APOE Ε4 Allele Research Articles

Association of PM2.5 Exposure and Alzheimer Disease Pathology in Brain Bank Donors-Effect Modification by APOE Genotype.

Fine particulate matter (PM2.5) exposure has been found to be associated with Alzheimer disease (AD) and is hypothesized to cause inflammation and oxidative stress in the brain, contributing to neuropathology. The APOE gene, a major genetic risk factor of AD, has been hypothesized to modify the association between PM2.5 and AD. However, little prior research exists to support these hypotheses. This study investigates the association between traffic-related PM2.5 and AD hallmark pathology, including effect modification by APOE genotype, in an autopsy cohort. A cross-sectional study was conducted using brain tissue donors enrolled in the Emory Goizueta AD Research Center who died before 2020 (n = 224). Donors were assessed for AD pathology including the Braak stage, Consortium to Establish a Registry for AD (CERAD) score, and combined AD neuropathologic change (ABC) score. Traffic-related PM2.5 concentrations were modeled for the metro-Atlanta area during 2002-2019 with a spatial resolution of 200-250 m. One-year, 3-year, and 5-year average PM2.5 concentrations before death were matched to participants' home address. We assessed the association between traffic-related PM2.5 and AD hallmark pathology and effect modification by APOE genotype, using adjusted ordinal logistic regression models. Among the 224 participants, the mean age of death was 76 years, and 57% had at least 1 APOE ε4 copy. Traffic-related PM2.5 was significantly associated with the CERAD score for the 1-year exposure window (odds ratio [OR] 1.92; 95% CI 1.12-3.30) and the 3-year exposure window (OR 1.87; 95% CI 1.01-3.17). PM2.5 was also associated with higher Braak stage and ABC score albeit nonsignificantly. The strongest associations between PM2.5 and neuropathology markers were among those without APOE ε4 alleles (e.g., for the CERAD score and 1-year exposure window, OR 2.31; 95% CI 1.36-3.94), though interaction between PM2.5 and APOE genotype was not statistically significant. Our study found traffic-related PM2.5 exposure was associated with the CERAD score in an autopsy cohort, contributing to epidemiologic evidence that PM2.5 affects β-amyloid deposition in the brain. This association was particularly strong among donors without APOE ε4 alleles. Future studies should further investigate the biological mechanisms behind this association.

Associations between cardiometabolic multimorbidity and cerebrospinal fluid biomarkers of Alzheimer’s disease pathology in cognitively intact adults: the CABLE study

BackgroundCardiometabolic multimorbidity is associated with an increased risk of dementia, but the pathogenic mechanisms linking them remain largely undefined. We aimed to assess the associations of cardiometabolic multimorbidity with cerebrospinal fluid (CSF) biomarkers of Alzheimer’s disease (AD) pathology to enhance our understanding of the underlying mechanisms linking cardiometabolic multimorbidity and AD.MethodsThis study included 1464 cognitively intact participants from the Chinese Alzheimer’s Biomarker and LifestylE (CABLE) database. Cardiometabolic diseases (CMD) are a group of interrelated disorders such as hypertension, diabetes, heart diseases (HD), and stroke. Based on the CMD status, participants were categorized as CMD-free, single CMD, or CMD multimorbidity. CMD multimorbidity is defined as the coexistence of two or more CMDs. The associations of cardiometabolic multimorbidity and CSF biomarkers were examined using multivariable linear regression models with demographic characteristics, the APOE ε4 allele, and lifestyle factors as covariates. Subgroup analyses stratified by age, sex, and APOE ε4 status were also performed.ResultsA total of 1464 individuals (mean age, 61.80 years; age range, 40–89 years) were included. The markers of phosphorylated tau-related processes (CSF P-tau181: β = 0.165, P = 0.037) and neuronal injury (CSF T-tau: β = 0.065, P = 0.033) were significantly increased in subjects with CMD multimorbidity (versus CMD-free), but not in those with single CMD. The association between CMD multimorbidity with CSF T-tau levels remained significant after controlling for Aβ42 levels. Additionally, significantly elevated tau-related biomarkers were observed in patients with specific CMD combinations (i.e., hypertension and diabetes, hypertension and HD), especially in long disease courses.ConclusionsThe presence of cardiometabolic multimorbidity was associated with tau phosphorylation and neuronal injury in cognitively normal populations. CMD multimorbidity might be a potential independent target to alleviate tau-related pathologies that can cause cognitive impairment.

Speech markers of depression dimensions across cognitive status.

Depression and its components significantly impact dementia prediction and severity, necessitating reliable objective measures for quantification. We investigated associations between emotion-based speech measures (valence, arousal, and dominance) during picture descriptions and depression dimensions derived from the geriatric depression scale (GDS, dysphoria, withdrawal-apathy-vigor (WAV), anxiety, hopelessness, and subjective memory complaint). Higher WAV was associated with more negative valence (estimate=-0.133, p=0.030). While interactions of apolipoprotein E (APOE) 4 status with depression dimensions on emotional valence did not reach significance, there was a trend for more negative valence with higher dysphoria in those with at least one APOE4 allele (estimate=-0.404, p=0.0846). Associations were similar irrespective of dementia severity. Our study underscores the potential utility of speech biomarkers in characterizing depression dimensions. In future research, using emotionally charged stimuli may enhance emotional measure elicitation. The role of APOE on the interaction of speech markers and depression dimensions warrants further exploration with greater sample sizes. Participants reporting higher apathy used more negative words to describe a neutral picture.Those with higher dysphoria and at least one APOE4 allele also tended to use more negative words.Our results suggest the potential use of speech biomarkers in characterizing depression dimensions.

Neuropsychiatric symptoms and ApoE genotype in older adults without dementia: a cross-sectional study.

The ApoE genotype and neuropsychiatric symptoms (NPS) are known risk factors for cognitive decline in older adults. However, the interaction between these variables is still unclear. The aim of this study was to determine the association between the presence of the ApoE ε4 allele and the occurrence of NPS in older adults without dementia. In this cross-sectional investigation we determined the apolipoprotein E (ApoE) genotype of 74 older adults who were either cognitively normal (20.3% / Clinician Dementia Rating Scale (CDR): 0) or had mild cognitive impairment (MCI: 79.7% / CDR: 0.5). We used a comprehensive cognitive assessment protocol, and NPS were estimated by the Neuropsychiatric Inventory-Clinician Rating Scale (NPI-C), Mild Behavioural Impairment-Checklist (MBI-C), Hamilton Rating Scale for Depression (HAM-D), and Apathy Inventory. ApoE ε4 carriers had higher MBI-C total scores than ApoE ε4 noncarriers. Correlations between NPS and ApoE genotype were observed for two NPI-C domains, although in opposite directions: the ApoE ε4 allele was associated with a 1.8 unit decrease in the estimated aberrant motor disturbance score and with a 1.3 unit increase in the estimated appetite/eating disorders score. All fitted models were significant, except for the one fitted for the domain delusions from the NPI-C. Among individuals with amnestic MCI, ε4 carriers presented higher depression score (HAM-D) than noncarriers; in turn, ε4 noncarriers exhibited higher aggression score (NPI-C) than ε4 carriers. Our analyses showed associations between NPS and the presence of the ApoE ε4 allele in two NPI-C domains, despite the sample size. Furthermore, compared to noncarriers, the presence of the ApoE ε4 correlated positively with appetite/eating disorders and negatively with aberrant motor disturbance domain. Examination of the amnestic MCI group displayed significant, although weak, associations. Therefore, ε4 carriers exhibited higher depression scores according to the HAM-D scale compared to ε4 noncarriers. Conversely, ε4 noncarriers had higher scores in the aggression domain of the NPI-C than ε4 carriers.

APOE genotype, eicosapentaenoic acid (EPA) supplementation and n-3 highly unsaturated fatty acid (HUFA) levels in patients with multiple colorectal polyps: A secondary analysis of the seAFOod polyp prevention trial

IntroductionWe examined the relationship between Apolipoprotein E (APOE) genotype and n-3 highly unsaturated fatty acid (HUFA) levels in participants of the seAFOod trial, who were undergoing colonoscopy surveillance after removal of colorectal polyps. MethodsBaseline and on-treatment (eicosapentaenoic acid [EPA] 2 g daily or placebo for 6 months) levels of n-3 HUFAs, and plasma 18-hydroxyeicosapentaenoic acid (HEPE), were analysed according to APOE genotype (based on polymorphisms rs429358 and rs7412) in 584 participants. ResultsBefore treatment, APOE2/2 individuals had lower levels, and APOE4/4 participants had higher levels, of n-3 HUFAs, including EPA, than APOE3/3 counterparts (P < 0.01 for the APOE2/2 versus APOE4/4 comparison). After EPA supplementation, n-3 HUFA levels were not significantly different when stratified by APOE genotype, although APOE4 carriers displayed lower plasma 18-HEPE levels than individuals without an APOE4 allele (P = 0.002). ConclusionsAPOE genotype is associated with differential n-3 HUFA and 18-HEPE levels in individuals with multiple colorectal polyps.

Abstract WP239: Apolipoprotein E4 Allele Effect on the Prevalence of Intracranial Large Artery Stenosis

Introduction: Apolipoprotein E4 (ApoE4) allele is linked to increased LDL-Cholesterol, one of the main risk factors for intracranial large artery stenosis (ICAS). Evidence shows that in diabetic men, intima-media thickness is significantly higher in those with ApoE4 than those with ApoE3. While the link between ApoE4 and extracranial atherosclerosis and vascular risk factors is established, the association of these vascular factors with ICAS is unknown. This study investigates the relationship between ApoE4 carrier status and ICAS and whether vascular risk factors influence this relationship. Methods: We rated intracranial large arteries on MR-angiography for their degree of stenosis as 0=no stenosis, 1=&lt;50% stenosis, 2=50-69%, 3=70% or flow gap. We added the score of each of the 11 intracranial arteries to reflect a composite measure of the severity of ICAS. We then related ApoE4 carrier status to the ICAS score using generalized linear models with a Poisson link, adjusting for demographics, vascular risk factors, and cohort. We ran pre-specified interaction models with demographics and vascular risk factors. Results: 4099 individuals from six cohorts were included; 58% were women, the prevalence of hypertension was 76%, diabetes 31%, dyslipidemia 64%, and current smoking 13% (Table). There was no association between ApoE4 carrier and ICAS score (B= 0.08+0.06, p=0.19), but we found statistical interactions between ApoE4 carrier and male sex (p=&lt;0.001), current smoking (p=0.05), and hypertension (p=0.003). ApoE4 carrier status was associated with higher ICAS score among hypertensive men (B=0.52±0.11, P=&lt;0.001) and hypertensive people who smoke (B=0.58±0.20, p=0.01. Conclusion: ApoE4 carrier status was not associated with ICAS overall, but there were associations in subgroups defined by sex, hypertension, and smoking. Whether these interactions influence the risk of stroke and dementia should be further investigated.

Phenotypic Spectrum of Progressive Supranuclear Palsy: Clinical Study and Apolipoprotein E Effect.

Progressive supranuclear palsy (PSP) is a rare neurodegenerative disorder encompassing several phenotypes with various motor and cognitive deficits. We aimed to study motor and cognitive characteristics across PSP phenotypes and to assess the influence of apolipoprotein E (APOE) gene variants on PSP phenotypic expression. In this 20-year cross-sectional study, we retrospectively reviewed the charts of all patients classified as PSP patients and recategorized them according to phenotype using the Movement Disorder Society criteria (2017). Phenotypes were divided into three subgroups, Richardson's syndrome (PSP-RS), PSP-cortical (PSP with predominant frontal presentation [PSP-F] + PSP with predominant speech/language disorder [PSP-SL] + PSP with predominant corticobasal syndrome [PSP-CBS]) and PSP-subcortical (PSP with predominant parkinsonism [PSP-P] + PSP with progressive gait freezing [PSP-PGF] + PSP with predominant postural instability [PSP-PI] + PSP with predominant ocular motor dysfunction [PSP-OM] + PSP with cerebellar ataxia [PSP-C] + PSP with primary lateral sclerosis [PSP-PLS]), based on clinical presentation during the first 3 years after symptom onset, which defines the early disease stage. Clinical and neuropsychological assessment data were collected. Genotyping of APOE was performed using restriction fragment length polymorphism polymerase chain reaction and verified by Sanger sequencing. We included 112 PSP patients comprising 10 phenotypes classified into 48 PSP-RS, 34 PSP-cortical (PSP-CBS, 17.6%; PSP-F, 9.4%; PSP-SL, 8.2%) and 30 PSP-subcortical (PSP-P, 11.6%; PSP-PI, 8%; PSP-OM, 2.7%; PSP-PGF, 1.8%; PSP-C, 1.8%; PSP-PLS, 0.9%) subgroups. PSP-RS patients were older at disease onset (p = 0.009) and had more akinetic-rigid and levodopa-resistant parkinsonism (p = 0.006), while PSP-cortical patients had more tremors and asymmetric and/or levodopa-responsive parkinsonism (p = 0.025). Cognitive domains were significantly less altered in the PSP-subcortical subgroup. Overall, PSP-APOEε4 carriers developed parkinsonism earlier (p = 0.038), had earlier oculomotor dysfunction (p = 0.052) and had more altered cognitive profiles. The APOEε4 allele was also associated with a younger age of parkinsonism onset in the PSP-RS phenotype group (p = 0.026). This study demonstrated the wide phenotypic spectrum of PSP among Tunisians. Disease onset and akinetic-rigid and levodopa-resistant parkinsonism were the hallmarks of the PSP-RS phenotype, while milder cognitive impairment was characteristic of the PSP-subcortical subgroup. The APOEε4 allele was associated with earlier parkinsonism and oculomotor dysfunction and seemed to play a role in defining a more altered cognitive profile in PSP patients.

Review of the determinants contributing to the demographics of Alzheimer’s syndrome: Prevention techniques, risk factors, and insights for public health

Alzheimer's disease (AD) is the leading cause of memory loss, accounting for 80% of cases and severely impacting daily life and social interactions. The prevalence of AD is expected to grow over the globe as life expectancy improves and the population ages in developing countries will result in a costly disease burden. A combination of societal circumstances and inherent sensitivity that extends throughout a person’s lifetime can cause AD, a challenging and varied disorder. This study aims to provide a comprehensive analysis of the factors that shape the demographics of AD, with a focus on prevention measures. risk factors and their public health consequences. Interventions aimed at addressing multiple risk indicators in non-demented older adults, including those in their middle age, can be able to prevent or postpone the development of AD since the illness is thought to begin generations before clinical evidence appears. Addressing the intricate connection between social and psychological characteristics and Alzheimer’s demography is critical for devising effective preventative measures, early treatments and individualized care for at-risk communities. AD is known to be associated with genetic variables, particularly the APOE ε4 allele. Identifying the disease’s genetic causes is essential for specific preventive and early intervention methods. A balanced diet, frequent physical exercise, cognitive stimulation and social involvement are the preventative treatments for AD. Early identification and intervention hold promise for reducing disease development and public health measures that promote knowledge as well as healthy lives are essential.

Association between body composition and cardiometabolic disease risk: role of dietary fat intake and APOLIPOPROTEIN E genotype on this relationship.

Excess body weight is associated with increased mortality and risk of developing CVD. Body fat distribution is now considered a better indicator of disease risk than BMI, with central adiposity associated with dyslipidaemia and insulin resistance. Dietary modification is unquestionably important in the prevention of obesity and CVD, with the type but not the amount of dietary fat emerging as an important determinant of both diseases. Although reducing SFA intake via replacement with unsaturated fatty acids (UFA) is a key public health strategy for CVD prevention, variability in the lipid lowering response has been observed. This narrative review aims to investigate the link between adiposity and CVD risk, and the role of dietary fat composition and APOLIPOPROTEIN (APO)E genotype on this relationship. In the absence of weight loss, replacing dietary SFA with UFA reduces central adiposity and anthropometric measures, and is linked with lower total and LDL-cholesterol concentrations. However, differences in study populations and body composition techniques need to be taken into consideration. To date, only a limited number of studies have determined the role of APOE on body composition and CVD risk, but findings are inconsistent. Both APOE2 and APOE4 alleles have been correlated with adiposity related markers, and an APOE genotype-BMI interaction has been reported on fasting lipids. However, studies are often performed retrospectively leading to small sample sizes within the genotype groups. Further studies are needed to confirm the relationship between APOE genotype, adiposity and circulating CVD risk markers.

Association Between β-Amyloid Accumulation and Incident Dementia in Individuals 80 Years or Older Without Dementia.

While the highest prevalence of dementia occurs in individuals older than 80 years, most imaging studies focused on younger populations. The rates of β-amyloid (Aβ) accumulation and the effect of Alzheimer disease (AD) pathology on progression to dementia in this age group remain unexplored. In this study, we examined the relationship between changes in Aβ deposition over time and incident dementia in nondemented individuals followed during a period of 11 years. We examined 94 participants (age 85.9 + 2.8 years) who had up to 5 measurements of Pittsburgh compound-B (PiB)-PET and clinical evaluations from 2009 to 2020. All 94 participants had 2 PiB-PET scans, 76 participants had 3 PiB-PET scans, 18 participants had 4 PiB-PET scans, and 10 participants had 5 PiB-PET scans. The rates of Aβ deposition were compared with 120 nondemented individuals younger than 80 years (69.3 ± 5.4 years) from the Australian Imaging, Biomarker, and Lifestyle (AIBL) study who had 3 or more annual PiB-PET assessments. By 2020, 49% of the participants developed dementia and 63% were deceased. There was a gradual increase in Aβ deposition in all participants whether they were considered Aβ positive or negative at baseline. In a Cox model controlled for age, sex, education level, APOE-4 allele, baseline Mini-Mental State Examination, and mortality, short-term change in Aβ deposition was not significantly associated with incident dementia (HR 2.19 (0.41-11.73). However, baseline Aβ burden, cortical thickness, and white matter lesions volume were the predictors of incident dementia. Aβ accumulation was faster (p = 0.01) in the older cohort (5.6%/year) when compared with AIBL (4.1%/year). In addition, baseline Aβ deposition was a predictor of short-term change (mean time 1.88 years). There was an accelerated Aβ accumulation in cognitively normal individuals older than 80 years. Baseline Aβ deposition was a determinant of incident dementia and short-term change in Aβ deposition suggesting that an active Aβ pathologic process was present when these participants were cognitively normal. Consequently, age may not be a limiting factor for the use of the emergent anti-Aβ therapies.

Atrophy of the cholinergic regions advances from early to late mild cognitive impairment.

We investigated the volumetric changes in the components of the cholinergic pathway for patients with early mild cognitive impairment (EMCI) and those with late mild cognitive impairment (LMCI). The effect of patients' apolipoprotein 4 (APOE-ε4) allele status on the structural changes were analyzed. Structural magnetic resonance imaging data were collected. Patients' demographic information, plasma data, and validated global cognitive composite scores were included. Relevant features were extracted for constructing machine learning models to differentiate between EMCI (n = 312) and LMCI (n = 541) and predict patients' neurocognitive function. The data were analyzed primarily through one-way analysis of variance and two-way analysis of covariance. Considerable differences were observed in cholinergic structural changes between patients with EMCI and LMCI. Cholinergic atrophy was more prominent in the LMCI cohort than in the EMCI cohort (P < 0.05 family-wise error corrected). APOE-ε4 differentially affected cholinergic atrophy in the LMCI and EMCI cohorts. For LMCI cohort, APOE-ε4 carriers exhibited increased brain atrophy (left amygdala: P = 0.001; right amygdala: P = 0.006, and right Ch123, P = 0.032). EMCI and LCMI patients showed distinctive associations of gray matter volumes in cholinergic regions with executive (R2 = 0.063 and 0.030 for EMCI and LMCI, respectively) and language (R2 = 0.095 and 0.042 for EMCI and LMCI, respectively) function. Our data confirmed significant cholinergic atrophy differences between early and late stages of mild cognitive impairment. The impact of the APOE-ε4 allele on cholinergic atrophy varied between the LMCI and EMCI groups.

THE INFLUENCE OF THE APOEε4 ALLELE ON PRO-INFLAMMATORY CYTOKINE LEVELS IN THE CEREBROSPINAL FLUID OF PATIENTS WITH ALZHEIMER’S DISEASE

Single nucleotide polymorphisms (SNPs) rs429358 and rs7412, the most commonly investigated variants in the apolipoprotein E gene (APOE) are crucial for APOEε4 carrier status determination. However, their association with inflammatory cytokine levels in patients with dementia due to Alzheimer’s disease (AD) remains unclear. This study aimed to investigate the influence of the APOEε4 allele on pro-inflammatory cytokine levels in the cerebrospinal fluid of patients with AD dementia. The research was conducted on 36 patients with probable dementia due to AD. APOE rs429358 and rs7412 were analyzed using the Real-Time PCR method with allele-specific TaqMan assays, followed by the analysis of APOEε4 allele carrier status. Patients carrying at least one APOEε4 allele were assigned as APOEε4+. Core biomarkers (Aβ42/40 ratio, t-Tau, p-Tau levels), as well as pro-inflammatory cytokine (Tumor necrosis factor-a (TNF-a) and interleukin-1b (IL-1b)) levels, were determined in the patient’s cerebrospinal fluid (CSF) using Enzyme-linked Immunosorbent Assay (ELISA). Seventeen patients (47.22%) were assigned as APOEε4+. CSF TNF-α levels were significantly higher in APOEε4+ AD dementia patients in comparison to APOEε4- patients (p&lt;0.001), while no significant differences in IL-1b levels between these two groups were obtained. Correlation analysis showed that TNF-α negatively correlated with the Aβ42/40 ratio (p=0.033), while positive correlation with t-Tau and p-Tau was observed (p=0.001, p=0.015, respectively). These findings highlight the potential significance of TNF-α in the context of APOEε4 positivity and its implications in AD pathology.

Advertisement by medical facilities as an opportunity route of APOE genetic testing in Japan: a website analysis

The APOE-ε4 allele(s) is a strong risk factor for Alzheimer’s disease (AD). A significant point of access for this allele testing is through services provided by medical facilities in Japan, which advertise out-of-insurance APOE testing on their websites. There is a concern that website advertisements for APOE testing may influence the ability for individuals to adequately self-determine whether to undergo APOE testing. We conducted a cross-sectional survey on medical facility websites in Japan advertising APOE genetic testing. We predefined desirable features for advertisement descriptions based on legal regulations and guidelines published by relevant professional societies and evaluated each website according to these features. We identified 220 medical facilities that had posted advertisements on their websites for the provision of APOE genetic testing, of which 85% were small clinics. Contact information, details, and costs of testing were described in most of the websites. Meanwhile, features such as “explaining APOE as a risk gene,” “notes on interpreting APOE results,” or “explaining examination methods” (e.g., blood sampling) were described to a variable degree depending on individual facilities. “Notes on genetic testing” or “referring to genetic counseling” were hardly referred to, and specialists with appropriate expertise were considered to participate in clinical practice in approximately one-third of these facilities providing APOE testing services. These website evaluation results showed moderate to substantial reliability between independent raters. These results suggest that self-determination of pursuing out-of-insurance APOE testing at some medical facilities in Japan may possibly be influenced in an inappropriate manner, at least in its entry route of taking the test.

APOE-ε4 allele[s]-associated adverse events reported from placebo arm in clinical trials for Alzheimer's disease: implications for anti-amyloid beta therapy.

APOE-ε4 allele[s] is a risk factor for Alzheimer's disease (AD) and Amyloid-Related Imaging Abnormalities (ARIA) in anti-amyloid beta therapy, and is also associated with cerebrovascular risk factors such as hyperlipidemia or atherosclerosis. During AD clinical trials, APOE-ε4 carriers may experience neuropsychiatric adverse events (AEs) related to these risks, complicating the differentiation of ARIA from cerebrovascular events based on symptoms. This study aimed to examine the hypothetical impact of considering the APOE-ε4 allele's risk for non-ARIA AEs during AD clinical trials. We used data from the Critical Path for Alzheimer's Disease (CPAD) from the placebo arm of randomized controlled trials (RCT) for AD treatment. We determined whether AEs were reported more frequently in APOE-ε4 carriers, quantifying with reporting odds ratio (ROR) using a mixed effect model. We also evaluated the association between ROR levels and the prior probability that an AE is symptomatic ARIA. We analyzed 6,313 patients with AD or mild cognitive impairment in 28 trials. Of the prespecified 35 neuropsychiatric or related AEs, several had a significantly high ROR: "delusion" (ROR = 4.133), "confusional state" (ROR = 1.419), "muscle spasms" (ROR = 9.849), "irritability" (ROR = 12.62), "sleep disorder" (ROR = 2.944), or "convulsion" (ROR = 13.00). However, none remained significant after adjusting for Mini-Mental State Examination scores. There is no strong evidence to suggest that specific neuropsychiatric AEs occur more frequently without drug treatment association among APOE-ε4 carriers. The influence of APOE-ε4 allele[s] on the clinicians' assessment of the likelihood of ARIA during safety monitoring in anti-amyloid beta monoclonal antibody treatment might be unchanged, thus maintaining the current level of awareness of clinicians of AEs.

Polymorphisms of APOE and APOB genes and dyslipidemias in a South Brazilian Cohort

Dyslipidemias are closely associated to the development of cardiovascular and cerebrovascular diseases, and therefore of great importance in public health. Many genes influence lipid levels, such as APOE and APOB. The present study aimed to investigate the effects of APOE gene alleles (rs7412: C&gt;T and rs429358: T&gt;C), and R3500Q mutation of APOB gene (rs5742904: G&gt;A) in lipid levels in a South Brazilian cohort. 214 individuals were analyzed and the frequencies of APOE ε2, ε3 and ε4 alleles were found respectively as 9.25 ± 0.4625; 70.5 ± 3.525 and 20.25%± 1.401, while the frequency of R3500Q mutation of the APOB gene was 4.46 ± 1.00%. The ε4 allele was significantly more frequent in subjects with higher TC (Total Cholesterol) and LDL-C levels, while significantly higher frequency of the ε2 allele was found in individuals with higher HDL-C levels. The R3500Q mutation was suggested as a risk factor for higher TC levels, regardless gender and age (β = 21.326 ± 10377.78, p = 0.001).

APOEε4 genotype and DHA and EPA supplementation on the outcomes of cognitive decline: A systematic review of randomized clinical trials

Docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA) supplementation has been used to improve cognitive outcomes in diseases associated with cognition. However, the influence of APOEε4 genotype on these relationships remains unclear. Therefore, this systematic review aims to discuss the evidence regarding the effects of DHA and EPA supplementation on cognitive decline variables and relate them to APOEε4 genotype in middle-aged and older adults. The Medline (via PubMed), Scopus, Web of Science, and Bireme/Lilacs databases were searched for studies, retrieving 1863 articles. After the step selection, two randomized clinical trials (RCTs) that evaluated the effects of EPA and DHA supplementation on cognitive variables were included. All the methodological steps were performed by two raters. The results of the RCTs were not congruent, as the non-carriers in the APOEε4 supplemented group performed worse in the quick-choice reaction time cognitive domain, whereas the carriers improved in the reasoning domain. The increase in DHA concentration in the supplemented group was lower in APOEε4 carriers than in individuals with other genotypes. Additionally, a smaller decline in right hippocampal brain volume correlated with higher EPA concentrations after supplementation in APOEε4 non-carriers. The dosage and supplementation time (18 months) were similar between studies. In conclusion, DHA and EPA supplementation showed no pragmatic effects on cognitive variables when considering the presence of the APOEε4 allele.

Association of lifestyle and apolipoprotein E gene with risk for cognitive frailty in elderly population in China

Objective: To investigate the impact of lifestyle, apolipoprotein E (ApoE) gene, and their interaction on the risk for cognitive frailty in the elderly population in China. Methods: The study participants were from the Chinese Longitudinal Healthy Longevity Survey. The information about their lifestyles were collected by questionnaire survey, and a weighted lifestyle score was constructed based on β coefficients associated with specific lifestyles to assess the combined lifestyle. ApoE genotypes were assessed by rs429358 and rs7412 single nucleotide polymorphisms. Cognitive frailty was assessed based on cognitive function and physical frailty. Cox proportional hazards regression model was used to analyze the association of lifestyle and ApoE gene with the risk for cognitive frailty and evaluate the multiplicative and additive interactions between lifestyle and ApoE gene. Results: A total of 5 676 elderly persons, with median age [M (Q1, Q3)] of 76 (68, 85) years, were included, in whom 615 had cognitive frailty. The analysis by Cox proportional hazards regression model indicated that moderate and high levels of dietary diversity could reduce the risk for cognitive frailty by 18% [hazard ratio (HR)=0.82, 95%CI: 0.68-1.00] and 28% (HR=0.72, 95%CI: 0.57-0.91), respectively; moderate and high levels of physical activity could reduce the risk by 31% (HR=0.69, 95%CI: 0.56-0.85) and 23% (HR=0.77, 95%CI: 0.64-0.93), respectively. Healthy lifestyle was associated with a 40% reduced risk for cognitive frailty (HR=0.60, 95%CI: 0.46-0.78). ApoE ε4 allele was associated with a 26% increased risk for cognitive frailty (HR=1.26, 95%CI: 1.02-1.56). No multiplicative or additive interactions were found between lifestyle and ApoE gene. Conclusions: Dietary diversity and regular physical activity have protective effects against cognitive frailty in elderly population. Healthy lifestyle can reduce the risk for cognitive frailty in elderly population regardless of ApoE ε4 allele carriage status.

Rescue of ApoE4-related lysosomal autophagic failure in Alzheimer’s disease by targeted small molecules

Homozygosity for the ε4 allele of APOE increases the odds of developing Alzheimer’s by 12 to 15 times relative to the most common ε3;ε3 genotype, and its association with higher plaque loads comports with evidence that APOEε4 compromises autophagy. The ApoE4 protein specifically binds a cis element (“CLEAR”) in the promoters of several autophagy genes to block their transcription. We used a multifaceted approach to identify a druggable site in ApoE4, and virtual screening of lead-like compounds identified small molecules that specifically bind to this site to impede ApoE4::DNA binding. We validated these molecules both in vitro and in vivo with models expressing ApoE4, including ApoE4 targeted-replacement mice. One compound was able to significantly restore transcription of several autophagy genes and protected against amyloid-like aggregation in a C. elegans AD model. Together, these findings provide proof-of-principle evidence for pharmacological remediation of lysosomal autophagy by ApoE4 via ApoE4-targeted lead molecules that represent a novel tack on neurodegenerative disorders.

Interest in genetic susceptibility testing and disclosure of AD dementia risk in cognitively normal adults: a survey study

BackgroundApolipoprotein-E (APOE) genetic testing for Alzheimer’s disease is becoming more important as clinical trials are increasingly targeting individuals carrying APOE-ε4 alleles. Little is known about the interest in finding out one’s genetic risk for Alzheimer’s disease in the general population. Our objective was to examine this in a sample of cognitively normal (CN) adults within a population-based online research registry with the goal to implement APOE-ε4 status for trial recruitment.MethodsAn online survey was completed by 442 CN participants between the age of 49 and 75 years (56% female) from the Dutch Brain Research Registry. The survey assessed interest in participation in research into, and disclosure of, genetic risk for dementia. The survey assessed interest in participation in research into, and disclosure of, genetic risk for dementia and knowing their genetic risk in different hypothetical risk scenarios (10%, 30%, and 50% genetic risk for dementia at age 85, corresponding to APOEε2/ε2 or ε2/ε3, APOEε3/ε4 or ε2ε4, and APOE-ε4/ε4 genotypes). Cochran’s Q and post hoc McNemar tests were used to analyse differences in frequencies across scenarios.ResultsMost participants were interested in participating in research into and disclosure of their genetic risk (81%). The most reported reason was to contribute to scientific research (94%). Interest was higher in males, whilst lower-educated participants were more often undecided. When provided with different risk scenarios, interest in knowing their risk was somewhat higher in the scenarios with higher risk, i.e. in the 50% (79%) compared to the 10% scenario (73%;χ2(2) = 7.98; p = .005). Most individuals expected they would share their genetic risk with close relatives (77–89%), would participate in medication trials (79–88%), and would make long-term arrangements, e.g. retirement, health care, will (69–82%), with larger proportions for scenarios with higher hypothetical genetic risk.ConclusionsOur findings indicate that the vast majority of CN adults participating in a research registry expresses interest in AD genetic risk research and disclosure. Interest in genetic risk disclosure is higher in scenarios corresponding to the APOE-ε4 genotype. This suggests APOE-ε4 screening within an online research registry is potentially a well-received method to accelerate inclusion for trials.

Modulation of Bone Mineral Density and Its Response to Menopausal Hormone Therapy according to the Apolipoprotein E Genotype in Postmenopausal Korean Women.

Genetic factors are a major cause of osteoporosis. The present study evaluated the association of the apolipoprotein E (ApoE) genotype with bone mineral density (BMD) and its response to menopausal hormone therapy (MHT) in postmenopausal Korean women. This retrospective cohort study included 172 postmenopausal women with no endocrine diseases, medications, or lifestyles that would affect bone metabolism and who were continuously treated with MHT for at least 2 years. BMDs were measured at baseline and periodically. Linear regression analysis demonstrated similar baseline BMDs at the lumbar spine, but significantly lower at the femur neck and total hip in the ApoE ε4 carrier than in the noncarrier group, after controlling for age, body mass index, and history of MHT usage. Overall, the Wilcoxon signed rank test demonstrated that MHT increased the BMD percentage change at all three regions, and the Generalized Estimating Equation (GEE) demonstrated significant time trends at the lumbar spine and femur neck. ApoE ε4 noncarriers exhibited a significant time trend in BMD changes at the femur neck, whereas ε4 carriers exhibited a time trend at the lumbar spine. However, BMD changes at each time point were comparable at all regions between the groups. Notably, GEE adjusted for baseline characteristics and BMD revealed a significant interaction effect of time and ApoE ε4 allele in BMD changes at the femur neck. Postmenopausal Korean women carrying the ApoE ε4 allele demonstrated a lower hip BMD compared with ε4 noncarriers. Furthermore, the ε4 allele may modulate hip BMD responses to MHT.