APOE Ε4 Allele Research Articles

In‐Vivo Characterization of Blood‐Brain Barrier Permeability in Cognitively Normal APOE e4 Carriers and Non‐Carriers

AbstractBackgroundAn intact blood‐brain barrier (BBB) is critical for optimal brain health, and even transient or highly localized disruption of the BBB can have devastating consequences for neural functioning. BBB breakdown has been implicated in Alzheimer’s Disease (AD) pathogenesis, and elevated BBB permeability has been observed in APOE e4 carriers compared to non‐carriers. As prior studies have focused on a priori, AD‐vulnerable regions rather than whole‐brain analyses, little is understood about broader patterns of BBB breakdown that may relate to AD risk. This study aims to identify preclinical cerebrovascular differences in cognitively normal individuals who are genetically at high‐risk for AD.MethodDynamic contrast‐enhanced magnetic resonance imaging (DCE‐MRI) was performed on 34 cognitively normal older adults (average age = 76.6 years; 18 women) from the UC San Diego Alzheimer’s Disease Research Center, evenly split by APOE e4 status. Data were processed using ROCKETSHIP and average BBB permeability values were extracted from the Desikan‐Killiany atlas cortical gray matter regions. Permeability values were averaged across hemispheres, resulting in 34 measurements. ANCOVAs predicted BBB permeability within each region from e4 status, age, sex, and the interaction between sex and e4 status.ResultAPOE e4 carriers showed elevated BBB permeability throughout the superolateral frontal and parietal cortices and some occipital cortex compared to non‐carriers. The strongest effects were found in the caudal‐middle and superior frontal, pre‐ and paracentral, and superior parietal gyri. Further, there was a pattern of sex by e4 carrier status interaction whereby the e4 effect was stronger in men than women.ConclusionOlder adults who carry at least one APOE e4 allele show increased BBB permeability compared to e4 non‐carriers primarily in superior frontal and parietal regions, a spatial pattern that is notably distinct from the typical topography of AD pathology. This effect may be moderated by sex, such that men may be more vulnerable to the detrimental effects of APOE e4 on certain regions of the BBB compared to women. These findings raise implications for important questions regarding APOE4 dose effects, the mechanisms by which APOE regulates BBB functioning, and the evolution of BBB permeability through the disease course.

Blood biomarkers of amyloid and tau pathologies, brain degeneration, inflammation, and oxidative stress in early‐ and late‐onset Alzheimer's disease

AbstractBackgroundBlood biomarkers provide a non‐invasive and accessible means of detection for Alzheimer's disease (AD). Specifically, biomarkers associated with early‐onset AD (EOAD) illuminate the underlying mechanisms and provide valuable guidance for potential therapies. We aim to present blood biomarker evidence in individuals with both EOAD and late‐onset AD (LOAD), as well as in age‐matched healthy controls.MethodsA total of 95 participants were enrolled in the study. We assessed levels of 18 distinct blood biomarkers, and concurrently examined cerebrospinal fluid amyloid and tau markers, neuropsychological test scores, APOEε4 carrier status, and neuroimaging markers. Group disparities, correlations, and the diagnostic utility of these biomarkers were investigated.ResultsIn patients with EOAD, levels of blood IL‐4, IL‐6, and TNF‐α were notably lower when compared to LOAD. AD patients exhibited higher blood levels of p‐tau181, NfL, GFAP, tAOC, and MDA, as well as lower levels of Aβ1‐42, SOD, and IL‐12p70. Intricate interactions were observed among these blood biomarkers, with inflammatory markers demonstrating correlations with neuroimaging markers within the AD cohort. Individuals carrying the APOEε4 allele displayed elevated levels of GFAP and IL‐4 in comparison to non‐carriers. Additionally, blood levels of Aβ1‐42, p‐tau181, NfL, and GFAP were found to correlate with neuropsychological scores and proved effective in distinguishing AD, with GFAP exhibiting particular relevance in early‐onset cases.ConclusionThe study demonstrated that individuals with EOAD may experience less inflammatory responses than older patients. Peripheral inflammation was associated with amyloid and tau pathologies, astrogliosis, oxidative stress, and alterations in brain structure and function. Blood Aβ1‐42, p‐tau181, NfL, and GFAP showed promise in detecting cognitive decline and AD, with GFAP exhibiting relevance in early‐onset cases.

Elevated brain miR298 is associated with a reduced risk of Alzheimer’s disease

AbstractBackgroundNon‐coding RNA species, such as microRNA (miRNA), regulate multiple biological and pathological processes by binding to target mRNAs and facilitating alteration of translation levels via complexes such as RNA‐induced silencing complex (RISC). Disrupting this process could contribute to AD pathogenesis by fostering aggregation of hyperphosphorylated microtubule‐associated protein tau and amyloid‐β (Aβ) peptides, and neuroinflammation. Understanding how these pathological changes are regulated remains our research focus. We report that miR298 plays a vital role in maintaining APP and tau homeostasis and that miR298 imbalances may impact AD progression.MethodLevels of miR298 from non‐cognitively impaired (NCI) and AD subject brain tissue samples from different recognized sources were measured by qRT‐PCR and assessed for associations with AD risk and potential covariates such as age and APOE genotype. Other biomarkers were assessed in cortical samples from the same subjects, as we previously described. Further, APP, tau, and cytokines were profiled in miR298 mimic‐ or its antagomiR‐expressing human neuronal and astrocyte cultures.ResultLevels of miR298 varied in postmortem temporal lobe between AD patients and age‐matched NCI controls. Higher brain miR298 levels were associated with a reduced risk of AD. Subject age and APOE genotype altered this association; specifically, greater age and dose of the APOEε4 allele were associated with an increased risk of AD. However, APOEε4 dose‐associated risk reduced as age increased. We identified putative binding sites for miR298 on APP, BACE1, MAPT, IL1α, and IL6 mRNAs to form RISC. We showed that treatment by miR298 reduced tau, APP, and BACE1 proteins and mRNA levels in cell cultures.ConclusionThese studies suggest that miR298 regulates a coordinated network of AD‐related proteins APP, BACE1, and tau. Hence, such network regulation may represent a rational therapeutic target for reducing AD risk and disease modification. In addition to late‐onset cases, we will profile miR298 in brain tissue samples from early‐onset AD cases. Future work involves testing miR298 in AD animal models, such as in human tau‐overexpressing transgenic mice. We sincerely thank grant support from NIA/NIH.

APOE4 Alters Tau Propagation in Regions Associated with Early Alzheimer’s Disease in a Humanized Mouse Model of Tau Spread

AbstractBackgroundPossession of the APOE4 allele is the strongest genetic risk factor for developing the sporadic form of Alzheimer’s disease (AD). Studies investigating APOE4’s associated AD risk have largely centered on APOE4’s propensity to regulate the deposition of extracellular amyloid beta plaques. More recent attempts to characterize APOE4’s role in AD have brought into question the role APOE4 may possess in modulating the pathogenesis of intracellular tau tangles. However, to date, it remains unclear if APOE4 can alter pathological tau spread and if these effects are dependent on regions associated with early tau accumulation in AD.MethodTo recapitulate tau spread observed early in AD, we developed a novel human APOE mouse that expresses misfolded human tau localizing to the entorhinal cortex (EC). These mice were generated by crossing homozygous mice possessing various humanized APOE alleles to mice harboring the human MAPT P301L mutation. Human MAPT was placed under control of the neuropsin‐tTa promoter to selectively expresses misfolded tau to the EC. Both male and female mice were analyzed at various ages up until 27 months using various in‐vivo and ex‐vivo techniques to measure tau pathology and propagation, spatial memory defects, and neurodegeneration.ResultWe observed differential tau spread and neurodegeneration altered by APOE genotype in both a sex‐dependent and age‐dependent manner. Our results point predominantly to decreased tau pathology in regions associated with early AD in homozygous APOE4 mice. Analysis of the middle‐aged cohort revealed a significant decrease in tau propagation and associated atrophy to the hippocampus and lateral EC in homozygous female APOE4 mice. The observed effect on neurodegeneration and tau burden were attenuated in both male counterparts.ConclusionHere we report the generation and characterization of a novel APOE‐tau mouse model that recapitulates the region‐specific tau pathogenesis observed in early AD. Our results offer novel insights into APOE4’s role in AD by altering the sex‐dependent propagation of pathological tau along anatomically connected, vulnerable AD brain regions.

Expression of the APOE4 allele influences the systemic environment to alter hippocampal phenotypes

AbstractBackgroundThe apolipoprotein E (APOE) ε4 allele is the strongest genetic risk factor for Alzheimer’s disease (AD), increasing risk from 3‐12‐fold relative to the common ε3 allele. Seminal studies have revealed that age‐related changes in blood‐CNS communication regulate cognitive function. More recently, youth‐associated blood‐borne proteins revitalize the aged brain, improving hippocampal function and increasing adult neurogenesis and dendritic spine plasticity. Characterizing plasma proteomic changes across various systemic contexts may thus be critical for development of novel therapeutic strategies to combat AD. We hypothesized that the plasma proteome differs between APOE4 and APOE3 individuals, and these systemic changes account for differences in brain function according to APOE genotype.MethodUsing an aptamer‐based platform to profile the plasma proteome from human APOE4/4 and APOE3/3 subjects, we identified allele‐specific changes in protein expression and canonical pathways linked to CNS functions and processes. Next, we examined the plasma proteome in APOE knock‐in mice expressing human APOE3 or APOE4 and evaluated those pathways that are conserved across species. To examine molecular processes within the brain regulated by opposing APOE alleles from the systemic environment, we characterized transcriptomic changes in the hippocampi of mice in which blood is shared between APOE4 and APOE3 mice by parabiosis relative to isogenic control pairs.ResultIn both mouse and human subjects, expression of APOE4 is associated with perturbations of plasma proteins related to extracellular matrix (ECM) and inflammation pathways relative to expression of APOE3. Several pathways shown to be associated with APOE3 expression in the hippocampus and disrupted in APOE4‐KI hippocampus were found to be restored in APOE4‐KI mice exposed to APOE3 blood via parabiosis. Specific deleterious phenotypes were identified in the hippocampi of APOE3 mice exposed to APOE4 blood, suggesting that APOE4‐associated brain phenotypes are, in part, mediated by how APOE4 alters the systemic compartment.ConclusionWe find that APOE alleles differentially alter the systemic environment to confer changes in brain phenotypes. Ongoing experiments focus on investigating the protective impact of the APOE3 systemic environment on molecular processes within the APOE4 hippocampus, which may ultimately inform our understanding of increased AD risk in APOE4 subjects.

Cerebral vascular mitochondrial function is dependent on APOE genotype and estrogen status

AbstractBackgroundPostmenopausal females who carry an APOE4 allele are at higher risk of late‐onset Alzheimer’s Disease (LOAD) compared to age‐matched APOE4 males. Estrogen deficiency predisposes females to an increased risk of vascular, cognitive and metabolic impairments. Estrogen and APOE genotype are known to impact metabolic and mitochondrial function in the brain, but their effects on cerebral vessels are unknown. Thus, the purpose of this study was to determine the interaction between APOE genotype and estrogen deficiency in relation to cerebrovascular mitochondrial function.MethodYoung female homozygous APOE3 and APOE4 mice (n = 6‐8 per group; 6 months old) fed a high‐fat diet were ovariectomized (“ovx”), ovariectomized and supplemented with 17β‐estradiol (0.36 mg, 60‐day release, “estradiol”), or left intact (“sham”). At 2 months after ovariectomy, a glucose tolerance test (GTT) was performed, then cerebral arteries and arterioles were dissected, incubated in saponin, then assessed for mitochondrial respiration in response to substrates probing carbohydrate metabolism (Oroboros). Data are presented as mean±SEM.ResultThere was an interaction between APOE genotype and ovx/estradiol status in relation to cerebrovascular complex I (CI)‐ (p = 0.04) and complex II (CII)‐coupled respiration (p = 0.04). Additionally, there was a significant effect of genotype, such that vessels from APOE3 mice had greater CI‐coupled respiration than vessels from APOE4 mice (p = 0.02). When examining differences between APOE3 groups, APOE3‐estradiol mice had a 53% greater CI‐coupled respiration than APOE3‐sham mice (15.4±3.4 vs. 7.2±1.2 pmol/(s*mg), p = 0.03) and a 60% greater CI‐coupled respiration than APOE3‐ovx mice (6.2±1.6 pmol/(s*mg), p = 0.007). The APOE3‐estradiol group also had greater CI+CII‐coupled respiration compared to both APOE3‐sham (50.8±7.1 vs. 27.3±1.7 pmol/(s*mg), p = 0.006) and ovx groups (28.0±5.7 pmol/(s*mg), p = 0.009). Interestingly, CI and CI+CII coupled respiration did not differ between sham, ovx, and estradiol in APOE4 mice (p>0.05). Maximal uncoupled respiration was greater in the APOE3 mice than APOE4 mice (p = 0.01). Whole‐body glucose tolerance did not differ between groups (all p>0.05).ConclusionOverall, these results indicate that APOE genotype modulates the impact of estrogen on the cerebrovasculature. We found that 17β‐estradiol enhances cerebrovascular mitochondrial function in APOE3 mice but not APOE4 mice. The results suggest that estradiol supplementation may have more therapeutic benefit for APOE4 non‐carriers.

ApoE4 Status Moderates the Association between Vascular Risks, Cerebral Perfusion and Cognitive Performance in a Southeast Asian Population

AbstractBackgroundFactors contributing to cognitive decline in adults include vascular risk factors (hypertension, hyperlipidemia, diabetes), lower education, age, Apolipoprotein E4(ApoE4) and cerebral hypoperfusion. The interplay between aging and vascular processes disrupts cerebral hemodynamics, heightening the risk of cognitive impairment and neurological disorders. Similarly, ApoE4 gene increases the risk of vascular‐related cognitive impairment and small vessel disease. The interaction between vascular risk factors, cerebral perfusion and ApoE4 carrier status on cognitive performance needs further exploration in a Southeast Asian population.Method601 participants(Age=62.53±10.19) were recruited from the community‐based BIOCIS study at Dementia Research Centre(Singapore). Participants with a research diagnosis of Subjective Cognitive Decline(SCD), Mild Cognitive Impairment(MCI) or dementia were included and stratified into midlife (45‐65, n=327) and later‐life (>65, n=274).Participants were administered global cognitive tests: Montreal Cognitive Assessment(MoCA), Visual Cognitive Assessment Test(VCAT), and a comprehensive neuropsychological test battery including tests for episodic memory(EM). Vascular risk factors included averaged systolic blood pressure(BP) and fasting HBA1C levels. ApoE allelic variation was determined via Taqman SNP genotyping qRT‐PCR methodology. Arterial Spin Labelling MRI data was used to quantify cerebral perfusion using the BASIL toolbox.ResultDuring midlife, linear regression analyses indicted elevated levels of vascular risk factors(BP and HBA1C) and positive ApoE4 carrier status were associated with poorer cognitive performance. The results demonstrated a significant interaction effect between BP and ApoE4 carrier status on global cognition: VCAT(β=‐0.031, p=0.050), MoCA (β=‐0.037, p=0.045) and between HBA1C and ApoE4 carrier status on EM scores: RAVLT delayed trial(β=‐2.68, p=0.001).During later‐life, lowered levels of cerebral perfusion were associated with poorer cognitive performance in ApoE4 carriers only. The results found a marginally significant interaction effect between cerebral perfusion and ApoE4 carrier status on global cognition: VCAT(β=0.2286, p=0.060), and EM: RAVLT delayed (β=0.298, p=0.024), WAIS‐Logical Story (β=0.392, p=0.007). All results remained significant despite controlling for age, education, syndrome severity and consumption of medication.ConclusionThe presence of ApoE4 allele and vascular risk factors lead to a decline in global cognition and EM scores during midlife for a Southeast Asian population. ApoE4 moderates the relationship between reduced cerebral perfusion and poorer global cognition and EM scores in later‐life. Aggressively treating vascular risk during midlife, especially for ApoE4 carriers may prevent further cognitive decline during later‐life.

Platelet aggregation and ApoE genotypes in the Framingham Heart Study

AbstractBackgroundApolipoprotein (Apo) E4, a main susceptibility gene for Alzheimer’s disease (AD) is associated with increased vascular dysfunction, amyloid pathology, and neurodegeneration. The effector pathways leading to increased vascular risk in ApoE4 carriers needs to be established. Platelet aggregation is a key marker of vascular dysfunction and studies need to examine whether a relationship of ApoE4 allele status and platelet biology existsMethodWe examined cross‐sectional associations of platelet aggregation with ApoE genotypes (E2 or E4 against E3, the most common) in middle‐aged cognitively normal participants at the Framingham Heart Study (FHS) Gen3, New Offspring Spouse (NOS), and Omni2 Cohorts. Status was determined by PCR and defined as E4 when at least one copy of the E4 allele was present, or E2 when at least one copy of the E2 was present, after excluding E4 cases. The primary outcome was the platelet aggregation response to 0.98uM ADP stimulation measured by light transmission aggregometry, and additional agonists and stimulation doses were used for sensitivity. Linear regression models adjusted for age, sex, race, CVD risk, and the use of platelet modifying treatments (PMT) were used. Interactions with the same covariates were also examined. Data from the FHS Gen2 Cohort containing platelet aggregation and ApoE status was used for validation.ResultThe final primary sample included 3,169 participants (median [Q1, Q3] age, 55 [48, 61]; 54.2% women) of which 22.1% were on PMT. (Table 1). 716 (22.6%) were ApoE4 positive and 402 were E2 (16.4% of the sample after excluding E4). Being an ApoE4 carrier was not associated with platelet aggregation (β±SE: 0.41±1.05, P>0.05). ApoE2 was also not associated (‐0.72±1.33, P>0.05) (Figure 1). No associations with the secondary outcomes or interactions with covariates were detected. No associations were observed in the external validation cohort (n = 2,469)ConclusionOur results in a middle‐aged cohort indicate that the ApoE genotypes (E2 and E4) are not associated with platelet aggregation. The pathways leading to increased vascular dysfunction in ApoE4 carriers may not involve platelet activity, at least in midlife

Genotype specific microbiome divergence of humanized APOE 2, 3, and 4 mice after microbiome standardization

AbstractBackgroundApolipoprotein E (ApoE) is a lipid cargo binding protein that has three variants in humans, ApoE 2, 3, and 4. The ApoE 4 allele is the greatest known genetic factor for sporadic Alzheimer’s Disease. The gut microbiome (GMB) is a key essential to health, and bacterial dysbiosis can lead to poorer outcomes for disease states and an increase in microbiota and their metabolites in the peripheral. The intersection of sex, ApoE, inflammation, and gut microbiota is incompletely understood. Previous studies in humans and humanized APOE mice have demonstrated APOE‐genotype differences in the GMB. However, the vast majority of these studies used methods unable to resolve the bacteria to the genus or species level. It remains unknown if APOE genotype is a driver of GMB divergence over time and how GMB changes with age and sex in the context of APOE genotype.MethodsIn this study, humanized targeted replacement mice with either APOE 2, 3, or 4 (APOE‐TR) were purchased from JAX. Each APOE‐TR male was bred with one of the same two C57BL/6 sisters to standardize microbiomes across lines and monitor divergence based on APOE allele inheritance. Stool samples were collected from the parents at breeder set up and 6 months old and from heterozygous pups at wean, and 6 months old and will be collected every 6 months, including from the homozygous F2 generation. Stool was assessed via shallow shotgun sequencing to increase the sequencing depth and enable species and strain level taxonomic resolution.ResultsThe pup’s microbiome resembled each other at wean despite genotype. However, by 6 months old, GMB diverged based on sex and APOE genotype, with genotype‐specific alterations including changes in Lachnospiraceae (p<0.001 by PERMANOVA).ConclusionsThese are the first data demonstrating GMB divergence over time driven by APOE genotype. Studying genotype specific changes in GMB and how specific APOE‐specific bacteria impact inflammatory responses can aid in understanding and potentially treating some of the underlining diseases associated ApoE 4 allele including cardiovascular disease and Alzheimer’s Disease (AD).

Role of ApoE polymorphism in Dementia

AbstractBackgroundApoE polymorphism especially APOE ε4 play a central role in AD pathophysiology through Aβ‐dependent and Aβ‐independent neuropathogenic pathway in the Alzheimer’s disease.MethodA cross‐sectional study was performed on non diseased and diseased subjects with stroke from outpatient services of Neurology department of Institute of Human Behavior & Allied Sciences (IHBAS), New Delhi (India). Subjects diagnosed with various dementias including Alzheimer’s disease, non AD dementias and dementia with Behavior & Psychological symptoms were taken. APOE genotyping was done in all subjects by ARMS‐PCR method.ResultThe most common allele APOE ε3ε3 was observed across all dementia groups (AD, non AD dementia. Dementia with BPSD & forgetfulness, whereas ε2ε4 was least commonly observed. Multivariable logistic regression analysis showed that the presence of APOE ε4 genotyping is significantly increasing the risk of AD three times more as compared to other alleles (Adjusted Odds Ratio: 3.07, 95% CI: 1.39 ‐ 6.78). The age and gender did not emerge out as significant contributors in AD. In group of AD with BPSD, the most common Behavior & Psychological symptoms observed was paranoid & delusional ideation.ConclusionAPOE ε4 is a risk factor for Alzheimer's disease.

A DAT1 gene and APOE ε4 interaction is associated with apathy and structural brain changes in mild cognitive impairment and Alzheimer's disease.

Apathy in patients with Alzheimer's disease (AD) is associated with significant morbidity and is often one of the first neuropsychiatric symptoms to present in mild cognitive impairment (MCI). Apathy is associated with accelerated cognitive decline and atrophy in fronto-striatal regions of the brain. Previous work has shown a link between apathy and the APOE gene in the context of AD, as the APOE ε4 allele is already known to be associated with the onset of AD. However, other genetic associations with apathy are largely unexplored. To examine whether interactions between genetic variants related to neurotransmitter systems and regional brain atrophy are associated with apathy in patients with MCI and AD. In a sample of individuals with AD (n = 266), MCI (n = 518), and cognitively normal controls (n = 378), a partial least squares correspondence analysis modeled interactions between single nucleotide polymorphisms, structural whole-brain imaging variables, and apathy. An interaction was found between apathy, the possession of an APOE ε4 allele combined with minor homozygosity for the DAT1 (dopamine transporter 1) gene, and regional brain atrophy. This interaction was closely linked to the MCI and AD groups. The results point to an association of a dopaminergic genetic marker and apathy in the AD continuum and may inform future design of clinical trials of apathy, as well as new treatment targets.

Prevalence of ApoE Alleles in a Spanish Population of Patients with a Clinical Diagnosis of Alzheimer's Disease: An Observational Case-Control Study.

Background and Objectives: Alzheimer's dementia is a progressive neurodegenerative disease that affects memory abilities due to genetic and environmental factors. A well-known gene that influences the risk of Alzheimer's disease is the apolipoprotein E (APOE) gene. The APOE gene is involved in the production of a protein that helps transport cholesterol and other types of fat in the bloodstream. Problems in this process are thought to contribute to the development of Alzheimer's disease. APOE comes in several forms, which are called alleles (ε2, ε3, ε4). Materials and Methods: Therefore, our study aims to identify those subjects with a higher genetic risk through the polymorphism of the APOE gene, using a population screening in patients with a clinical diagnosis of AD in a region of Spain, Castilla y León, as potential biomarkers and to identify individuals at increased genetic risk by polymorphism of the APOE gene. An observational case-control study was conducted in Castilla y León (Spain). Saliva samples were collected and the ApoE gene was analyzed by PCR and agarose gel electrophoresis, respecting ethical criteria. Results: In the Alzheimer's population in Castilla y León, a high prevalence of ApoE3 (74%) was found, followed by ApoE4 (22%); in addition, a higher presence of the ε4 allele was found in the Alzheimer's disease (AD) group than in the control group. It was also observed that the ε2/ε2 genotype was not found in any individual with AD but was found in healthy subjects and that the opposite was observed for the ε4/ε4 genotype. The odds ratio (OR) indicated a risk four times greater of having AD if having the ε4 allele. Conclusions: The demonstrated relation between the different isoforms and the likelihood of developing AD has led to its consideration as a biomarker and a potential pre-symptomatic therapy. The molecular mechanisms that confer a disruptive and protective role to ApoE4 and ApoE2, respectively, are still being studied.

Factors associated with unfavorable outcomes in older patients with traumatic brain injury: analysis from the "All of Us" research program.

Traumatic brain injury (TBI) afflicts approximately 70 million people worldwide annually, with patients aged 65 years and older accounting for an increasing proportion of TBI patients. Older patients also experience increased morbidity and mortality post-TBI compared to their younger counterparts. Nevertheless, clinical trials often exclude older TBI patients, and age-specific TBI treatment is lacking. We hypothesized that the APOE genotype and age-associated comorbidities, such as heart disease, are associated with unfavorable outcomes following TBI in older patients. We utilized a dataset from the "All of Us research" (AoU) to study this vulnerable population post-TBI. Launched by the National Institutes of Health (NIH), AoU is a nationwide prospective cohort study aiming to enroll 1 million or more individuals by emphasizing traditionally underrepresented populations in the United States. We defined patients diagnosed with post-concussion syndromes (PCS) as those with unfavorable TBI outcomes, and we also assessed the associations between PCS observed in older patients and different comorbidities variables/APOE genotypes via multiple logistic regression models. Consequently, APOE ε4 allele was strongly associated with PCS in patients aged 65 and older. Our findings provide direct evidence for developing better predictive tools and potentially improving the clinical guidance and management of older adults with TBI.

Abstract 4137155: Relationship between Subclinical Myocardial Injury and Global Cognitive Performance: The Multi-Ethnic Study of Atherosclerosis (MESA)

Background: With demographic trends transitioning towards older adults, dementia and cognitive impairment are predicted to increase dramatically. We aim to elucidate the relationship between subclinical myocardial injury, as indicated by asymptomatic increased levels of high-sensitivity cardiac Troponin (hs-cTnT), and cognitive performance. Methods: We studied MESA participants from Exam 1 (2000-02) to Exam 6 (2016-18), categorizing them based on baseline hs-cTnT at Exam 1. Cognitive decline was defined as a decrease of ≥5 units in CASI between Exam 5&6. We used Pearson correlation and linear regression to analyze the association of hs-cTnT levels with CASI scores, and logistic regression to examine the association with cognitive decline. We also explored the relationship between different hs-cTnT categories and cognitive measures. Models were adjusted for demographics, lifestyle, APOE status, comorbidities, and medication use ( Figure ). Results: 4445 participants had both baseline hs-cTnT and valid Exam 5 CASI scores while only 1776 participants had valid Exam 6 CASI scores. Cohort was predominantly female (53%), mean age of 60 years, and 27% had at least one APOE e4 allele. Median hs-cTnT was 6.32 ng/L, and median CASI scores were 89 at Exam 5 and 91.5 at Exam 6. We found a negative correlation between the log-hs-cTnT at Exam 1 and Exam 5 with CASI scores at Exam 5. An increase of one unit in log-hs-cTnT level was associated with a decrease of 0.67 (CI -1.17, -0.17) in CASI and corresponded to higher odds (OR: 1.44; CI 1.05-1.95) of cognitive decline, after adjusting for covariates. When comparing various categories of hs-cTnT with category 1, we observe that the odd of cognitive decline increases as the category increases. However, this trend does not hold for category 5 with significantly lower sample size ( Figure ). Conclusion: Our findings indicate an inverse relationship between hs-cTnT and cognitive function years later, which is significantly attenuated by known risk factors for cognitive decline. Further research is needed to determine hs-cTnT as a predictor of future global cognitive functions.

DNA methylation biomarkers for cumulative lead exposures and cognitive impairment

Recent evidence suggests that cumulative low-level lead exposure has adverse effects on cognitive function in the elderly. To date, the few studies that have measured bone lead exposure relied on K-X-ray fluorescence (KXRF), methods that are mostly unavailable in large community-based studies. Here, we employ a methylation-based estimation method for bone and blood lead in the Alzheimer's Disease Neuroimaging Initiative (ADNI) cohort. Tibia, patella, and blood lead levels were estimated using blood DNA methylation (DNAm) biomarkers in 625 participants from the ADNI cohort. Cognitive function was assessed using the Montreal Cognitive Assessment (MoCA). Longitudinal analyses were conducted using linear mixed-effect regression models. Participants had different years of baseline (2010-2014) and follow-up visits (2014-2015). DNAm derived tibia and patella lead levels were negatively associated with MoCA scores throughout follow-up, while DNAm derived blood lead level was not associated with MoCA scores. On average, we observed lower MoCA scores with increasing DNAm tibia lead (per interquartile range (IQR): β=-0.23; 95% CI: -0.44, -0.03) and DNAm patella lead, albeit the latter was weaker (per IQR: β=-0.19; 95% CI: -0.41, 0.04). When stratifying by gender, women showed a stronger decrease in cognitive function with increasing DNAm tibia lead (per IQR β=-0.34; 95% CI: -0.65, -0.04) than men (per IQR β=-0.15; 95% CI: -0.42, 0.13). The estimated decrease in MoCA scores per DNAm tibia lead IQR increase was stronger among participants with one or two APOE4 alleles (per IQR β=-0.37; 95% CI: -0.74, -0.01) than those with zero alleles (per IQR β=-0.14; 95% CI: -0.38, 0.10). These findings strengthen the evidence that cumulative long-term lead exposure levels are associated with decreased cognitive function in the elderly, especially among women and carriers of one or two APOE4 alleles. These findings based on whole blood methylation data corroborate previous epidemiologic studies that used KXRF for measuring bone lead.

Facial aging, cognitive impairment, and dementia risk

BackgroundFacial aging, cognitive impairment, and dementia are all age-related conditions. However, the temporal relation between facial age and future risk of dementia was not systematically examined.ObjectivesTo investigate the relationship between facial age (both subjective/perceived and objective) and cognitive impairment and/or dementia risk.MethodsThe study included 195,329 participants (age ≥ 60 y) from the UK Biobank (UKB) with self-perceived facial age and 612 participants from the Nutrition and Health of Aging Population in China Project (NHAPC) study (age ≥ 56 y) with objective assessment of facial age. Cox proportional hazards model was used to prospectively examine the hazard ratios (HRs) and their 95% confidence intervals (CIs) of self-perceived facial age and dementia risk in the UKB, adjusting for age, sex, education, APOE ε4 allele, and other potential confounders. Linear and logistic regressions were performed to examine the cross-sectional association between facial age (perceived and objective) and cognitive impairment in the UKB and NHAPC, with potential confounders adjusted.ResultsDuring a median follow-up of 12.3 years, 5659 dementia cases were identified in the UKB. The fully-adjusted HRs comparing high vs. low perceived facial age were 1.61 (95% CI, 1.33 ~ 1.96) for dementia (P-trend ≤ 0.001). Subjective facial age and cognitive impairment was also observed in the UKB. In the NHAPC, facial age, as assessed by three objective wrinkle parameters, was associated with higher odds of cognitive impairment (P-trend < 0.05). Specifically, the fully-adjusted OR for cognitive impairment comparing the highest versus the lowest quartiles of crow’s feet wrinkles number was 2.48 (95% CI, 1.06 ~ 5.78).ConclusionsHigh facial age was associated with cognitive impairment, dementia and its subtypes after adjusting for conventional risk factors for dementia. Facial aging may be an indicator of cognitive decline and dementia risk in older adults, which can aid in the early diagnosis and management of age-related conditions.

AAVrh.10 delivery of novel APOE2-Christchurch variant suppresses amyloid and Tau pathology in Alzheimer’s disease mice

Gene therapy to treat hereditary disorders conventionally delivers the normal allele to compensate for loss-of-function mutations. More effective gene therapy may be achieved using a gain-of-function variant. We tested the hypothesis that AAVrh.10-mediated CNS delivery of the human APOE2 allele with the Christchurch mutation (R136S) (E2Ch) will provide superior protection against APOE4-associated Alzheimer's disease (AD) in mice compared to the unmodified APOE2 allele(E2). The vectors were assessed in two mouse strains with humanized APOE4: APP.PSEN1/TRE4 "amyloid mice" and P301S/TRE4, "tau mice." Both the E2Ch and E2 vectors prevented Aβ42 and Aβ40 accumulation and decreased β-amyloid aggregates in amyloid mice, but only the E2Ch vector suppressed tau tangles in tau mice. Microglial activation and reactive astrocytes were significantly suppressed by both vectors in amyloid mice but only the E2Ch vector mediated significant suppression of Iba1 and glial fibrillary acidic protein (GFAP) in tau mice. In four behavioral assays, the E2 and E2Ch vectors had similar benefits in amyloid mice, but E2Ch outperformed E2 in tau mice. In summary, while E2 is effective in suppressing amyloid pathology, the novel E2 variant E2Chmore effectively treats both the amyloid and tau pathology of murine AD inAPOE4 background, supporting the development of AAVrh.10APOE2Ch as a therapy for APOE4-associated AD.

Anthropometric and Demographic Features Affect the Interpretation of Cerebrospinal Fluid Biomarkers in Patients with Different Dementia Syndromes and Cognitively Healthy Adults.

Clinical distinction between dementia with Lewy bodies (DLB) and late-onset Alzheimer's disease (AD) is difficult, while several features might affect the analyses of biomarkers. This study aimed to verify associations of anthropometric and demographic features with cerebrospinal fluid biomarkers, their ratios, and restructured traditional regression formulas in patients with DLB and AD, as well as in cognitively healthy controls. Consecutive outpatients with DLB were paired with outpatients with AD according to sex, dementia stage, and cognitive status, and with controls according to sex and age to investigate associations of sex, age, dementia duration, total sleep time, body mass index, alcohol use, smoking, sanitation, and APOE-ε4 alleles on the measurement of cerebrospinal fluid α-synuclein, biomarker ratios, and restructured traditional regression formulas involving amyloid-β (Aβ42,Aβ40,Aβ38), tau, and phospho-tau Thr181. Overall, 81 participants were included with DLB (n = 27;11 APOE-ε4 +) or AD (n = 27;12 APOE-ε4 +), and controls (n = 27;4 APOE-ε4 +); two thirds were women. Cerebrospinal fluid evidence of amyloidosis and tauopathy was more prevalent among women with AD, while Aβ42/Aβ38 could also discriminate men with DLB from men with AD. Restructured traditional regression formulas had higher diagnostic accuracy for women with AD. Aging, higher body mass index, and APOE-ε4 alleles were associated with amyloidosis in DLB, while only in AD were higher body mass index associated with lower tau pathology load, and more alcohol use associated with higher phospho-tau Thr181/Aβ42. These findings confirm the effects of anthropometric and demographic features on cerebrospinal fluid biomarkers, and also differences in aberrant amyloidosis and tauopathy between DLB and AD.

Association of polymorphism of apolipoprotein e gene with acute myocardial infarction and its short term clinical outcome

Abstract Background/Introduction Myocardial infarction (MI) is a multifactorial disease influenced by environmental and genetic factors. Apolipoprotein E (ApoE) is a protein incorporated into serum lipoproteins directing their catabolism via binding to receptors. It is a structural component of both chylomicrons and very low density lipoprotein (VLDL) remnants. ApoE is thought to play a central role in atherosclerosis by participating in overall plasma cholesterol homeostasis. In addition to other classical risk factors, positive family history of cardiovascular disease (CVD) has been found to be significantly and independently associated with MI in epidemiological studies (1). Besides traditional cardiovascular risk factors it is likely that additional genetic factors like ApoE gene polymorphism may interact with environmental factors to determine overall cardiovascular risk of an individual to develop MI. Purpose The purpose of our study was to determine the risk of association of variants of ApoE gene with Acute Myocardial Infarction. Moreover, we also wanted to study the impact of ApoE gene polymorphism in short term major adverse cardiac events (MACE) in patients with MI not willing for coronary intervention. Methods In this case control study a total of 200 consecutively admitted AMI patients admitted to the coronary care unit of our hospital were enrolled to the study along with 200 age and gender matched controls admitted during the same time period . ApoE gene polymorphism was detected by DNA extraction, DNA amplification by PCR in a DNA thermal cycler followed by restriction enzyme digestion(2). Chi square test was used to investigate the difference in genotype and allele frequencies in casend controls and also between observed and expected frequencies in the realm of Hardy-Weinberg equilibrium. Odds Ratio (OR) with 95 % confidence interval and p values were calculated while analysing the association of different genotypes of ApoE genetic polymorphism with the disease and MACE. Logistic regression analysis was carried out amongst the groups under consideration to find the unadjusted OR and adjusted OR of the genotypes in relation to the disease.p&amp;lt;0.05 was considered as significant Analysis was done in SPSS software. Results Besides the traditional risk factors Apo E4 allele (OR 2.298, CI 1.305-4.044 ) and Apo E3/E4 genotype (OR 2.116, CI 1.008-4.443, p=0.048) showed strong of association with the disease. There was a higher population of Apo E3/E4 genotypes and Apo E2/E3 genotypes with MACE events (25.6% and 28.6%), while the common ApoE3/E3 genotypes had a MACE event of 10.5 %. However, the difference was not significant (p=0.071, Χ 2 =8.63 df =4). Similarly, ApoE4 allele showed a non significantly higher MACE events (p=0.22, Χ 2 =3.01 df =4) Conclusion ApoE4 allele and ApoE3/E4 genotype are strongly and independently associated with AMI.RISK FACTORS AND RISK OF MIGenotype and MACE

African origin haplotype protective for Alzheimer's disease in APOEε4 carriers: exploring potential mechanisms.

APOEε4 is the strongest genetic risk factor for Alzheimer's disease (AD) with approximately 50% of AD patients carrying at least one APOEε4 allele. Our group identified a protective interaction between APOEε4 with the African-specific A allele of rs10423769, which reduces the AD risk effect of APOEε4 homozygotes by approximately 75%. The protective variant lies 2Mb from APOE in a region of segmental duplications (SD) of chromosome 19 containing a cluster of pregnancy specific beta-1 glycoprotein genes (PSGs) and a long non-coding RNA. Using both short and long read sequencing, we demonstrate that rs10423769_A allele lies within a unique single haplotype inside this region of segmental duplication. We identified the protective haplotype in all African ancestry populations studied, including both West and East Africans, suggesting the variant has an old origin. Long-read sequencing identified both structural and DNA methylation differences between the protective rs10423769_A allele and non-protective haplotypes. An expanded variable number tandem repeat (VNTR) containing multiple MEF2 family transcription factor binding motifs was found associated with the protective haplotype (p-value = 2.9e-10). These findings provide novel insights into the mechanisms of this African-origin protective variant for AD in APOEε4 carriers and supports the importance of including all ancestries in AD research.