relationship between blood tau phosphorylated at threonine 181 (p-tau181) levels and β-amyloid (Aβ) levels, this study took the potential role of sex differences and apolipoprotein E (APOE)-ε4 status into account. MethodsWe examined 620 participants with normal cognition (n = 178) and mild cognitive impairment (n = 442). Three-way interactions between sex, APOE ε4 status, and the levels of plasma p-tau181 were examined with linear regression models for Aβ levels adjusting for age, education, and diagnosis. The correlation analysis was performed to detect the association of the levels of plasma p-tau181 with brain Aβ stratified for APOE status and sex. ResultsBlood p-tau181 levels were higher in APOE ε4+ participants as compared to APOE ε4 – participants (p < 0.001). A comparison of APOE ε4 status within each gender showed that APOE ε4 carriers had higher levels of plasma p-tau181 and amyloid-β than APOE ε4 noncarriers in both men and women (p < 0.001). In sex/APOE-stratified analyses, individuals with the APOE ε4 allele showed stronger correlations between plasma p-tau181 and brain Aβ levels in both females (r = 0.49, p < 0.001 for APOE ε4 carriers vs r = 0.28, p < 0.001 for APOE ε4 noncarrier.) and males (r = 0.34, p < 0.001 for APOE ε4 carriers vs r = 0.21, p = 0.04 for APOE ε4 noncarriers.). In interactive analysis, the association of plasma p-tau181 and Aβ levels was significant in the female APOE ε4 carriers (p < 0.003). DiscussionAPOE ε4 status and female sex interact to impact the correlation between plasma p-tau181 and Aβ levels. Although the APOE ε4 genotype is one of the most important risky genes for AD, sex differences may also modify the degree of risk at critical times among non-demented older adults.

Association between healthy lifestyle and memory decline in older adults: 10 year, population based, prospective cohort study

ObjectiveTo identify an optimal lifestyle profile to protect against memory loss in older individuals.DesignPopulation based, prospective cohort study.SettingParticipants from areas representative of the north, south, and west of China.ParticipantsIndividuals aged...

Gait and balance in apolipoprotein Ɛ4 allele carriers in older adults and Parkinson’s disease

BackgroundGait and balance impairments are among the most troublesome and heterogeneous in Parkinson’s disease (PD). This heterogeneity may, in part, reflect genetic variation. The apolipoprotein E (APOE) gene has three major allelic variants (ε2, ε3 and ε4). Previous work has demonstrated that older adult (OA) APOE ε4 carriers demonstrate gait deficits. This study compared gait and balance measures between APOE ε4 carriers and non-carriers in both OA and PD. Methods334 people with PD (81 APOE ε4 carriers and 253 non-carriers) and 144 OA (41 carriers and 103 non-carriers) were recruited. Gait and balance were assessed using body-worn inertial sensors. Two-way analyses of covariance (ANCOVA) compared gait and balance characteristics between APOE ε4 carriers and non-carriers in people with PD and OA, controlling for age, gender, and testing site. ResultsGait and balance were worse in people with PD compared to OA. However, there were no differences between APOE ε4 carriers and non-carriers in either the OA or PD group. In addition, there were no significant group (OA/PD) by APOE ε4 status (carrier/non-carrier) interaction effects for any measures of gait or balance. ConclusionsAlthough we found expected impairments in gait and balance in PD compared to OA, gait and balance characteristics did not differ between APOE ε4 carriers and non-carriers in either group. While APOE status did not impact gait and balance in this cross-sectional study, future work is needed to determine whether progression of gait and balance deficits is faster in PD APOE Ɛ4 carriers.

Association of CSF GAP-43 and APOE ε4 with Cognition in Mild Cognitive Impairment and Alzheimer's Disease.

The growth-associated protein 43 (GAP-43) is a presynaptic phosphoprotein in cerebrospinal fluid (CSF). The ε4 allele of apolipoprotein E (APOE) is an important genetic risk factor for Alzheimer's disease (AD). We aimed to evaluate the association of CSF GAP-43 with cognition and whether this correlation was related to the APOE ε4 status. We recruited participants from the Alzheimer's Disease Neuroimaging Initiative (ADNI) database, and they were divided into cognitively normal (CN) ε4 negative (CN ε4-), CN ε4 positive (CN ε4+), mild cognitive impairment (MCI) ε4 negative (MCI ε4-), MCI ε4 positive (MCI ε4+), AD ε4 negative (AD ε4-), and AD ε4 positive (AD ε4+) groups. Spearman's correlation was utilized to evaluate the relationship between CSF GAP-43 and core AD biomarkers at the baseline. We performed receiver-operating characteristic (ROC) curve analyses to investigate the diagnostic accuracy of CSF GAP-43. The correlations between CSF GAP-43 and the Mini-Mental State Examination (MMSE) scores and brain atrophy at baseline were assessed by using multiple linear regression, while the association between CSF GAP-43 and MMSE scores at the follow-up was tested by performing the generalized estimating equation (GEE). The role of CSF GAP-43 in the conversion from MCI to AD was evaluated using the Cox proportional hazard model. We found that the CSF GAP-43 level was significantly increased in MCI ε4+, AD ε4- and AD ε4+ groups compared with CN ε4- or MCI ε4- group. The negative associations between the CSF GAP-43 and MMSE scores at the baseline and follow-up were found in MCI ε4- and MCI ε4+ groups. In addition, baseline CSF GAP-43 was able to predict the clinical progression from MCI to AD. CSF GAP-43 may be a promising biomarker to screen cognition for AD. The effects of CSF GAP-43 on cognition were suspected to be relevant to APOE ε4 status.

TNFR-1 and GDF-15 Are Associated With Plasma Neurofilament Light Chain and Progranulin Among Community-Dwelling Older Adults: A Secondary Analysis of the MAPT Study.

There is growing evidence that cognitive decline can be affected by both nutritional aspects and inflammation. Plasma neurodegenerative biomarkers stand out as minimally invasive useful measures to monitor the potential risk of cognitive decline. This study aimed to investigate the associations between biomarkers of neurodegeneration, nutrition, and inflammation among community-dwelling older adults, and to verify if associations differed according to apolipoprotein E (APOE) ε4 status. This cross-sectional analysis included 475 participants ≥70 years old from the Multidomain Alzheimer Preventive Trial (MAPT), mean age 76.8 years (SD = 4.5), 59.4% women. Biomarkers of neurodegeneration (plasma amyloid-β 42/40-Aβ 42/40, neurofilament light chain-NfL, progranulin), nutrition (erythrocyte docosahexaenoic acid, eicosapentaenoic acid, omega-3 index; plasma homocysteine-Hcy, 25 hydroxyvitamin D), inflammation (plasma tumor necrosis factor receptor 1-TNFR-1, monocyte chemoattractant protein 1-MCP-1, interleukin 6-IL-6), and cellular stress (plasma growth differentiation factor 15-GDF-15) were assessed. Linear regression analyses were performed to investigate the associations between nutritional and inflammatory biomarkers (independent variables) and neurodegenerative biomarkers (dependent variables), with adjustments for age, sex, education, body mass index, physical activity, allocation to MAPT groups, and APOE ε4 status. After adjusting for confounders, Aβ 42/40 was not associated with nutritional or inflammatory markers. NfL was positively associated with GDF-15, TNFR-1, IL-6, and Hcy. Progranulin was positively associated with GDF-15, TNFR-1, and MCP-1. Analyses restricted to APOE ε4 carriers (n = 116; 26.9%) or noncarriers were mostly similar. Our cross-sectional study with community-dwelling older adults corroborates previous evidence that inflammatory pathways are associated to plasma markers of neurodegeneration. Clinical Trials Registration Number: NCT00672685.

Interactions between the apolipoprotein E4 gene and modifiable risk factors for cognitive impairment: a nationally representative panel study

BackgroundFew studies using rigorous clinical diagnosis have considered whether associations with cognitive decline are potentiated by interactions between genetic and modifiable risk factors. Given the increasing burden of cognitive impairment (CI) and dementia, we assessed whether Apolipoprotein E ε4 (APOE4) genotype status modifies the association between incident CI and key modifiable risk factors .MethodsOlder adults (70+) in the US were included. APOE4 status was genotyped. Risk factors for CI were self-reported. Cognitive status (normal, CI, or dementia) was assigned by clinical consensus panel. In eight separate Cox proportional hazard models, we assessed for interactions between APOE4 status and other CI risk factors.ResultThe analytical sample included 181 participants (mean age 77.7 years; 45.9% male). APOE4 was independently associated with a greater hazard of CI in each model (Hazard Ratios [HR] between 1.81–2.66, p < 0.05) except the model evaluating educational attainment (HR 1.65, p = 0.40). The joint effects of APOE4 and high school education or less (HR 2.25, 95% CI: 1.40–3.60, p < 0.001), hypertension (HR 2.46, 95% CI: 1.28–4.73, p = 0.007), elevated depressive symptoms (HR 5.09, 95% CI: 2.59–10.02, p < 0.001), hearing loss (HR 3.44, 95% CI: 1.87–6.33, p < 0.0001), vision impairment (HR 5.14, 95% CI: 2.31–11.43, p < 0.001), smoking (HR 2.35, 95% CI: 1.24–4.47, p = 0.009), or obesity (HR 3.80, 95% CI: 2.11–6.85, p < 0.001) were associated with the hazard of incident CIND (compared to no genetic or modifiable risk factor) in separate models. The joint effect of Apolipoprotein ε4 and type 2 diabetes was not associated with CIND (HR 1.58, 95% CI: 0.67–2.48, p = 0.44).DiscussionThe combination of APOE4 and selected modifiable risk factors conveys a stronger association with incident CI than either type of risk factor alone.

Interactions between apolipoprotein E, sex, and amyloid‐beta on cerebrospinal fluid p‐tau levels in the European Prevention of Alzheimer’s Dementia Longitudinal Cohort Study (EPAD LCS)

AbstractBackgroundAlzheimer’s Disease, the leading cause of dementia, is over‐represented in females. The apolipoprotein E (APOE) ε4 allele is the strongest genetic risk factor for late‐onset AD and is associated with aberrant cerebrospinal fluid levels (CSF) of total tau (t‐tau), phosphorylated tau (p‐tau), and amyloid‐β (Aβ). There is some evidence that sex may mediate the relationship between APOE status and CSF tau, however, evidence is mixed.MethodWe aimed to examine the association between sex, APOE ε4 status, CSF Aβ on t‐tau and p‐tau in 1776 mid‐to‐late life individuals without a diagnosis of dementia in the European Prevention of Alzheimer’s Dementia (EPAD) longitudinal cohort study.ResultWe found a significant interaction between APOE status, sex, and CSF Aβ on CSF p‐tau levels. Specifically, the association between CSF Aβ and CSF p‐tau was stronger in male ε4 carriers relative to female ε4 carriers. Further, in females with high Aβ levels (reflecting less cortical deposition), ε4 carriers had significantly elevated p‐tau levels relative to non‐carriers. However, there were no significant differences in p‐tau between male ε4 carriers and non‐carriers with high Aβ.ConclusionAn interaction between sex and cerebrospinal fluid Aβ may mediate the relationship between APOE status and CSF p‐tau. These data suggest tau accumulation may be independent of Aβ in females, but not males. Future work would benefit from replication in separate cohorts, longitudinal examination, and the consideration of the role of sex hormones on CSF markers.

Air pollution exposure during pregnancy and childhood, APOE ε4 status and Alzheimer polygenic risk score, and brain structural morphology in preadolescents

BackgroundAir pollution exposure is associated with impaired neurodevelopment, altered structural brain morphology in children, and neurodegenerative disorders. Differential susceptibility to air pollution may be influenced by genetic features. ObjectivesTo evaluate whether the apolipoprotein E (APOE) genotype or the polygenic risk score (PRS) for Alzheimer's Disease (AD) modify the association between air pollution exposure during pregnancy and childhood and structural brain morphology in preadolescents. MethodsWe included 1186 children from the Generation R Study. Concentrations of fourteen air pollutants were calculated at participants’ home addresses during pregnancy and childhood using land-use-regression models. Structural brain images were collected at age 9–12 years to assess cortical and subcortical brain volumes. APOE status and PRS for AD were examined as genetic modifiers. Linear regression models were used to conduct single-pollutant and multi-pollutant (using the Deletion/Substitution/Addition algorithm) analyses with a two-way interaction between air pollution and each genetic modifier. ResultsHigher pregnancy coarse particulate matter (PMcoarse) and childhood polycyclic aromatic hydrocarbons exposure was differentially associated with larger cerebral white matter volume in APOE ε4 carriers compared to non-carriers (29,485 mm3 (95% CI 6,189; 52,781) and 18,663 mm3 (469; 36,856), respectively). Higher pregnancy PMcoarse exposure was differentially associated with larger cortical grey matter volume in children with higher compared to lower PRS for AD (19436 mm3 (825, 38,046)). DiscussionAPOE status and PRS for AD possibly modify the association between air pollution exposure and brain structural morphology in preadolescents. Higher air pollution exposure is associated with larger cortical volumes in APOE ε4 carriers and children with a high PRS for AD. This is in line with typical brain development, suggesting an antagonistic pleiotropic effect of these genetic features (i.e., protective effect in early-life, but neurodegenerative effect in adulthood). However, we cannot discard chance findings. Future studies should evaluate trajectorial brain development using a longitudinal design.

Air Pollution Exposure during Pregnancy and Childhood, APOE ε4 Status and Polygenic Risk Score for Alzheimer’s Disease, and Brain Structural Morphology in Preadolescents

Background and Aim. Air pollution exposure is associated with impaired neurodevelopment, altered structural brain morphology in children and neurodegenerative disorders. Differential susceptibility to air pollution may be influenced by genetic features. We aimed to evaluate whether the apolipoprotein E (APOE) genotype or the polygenic risk score (PRS) for Alzheimer’s Disease (AD), modify the association between air pollution exposure during pregnancy and childhood and structural brain morphology in preadolescents. Methods. We included 1186 children from the Generation R Study. Concentrations of 14 air pollutants were calculated at the participants’ home address during pregnancy and childhood using land-use-regression models. Structural brain images were collected at age 9–12 years to assess (sub)cortical brain volumes. APOE status and PRS for AD were examined as effect modifiers. We conducted single-pollutant analyses with a two-way interaction between air pollution and APOE status or PRS for AD and multi-pollutant analyses with the two-way interaction. Results. Higher pregnancy PMcoarse and childhood PAHs exposure was differentially associated with larger cerebral white matter volume in APOE ε4 carriers compared to non-carriers (29485 mm3 [95% CI 6189, 52781] and 18663 mm3 [469, 36856], respectively). Higher pregnancy PMcoarse exposure was differentially associated with larger cortical grey matter volume in children with higher compared to lower PRS for AD (19436 mm3 [825, 38046]). Conclusions. APOE status and PRS for AD have a possible modifying effect on the association between air pollution exposure and brain structural morphology in preadolescents. Both seem to modify the association towards the typical development of the brain, with increasing cortical volumes, highlighting the possibility of the antagonistic pleiotropic effect (i.e., protective effect in early life but altered neurodegenerative processes in adulthood). Future studies should research this antagonistic pleiotropic effect and study trajectorial brain development using a longitudinal design. Keywords. environmental pollution, neurodevelopment, neuroimaging, genetic modifiers

Interactions between apolipoprotein E, sex, and amyloid-beta on cerebrospinal fluid p-tau levels in the European prevention of Alzheimer's dementia longitudinal cohort study (EPAD LCS).

SummaryBackgroundAlzheimer's Disease, the leading cause of dementia, is over-represented in females. The apolipoprotein E (APOE)ε4 allele is the strongest genetic risk factor for late-onset AD and is associated with aberrant cerebrospinal fluid levels (CSF) of total tau (t-tau), phosphorylated tau (p-tau), and amyloid-β (Aβ). There is some evidence that sex may mediate the relationship between APOE status and CSF tau, however, evidence is mixed.MethodsWe aimed to examine the interaction between sex, APOE ε4 status, CSF Aβ on t-tau and p-tau in 1599 mid-to-late life individuals without a diagnosis of dementia in the European Prevention of Alzheimer's Dementia (EPAD) longitudinal cohort study.FindingsWe found a significant interaction between APOE status, sex, and CSF Aβ on CSF p-tau levels (β = 0·18, p = 0·04). Specifically, there was a stronger association between APOE status and CSF Aβ42 on CSF p-tau in males compared to females. Further, in females with high Aβ levels (reflecting less cortical deposition), ε4 carriers had significantly elevated p-tau levels relative to non-carriers (W = 39663, p = 0·01). However, there were no significant differences in p-tau between male ε4 carriers and non-carriers with high Aβ (W = 23523, p = 0·64).InterpretationAn interaction between sex and cerebrospinal fluid Aβ may mediate the relationship between APOE status and CSF p-tau. These data suggest tau accumulation may be independent of Aβ in females, but not males.FundingInnovative Medicines Initiative, Swedish Research Council, Alzheimer Drug Discovery Foundation, Swedish Alzheimer Foundation, the Swedish state under the agreement between the Swedish government and the County Councils: the ALF-agreement, and the Alzheimer's Association 2021 Zenith Award.

Dietary Glycemic Load and Plasma Amyloid-β Biomarkers of Alzheimer's Disease.

Previous studies have highlighted links between a high-glycemic-load (GL) diet and Alzheimer’s disease in apolipoprotein E ε4 (APOE4) carriers. However, the impact of high-GL diet on plasma amyloid-β (Aβ), an Alzheimer’s disease hallmark that can be detected decades before clinical symptomatology, is unknown. This study examined the association between plasma Aβ peptides (Aβ40, Aβ42 concentration and Aβ42/Aβ40 ratio) and GL. The influence of the GL of four meal types (breakfast, lunch, afternoon snack, and dinner) was also determined. From the prospective Three-City study, 377 participants with plasma Aβ measurements, and who completed the Food Frequency Questionnaire, were selected. The association between plasma Aβ and GL was tested using an adjusted linear regression model. Lunch GL was associated with a lower plasma Aβ42 concentration (β = −2.2 [CI = −4.27, −0.12], p = 0.038) and lower Aβ42/Aβ40 ratio (β = −0.009 [CI = −0.0172, −0.0007], p = 0.034) in the model adjusted for center, age, sex, education level, APOE4 status, energy intake, serum creatinine, total cholesterol, and Mediterranean-like diet. No significant association was found with the GL of the other meal types. These results suggest that dietary GL may independently modulate the plasma Aβ of the APOE4 status. The mechanism underlying diet, metabolic response, and Aβ peptide regulation must be elucidated.

Sex- and age-specific associations between cardiometabolic risk and white matter brain age in the UK Biobank cohort.

Cardiometabolic risk (CMR) factors are associated with accelerated brain aging and increased risk for sex‐dimorphic illnesses such as Alzheimer's disease (AD). Yet, it is unknown how CMRs interact with sex and apolipoprotein E‐ϵ4 (APOE4), a known genetic risk factor for AD, to influence brain age across different life stages. Using age prediction based on multi‐shell diffusion‐weighted imaging data in 21,308 UK Biobank participants, we investigated whether associations between white matter Brain Age Gap (BAG) and body mass index (BMI), waist‐to‐hip ratio (WHR), body fat percentage (BF%), and APOE4 status varied (i) between males and females, (ii) according to age at menopause in females, and (iii) across different age groups in males and females. We report sex differences in associations between BAG and all three CMRs, with stronger positive associations among males compared to females. Independent of APOE4 status, higher BAG (older brain age relative to chronological age) was associated with greater BMI, WHR, and BF% in males, whereas in females, higher BAG was associated with greater WHR, but not BMI and BF%. These divergent associations were most prominent within the oldest group of females (66–81 years), where greater BF% was linked to lower BAG. Earlier menopause transition was associated with higher BAG, but no interactions were found with CMRs. In conclusion, the findings point to sex‐ and age‐specific associations between CMRs and brain age. Incorporating sex as a factor of interest in studies addressing CMR may promote sex‐specific precision medicine, consequently improving health care for both males and females.