APOE Ε4 Allele Research Articles

Polygenic scores and Mendelian randomization identify plasma proteins causally implicated in Alzheimer's disease.

An increasing body of evidence suggests that neuroinflammation is one of the key drivers of late-onset Alzheimer's disease (LOAD) pathology. Due to the increased permeability of the blood-brain barrier (BBB) in older adults, peripheral plasma proteins can infiltrate the central nervous system (CNS) and drive neuroinflammation through interactions with neurons and glial cells. Because these inflammatory factors are heritable, a greater understanding of their genetic relationship with LOAD could identify new biomarkers that contribute to LOAD pathology or offer protection against it. We used a genome-wide association study (GWAS) of 90 different plasma proteins (n = 17,747) to create polygenic scores (PGSs) in an independent discovery (cases = 1,852 and controls = 1,990) and replication (cases = 799 and controls = 778) cohort. Multivariate logistic regression was used to associate the plasma protein PGSs with LOAD diagnosis while controlling for age, sex, principal components 1-2, and the number of APOE-e4 alleles as covariates. After meta-analyzing the PGS-LOAD associations between the two cohorts, we then performed a two-sample Mendelian randomization (MR) analysis using the summary statistics of significant plasma protein level PGSs in the meta-analysis as an exposure, and a GWAS of clinically diagnosed LOAD (cases = 21,982, controls = 41,944) as an outcome to explore possible causal relationships between the two. We identified four plasma protein level PGSs that were significantly associated (FDR-adjusted p < 0.05) with LOAD in a meta-analysis of the discovery and replication cohorts: CX3CL1, hepatocyte growth factor (HGF), TIE2, and matrix metalloproteinase-3 (MMP-3). When these four plasma proteins were used as exposures in MR with LOAD liability as the outcome, plasma levels of HGF were inferred to have a negative causal relationship with the disease when single-nucleotide polymorphisms (SNPs) used as instrumental variables were not restricted to cis-variants (OR/95%CI = 0.945/0.906-0.984, p = 0.005). Our results show that plasma HGF has a negative causal relationship with LOAD liability that is driven by pleiotropic SNPs possibly involved in other pathways. These findings suggest a low transferability between PGS and MR approaches, and future research should explore ways in which LOAD and the plasma proteome may interact.

Drugs targeting APOE4 that regulate beta-amyloid aggregation in the brain: Therapeutic potential for Alzheimer's disease.

Alzheimer's disease is characterized by progressive cognitive decline, and behavioural and psychological symptoms of dementia are common. The APOE ε4 allele, a genetic risk factor, significantly increases susceptibility to the disease. Despite efforts to effectively treat the disease, only seven drugs are approved for its treatment, and only two of these prevent its progression. This highlights the need to identify new pharmacological options. This review focuses on mimetic peptides, small molecule correctors and HAE-4 antibodies that target ApoE. These drugs reduce β-amyloid-induced neurodegeneration in preclinical models. In addition, loop diuretics such as bumetanide and furosemide show the potential to reduce the prevalence of Alzheimer's disease in humans, and antidepressants such as imipramine improve cognitive function in individuals diagnosed with Alzheimer's disease. Consistent with this, both classes of drugs have been shown to exert neuroprotective effects by inhibiting ApoE4-catalysed Aβ aggregation in preclinical models. Moreover, peroxisome proliferator-activated receptor ligands, particularly pioglitazone and rosiglitazone, reduce ApoE4-induced neurodegeneration in animal models. However, they do not prevent the cognitive decline in APOE ε4 allele carriers. Finally, ApoE4 impairs the integrity of the blood-brain barrier and haemostasis. On this basis, ApoE4 modulation is a promising avenue for the treatment of late-onset Alzheimer's disease.

Associations of endogenous estrogens, plasma Alzheimer's disease biomarkers, and APOE4 carrier status on regional brain volumes in postmenopausal women.

Women carrying the APOE4 allele are at greater risk of developing Alzheimer's disease (AD) from ages 65-75 years compared to men. To better understand the elevated risk conferred by APOE4 carrier status among midlife women, we investigated the separate and interactive associations of endogenous estrogens, plasma AD biomarkers, and APOE4 carrier status on regional brain volumes in a sample of late midlife postmenopausal women. Participants were enrolled in MsBrain, a cohort study of postmenopausal women (n = 171, mean age = 59.4 years, mean MoCA score = 26.9; race = 83.2% white, APOE4 carriers = 40). Serum estrone (E1) and estradiol (E2) levels were assessed using liquid chromatography-tandem mass spectrometry. APOE genotype was determined using TaqMan SNP genotyping assays. Plasma AD biomarkers were measured using single molecule array technology. Cortical volume was measured and segmented by FreeSurfer software using individual T1w MPRAGE images. Multiple linear regression models were conducted to determine whether separate and interactive associations between endogenous estrogen levels, plasma AD biomarkers (Aβ42/Aβ40, Aβ42/p-tau181), and APOE4 carrier status predict regional brain volume (21 regions per hemisphere, selected a priori); and, whether significant interactive associations between estrogens and AD biomarkers on brain volume differed by APOE4 carrier status. There was no main effect of APOE4 carrier status on regional brain volumes, endogenous estrogen levels, or plasma AD biomarkers. Estrogens did not associate with regional brain volumes, except for positive associations with left caudal middle frontal gyrus and fusiform volumes. The interactive association of estrogens and APOE4 carrier status on brain volume was not significant for any region. The interactive association of estrogens and plasma AD biomarkers predicted brain volume of several regions. Higher E1 and E2 were more strongly associated with greater regional brain volumes among women with a poorer AD biomarker profile (lower Aβ42/40, lower Aβ42/p-tau181 ratios). In APOE4-stratified analyses, these interactions were driven by non-APOE4 carriers. We demonstrate that the brain volumes of postmenopausal women with poorer AD biomarker profiles benefit most from higher endogenous estrogen levels. These findings are driven by non-APOE4 carriers, suggesting that APOE4 carriers may be insensitive to the favorable effects of estrogens on brain volume in the postmenopause.

Multiple Roles of Apolipoprotein E4 in Oxidative Lipid Metabolism and Ferroptosis During the Pathogenesis of Alzheimer’s Disease

Alzheimer’s disease (AD) is the most prevalent neurodegenerative disease worldwide and has a great socio-economic impact. Modified oxidative lipid metabolism and dysregulated iron homeostasis have been implicated in the pathogenesis of this disorder, but the detailed pathophysiological mechanisms still remain unclear. Apolipoprotein E (APOE) is a lipid-binding protein that occurs in large quantities in human blood plasma, and a polymorphism of the APOE gene locus has been identified as risk factors for AD. The human genome involves three major APOE alleles (APOE2, APOE3, APOE4), which encode for three subtly distinct apolipoprotein E isoforms (APOE2, APOE3, APOE4). The canonic function of these apolipoproteins is lipid transport in blood and brain, but APOE4 allele carriers have a much higher risk for AD. In fact, about 60% of clinically diagnosed AD patients carry at least one APOE4 allele in their genomes. Although the APOE4 protein has been implicated in pathophysiological key processes of AD, such as extracellular beta-amyloid (Aβ) aggregation, mitochondrial dysfunction, neuroinflammation, formation of neurofibrillary tangles, modified oxidative lipid metabolism, and ferroptotic cell death, the underlying molecular mechanisms are still not well understood. As for all mammalian cells, iron plays a crucial role in neuronal functions and dysregulation of iron homeostasis has also been implicated in the pathogenesis of AD. Imbalances in iron homeostasis and impairment of the hydroperoxy lipid-reducing capacity induce cellular dysfunction leading to neuronal ferroptosis. In this review, we summarize the current knowledge on APOE4-related oxidative lipid metabolism and the potential role of ferroptosis in the pathogenesis of AD. Pharmacological interference with these processes might offer innovative strategies for therapeutic interventions.

Prolonged ventricular repolarization associated with mild cognitive impairment and white matter hyperintensities: a cross-sectional study

Prolonged ventricular repolarization has been associated with cardiovascular disease. We sought to investigate the association of prolonged ventricular repolarization with mild cognitive impairment (MCI) and the potential underlying neuropathological mechanisms in older adults. This cross-sectional study included 4328 dementia-free participants (age ≥ 65 years; 56.8% female) in the baseline examination of the Multidomain INterventions to delay dementia and Disability in rural China; of these, 989 undertook structural brain magnetic resonance imaging (MRI) scans. QT, QTc, JT, JTc, and QRS intervals were derived from 12-lead electrocardiograph. MCI, amnestic MCI (aMCI), and non-amnestic MCI (naMCI) were defined following the Petersen’s criteria. Volumes of gray matter (GM), white matter, cerebrospinal fluid, total white matter hyperintensities (WMH), periventricular WMH (PWMH), and deep WMH (DWMH) were automatically estimated. Data were analyzed using logistic and general linear regression models. Prolonged QT, QTc, JT, and JTc intervals were significantly associated with an increased likelihood of MCI and aMCI, but not naMCI (p < 0.05). In the MRI subsample, QT, QTc, JT, and JTc intervals were significantly associated with larger total WMH and PWMH volumes (p < 0.05), but not with DWMH volume. Statistical interactions were detected, such that prolonged QT and JT intervals were significantly associated with reduced GM volume only among participants with coronary heart disease or without APOE ε4 allele (p < 0.05). Prolonged ventricular repolarization is associated with MCI and cerebral microvascular lesions in a general population of older adults. This underlies the importance of cognitive assessments and brain MRI examination among older adults with prolonged QT interval.

Genetic factors associated to Alzheimer’s Disease

Alzheimer's disease is a neurological condition that gradually impairs memory, self-awareness, and cognitive capacities. It is the most frequent cause of dementia and a major factor in senior patient deaths. It is generally acknowledged that the condition is multifactorial, resulting from intricate interactions between age, genetics, and environment, even though the exact cause is unknown. Early start of the condition can be caused by mutations in the APP, PSEN1, and PSEN2 genes, which can result in an autosomal dominant inheritance pattern. The most prevalent kind is late-onset, in which the APOE ε4 allele is the primary genetic risk factor. TREM2, CLU, and PICALM are among the other genes that raise the risk. The primary molecular pathways are the build-up of beta-amyloid proteins, which result in amyloid plaques, and the hyperphosphorylation of tau, which forms neurofibrillary tangles and causes neuronal death by necrosis, autophagy, and apoptosis. Acetylcholine, glutamate, GABA, and noradrenaline neurotransmission are all impacted, which has an effect on cognition and memory.In conclusion, Alzheimer's disease is a complicated neurological disorder that causes progressive cognitive impairment due to both hereditary and molecular components.

Snoring and risk of dementia: a prospective cohort and Mendelian randomization study.

The association between snoring, a very common condition that increases with age, and dementia risk is controversial. We aimed to investigate the observational and causal relationship between snoring and dementia, and to elucidate the role of body mass index (BMI). Using data from 451,250 participants who were dementia-free at baseline, we examined the association between self-reported snoring and incident dementia using Cox proportional-hazards models. Causal relationship between snoring and Alzheimer's disease (AD) was examined using bidirectional two-sample Mendelian randomization (MR) analysis. During a median follow-up of 13.6 years, 8,325 individuals developed dementia. Snoring was associated with a lower risk of all-cause dementia (hazard ratio [HR] 0.93; 95% confidence interval [CI] 0.89 to 0.98) and AD (HR 0.91; 95% CI 0.84 to 0.97). The association was slightly attenuated after adjusting for BMI, and was stronger in older individuals, APOE ε4 allele carriers, and during shorter follow-up periods. MR analyses suggested no causal effect of snoring on AD, however, genetic liability to AD was associated with a lower risk of snoring. Multivariable MR indicated that the effect of AD on snoring was primarily driven by BMI. The phenotypic association between snoring and lower dementia risk likely stems from reverse causation, with genetic predisposition to AD associated with reduced snoring. This may be driven by weight loss in prodromal AD. Increased attention should be paid to reduced snoring and weight loss in older adults as potential early indicators of dementia risk.

Changes in expression of VGF, SPECC1L, HLA-DRA and RANBP3L act with APOE E4 to alter risk for late onset Alzheimer’s disease

While there are currently over 40 replicated genes with mapped risk alleles for Late Onset Alzheimer’s disease (LOAD), the Apolipoprotein E locus E4 haplotype is still the biggest driver of risk, with odds ratios for neuropathologically confirmed E44 carriers exceeding 30 (95% confidence interval 16.59–58.75). We sought to address whether the APOE E4 haplotype modifies expression globally through networks of expression to increase LOAD risk. We have used the Human Brainome data to build expression networks comparing APOE E4 carriers to non-carriers using scalable mixed-datatypes Bayesian network (BN) modeling. We have found that VGF had the greatest explanatory weight. High expression of VGF is a protective signal, even on the background of APOE E4 alleles. LOAD risk signals, considering an APOE background, include high levels of SPECC1L, HLA-DRA and RANBP3L. Our findings nominate several new transcripts, taking a combined approach to network building including known LOAD risk loci.

Multifaceted roles of APOE in Alzheimer disease.

For the past three decades, apolipoprotein E (APOE) has been known as the single greatest genetic modulator of sporadic Alzheimer disease (AD) risk, influencing both the average age of onset and the lifetime risk of developing AD. The APOEε4 allele significantly increases AD risk, whereas the ε2 allele is protective relative to the most common ε3 allele. However, large differences in effect size exist across ethnoracial groups that arelikely todepend on both global genetic ancestry and local genetic ancestry, as well as gene-environment interactions. Although early studies linked APOE to amyloid-β - one of the two culprit aggregation-prone proteins that define AD - in the past decade, mountingwork has associated APOE with other neurodegenerative proteinopathies and broader ageing-related brain changes, such as neuroinflammation, energy metabolism failure, loss of myelin integrity and increased blood-brain barrier permeability, with potential implications for longevity and resilience to pathological protein aggregates. Novel mouse models and other technological advances have also enabled a number of therapeutic approaches aimed at either attenuating the APOEε4-linked increased AD risk or enhancing theAPOEε2-linked AD protection. This Review summarizes this progress and highlights areas for future research towards the development of APOE-directed therapeutics.

MTOR inhibition enhances synaptic and mitochondrial function in Alzheimer’s disease in an APOE genotype-dependent manner

Apolipoprotein ε4 (APOE4) carriers develop brain metabolic dysfunctions decades before the onset of Alzheimer’s disease (AD). A goal of the study is to identify if rapamycin, an inhibitor for the mammalian target of rapamycin (mTOR) inhibitor, would enhance synaptic and mitochondrial function in asymptomatic mice with human APOE4 gene (E4FAD) before they showed metabolic deficits. A second goal is to determine whether there may be genetic-dependent responses to rapamycin when compared to mice with human APOE3 alleles (E3FAD), a neutral AD genetic risk factor. We fed asymptomatic E4FAD and E3FAD mice with control or rapamycin diets for 16 weeks from starting from 3 months of age. Neuronal mitochondrial oxidative metabolism and excitatory neurotransmission rates were measured using in vivo 1H-[13C] proton-observed carbon-edited magnetic resonance spectroscopy, and isolated mitochondrial bioenergetic measurements using Seahorse. We found that rapamycin enhanced neuronal mitochondrial function, glutamate-glutamine cycling, and TCA cycle rates in the asymptomatic E4FAD mice. In contrast, rapamycin enhances glycolysis, non-neuronal activities, and inhibitory neurotransmission of the E3FAD mice. These findings indicate that rapamycin might be able to mitigate the risk for AD by enhancing brain metabolic functions for cognitively intact APOE4 carriers, and the responses to rapamycin are varied by APOE genotypes. Consideration of precision medicine may be needed for future rapamycin therapeutics.

Classification of Mild Cognitive Impairment and Alzheimer’s Disease Using Manual Motor Measures

Introduction: Manual motor problems have been reported in mild cognitive impairment (MCI) and Alzheimer’s disease (AD), but the specific aspects that are affected, their neuropathology, and potential value for classification modeling is unknown. The current study examined if multiple measures of motor strength, dexterity, and speed are affected in MCI and AD, related to AD biomarkers, and are able to classify MCI or AD. Methods: Fifty-three cognitively normal (CN), 33 amnestic MCI, and 28 AD subjects completed five manual motor measures: grip force, Trail Making Test A, spiral tracing, finger tapping, and a simulated feeding task. Analyses included (1) group differences in manual performance; (2) associations between manual function and AD biomarkers (PET amyloid β, hippocampal volume, and APOE ε4 alleles); and (3) group classification accuracy of manual motor function using machine learning. Results: Amnestic MCI and AD subjects exhibited slower psychomotor speed and AD subjects had weaker dominant hand grip strength than CN subjects. Performance on these measures was related to amyloid β deposition (both) and hippocampal volume (psychomotor speed only). Support vector classification well-discriminated control and AD subjects (area under the curve of 0.73 and 0.77, respectively) but poorly discriminated MCI from controls or AD. Conclusion: Grip strength and spiral tracing appear preserved, while psychomotor speed is affected in amnestic MCI and AD. The association of motor performance with amyloid β deposition and atrophy could indicate that this is due to amyloid deposition in and atrophy of motor brain regions, which generally occurs later in the disease process. The promising discriminatory abilities of manual motor measures for AD emphasize their value alongside other cognitive and motor assessment outcomes in classification and prediction models, as well as potential enrichment of outcome variables in AD clinical trials.

APOE2 protects against Aβ pathology by improving neuronal mitochondrial function through ERRα signaling

BackgroundAlzheimer’s disease (AD) is a progressive neurodegenerative disease and apolipoprotein E (APOE) genotypes (APOE2, APOE3, and APOE4) show different AD susceptibility. Previous studies indicated that individuals carrying the APOE2 allele reduce the risk of developing AD, which may be attributed to the potential neuroprotective role of APOE2. However, the mechanisms underlying the protective effects of APOE2 is still unclear.MethodsWe analyzed single-nucleus RNA sequencing and bulk RNA sequencing data of APOE2 and APOE3 carriers from the Religious Orders Study and Memory and Aging Project (ROSMAP) cohort. We validated the findings in SH-SY5Y cells and AD model mice by evaluating mitochondrial functions and cognitive behaviors respectively.ResultsThe pathway analysis of six major cell types revealed a strong association between APOE2 and cellular stress and energy metabolism, particularly in excitatory and inhibitory neurons, which was found to be more pronounced in the presence of beta-amyloid (Aβ). Moreover, APOE2 overexpression alleviates Aβ1-42-induced mitochondrial dysfunction and reduces the generation of reactive oxygen species in SH-SY5Y cells. These protective effects may be due to ApoE2 interacting with estrogen-related receptor alpha (ERRα). ERRα overexpression by plasmids or activation by agonist was also found to show similar mitochondrial protective effects in Aβ1-42-stimulated SH-SY5Y cells. Additionally, ERRα agonist treatment improve the cognitive performance of Aβ injected mice in both Y maze and novel object recognition tests. ERRα agonist treatment increased PSD95 expression in the cortex of agonist-treated-AD mice.ConclusionsAPOE2 appears to enhance neural mitochondrial function via the activation of ERRα signaling, which may be the protective effect of APOE2 to treat AD.

Association of APOE genotype and cerebrospinal fluid Aβ and tau biomarkers with cognitive and motor phenotype in amyotrophic lateral sclerosis.

Little is known about amyotrophic lateral sclerosis (ALS)-nonspecific cognitive deficits - most notably memory disturbance - and their biological underpinnings. We investigated the associations of the Alzheimer's disease (AD) genetic risk factor APOE and cerebrospinal fluid (CSF) biomarkers Aβ and tau proteins with cognitive and motor phenotype in ALS. APOE haplotype was determined in 281 ALS patients; for 105 of these, CSF levels of Aβ42, Aβ40, total tau (T-tau), and phosphorylated tau (P-tau181) were quantified by chemiluminescence enzyme immunoassay (CLEIA). The Edinburgh Cognitive and Behavioural ALS Screen (ECAS) was employed to evaluate the neuropsychological phenotype. APOE-E4 allele was associated with worse ECAS memory score (median, 14.0 in carriers vs. 16.0 in non-carriers) and lower CSF Aβ42 (-0.8 vs. 0.1, log-transformed values) and Aβ42/40 ratio (-0.1 vs. 0.3). Some 37.1% of ALS patients showed low Aβ42 levels, possibly reflecting cerebral Aβ deposition. While lower Aβ42/40 correlated with lower memory score (β = 0.20), Aβ42 positively correlated with both ALS-specific (β = 0.24) and ALS-nonspecific (β = 0.24) scores. Although Aβ42/40 negatively correlated with T-tau (β = -0.29) and P-tau181 (β = -0.33), we found an unexpected positive association of Aβ42 and Aβ40 with both tau proteins. Regarding motor phenotype, lower levels of Aβ species were associated with lower motor neuron (LMN) signs (Aβ40: β = 0.34; Aβ42: β = 0.22). APOE haplotype and CSF Aβ biomarkers are associated with cognitive deficits in ALS and particularly with memory impairment. This might partly reflect AD-like pathophysiological processes, but additional ALS-specific mechanisms could be involved.

Impact of work type and APOE-e4 status on cognitive functioning in older women

Prior research indicates that APOE-e4 allele(s) and working without compensation may be independently associated with risk for cognitive decline. This study investigated whether the interaction of type of work (paid versus unpaid) and presence of APOE-e4 allele(s) was associated with cognitive dysfunction in women in mid- and late-life. Participants included 340 females (mean age = 74.7 years) from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) dataset. A two-way ANOVA to assess the simple main effects of type of work and APOE-e4 allele status on cognition as well as their interaction was performed. A two-way ANCOVA including age, education, and marital status as covariates was also conducted. The presence of one or two APOE-e4 allele(s) and unpaid work was associated with greater cognitive dysfunction. A significant interaction effect revealed engagement in paid work, regardless of the presence of APOE-e4 allele(s), was associated with better cognitive functioning. Consistent with prior literature, women who engage in unpaid forms of labor for the majority of their life may be at higher risk for cognitive decline, regardless of presence of APOE-e4 allele(s). Further research is needed to identify the factors related to unpaid labor that may increase risk for cognitive dysfunction.

Mid-life sleep is associated with cognitive performance later in life in aging American Indians: data from the Strong Heart Study.

Sleep-related disorders have been associated with cognitive decline and neurodegeneration. American Indians are at increased risk for dementia. Here, we aim to characterize, for the first time, the associations between sleep characteristics and subsequent cognitive performance in a sample of aging American Indians. We performed analyses on data collected in two ancillary studies from the Strong Heart Study, which occurred approximately 10 years apart with an overlapping sample of 160 American Indians (mean age at follow-up 73.1, standard deviation 5.6; 69.3% female and 80% with high school completion). Sleep measures were derived by polysomnography and self-reported questionnaires, including sleep timing and duration, sleep latency, sleep stages, indices of sleep-disordered breathing, and self-report assessments of poor sleep and daytime sleepiness. Cognitive assessment included measures of general cognition, processing speed, episodic verbal learning, short and long-delay recall, recognition, and phonemic fluency. We performed correlation analyses between sleep and cognitive measures. For correlated variables, we conducted separate linear regressions. We analyzed the degree to which cognitive impairment, defined as more than 1.5 standard deviations below the average Modified Mini Mental State Test score, is predicted by sleep characteristics. All regression analyses were adjusted for age, sex, years of education, body mass index, study site, depressive symptoms score, difference in age from baseline to follow-up, alcohol use, and presence of APOE e4 allele. We found that objective sleep characteristics measured by polysomnography, but not subjective sleep characteristics, were associated with cognitive performance approximately 10 years later. Longer sleep latency was associated with worse phonemic fluency (β = -0.069, p = 0.019) and increased likelihood of being classified in the cognitive impairment group later in life (odds ratio 1.037, p = 0.004). Longer duration with oxygen saturation < 90% was associated with better immediate verbal memory, and higher oxygen saturation with worse total learning, short and long-delay recall, and processing speed. In a sample of American Indians, sleep characteristics in midlife were correlated with cognitive performance a decade later. Sleep disorders may be modifiable risk factors for cognitive impairment and dementia later in life, and suitable candidates for interventions aimed at preventing neurodegenerative disease development and progression.

Apolipoprotein E4 interferes with lipid metabolism to exacerbate depression-like behaviors in 5xFAD mice.

Apolipoprotein E4 (ApoE4) allele is the strongest genetic risk factor for late-onset Alzheimer's disease, and it can aggravate depressive symptoms in non-AD patients. However, the impact of ApoE4 on AD-associated depression-like behaviors and its underlying pathogenic mechanisms remain unclear. This study developed a 5xFAD mouse model overexpressing human ApoE4 (E4FAD). Behavioral assessments and synaptic function tests were conducted to explore the effects of ApoE4 on cognition and depression in 5xFAD mice. Changes in peripheral and central lipid metabolism, as well as the levels of serotonin (5-HT) and γ-aminobutyric acid (GABA) neurotransmitters in the prefrontal cortex, were examined. In addition, the protein levels of 24-dehydrocholesterol reductase/glycogen synthase kinase-3 beta/mammalian target of rapamycin (DHCR24/GSK3β/mTOR) and postsynaptic density protein 95/calmodulin-dependent protein kinase II/brain-derived neurotrophic factor (PSD95/CaMK-II/BDNF) were measured to investigate the molecular mechanism underlying the effects of ApoE4 on AD mice. Compared with 5xFAD mice, E4FAD mice exhibited more severe depression-like behaviors and cognitive impairments. These mice also exhibited increased amyloid-beta deposition in the hippocampus, increased astrocyte numbers, and decreased expression of depression-related neurotransmitters 5-HT and GABA in the prefrontal cortex. Furthermore, lipid metabolism disorders were observed in E4FAD, manifesting as elevated low-density lipoprotein cholesterol and reduced high-density lipoprotein cholesterol in peripheral blood, decreased cholesterol level in the prefrontal cortex, and reduced expression of key enzymes and proteins related to cholesterol synthesis and homeostasis. Abnormal expression of proteins related to the DHCR24/GSK3β/mTOR and PSD95/CaMK-II/BDNF pathways was also observed. This study found that ApoE4 overexpression exacerbates depression-like behaviors in 5xFAD mice and confirmed that ApoE4 reduces cognitive function in these mice. The mechanism may involve the induction of central and peripheral lipid metabolism disorders. Therefore, modulating ApoE expression or function to restore cellular lipid homeostasis may be a promising therapeutic target for AD comorbid with depression. This study also provided a better animal model for studying AD comorbid with depression.

Risk factors for severe COVID-19 disease increase SARS-CoV-2 infectivity of endothelial cells and pericytes.

Coronavirus disease 2019 (COVID-19) was initially considered a primarily respiratory disease but is now known to affect other organs including the heart and brain. A major route by which COVID-19 impacts different organs is via the vascular system. We studied the impact of apolipoprotein E (APOE) genotype and inflammation on vascular infectivity by pseudo-typed severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) viruses in mouse and human cultured endothelial cells and pericytes. Possessing the APOE4 allele or having existing systemic inflammation is known to enhance the severity of COVID-19. Using targeted replacement human APOE3 and APOE4 mice and inflammation induced by bacterial lipopolysaccharide (LPS), we investigated infection by SARS-CoV-2. Here, we show that infectivity was higher in murine cerebrovascular pericytes compared to endothelial cells and higher in cultures expressing APOE4. Furthermore, increasing the inflammatory state of the cells by prior incubation with LPS increased infectivity into human and mouse pericytes and human endothelial cells. Our findings provide insights into the mechanisms underlying severe COVID-19 infection, highlighting how risk factors such as APOE4 genotype and prior inflammation may exacerbate disease severity by augmenting the virus's ability to infect vascular cells.

Association between ABO genotypes and risk of dementia and neuroimaging markers: roles of sex and APOE status.

Whether the relationships between ABO blood genotypes (AA, AO, BB, BO, AB, and OO) and dementia are modified by gender and APOE status has been unclear. We used data from the UK Biobank, a population-based cohort study of 487,425 individuals. Cox proportional hazards models were used to estimate hazard ratios (HRs) and 95% confidence intervals (CI) between ABO genotypes and risk of dementia. Multivariable linear regression models were used to estimate the relationship between ABO genotypes and MRI-based brain indices. Overall, 487,425 participants were included at baseline. After 34 million person-years follow up, 7,548 patients developed all-cause dementia. Before stratifying by sex and APOE status, compared to OO genotype, BB genotype was associated with increased risk of all-cause dementia (1.36, 1.03-1.80) and other types dementia (1.65, 1.20-2.28). After stratifying by sex, only in males, BB genotype was associated with higher risk of all-cause dementia (1.44, 1.02-2.09) and other types of dementia (1.95, 1.30-2.93). AB genotype in males was also associated with increased AD (1.34, 1.04-1.72). After further stratifying by APOE e4 status, BB genotype with two APOE e4 alleles showed even stronger association with all-cause dementia 4.29 (1.57, 11.72) and other types dementia (5.49, 1.70-17.69) in males. Also in males, AA genotype with one APOE e4 was associated with increased risks of all-cause dementia (1.27, 1.04-1.55), AD (1.45, 1.09-1.94) and other types dementia (1.40, 1.08-1.81). Linear regression models showed that in both sexes with APOE e4, AA genotype was associated with reduced total grey matter volume. Sex and APOE e4 carrier status modified the association between ABO genotypes and risk of dementia. In males, BB genotype was consistently associated with increased risk of dementia, especially in those with two APOE e4 alleles. Also, in males with one APOE e4, AA genotype might be linked to higher risk of dementia.

Clinical characteristics of cerebral amyloid angiopathy and risk factors of cerebral amyloid angiopathy related intracerebral hemorrhage.

There is limited understanding of the differences between cerebral amyloid angiopathy (CAA) with and without intracerebral hemorrhage (ICH). This article aimed to describe the characteristics of CAA and identify the risk factors of CAA-ICH in a multicenter cohort. Patients consecutively enrolled in the national multicenter prospective Cerebral Small Vessel Disease Cohort Study who met the Boston diagnostic criteria for CAA or CAA-related inflammation were included in this study. The demographic characteristics and clinical data were collected. The clinical and radiographic differences between CAA with and without ICH were compared to identify the risk factors for CAA-ICH. A total of 219 CAA patients were included, with an average age of 67.12 ± 9.93. Of all patients, 26.0% were CAA with ICH. Univariate analysis showed that CAA-ICH is associated with carrying more APOE ε2 allele, less lobar cerebral microbleeds (CMBs), cortical superficial siderosis (cSS), lower Fazekas scale, a tendency of gait disorder, and acute onset (P < 0.05). The generalized linear mixed model yielded statistically significant associations between CAA with ICH and carrying the APOE ε2 allele, cSS, the lower number of lobar CMBs, and the lower Fazekas scale (P < 0.05). It is meaningful to classify CAA with and without ICH, as there may be different mechanisms between the two. CAA with ICH has a susceptibility to carrying APOE ε2, cSS, and a relatively small number of CMBs. Fewer CMBs do not mean lower susceptibility to ICH in CAA. Larger prospective cohort studies are necessary to further clarify these conclusions.

Temporal Characterization of the Amyloidogenic APPswe/PS1dE9;hAPOE4 Mouse Model of Alzheimer's Disease.

Alzheimer's disease (AD) is a devastating disorder with a global prevalence estimated at 55 million people. In clinical studies administering certain anti-beta-amyloid (Aβ) antibodies, amyloid-related imaging abnormalities (ARIAs) have emerged as major adverse events. The frequency of these events is higher among apolipoprotein ε4 allele carriers (APOE4) compared to non-carriers. To reflect patients most at risk for vascular complications of anti-Aβ immunotherapy, we selected an APPswe/PS1dE9 transgenic mouse model bearing the human APOE4 gene (APPPS1:E4) and compared it with the same APP/PS1 mouse model bearing the human APOE3 gene (APOE ε3 allele; APPPS1:E3). Using histological and biochemical analyses, we characterized mice at three ages: 8, 12, and 16 months. Female and male mice were assayed for general cerebral fibrillar and pyroglutamate (pGlu-3) Aβ deposition, cerebral amyloid angiopathy (CAA), microhemorrhages, apoE and cholesterol composition, astrocytes, microglia, inflammation, lysosomal dysfunction, and neuritic dystrophy. Amyloidosis, lipid deposition, and astrogliosis increased with age in APPPS1:E4 mice, while inflammation did not reveal significant changes with age. In general, APOE4 carriers showed elevated Aβ, apoE, reactive astrocytes, pro-inflammatory cytokines, microglial response, and neuritic dystrophy compared to APOE3 carriers at different ages. These results highlight the potential of the APPPS1:E4 mouse model as a valuable tool in investigating the vascular side effects associated with anti-amyloid immunotherapy.