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Apolipoprotein E ε4/4 genotype limits response to dietary induction of hyperhomocysteinemia and resulting inflammatory signaling.

ABSTRACT: Vascular contributions to cognitive impairment and dementia (VCID) are the second leading cause of dementia behind Alzheimer's disease. Apolipoprotein E (ApoE) is a lipid transporting lipoprotein found within the brain and periphery. The APOE ε4 allele is the strongest genetic risk factor for late onset Alzheimer's disease and is a risk factor for VCID. Our lab has previously utilized a dietary model of hyperhomocysteinemia (HHcy) to induce VCID pathology and cognitive deficits in mice. This diet induces perivascular inflammation through cumulative oxidative damage leading to glial mediated inflammation and blood brain barrier breakdown. Here, we examine the impact of ApoE ε4 compared to ε3 alleles on the progression of VCID pathology and inflammation in our dietary model of HHcy. We report a significant resistance to HHcy induction in ε4 mice, accompanied by a number of related differences related to homocysteine (Hcy) metabolism and methylation cycle, or 1-C, metabolites. There were also significant differences in inflammatory profiles between ε3 and ε4 mice, as well as significant reduction in Serpina3n, a serine protease inhibitor associated with ApoE ε4, expression in ε4 HHcy mice relative to ε4 controls. Finally, we find evidence of pervasive sex differences within both genotypes in response to HHcy induction.

SUBMITTER: Seaks CE

PROVIDER: S-EPMC9254035 | biostudies-literature | 2022 May

REPOSITORIES: biostudies-literature

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Apolipoprotein E ε4/4 genotype limits response to dietary induction of hyperhomocysteinemia and resulting inflammatory signaling.

Seaks Charles E CE Weekman Erica M EM Sudduth Tiffany L TL Xie Kevin K Wasek Brandi B Fardo David W DW Johnson Lance A LA Bottiglieri Teodoro T Wilcock Donna M DM

Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism 20220113 5

Vascular contributions to cognitive impairment and dementia (VCID) are the second leading cause of dementia behind Alzheimer's disease. Apolipoprotein E (ApoE) is a lipid transporting lipoprotein found within the brain and periphery. The <i>APOE</i> ε4 allele is the strongest genetic risk factor for late onset Alzheimer's disease and is a risk factor for VCID. Our lab has previously utilized a dietary model of hyperhomocysteinemia (HHcy) to induce VCID pathology and cognitive deficits in mice. T ...[more]

PMID: 35023380

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Project description:ImportanceEmerging evidence suggests that long-term exposure to ball heading in soccer, the most popular sport in the world, confers risk for adverse cognitive outcomes. However, the extent to which the apolipoprotein E ε4 (APOE ε4) allele, a common risk factor for neurodegeneration, and ball heading are associated with cognition in soccer players remains unknown.ObjectiveTo determine whether the APOE ε4 allele and 12-month ball heading exposure are associated with verbal memory in a cohort of adult amateur soccer players.Design, settings, and participantsA total of 379 amateur soccer players were enrolled in the longitudinal Einstein Soccer Study from November 11, 2013, through January 23, 2018. Selection criteria included participation in soccer for more than 5 years and for more than 6 months per year. Of the 379 individuals enrolled in the study, 355 were genotyped. Three players were excluded for reporting extreme levels of heading. Generalized estimating equation linear regression models were employed to combine data across visits for a cross-sectional analysis of the data.ExposuresAt each study visit every 3 to 6 months, players completed the HeadCount 12-Month Questionnaire, a validated, computer-based questionnaire to estimate 12-month heading exposure that was categorized as low (quartiles 1 and 2), moderate (quartile 3), and high (quartile 4).Main outcome and measuresVerbal memory was assessed at each study visit using the International Shopping List Delayed Recall task from CogState.ResultsA total of 352 soccer players (256 men and 96 women; median age, 23 years [interquartile range, 21-28 years]) across a total of 1204 visits were analyzed. High levels of heading were associated with worse verbal memory performance (β = -0.59; 95% CI, -0.93 to -0.25; P = .001). There was no main association of APOE ε4 with verbal memory (β = 0.09; 95% CI, -0.24 to 0.42; P = .58). However, there was a significant association of APOE ε4 and heading with performance on the ISRL task (χ2 = 7.22; P = .03 for overall interaction). In APOE ε4-positive players, poorer verbal memory associated with high vs low heading exposure was 4.1-fold greater (APOE ε4 negative, β = -0.36; 95% CI, -0.75 to 0.03; APOE ε4 positive, β = -1.49; 95% CI, -2.05 to -0.93), and poorer verbal memory associated with high vs moderate heading exposure was 8.5-fold greater (APOE ε4 negative, β = -0.13; 95% CI, -0.54 to 0.29; APOE ε4 positive, β = -1.11, 95% CI, -1.70 to -0.53) compared with that in APOE ε4-negative players.Conclusions and relevanceThis study suggests that the APOE ε4 allele is a risk factor for worse memory performance associated with higher heading exposure in the prior year, which highlights that assessing genetic risks may ultimately play a role in promoting safer soccer play.

Project description:BackgroundLittle is known regarding the leading risk factors for dementia/Alzheimer's disease (AD) in individuals with and without APOE4. The identification of key risk factors for dementia/Alzheimer's disease (AD) in individuals with and without the APOE4 gene is of significant importance in global health.MethodsOur analysis included 110,354 APOE4 carriers and 220,708 age- and sex-matched controls aged 40-73 years at baseline (between 2006-2010) from UK Biobank. Incident dementia was ascertained using hospital inpatient, or death records until January 2021. Individuals of non-European ancestry were excluded. Furthermore, individuals without medical record linkage were excluded from the analysis. Moderation analysis was tested for 134 individual factors.ResultsDuring a median follow-up of 11.9 years, 4,764 cases of incident all-cause dementia and 2065 incident AD cases were documented. Hazard ratios (95% CIs) for all-cause dementia and AD associated with APOE4 were 2.70(2.55-2.85) and 3.72(3.40-4.07), respectively. In APOE4 carriers, the leading risk factors for all-cause dementia included low self-rated overall health, low household income, high multimorbidity risk score, long-term illness, high neutrophil percentage, and high nitrogen dioxide air pollution. In non-APOE4 carriers, the leading risk factors included high multimorbidity risk score, low overall self-rated health, low household income, long-term illness, high microalbumin in urine, high neutrophil count, and low greenspace percentage. Population attributable risk for these individual risk factors combined was 65.1%, and 85.8% in APOE4 and non-APOE4 carriers, respectively. For 20 risk factors including multimorbidity risk score, unhealthy lifestyle habits, and particulate matter air pollutants, their associations with incident dementia were stronger in non-APOE4 carriers. For only 2 risk factors (mother's history of dementia, low C-reactive protein), their associations with incident all-cause dementia were stronger in APOE4 carriers.ConclusionsOur findings provide evidence for personalized preventative approaches to dementia/AD in APOE4 and non-APOE4 carriers. A mother's history of dementia and low levels of C-reactive protein were more important risk factors of dementia in APOE4 carriers whereas leading risk factors including unhealthy lifestyle habits, multimorbidity risk score, inflammation and immune-related markers were more predictive of dementia in non-APOE4 carriers.

Project description:ImportanceRisk of Alzheimer disease (AD) is particularly high for individuals with Down syndrome (DS). The ε4 allele of the apolipoprotein E gene (APOE ε4) is associated with an additional risk for AD. In typical development, there is evidence that the APOE ε4 genotype is associated with an early cognitive advantage. Here we investigate associations of APOE ε4 with attention across the life span of individuals with DS.ObjectiveTo investigate associations between APOE ε4 and attentional abilities in young children and in adults with DS.Design, settings, and participantsIn this cross-sectional study, data were collected from 80 young children with DS (8-62 months of age) and 240 adults with DS (16-71 years of age) during the period from 2013 to 2018 at a research center to examine the association between APOE status (ε4 carrier vs ε4 noncarrier) and attentional abilities.ExposureAPOE status (ε4 carrier vs ε4 noncarrier).Main outcomes and measuresFor the children, attentional ability was assessed using an eye-tracking paradigm, the gap-overlap task; the size of the gap effect was the primary outcome. For the adults, attentional ability was assessed using the CANTAB simple reaction time task; the standard deviation of response time latencies was the primary outcome. Cross-sectional developmental trajectories were constructed linking attentional ability with age in ε4 carriers and ε4 noncarriers for children and adults separately.ResultsThe child sample comprised 23 ε4 carriers and 57 ε4 noncarriers. The adult sample comprised 61 ε4 carriers and 179 ε4 noncarriers. For the children, a significant difference between trajectory intercepts (ηp2 = 0.14) indicated that ε4 carriers (B = 100.24 [95% CI, 18.52-181.96]) exhibited an attentional advantage over ε4 noncarriers (B = 314.78 [95% CI, 252.17-377.39]). There was an interaction between APOE status and age (ηp2 = 0.10); while the gap effect decreased with age for ε4 noncarriers (B = -4.58 [95% CI, -6.67 to -2.48]), reflecting the development of the attention system, there was no change across age in ε4 carriers (B = 0.77 [95% CI, -1.57 to 3.12]). For the adults, there was no main effect of ε4 carrier status, but there was an interaction between APOE status and age (B = 0.02 [95% CI, 0.004-0.07]), so that ε4 carriers had poorer attentional ability than ε4 noncarriers at older ages.Conclusions and relevanceAPOE ε4 is associated with an attentional advantage early in development and a disadvantage later in life for individuals with DS, similar to the pattern reported in typical development. Understanding the differential role of APOE across the life span is an important step toward future interventions.

Dataset Information

Apolipoprotein E ε4/4 genotype limits response to dietary induction of hyperhomocysteinemia and resulting inflammatory signaling.

Publications

Apolipoprotein E ε4/4 genotype limits response to dietary induction of hyperhomocysteinemia and resulting inflammatory signaling.

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