ApoE Research Articles

Lumipulse-Measured Cerebrospinal Fluid Biomarkers for the Early Detection of Alzheimer Disease.

CSF biomarkers of Aβ42 and phosphorylated tau (p-tau181) are used clinically for the detection of Alzheimer disease (AD) pathology during life. CSF biomarker validation studies have largely used clinical diagnoses and/or amyloid PET imaging as the reference standard. The few existing CSF-to-autopsy studies have been restricted to late-stage AD. This CSF-to-autopsy study investigated associations between CSF biomarkers of AD and AD neuropathologic changes among brain donors who had normal cognition at the time of lumbar puncture (LP). This was a retrospective study of brain donors from the National Alzheimer's Coordinating Center who had normal cognition at the time of LP and who had measurements of CSF Aβ42 and p-tau181 performed with Lumipulse assays. All brain donors were from Washington University Knight ADRC. Staging of AD neuropathologic change (ADNC) was made based on National Institute on Aging-Alzheimer's Association criteria. For this study, participants were divided into 2 categories: "AD-" (no AD/low ADNC) and "AD+" (intermediate/high ADNC). Accuracy of each biomarker for discriminating AD status was evaluated using area under the curve (AUC) statistics generated using predicted probabilities from binary logistic regressions that controlled for age, sex, APOE ε4, and interval between LP and death. The average age at LP was 79.3 years (SD = 5.6), and the average age at death was 87.1 years (SD = 6.5). Of the 49 brain donors, 24 (49%) were male and 47 (95.9%) were White. 20 (40.8%) had autopsy-confirmed AD. The average interval from LP until death was 7.76 years (SD = 4.31). CSF p-tau181/Aβ42 was the optimal predictor of AD, having excellent discrimination accuracy (AUC = 0.97, 95% CI 0.94-1.00, p = 0.003). CSF p-tau181 alone had the second-best discrimination accuracy (AUC = 0.92, 95% CI 0.84-1.00, p = 0.001), followed by CSF Aβ42 alone (AUC = 0.92, 95% CI 0.85-1.00, p = 0.007), while CSF t-tau had the numerically lowest discrimination accuracy (AUC = 0.87, 95% CI 0.76-0.97, p = 0.005). Effects remained after controlling for prevalent comorbid neuropathologies. CSF p-tau181/Aβ42 was strongly associated with CERAD ratings of neuritic amyloid plaque scores and Braak staging of NFTs. This study supports Lumipulse-measured CSF Aβ42 and p-tau181 and, particularly, the ratio of p-tau181 to Aβ42, for the early detection of AD pathophysiologic processes. This study provides Class II evidence that Lumipulse measures of p-tau181/Aβ42 in the CSF accurately discriminated cognitively normal participants with and without Alzheimer disease neuropathologic change.

Cerebral Amyloid Angiopathy, Dementia, and Alzheimer Neuropathologic Changes: Findings From the ACT Autopsy Cohort.

Cerebral amyloid angiopathy (CAA) is common in older adults and is associated with dementia. Less is known whether this association is mediated by Alzheimer disease (AD) neuropathologic changes, the examination of which was the objective of this study. This was a retrospective cross-sectional examination of the Kaiser Permanente Washington database of the Adult Changes in Thought (ACT) autopsy cohort with information on CAA, dementia, the Consortium to Establish a Registry for Alzheimer's Disease (CERAD) (amyloid neuritic plaques), and Braak (tau neurofibrillary tangles). CAA was diagnosed by immunohistochemistry and dementia by ACT Consensus Diagnostic Conference. AD neuropathology was categorized by CERAD scores and Braak stages. Multivariable logistic regression models were used to estimate odds ratios (ORs) and 95% CIs of the associations of CAA with dementia, adjusting for age at death and sex, and with additional adjustments separately for CERAD scores (moderate-severe vs mild-absent), Braak stages (V-VI vs 0-IV), APOE ε4, and stroke. Formal mediation analyses were conducted to estimate age-sex-adjusted OR (95% CI) for natural indirect effects (NIEs) of CERAD scores and Braak stages. The 848 participants had a mean age of 86.7 ± 4.6 years at death, and 57.6% were female. CAA was present in 322 participants (38.0%), of whom 152, 145, and 25 had mild, moderate, and severe CAA, respectively. Dementia was present in 384 participants (45.3%), of whom 317 had AD. Dementia was more common in those with CAA than without (53.7% vs 40.1%; age-sex-adjusted OR 1.57, 95% CI 1.18-2.10). This association remained significant after separate adjustment for other covariates but lost significance when adjusted for CERAD scores (OR 1.27, 95% CI 0.93-1.71) and Braak stages (OR 0.96, 95% CI 0.69-1.33). Findings from our formal mediation analyses show that ORs (95% CIs) for NIE of CERAD scores and Braak stages were 1.25 (1.13-1.37) and 1.63 (1.38-1.88), respectively, and CERAD scores and Braak stages mediated 53% and 111% of the total association, respectively. We observed a significant association between CAA and dementia that disappeared when adjusted for CERAD or Braak stages. Findings from our mediation analyses suggest that the CAA-dementia association may be potentially mediated by AD neuropathologic changes. This hypothesis needs to be tested in future mechanistic studies in AD accounting for unmeasured confounders.

Effects of COVID-19 virus-like particles on the behavioral and cognitive performance of human apolipoprotein E targeted replacement mice

IntroductionThe effects of viral infections might be apolipoprotein E (apoE) isoform-dependent. In humans, there are three major apoE isoforms, E2, E3, and E4. E4 is associated with the enhanced entry of several viruses into the brain and their disease progression. A concern of infection by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the development of post-acute COVID-19 syndrome, also known as long COVID. Genetic risk factors for developing long COVID were reported.MethodsIn this study, we used virus-like particles (VLPs) that include expression of the SARS-CoV-2 nucleocapsid (N), membrane (M), and envelope (E) structural proteins together with S. In the current study, we used human E2, E3, and E4 targeted replacement mice to assess whether these VLPs affect body weight, behavioral and cognitive performance, and circadian body temperatures. Using VLPs allow working outside an ABSL-3 facility.ResultsThe effects of VLPs on some behavioral measures were apoE isoform-dependent, with the E2 mice being more affected than E3 or E4 mice. The overall decreased activity in the open field containing objects in week 2 indicate that VLPs can also reduce activity levels in an apoE isoform-independent fashion.DiscussionThe results of the current study indicate that even in the absence of viral replication, detrimental effects of VLPs on behavioral measures and circadian body temperatures are seen.

Cognitive Intra-individual Variability in Cognitively Healthy APOE ε4 Carriers, Mild Cognitive Impairment, and Alzheimer's Disease: a Meta-analysis.

Intra-individual variability (IIV) quantifies an individual's scatter in performances across a test battery (dispersion) or across reaction times within a single task (consistency). No studies have meta-analyzed the cross-sectional IIV literature in those with mild cognitive impairment (MCI) and Alzheimer's dementia (AD). An additional aim of this meta-analysis was to examine IIV in APOE ε4 + healthy control (HC) samples. A systematic search strategy was applied to six databases (Academic Search Complete, PsycINFO, MEDLINE, CINAHL Complete, ERIC, and ProQuest Dissertations & Theses) to identify studies comparing the extent of dispersion- and consistency-based cognitive IIV between clinical (MCI, AD) and HC samples. Thirty-five studies met the inclusion criteria for our random-effects cross-sectional meta-analysis. Hedges' g was used to aggregate between-group effect sizes, with higher positive values indicating clinical > HC IIV. Meta-regression and subgroup-analyses were conducted to evaluate continuous and categorical moderator variables, respectively. Omnibus models yielded analogous moderate-strength, albeit heterogeneous, effects for dispersion and consistency (g = 0.65). Clinical severity was a robust moderator of dispersion (MCI = 0.47, AD = 1.16) and consistency (MCI = 0.51, AD = 1.31) effects. Supplemental analysis of APOE ε4 status in HCs revealed a nonsignificant trend of elevated overall (i.e., dispersion + consistency) IIV in APOE ε4 + vs. APOE ε4 - HC samples (g = 0.24). Cognitive IIV is sensitive to the presence of AD-related genetic risk as well as neurocognitive impairment across the neurocognitive disorder severity spectrum, with a graded-pattern of HC < MCI < AD samples.

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

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

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&amp;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.

APOE4 rat model of Alzheimer’s disease: sex differences, genetic risk and diet

The strongest genetic risk factor for Alzheimer’s disease (AD) is the ε4 allele of apolipoprotein E (ApoE ε4). A high fat diet also adds to the risk of dementia and AD. In addition, there are sex differences as women carriers have a higher risk of an earlier onset and rapid decline in memory than men. The present study looked at the effect of the genetic risk of ApoE ε4 together with a high fat/high sucrose diet (HFD/HSD) on brain function in male and female rats using magnetic resonance imaging. We hypothesized female carriers would present with deficits in cognitive behavior together with changes in functional connectivity as compared to male carriers. Four-month-old wildtype and human ApoE ε4 knock-in (TGRA8960), male and female Sprague Dawley rats were put on a HFD/HSD for four months. Afterwards they were imaged for changes in function using resting state BOLD functional connectivity. Images were registered to, and analyzed, using a 3D MRI rat atlas providing site-specific data on 173 different brain areas. Resting state functional connectivity showed male wildtype had greater connectivity between areas involved in feeding and metabolism while there were no differences between female and male carriers and wildtype females. The data were unexpected. The genetic risk was overshadowed by the diet. Male wildtype rats were most sensitive to the HFD/HSD presenting with a deficit in cognitive performance with enhanced functional connectivity in neural circuitry associated with food consumption and metabolism.

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.

APOE ε4 and Dietary Patterns in Relation to Cognitive Function: An Umbrella Review of Systematic Reviews.

Carrying the apolipoprotein ε4 allele (APOE ε4) is the strongest genetic risk factor for late-onset Alzheimer's disease. There is some evidence suggesting that APOE ε4 may modulate the influence of diet on cognitive function. This umbrella review of systematic reviews evaluates the existing literature on the effect of dietary interventions on cognitive and brain-imaging outcomes by APOE status. PubMed, EMBASE, Web of Science, and Scopus were searched using terms appropriate to each area of research, from their respective starting dates of coverage until March 2023. Two independent reviewers conducted data extraction and performed a quality appraisal using the Measurement Tool to Assess Systematic Reviews (AMSTAR) 2. Six total reviews were included in the final analysis. Four reviews evaluated randomized controlled trials on individuals aged 50-93 years ranging the entire cognitive continuum. One review combined observational studies and clinical trials conducted on both cognitively healthy and cognitively impaired individuals (age range: 50-90), and 1 review included observational studies of both cognitively healthy and cognitively impaired adults (age range: 50-75). Both observational studies and clinical trials yielded inconclusive results attributed to both practical limitations associated with longitudinal follow-up and issues of methodological quality. Except for the Mediterranean diet, dietary interventions, such as the ketogenic diet, nutraceuticals, and supplements, were generally not effective in older APOE ε4 carriers. This review considers plausible biological mechanisms that might explain why older and cognitively impaired APOE ε4 carriers were less likely to benefit. This review identifies notable gaps in the literature, such as a shortage of studies conducted in middle-aged and cognitively healthy APOE ε4 carriers assessing the impact of dietary interventions and provides suggestions for novel trial designs.

The Icelandic Mutation (APP-A673T) Is Protective against Amyloid Pathology In Vivo.

A previous epidemiological study in Northern Europe showed that the A673T mutation (Icelandic mutation) in the amyloid precursor protein gene (APP) can protect against Alzheimer's disease (AD). While the effect of the A673T mutation on APP processing has been investigated primarily in vitro, its in vivo impact has not been evaluated. This is mainly because most existing AD mouse models carry the Swedish mutation. The Swedish and Icelandic mutations are both located near the β-cleavage site, and each mutation is presumed to have the opposite effect on β-cleavage. Therefore, in the AD mouse models with the Swedish mutation, its effects could compete with the effects of the Icelandic mutation. Here, we introduced the A673T mutation into App knock-in mice devoid of the Swedish mutation (AppG-F mice) to avoid potential deleterious effects of the Swedish mutation and generated AppG-F-A673T mice. APP-A673T significantly downregulated β-cleavage and attenuated the production of Aβ and amyloid pathology in the brains of these animals. The Icelandic mutation also reduced neuroinflammation and neuritic alterations. Both sexes were studied. This is the first successful demonstration of the protective effect of the Icelandic mutation on amyloid pathology in vivo. Our findings indicate that specific inhibition of the APP-BACE1 interaction could be a promising therapeutic approach. Alternatively, the introduction of the disease-protective mutation such as APP-A673T using in vivo genome editing technology could be a novel treatment for individuals at high risk for AD, such as familial AD gene mutation carriers and APOE ε4 carriers.

Is KIBRA polymorphism associated with memory performance and cognitive impairment in Alzheimer's disease?

Genetic variations in a common single nucleotide polymorphism in the ninth intron of the KIBRA gene have been linked to memory performance and risk of Alzheimer's disease (AD). We examined the risk of AD related to presence of KIBRA T allele (versus CC homozygote) and to memory performance. The role of established genetic risk factors APOE ε4 and BDNF Met was also considered. Participants were cognitively healthy individuals (n = 19), participants with amnestic mild cognitive impairment (aMCI) due to AD (n = 99) and AD dementia (n = 37) from the Czech Brain Aging Study. Binary and multinomial logistic regressions compared odds of belonging to a certain diagnostic category and multivariate linear regressions assessed associations with memory. KIBRA T allele was associated with increased AD dementia risk (odds ratio [OR] = 5.98, p = 0.012) compared to KIBRA CC genotype. In APOE ε4 negative individuals, KIBRA T allele was associated with a greater risk of both aMCI due to AD (OR = 6.68, p = 0.038) and AD dementia (OR = 15.75, p = 0.009). In BDNF Met positive individuals, the KIBRA T allele was associated with a greater risk of AD dementia (OR = 10.98, p = 0.050). In AD dementia, the association between KIBRA T allele and better memory performance approached significance (β = 0.42; p = 0.062). The link between possessing the KIBRA T allele and better memory reached statistical significance only among BDNF Met carriers (β = 1.21, p = 0.027). Findings suggest that KIBRA T allele may not fully protect against AD dementia but could potentially delay progression of post-diagnosis cognitive deficits.

Slowing Cognitive Decline in Major Depressive Disorder and Mild Cognitive Impairment

Older adults with major depressive disorder (MDD) or mild cognitive impairment (MCI) are at high risk for cognitive decline. To assess the efficacy of cognitive remediation (CR) plus transcranial direct current stimulation (tDCS) targeting the prefrontal cortex in slowing cognitive decline, acutely improving cognition, and reducing progression to MCI or dementia in older adults with remitted MDD (rMDD), MCI, or both. This randomized clinical trial was conducted at 5 academic hospitals in Toronto, Ontario, Canada. Participants were older adults who had rMDD (with or without MCI, age ≥65 y) or MCI without rMDD (age ≥60 y). Assessments were made at baseline, month 2, and yearly from baseline for 3 to 7 years. CR plus tDCS (hereafter, active) or sham plus sham 5 days a week for 8 weeks followed by twice-a-year 5-day boosters and daily at-home CR or sham CR. The primary outcome was change in global composite cognitive score. Secondary outcomes included changes in 6 cognitive domains, moderating effect of the diagnosis, moderating effect of APOE ε4 status, change in composite score at month 2, and progression to MCI or dementia over time. Of 486 older adults who provided consent, 375 (with rMDD, MCI, or both) received at least 1 intervention session (mean [SD] age, 72.2 [6.4] years; 232 women [62%] and 143 men [38%]). Over a median follow-up of 48.3 months (range, 2.1-85.9), CR and tDCS slowed cognitive decline in older adults with rMDD or MCI (adjusted z score difference [active - sham] at month 60, 0.21; 95% CI, 0.07 to 0.35; likelihood ratio test [LRT] P = .006). In the preplanned primary analysis, CR and tDCS did not improve cognition acutely (adjusted z score difference [active - sham] at month 2, 0.06, 95% CI, -0.006 to 0.12). Similarly, the effect of CR and tDCS on delaying progression from normal cognition to MCI or MCI to dementia was weak and not significant (hazard ratio, 0.66; 95% CI, 0.40 to 1.08; P = .10). Preplanned analyses showed treatment effects for executive function (LRT P = .04) and verbal memory (LRT P = .02) and interactions with diagnosis (P = .01) and APOE ε4 (P < .001) demonstrating a larger effect among those with rMDD and in noncarriers of APOE ε4. The study showed that CR and tDCS, both targeting the prefrontal cortex, is efficacious in slowing cognitive decline in older adults at risk of cognitive decline, particularly those with rMDD (with or without MCI) and in those at low genetic risk for Alzheimer disease. ClinicalTrials.gov Identifier: NCT02386670.

Pharmacogenomics of CRP response to statins: a GIST consortium study

Abstract Introduction Statins are first line treatments in the primary and secondary prevention of cardiovascular disease. Prior clinical studies have shown that statins act independently of lipid lowering mechanisms to decrease C-reactive protein (CRP), a marker of inflammation. Purpose To elucidate genetic loci associated with CRP response to statins. Methods CRP response was specified as the change from baseline in log CRP after at least 4 weeks of statin therapy. Cohort level Genome-wide Association Studies (GWAS) of this CRP response was performed by linear regression analysis adjusted for baseline CRP, age, sex and BMI covariates using genetic data imputed to 1000 Genomes, testing ~10 million single nucleotide polymorphisms (SNPs) of minor allele frequency (MAF) &amp;gt;2%. Following quality control with EasyQC, a meta-analysis was conducted with METAL to combine GWAS results from six different cohorts of European ancestry (CARDS, FHS, JUPITER, MESA, PARC, PROSPER) within the GIST consortium. 1Mb loci regions were defined, centred +/-500kb around the lead SNP. Conditional analysis was performed using GCTA. Results There were 11,075 statin-treated individuals. The meta-analysis results revealed two loci achieving genome wide significance (P&amp;lt;5e-8): APOE (chr 19) and HNF1A (chr 12) (Figure 1). A signal at the CRP locus was highly suggestive (P=2.3e-7). All three loci are known to be associated with CRP levels in the absence of statin. Conditional analysis did not reveal secondary signals. The most associated variant at the APOE locus was the missense SNP rs429358, which contributes to the APOE E4 haplotype and is a risk locus for both dyslipidaemia and Alzheimer’s dementia. It is a C&amp;gt;T missense variant of MAF 0.12 leading to a R/C amino acid change, more common in African ancestry populations (MAF 0.27), and least common in Asian populations (MAF 0.09). A nominally significant association (P=0.09) for interaction with randomized allocation to statin v. placebo within samples derived from clinical trials supports this pharmacogenetic effect at APOE beyond genetic effects on baseline CRP levels. The most associated variant at the HNF1A locus was the intronic SNP rs11065384, which is in strong LD with the HNF1A missense SNP (rs1169288). The HNF1A locus is associated with diabetes, cholesterol levels, and coronary artery disease. There was no between-study heterogeneity at the top three loci (P&amp;gt;0.1), and forest plots show contribution to these signals from all 6 studies within the meta-analysis (Figure 2 A,B,C). Conclusions APOE and HNF1A are associated with CRP response to statins at the level of genome-wide significance. TheAPOE E4 signal is also known to be associated with LDL-Cholesterol response to statins, whereas the HNF1A locus is identified here for the first time as a pharmacogenetic determinant of statin response. The effect of this interindividual variability in CRP response on non-cardiovascular clinical outcomes should be elucidated.Figure 1Figure 2 A,B,C

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.

Unraveling the proteomic signatures of coronary artery disease and hypercholesterolemia.

Atherosclerosis, a leading cause of coronary artery disease (CAD), is heavily influenced by hypercholesterolemia (HC). Proteomics research has shown promise in identifying biological markers for CAD diagnosis and prognosis. This cross-sectional study aimed to identify novel biomarkers for detecting HC and CAD. Through the analysis of proteome data from healthy controls (n=45) and patients diagnosed with HC (n=51) or CAD (n=32), distinct protein patterns associated with each condition were identified. Significant alterations in protein levels were identified with a false discovery rate (FDR)-corrected q-value of <0.05. Subsequent receiver operating characteristic (ROC) analysis, with an area under the curve (AUC) greater than 0.75, was conducted. CAD patients exhibited significantly increased levels of the cholesterol-metabolizing protein PCSK9 and varied levels of the angiogenesis-related protein SDF-1 compared to controls. In pairwise comparisons among the study groups, 65 proteins showed significant differential expression. Notably, 14 of these proteins had significant correlations with blood cholesterol levels. Additionally, 22 of the identified proteins were associated with CAD or HC pathways, with nine proteins being common to both conditions (Apo E, Apo E3, MMP-3, PCSK9, SDF-1, Apo B, PAFAH, HSP 60, and TAK1-TAB1). Nevertheless, this is an exploratory study, and validation studies are needed to confirm these potential protein biomarkers for CAD in the context of HC.

The Association Between Constipation and Positron Emission Tomography and Blood-Based Biomarkers in Older Cognitively Unimpaired Adults with Higher Amyloid-β Burden.

Constipation may be linked to cognitive decline and a higher risk of Alzheimer's disease (AD). We aimed to investigate the association between constipation and positron emission tomography (PET) and blood-based AD biomarkers in older cognitively unimpaired (CU) adults with higher Aβ burden. Constipation was diagnosed according to Rome IV criteria and the severity of constipation was evaluated by using a validated self-reported questionnaire. The participants underwent the examination of plasma AD biomarkers and 18F-florbetapir PET and 18F-MK6240 PET scans; the latter was only performed in the validation cohort. Correlation and multiple linear regression analyses were used to investigate the association between constipation and AD biomarkers. Two cohorts were included in our study. A total of 404 older participants with 126 of whom Aβ-PET positive were enrolled in the development cohort. Multiple linear regression analysis showed constipation was associated with plasma t-Tau, p-Tau-181, and neurofilament light chain (NfL) in participants with Aβ-PET (+). Meanwhile, no/mild constipation was associated with lower Aβ-PET standard uptake value ratio. The association between constipation and plasma biomarkers was different in the subgroups stratified by age, sex and APOE ε4 genotype. The above associations were further validated in the validation cohort containing 36 Aβ-PET (+) participants. Importantly, no/mild constipation was associated with lessTau burden evaluated by 18F-MK6240 PET Braak stages. Our data indicate that no/mild constipation may be associated with lower plasma t-Tau, p-Tau-181, and NfL as well as less Aβ and Tau burden in older CU adults with Aβ deposition. Improving constipation and being away from defecation disorders may help reduce the risk of AD development.

Whole-genome sequencing study in Koreans identifies novel loci for Alzheimer's disease.

The genetic basis of Alzheimer's disease (AD) in Koreans is poorly understood. We performed an AD genome-wide association study using whole-genome sequence data from 3540 Koreans (1583 AD cases, 1957 controls) and single-nucleotide polymorphism array data from 2978 Japanese (1336 AD cases, 1642 controls). Significant findings were evaluated by pathway enrichment and differential gene expression analysis in brain tissue from controls and AD cases with and without dementia prior to death. We identified genome-wide significant associations with APOE in the total sample and ROCK2 (rs76484417, p=2.71×10-8) among APOE ε4 non-carriers. A study-wide significant association was found with aggregated rare variants in MICALL1 (MICAL like 1) (p=9.04×10-7). Several novel AD-associated genes, including ROCK2 and MICALL1, were differentially expressed in AD cases compared to controls (p<3.33×10-3). ROCK2 was also differentially expressed between AD cases with and without dementia (p=1.34×10-4). Our results provide insight into genetic mechanisms leading to AD and cognitive resilience in East Asians. Novel genome-wide significant associations for AD identified with ROCK2 and MICALL1. ROCK2 and MICALL1 are differentially expressed between AD cases and controls in the brain. This is the largest whole-genome-sequence study of AD in an East Asian population.

APOE 𝜀4-related blood-brain barrier breakdown is associated with microstructural abnormalities.

Blood-brain barrier (BBB) dysfunction occurs in Alzheimer's disease (AD). Yet, the stage at which it appears along the AD time course and whether it contributes to neurodegeneration remain unclear. Older adults (61 to 90 years) from cognitively normal (CN) to mildly cognitively impaired (CI), enriched for APOE 𝜀4 and amyloid positivity, underwent dynamic contrast-enhanced (DCE) magnetic resonance imaging (MRI) and diffusion MRI to measure BBB permeability and brain microstructure. Analysis of variance compared BBB permeability according to cognitive status, amyloid beta (Aβ), and APOE4. Linear regressions assessed associations of BBB permeability with brain microstructure and interactions with Aβ and APOE4. BBB permeability was elevated for APOE4 carriers across the cortical gray matter, with the strongest differences among CN amyloid-negative individuals. Associations between entorhinal BBB permeability and microstructure interacted with Aβ and APOE4, with the strongest relationships in amyloid-positive individuals and APOE4 carriers. APOE4 may drive widespread BBB dysfunction in preclinical AD, which may contribute to neurodegenerative changes early along the AD cascade. Gray matter blood-brain barrier (BBB) permeability is elevated for APOE4 carriers. APOE4-related BBB breakdown appears in the absence of cognitive decline or amyloid. BBB leakage correlates with entorhinal cortex microstructural injury. Associations with microstructure are strongest for amyloid-positive APOE4 carriers.

The Role of Genetics in Neurological Disorders: From Rare Diseases to Common Conditions

Neurological disorders result from neurological diseases affecting the brain, spinal cord and peripheral nerves and include rare genetic diseases like Huntington’s disease and spinal muscular atrophy, as well as common diseases such as Alzheimer’s, Parkinson’s disease and epilepsy. These conditions are strongly influenced by genetics, and genetics contribute to the onset, the progression of the disease, the severity of symptoms and treatment responsiveness. Genetics is relevant not only to inheritance, but also to de novo mutations, polygenic risk factors and gene environment interactions that contribute to the clinical phenotype of these disorders. Although the many mutations and heredity patterns of neurological conditions have not been worked out completely, genetic research has come a long way to help us learn more about these conditions. Single gene mutations are invaluable particularly for rare disorders for early diagnosis and targeted interventions. For instance, predictive gene testing such as checking for the HTT gene mutation linked to Huntington's disease allows people to learn if they are at risk of the disease early on — before their symptoms develop. On the other hand, most common neurological disorders involve genetic landscapes much more complicated, with small increases in risk due to more than one gene. Since epigenetic factors and certain environmental factors can further influence these risks, prevention is always in order. For example, people with APOE ε4 allele are more likely to develop Alzheimer’s disease but lifestyle factors such as dietary and exercise may reduce this risk. Such complexity emphasizes the necessity for complete studies, including genome wide association studies (GWAS), epigenetics, and transcriptomics to define molecular mechanisms of these multifactorial disorders. Genetic testing has recently become one of the most important tools in neurology, allowing us to make early diagnosis with great precision and to offer a comprehensive and personalized treatment plan, based on patients' genetic profile. For instance, these genetic mutations can help physicians choose the best medicines for patients with epilepsy. Gene based therapies, including gene replacement, antisense oligonucleotides (ASOs), and gene editing (e.g., CRISPR-Cas9) are newly emerging as potential treatments for human disease and as a therapeutic for spinal muscular atrophy and Duchenne muscular dystrophy. Indeed, as these therapies become more common, these must be addressed as ethical concerns, such as issues of genetic privacy, risk of genetic discrimination, and unintended consequences of genetic manipulation. The focus of this review is to give a brief but detailed account of the genetic components of neurological disorders, ranging from rare monogenic diseases to common multifactorial disorders. It describes key genetic discoveries and discusses developing genetic diagnostic and therapeutic strategies and the ethical implications related to these developments. The integration of genetic insights directly into clinical practice has the potential to provide a personal roadmap that could lead to individualizing the diagnostic, treatment and prevention approaches for neurological disorders and enhance patient outcomes.