Association between serum apolipoprotein E and cognitive function in Chinese patients with temporal lobe epilepsy.

OBJECTIVE: To investigate the effect of serum apolipoprotein E (APOE) levels on cognitive function in patients with temporal lobe epilepsy (TLE). METHODS: Clinical data were collected from 190 subjects including 110 TLE patients and 80 healthy people. Cognitive function was assessed using the Addenbrooke's Cognitive Examination Revised (ACE-R) scale. Serum levels of APOE were measured using ELISA kits. Genotyping of APOE in peripheral blood was detected by microarray hybridization. RESULTS: Patients with TLE had significantly lower ACE-R total score, memory and verbal fluency scores compared to the healthy group. Serum levels of APOE were significantly higher in TLE patients than in the healthy subjects. Serum APOE levels were significantly negatively correlated with ACE-R total score, memory and verbal fluency scores. The cognitive function score of TLE with APOE ε4 allele was lower than that of TLE without APOE ε4 allele. SIGNIFICANCE: Our study showed that serum APOE levels were higher in TLE patients than in the healthy population. And serum APOE levels were associated with cognitive dysfunction in TLE patients. APOE ε4 allele carriers have poor cognitive function in TLE patients.

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

PURPOSE: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.

Circulating apoE4 protein levels from dried blood spots predict cognitive function in a large population-based survey setting.

INTRODUCTION: The apolipoprotein E (APOE) ε4 allele carries risk for cognitive impairment, but whether the level of circulating apoE4 protein in carriers affects cognition is unclear, as is how health and lifestyle impact circulating apoE4 levels. METHODS: We assayed apoE4 protein levels in dried blood spots of 12,532 adults aged 50+. Regression analyses tested the likelihood of cognitive impairment between groups and within those with detected apoE4 protein. Predictors of circulating apoE4 were assessed. RESULTS: We detected protein binding that indicates the presence of an APOE ε4 allele in 28.4% of this group. This group was more likely to have cognitive impairment, and this risk increases with age. However, higher apoE4 levels were associated with less likelihood of cognitive impairment within this group. Antihypertensive medication predicted apoE4 protein levels. DISCUSSION: The apoE4 isoform is associated with a deficient protein and worse cognition. This association is modulated by the level of circulating apoE4 protein in ε4 carriers. HIGHLIGHTS: An assay to quantify apoE4 levels from dried blood spot samples was applied. The apoE4 protein was detected as specific binding at ≥30,000 pg/mL in 28.4% of samples. Having the apoE4 protein was associated with worse cognitive performance. Higher apoE4 protein levels in those who have it were associated with better cognition. Cardiovascular factors influenced levels of apoE4 protein.

Synergistic Effect between the APOE ε4 Allele with Genetic Variants of GSK3B and MAPT: Differential Profile between Refractory Epilepsy and Alzheimer Disease.

Temporal Lobe Epilepsy (TLE) is a chronic neurological disorder characterized by recurrent focal seizures originating in the temporal lobe. Despite the variety of antiseizure drugs currently available to treat TLE, about 30% of cases continue to have seizures. The etiology of TLE is complex and multifactorial. Increasing evidence indicates that Alzheimer's disease (AD) and drug-resistant TLE present common pathological features that may induce hyperexcitability, especially aberrant hyperphosphorylation of tau protein. Genetic polymorphic variants located in genes of the microtubule-associated protein tau (MAPT) and glycogen synthase kinase-3ß (GSK3B) have been associated with the risk of developing AD. The APOE ε4 allele is a major genetic risk factor for AD. Likewise, a gene-dose-dependent effect of ε4 seems to influence TLE. The present study aimed to investigate whether the APOE ɛ4 allele and genetic variants located in the MAPT and GSK3B genes are associated with the risk of developing AD and drug-resistant TLE in a cohort of the Mexican population. A significant association with the APOE ε4 allele was observed in patients with AD and TLE. Additional genetic interactions were identified between this allele and variants of the MAPT and GSK3B genes.

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

BACKGROUND: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.

Racial differences in the effect of APOE-ε4 genotypes on trail making test B in Alzheimer's disease: A longitudinal study.

OBJECTIVES: The trail making test part B (TMT-B) evaluates executive functions, memory, and sensorimotor functions. No previous study was found to examine the longitudinal effect of APOE-ε4 genotypes on the TMT-B scores in Alzheimer's disease (AD) across racial groups. METHODS: This study used the data from Alzheimer's Disease Neuroimaging Initiative (ADNI): 382 participants with AD, 503 with cognitive normal (CN), 1293 with mild cognitive impairment (MCI) at baseline and follow-up of four years. The multivariable linear mixed model was used to investigate the effect of APOE-ε4 genotypes on changes in TMT-B scores. RESULTS: Compared with Whites, African Americans (AA) and Hispanics had higher TMT-B scores (poor cognitive function). Furthermore, Whites subjects with 1 or 2 APOE-ε4 alleles had significantly higher TMT-B scores compared with individuals without APOE-ε4 allele at baseline and four follow-up visits; however, no differences in TMT-B were found between APOE-ε4 alleles in the Hispanic and AA groups. No APOE-ε4 by visit interactions was found for 3 racial groups. Stratified by AD diagnosis, the APOE-ε4 allele was associated with TMT-B scores only in the MCI group, while there were significant interactions for visit by education, APOE-ε4 allele, and the Mini Mental State Examination (MMSE) score in the MCI group. In addition, TMT-B was significantly correlated with the MMSE, AD Assessment Scale-cognitive subscale 13 (ADAS13), tTau, pTau, Aß42, and hippocampus. CONCLUSIONS: APOE-ɛ4 allele is associated with TMT-B scores in Whites subjects, but not in the Hispanic and AA groups. APOE-ε4 showed interaction with visit in the MCI group.

Impact of the Apolipoprotein E ε4 Allele on the Relationship Between Healthy Lifestyle and Cognitive Decline: A Population-Based Study.

Adherence to a healthy lifestyle-characterized by abstaining from smoking, being physically and cognitively active, having a high-quality diet, and limiting alcohol use-is associated with slower cognitive decline in older adults, but whether this relationship extends to persons with a genetic predisposition (e.g., carriers of the ε4 allele of the apolipoprotein E gene (APOE*E4)) remains uncertain. Using data from a population-based study, the Chicago Health and Aging Project (Chicago, Illinois), we followed 3,886 individuals who underwent regular clinical and cognitive assessments from 1993 to 2012. Of 3,886 older adults, 1,269 (32.7%) were APOE*E4 carriers. Compared with noncarriers, APOE*E4 carriers had faster cognitive decline (ß = -0.027 units/year, 95% confidence interval (CI): -0.032, -0.023). In contrast, persons with 2-3 and 4-5 healthy lifestyle factors had slower cognitive decline (ß = 0.008 units/year (95% CI: 0.002, 0.014) and ß = 0.019 units/year (95% CI: 0.011, 0.026), respectively) compared with those with 0-1 factor. In analyses stratified by APOE*E4 status, adherence to a healthy lifestyle (e.g., 4-5 factors vs. 0-1 factors) was associated with a slower rate of cognitive decline in both APOE*E4 carriers (ß = 0.029, 95% CI: 0.013, 0.045) and noncarriers (ß = 0.013, 95% CI: 0.005, 0.022). These results underscore the impact of a healthy lifestyle on cognition, particularly among persons with a genetic predisposition, who are more vulnerable to cognitive decline as they age.

Apolipoprotein E ϵ4 allele and neuropsychiatric symptoms among older adults in Central Africa (EPIDEMCA study).

OBJECTIVES: To evaluate the association between neuropsychiatric symptoms and apolipoprotein E (APOE) ϵ4 allele among older people in Central African Republic (CAR) and the Republic of Congo (ROC). DESIGN: Multicenter population-based study following a two-phase design. SETTING: From 2011 to 2012, rural and urban areas of CAR and ROC. PARTICIPANTS: People aged 65 and over. MEASUREMENTS: Following screening using the Community Screening Interview for Dementia, participants with low cognitive scores (CSI-D ≤ 24.5) underwent clinical assessment. Dementia diagnosis followed the DSM-IV criteria and Peterson's criteria were considered for Mild Cognitive Impairment (MCI). Neuropsychiatric symptoms were evaluated through the brief version of the Neuropsychiatric Inventory (NPI-Q). Blood samples were taken from all consenting participants before APOE genotyping was performed by polymerase chain reaction (PCR). Logistic regression models were used to evaluate the association between the APOE ϵ4 allele and neuropsychiatric symptoms. RESULTS: Overall, 322 participants had complete information on both neuropsychiatric symptoms and APOE status. Median age was 75.0 years and 81.1% were female. Neuropsychiatric symptoms were reported by 192 participants (59.8%) and at least 1 APOE ϵ4 allele was present in 135 (41.9%). APOE ϵ4 allele was not significantly associated with neuropsychiatric symptoms but showed a trend toward a protective effect in some models. CONCLUSION: This study is the first one investigating the association between APOE ϵ4 and neuropsychiatric symptoms among older people in sub-Saharan Africa (SSA). Preliminary findings indicate that the APOE ϵ4 allele was not associated with neuropsychiatric symptoms. Further research seems, however, needed to investigate the protective trend found in this study.

Apolipoprotein E4 Is Associated with Right Ventricular Dysfunction in Dilated Cardiomyopathy-An Animal and In-Human Comparative Study.

ApoE abnormality represents a well-known risk factor for cardiovascular diseases. Beyond its role in lipid metabolism, novel studies demonstrate a complex involvement of apoE in membrane homeostasis and signaling as well as in nuclear transcription. Due to the large spread of apoE isoforms in the human population, there is a need to understand the apoE's role in pathological processes. Our study aims to dissect the involvement of apoE in heart failure. We showed that apoE-deficient rats present multiple organ damages (kidney, liver, lung and spleen) besides the known predisposition for obesity and affected lipid metabolism (two-fold increase in tissular damages in liver and one-fold increase in kidney, lung and spleen). Heart tissue also showed significant morphological changes in apoE-/- rats, mostly after a high-fat diet. Interestingly, the right ventricle of apoE-/- rats fed a high-fat diet showed more damage and affected collagen content (~60% less total collagen content and double increase in collagen1/collagen3 ratio) compared with the left ventricle (no significant differences in total collagen content or collagen1/collagen3 ratio). In patients, we were able to find a correlation between the presence of ε4 allele and cardiomyopathy (χ2 = 10.244; p = 0.001), but also with right ventricle dysfunction with decreased TAPSE (15.3 ± 2.63 mm in ε4-allele-presenting patients vs. 19.8 ± 3.58 mm if the ε4 allele is absent, p < 0.0001*) and increased in systolic pulmonary artery pressure (50.44 ± 16.47 mmHg in ε4-allele-presenting patients vs. 40.68 ± 15.94 mmHg if the ε4 allele is absent, p = 0.0019). Our results confirm that the presence of the ε4 allele is a lipid-metabolism-independent risk factor for heart failure. Moreover, we show for the first time that the presence of the ε4 allele is associated with right ventricle dysfunction, implying different regulatory mechanisms of fibroblasts and the extracellular matrix in both ventricles. This is essential to be considered and thoroughly investigated before the design of therapeutical strategies for patients with heart failure.

Neurotoxic Soluble Amyloid Oligomers Drive Alzheimer's Pathogenesis and Represent a Clinically Validated Target for Slowing Disease Progression.

A large body of clinical and nonclinical evidence supports the role of neurotoxic soluble beta amyloid (amyloid, Aß) oligomers as upstream pathogenic drivers of Alzheimer's disease (AD). Recent late-stage trials in AD that have evaluated agents targeting distinct species of Aß provide compelling evidence that inhibition of Aß oligomer toxicity represents an effective approach to slow or stop disease progression: (1) only agents that target soluble Aß oligomers show clinical efficacy in AD patients; (2) clearance of amyloid plaque does not correlate with clinical improvements; (3) agents that predominantly target amyloid monomers or plaque failed to show clinical effects; and (4) in positive trials, efficacy is greater in carriers of the ε4 allele of apolipoprotein E (APOE4), who are known to have higher brain concentrations of Aß oligomers. These trials also show that inhibiting Aß neurotoxicity leads to a reduction in tau pathology, suggesting a pathogenic sequence of events where amyloid toxicity drives an increase in tau formation and deposition. The late-stage agents with positive clinical or biomarker data include four antibodies that engage Aß oligomers (aducanumab, lecanemab, gantenerumab, and donanemab) and ALZ-801, an oral agent that fully blocks the formation of Aß oligomers at the clinical dose.

Effects of Apolipoprotein Ε Îµ4 allele on early postoperative cognitive dysfunction after anesthesia.

BACKGROUND: Postoperative cognitive dysfunction (POCD) is one of the main causes of morbidity after noncardiac surgery; however, the pathogenic mechanisms of POCD have remained unclear until now. In this study, we performed a pilot study to investigate the association between apolipoprotein E (ApoE) ε4 and POCD in older patients undergoing intravenous anesthesia (IVA) and inhalation anesthesia (IAA). METHODS: In total, 180 patients from Shenzhen People's Hospital were recruited and randomly divided into an IVA group and an IAA group. The IVA group and IAA group received propofol and sevoflurane treatment, respectively. Within 7 days after surgery, the mini-mental state examination (MMSE) was used daily to assess the cognitive function of both groups of patients. The genotypes of the ApoE gene were detected using the restriction fragment length polymorphism technique. In addition, the serum levels of (soluble protein-100ß) S­100ß and (Interleukin- 6) L­6 were also analyzed. RESULTS: Compared to the preoperative and IVA groups, the MMSE score in the IAA group significantly decreased at 3 days after surgery. Furthermore, the IAA group had a higher percentage of patients who scored less than 25 points than the IVA group at 3 days after surgery. The decrease in the MMSE score was closely related to the ApoE ε4 allele in the IAA group, but this correlation was not observed in the IVA group. The levels of S­100ß and IL­6 were increased sharply in patients with the ε4/ε4 genotype who received IAA compared with IVA at 1 day after surgery. CONCLUSION: The results of the study indicated that the ApoΕ Îµ4/ε4 genotype was a risk factor for early POCD in older patients undergoing sevoflurane anesthesia.

Apolipoprotein ε4 allele is associated with frailty syndrome: results from the hellenic longitudinal investigation of ageing and diet study.

Apolipoprotein (APOE) ε4 allele has been associated with a number of age-related diseases but previous studies failed to identify any link with Frailty syndrome. The aim of the present study is to investigate the association between APOE ε4 allele and frailty syndrome. We operationalised Frailty according to the Fried definition, and we determined the APOE genotype in 1234 participants of the hellenic longitudinal investigation of ageing and diet study. Logistic regression analyses were performed to examine the association between APOE ε4 allele and frailty. Models were adjusted for age, education, sex, presence (or absence) of hypertension, diabetes, myocardial infraction, coronary disease, congestive heart failure, arrhythmia or other heart disease, family history of dementia and current smoking. The same models were performed after exclusion of patients with dementia and participants with APOE ε2/ε4 genotype. In the fully adjusted model, carriers of APOE ε4 allele had 2.753 higher odds of frailty relative to non-carriers. After trichotomization of APOE genotype, APOE ε4 heterozygotes had 2.675 higher risk of frailty compared to non-carriers while exclusion of patients with dementia or/and APOE ε2/ε4 genotype did not alter the association. The APOE ε4 allele may be a significant biomarker of frailty with diagnostic and prognostic capacity.

APOE genotypes as a risk factor for age-dependent accumulation of cerebrovascular disease in older adults.

INTRODUCTION: Apolipoprotein E (APOE) is a susceptibility gene for late-onset Alzheimer's disease neuropathology; less is known about the relationship between APOE and cerebrovascular disease (CVD) neuropathology. METHODS: We investigated associations of APOE status with arteriolosclerosis, macroinfarcts and microinfarcts, and atherosclerosis in 1383 adults (65.9-108.2 years at death) with and without dementia. Excluding ε2/ε4 carriers, multivariable regressions for each CVD-related neuropathology compared ε4 and ε2 carriers to ε3/ε3 carriers adjusting for confounders including age and Alzheimer's neuropathology. RESULTS: Three hundred forty-two individuals (24.7%; ∼87.7 years at death; 39.9% nondemented) were ε3/ε4 or ε4/ε4, and 180 (13.0%; ∼89.9 years at death; 66.6% nondemented) were ε2/ε3 or ε2/ε2. ε4 carriers had higher odds of macroinfarcts (odds ratio = 1.41, 95% confidence interval: 1.02-1.94, P = .03), whereas ε2 carriers had higher odds of moderate-to-severe arteriolosclerosis (odds ratio = 1.68, 95% confidence interval: 1.15-2.45, P = .006) compared to ε3/ε3 carriers. Age-stratified analyses suggested that these relationships were driven by ε4 carriers <90 years at death and ε2 carriers ≥90 years at death, respectively. DISCUSSION: APOE differentially affects type and timing of CVD-related neuropathology.

Inverse effect of the APOE epsilon4 allele in late- and early-onset Alzheimer's disease.

In Alzheimer's disease patients (AD), the age at onset (AAO) ranges from 40 to 90. Usually, AD patients who develop symptoms before the age of 65 are classified as early onset (EO). The best known genetic risk factor for AD is the ε4 allele of the apolipoprotein E (APOE). In this study, 474 subjects with AD were consecutively recruited in the memory clinic of the Santa Lucia Foundation in Rome. The best fitting model  for the discrimination between EO and late onset (LO) was chosen based on lowest value of the Bayesian Information Criterion, which suggests the theoretical model with minimal deviation from the empirical distribution function of AAO in our sample. The FMM was used to compare EO and LO groups with respect to the following demographic and clinical variables: gender, age, education, MMSE and NPI. Furthermore a quantitative assessment of ADL and IADL was performed. Finally, the frequency of the APOE ε4 allele was compared in EO and LO groups. Using the admixture analysis, we established that the AAO discriminating EO from LO-AD was 63-64. Higher education was associated with earlier onset in the EO but not in LO, and duration of illness was associated with earlier onset only in LO. The ε4 allele was associated with later onset in EO but earlier onset in LO. Finally, increased impairment in ADL, IADL and NPI was associated with later onset only in the LO subgroup. Thus, the ε4 allele of the APOE gene was significantly associated with both EO and LO distributions but with opposite effect, suggesting genetic heterogeneity. Additional studies are needed to further clarify the genetic mechanisms differentiating EO- and LO-AD.

APOE ε4 allele modifies the association of lead exposure with age-related cognitive decline in older individuals.

BACKGROUND: Continuing chronic and sporadic high-level of lead exposure in some regions in the U.S. has directed public attention to the effects of lead on human health. Long-term lead exposure has been associated with faster cognitive decline in older individuals; however, genetic susceptibility to lead-related cognitive decline during aging has been poorly studied. METHODS: We determined the interaction of APOE-epsilon variants and environmental lead exposure in relation to age-related cognitive decline. We measured tibia bone lead by K-shell-x-ray fluorescence, APOE-epsilon variants by multiplex PCR and global cognitive z-scores in 489 men from the VA-Normative Aging Study. To determine global cognitive z-scores we incorporated multiple cognitive assessments, including word list memory task, digit span backwards, verbal fluency test, sum of drawings, and pattern comparison task, which were assessed at multiple visits. We used linear mixed-effect models with random intercepts for individual and for cognitive test. RESULTS: An interquartile range (IQR:14.23µg/g) increase in tibia lead concentration was associated with a 0.06 (95% confidence interval [95%CI]: -0.11 to -0.01) lower global cognition z-score. In the presence of both ε4 alleles, one IQR increase in tibia lead was associated with 0.57 (95%CI: -0.97 to -0.16; p-value for interaction: 0.03) lower total cognition z-score. A borderline association was observed in presence of one ε4 allele (Estimate-effect per 1-IQR increase: -0.11, 95%CI: -0.22, 0.01) as well as lack of association in individuals without APOE ε4 allele. CONCLUSIONS: Our findings suggest that individuals carrying both ε4 alleles are more susceptible to lead impact on global cognitive decline during aging.

Relationships between APOE, Type 2 Diabetes, and Cardiovascular Disease in Postmenopausal Women.

BACKGROUND: The Apolipoprotein E (APOE) ε4 allele, type 2 diabetes mellitus (T2DM), and cardiovascular disease (CVD) are well-established risk factors for dementia. Relationships between APOE and incidence of T2DM and CVD are not fully understood but may shed light on the mechanisms underlying dementia pathogenesis. METHODS: Postmenopausal women (N=6,795) from the Women's Health Initiative hormone therapy clinical trial with APOE genotyping and no prior diagnosis of T2DM or CVD were included. We examined associations of APOE status (APOE2+ [ε2/ε2, ε2/ε3], APOE3 [ε3/ε3], and APOE4+ [ε4/ε4, ε3/ε4] carriers) with incidence of T2DM, coronary heart disease (CHD), stroke, and total CVD events using Cox regression. CVD outcomes were examined in baseline non-statin users and adjusted for statin initiation over follow-up to account for possible confounding by statins. RESULTS: Among all participants (mean age 66.7±6.5 years, 100% non-Hispanic white), 451 (6.6%) were using statins at baseline. Over the follow-up (mean 14.9 and 16.0 years for T2DM and CVD, respectively), 1,564 participants developed T2DM and 1,578 developed CVD. T2DM incidence did not differ significantly by APOE status (ps≥0.09). Among non-statin users, APOE4+ had higher incidence of total CVD (hazard ratio [95% confidence interval]=1.18 [1.02-1.38], p=0.03) compared to APOE3 carriers, but risks for CHD (1.09 [0.87-1.36], p=0.47) and stroke (1.14 [0.91-1.44], p=0.27) were not significantly elevated when examined individually. CVD outcomes did not differ between APOE2+ and APOE3 carriers (ps≥0.11). CONCLUSIONS: T2DM risk did not differ by APOE status among postmenopausal women, but APOE4+ carriers not using statins had an increased risk of total CVD events.

APOE ε4 allele status modulates the spatial patterns of progressive atrophy in the temporal lobes after mild traumatic brain injury.

INTRODUCTION: We evaluated how the apolipoprotein E (APOE) ε4 allele modulated the spatial patterns of longitudinal atrophy in the Alzheimer's disease-vulnerable brain areas of patients with mild traumatic brain injury (mTBI) from the acute to chronic phase post injury. METHODS: Fifty-nine adult patients with acute mTBI and 48 healthy controls with APOE ε4 allele testing underwent T1-weighted magnetic resonance imaging and neuropsychological assessments with 6 to 12 months of follow-up. Progressive brain volume loss was compared voxel-wise in the temporal lobes. RESULTS: Patients with the APOE ε4 allele presented significant longitudinal atrophy in the left superior and middle temporal gyri, where the progressive gray matter volume loss predicted longitudinal impairment in language fluency, whereas mTBI APOE ε4 allele noncarriers showed mainly significant longitudinal atrophy in the medial temporal lobes, without significant neuropsychological relevance. DISCUSSION: The atrophy progression observed in mTBI patients with the APOE ε4 allele may increase the possibility of developing a specific phenotype of Alzheimer's disease with language dysfunction. Highlights: The apolipoprotein E (APOE) ε4 allele and mild traumatic brain injury (mTBI) are risk factors for Alzheimer's disease (AD) progression.It is unclear how the interaction of mTBI with the APOE ε4 allele impacts the progressive atrophy topography in AD-vulnerable brain regions.In this study, patients with the APOE ε4 allele showed progressive atrophy patterns similar to the early stage of logopenic variant of primary progressive aphasia (lvPPA) phenotype of AD. APOE ε4 allele carriers with mTBI history may be at the risk of developing a given AD phenotype with language dysfunction.

Associations of apolipoprotein E ε4 allele, regional cerebral blood flow, and serum liver function markers in patients with cognitive impairment.

Introduction: The ε4 allele of the apolipoprotein E gene (APOE4) is expressed abundantly in both the brain and peripheral circulation as a genetic risk factor for Alzheimer's disease (AD). Cerebral blood flow (CBF) dysfunction is an essential feature of AD, and the liver plays an important role in the pathogenesis of dementia. However, the associations of APOE4 with CBF and liver function markers in patients with cognitive impairment remains unclear. We aimed to evaluate the associations of APOE4 with CBF measured by arterial spin labeling (ASL) magnetic resonance imaging (MRI) and serum liver function markers in participants who were diagnosed with cognitive impairment. Methods: Fourteen participants with AD and sixteen with amnestic mild cognitive impairment (MCI) were recruited. In addition to providing comprehensive clinical information, all patients underwent laboratory tests and MRI. All participants were divided into carriers and noncarriers of the ε4 allele, and T-tests and Mann-Whitney U tests were used to observe the differences between APOE4 carriers and noncarriers in CBF and liver function markers. Results: Regarding regional cerebral blood flow (rCBF), APOE4 carriers showed hyperperfusion in the bilateral occipital cortex, bilateral thalamus, and left precuneus and hypoperfusion in the right lateral temporal cortex when compared with noncarriers. Regarding serum liver function markers, bilirubin levels (including total, direct, and indirect) were lower in APOE4 carriers than in noncarriers. Conclusion: APOE4 exerts a strong effect on CBF dysfunction by inheritance, representing a risk factor for AD. APOE4 may be related to bilirubin metabolism, potentially providing specific neural targets for the diagnosis and treatment of AD.

Associations of Apolipoprotein ε4 Genotypes with Motor and Nonmotor Symptoms in Parkinson's Disease: A Cross-Sectional Study.

Background: The apolipoprotein E (APOE) ε4 allele has been associated with cognitive decline in Parkinson's disease (PD), but little is known about its relationship with motor and other nonmotor symptoms and whether APOE ε4 retains an influence on cognition when other factors are considered. Objective: To investigate the impact of APOE ε4 on motor/nonmotor symptoms and its relationship with other factors affecting cognition in individuals with PD. Methods: We analyzed data from 7616 individuals, comparing motor/nonmotor symptoms in different APOE genotypes using binary logistic regression. Multivariate logistic regression examined factors associated with cognitive impairments, including APOE ε4, Geriatric Depression Scale (GDS) score, Non-motor Symptom Questionnaire (NMS) score, Movement Disorder Society-Sponsored Revision of the Unified Parkinson's Disease Rating Scale (MDS-UPDRS) Part II score, and physical activity level. Results: APOE ε4 heterozygosity was modestly associated with lower cognitive scores (odds ratio [OR], 0.92; 95% confidence interval [CI], 0.87-0.99), whereas no significant association was found for any other nonmotor and motor symptoms. However, in multivariate analysis, cognitive impairment was associated with higher GDS (OR, 1.28; 95% CI, 1.23-1.34), NMS (OR, 1.22; 95% CI, 1.19-1.25), and MDS-UPDRS Part II (OR, 1.07; 95% CI, 1.06-1.09) scores, whereas physical activity was negatively associated (OR, 0.99; 95% CI, 0.98-0.99). APOE ε4 was no longer significant after adjusting for these factors. Conclusions: There is a link between cognition and APOE ε4 in patients with PD; however, when considering multiple factors, APOE ε4 plays a subordinate role. Other factors, such as depression, physical activity, and other nonmotor symptoms, demonstrate a stronger influence on cognitive impairment.

Modulation of associations between education years and cortical volume in Alzheimer's disease vulnerable brain regions by Aß deposition and APOE ε4 carrier status in cognitively normal older adults.

Background: Education years, as a measure of cognitive reserve, have been shown to affect the progression of Alzheimer's disease (AD), both pathologically and clinically. However, inconsistent results have been reported regarding the association between years of education and intermediate structural changes in AD-vulnerable brain regions, particularly when AD risk factors were not considered during the preclinical phase. Objective: This study aimed to examine how Aß deposition and APOE ε4 carrier status moderate the relationship between years of education and cortical volume in AD-vulnerable regions among cognitively normal older adults. Methods: A total of 121 participants underwent structural MRI, [18F] flutemetamol PET-CT imaging, and neuropsychological battery assessment. Multiple regression analysis was conducted to examine the interaction between years of education and the effects of potential modifiers on cortical volume. The associations between cortical volume and neuropsychological performance were further explored in subgroups categorized based on AD risk factors. Results: The cortical volume of the left lateral occipital cortex and bilateral fusiform gyrus demonstrated a significant differential association with years of education, depending on the presence of Aß deposition and APOE ε4 carrier status. Furthermore, a significant relationship between the cortical volume of the bilateral fusiform gyrus and AD-nonspecific cognitive function was predominantly observed in individuals without AD risk factors. Conclusion: AD risk factors exerted varying influences on the association between years of education and cortical volume during the preclinical phase. Further investigations into the long-term implications of these findings would enhance our understanding of cognitive reserves in the preclinical stages of AD.