Humans ; Alzheimer Disease/genetics* ; Apolipoprotein E4/genetics* ; Amyloid beta-Peptides

Approximately 140 million people worldwide are homozygous carriers of APOE4 (ε4), a strong genetic risk factor for late onset familial and sporadic Alzheimer's disease (AD), 91% of whom will develop AD at earlier age than heterozygous carriers and noncarriers. Susceptibility to AD could be reduced by targeted editing of APOE4, but a technical basis for controlling the off-target effects of base editors is necessary to develop low-risk personalized gene therapies. Here, we first screened eight cytosine base editor variants at four injection stages (from 1- to 8-cell stage), and found that FNLS-YE1 variant in 8-cell embryos achieved the comparable base conversion rate (up to 100%) with the lowest bystander effects. In particular, 80% of AD-susceptible ε4 allele copies were converted to the AD-neutral ε3 allele in human ε4-carrying embryos. Stringent control measures combined with targeted deep sequencing, whole genome sequencing, and RNA sequencing showed no DNA or RNA off-target events in FNLS-YE1-treated human embryos or their derived stem cells. Furthermore, base editing with FNLS-YE1 showed no effects on embryo development to the blastocyst stage. Finally, we also demonstrated FNLS-YE1 could introduce known protective variants in human embryos to potentially reduce human susceptivity to systemic lupus erythematosus and familial hypercholesterolemia. Our study therefore suggests that base editing with FNLS-YE1 can efficiently and safely introduce known preventive variants in 8-cell human embryos, a potential approach for reducing human susceptibility to AD or other genetic diseases.
Humans ; Apolipoprotein E4/genetics* ; Cytosine ; Mutation ; Blastocyst ; Heterozygote ; Gene Editing ; CRISPR-Cas Systems

Objective: To understand the distribution characteristics of age of Alzheimer's disease (AD) onset and influencing factors. Methods: Based on the follow-up data of Alzheimer's Disease Neuroimaging Initiative from 2005 to 2022, participants with normal cognition (CN) or mild cognitive impairment (MCI) at baseline survey, and those with progression to AD during follow-up period were selected as study subjects. Univariate analysis and multiple linear regression analysis were performed to explore the associations of gender, race, number of ApoE ε4 genes carried, family history, years of education and marital status with the age of AD onset. Results: A total of 405 participants, with an average age of (74.0±6.9) years at baseline survey, progressed to AD during follow up period. The age of AD onset was (76.6±7.5) years, and age of onset in men was about 1.9 years later than women. Multiple linear regression analysis showed that for each increase in ApoE ε4 gene number, the age of AD onset was about 0.344 years earlier. The age of AD onset was 4.007 years earlier for those with MCI at baseline survey compared with those with CN. Years of education were not significantly associated with the age of onset of AD (P>0.05). Conclusion: Those who carry ApoE ε4 gene, and have MCI at baseline survey might have earlier age of AD onset.
Aged ; Aged, 80 and over ; Female ; Humans ; Male ; Alzheimer Disease/genetics* ; Apolipoprotein E4/genetics* ; Cognition ; Cognition Disorders ; Cognitive Dysfunction/genetics*

Alzheimer's disease (AD) is the most prevalent neurodegenerative disease featuring progressive cognitive impairment. Although the etiology of late-onset AD remains unclear, the close association of AD with apolipoprotein E (APOE), a gene that mainly regulates lipid metabolism, has been firmly established and may shed light on the exploration of AD pathogenesis and therapy. However, various confounding factors interfere with the APOE-related AD risk, raising questions about our comprehension of the clinical findings concerning APOE. In this review, we summarize the most debated factors interacting with the APOE genotype and AD pathogenesis, depict the extent to which these factors relate to APOE-dependent AD risk, and discuss the possible underlying mechanisms.
Alzheimer Disease/pathology* ; Apolipoprotein E4/genetics* ; Apolipoproteins E/genetics* ; Genotype ; Humans ; Lipid Metabolism ; Neurodegenerative Diseases ; Risk Factors

Alzheimer Disease/genetics* ; Animals ; Apolipoprotein E4/metabolism* ; Gene-Environment Interaction ; Hippocampus/metabolism* ; Male ; Noise/adverse effects* ; Rats

OBJECTIVETo explore the relations among apolipoprotein E4, Tau protein and glycogen synthase kinase 3β (GSK-3β).

METHODSU87 cells were transfected with pIRES-EGFP (control) or the recombinant plasmids ApoE4/pIRES-EGFP or ApoE3/pIRES-EGFP, and the expression levels of p-Tau/Tau and GSK-3β in the cells were examined with Western blotting. To further confirm the effect of ApoE on GSK-3β and p-Tau expressions, a short interfering RNA (siRNA) targeting ApoE (ApoE-siRNA) was transfected into U87 cells via Lipofectamine 2000 and the protein expressions were examined 24 h later.

RESULTSCompared with those in the control group, the expressions levels of both GSK-3β and p-Tau/Tau increased significantly in the cells transfected with ApoE4 and ApoE3 plasmids (P<0.01), and the ApoE4 plasmid produced a more potent effect than the ApoE3 plasmid on the protein expressions (P<0.01). ApoE knockdown resulted in significantly reduced expressions of GSK-3β (P<0.001) and p-Tau (P<0.01) in the cells.

CONCLUSIONApoE4 can enhance Tau phosphorylation though upregulating GSK-3β, which sheds light on a new role of ApoE4 in Alzheimer's disease.

Alzheimer Disease ; genetics ; Apolipoprotein E3 ; genetics ; Apolipoprotein E4 ; genetics ; Cell Line ; Gene Silencing ; Glycogen Synthase Kinase 3 beta ; genetics ; metabolism ; Humans ; Phosphorylation ; RNA, Small Interfering ; genetics ; Transfection ; tau Proteins ; metabolism

OBJECTIVETo investigate the relationship between apolipoprotein e4 allele and emergence agitation (EA) in patients undergoing general anesthesia.

METHODSA nested cohort study was conducted in elderly patients (over 60 years old) scheduled for major abdominal surgery requiring general anesthesia. A structured interview was conducted in PACU to determine EA, defined using the Sedation-Agitation Scale (SAS). Blood samples were obtained for measurement of the apolipoprotein genotypes.

RESULTSOf the 196 patients studied, 22.4% developed EA. Thirty-eight patients (19.4%) had the apolipoprotein e4 allele. The presence of the e4 allele and low level of education were both associated with an increased risk of EA (36.9% vs15.8%, P=0.005; 30% vs 14.3%, P=0.01). After adjustment for covariates, the patients with the copy of e4 allele were shown to have a greater likeliness of an increased risk of EA (odds ratio: 4.32; 95% CI: 1.75-10.05) than those without the e4 allele.

CONCLUSIONApolipoprotein e4 carrier status is associated with an increased risk for EA.

Abdomen ; surgery ; Aged ; Alleles ; Anesthesia Recovery Period ; Anesthesia, General ; adverse effects ; methods ; Apolipoprotein E4 ; genetics ; Female ; Genotype ; Humans ; Male ; Middle Aged ; Psychomotor Agitation ; etiology ; genetics ; Risk Factors

Alzheimer's disease (AD) is an increasing epidemic threatening public health. Both men and women are susceptible to the disease although women are at a slightly higher risk. The prevalence of AD rises exponentially in elderly people from 1% at age of 65 to approximately 40%-50% by the age of 95. While the cause of the disease has not been fully understood, genetics plays a role in the onset of the disease. Mutations in three genes (APP, PSEN1, and PSEN2) have been found to cause AD and APOE4 allele increases the risk of the disease. As human genomic research progresses, more genes have been identified and linked with AD. Genetic screening tests for persons at high risk of AD are currently available and may help them as well as their families better prepare for a later life with AD.
Aged ; Aged, 80 and over ; Aging ; genetics ; metabolism ; Alzheimer Disease ; diagnosis ; epidemiology ; genetics ; Amyloid beta-Protein Precursor ; genetics ; metabolism ; Apolipoprotein E4 ; genetics ; Genetic Predisposition to Disease ; genetics ; Genetic Testing ; trends ; Humans ; Mutation ; genetics ; Presenilins ; genetics ; metabolism ; Risk Factors

This study aimed to investigate the independent and interactive influences of apolipoprotein E (APOE) epsilon4 and beta-amyloid (Abeta) on multiple cognitive domains in a large group of cognitively normal (CN) individuals and patients with mild cognitive impairment (MCI) and Alzheimer's disease (AD). Participants were included if clinical and cognitive assessments, amyloid imaging, and APOE genotype were all available from the Alzheimer's Disease Neuroimaging Initiative database (CN = 324, MCI = 502, AD = 182). Individuals with one or two copies of epsilon4 were designated as APOE epsilon4 carriers (epsilon4+); individuals with no epsilon4 were designated as APOE epsilon4 non-carriers (epsilon4-). Based on mean florbetapir standard uptake value ratios, participants were classified as Abeta burden-positive (Abeta+) or Abeta burden-negative (Abeta-). In MCI, APOE epsilon4 effects were predominantly observed on frontal executive function, with epsilon4+ participants exhibiting poorer performances; Abeta positivity had no influence on this effect. Abeta effects were observed on global cognition, memory, and visuospatial ability, with Abeta+ participants exhibiting poorer performances. Measures of frontal executive function were not influenced by Abeta. Interactive effects of APOE epsilon4+ and Abeta were observed on global cognition and verbal recognition memory. Abeta, not APOE epsilon4+, influenced clinical severity and functional status. The influences of APOE epsilon4+ and Abeta on cognitive function were minimal in CN and AD. In conclusion, we provide further evidence of both independent and interactive influences of APOE epsilon4+ and Abeta on cognitive function in MCI, with APOE epsilon4+ and Abeta showing dissociable effects on executive and non-executive functions, respectively.
Aged ; Aged, 80 and over ; Alzheimer Disease/genetics/pathology ; Amyloid beta-Peptides/*metabolism ; Aniline Compounds/chemistry ; Apolipoprotein E4/*genetics ; Brain/radiography ; Cognition ; Databases, Factual ; Demography ; Ethylene Glycols/chemistry ; Female ; Genotype ; Humans ; Male ; Mild Cognitive Impairment/genetics/*pathology ; Positron-Emission Tomography

To explore the relationship between apolipoprotein E polymorphism and cognitive function in primary hypertension patients, we collected 200 Chinese primary hypertensive patients. Blood pressure (BP), heart rate (HR), height, body weight, waistline, hip circumference were measured. The Mini Mental State Examination (MMSE) was applied to test the cognitive function and compute score. Full-automatic bio-chemistry analyzer was used to determine total cholesterol (TC) and triglyeride (TG) and fasting glucose. The polymerase chain reaction-restriction fragment length polymorphism (PCR-RELP) was used for the analysis of the apolipoprotein E polymorphism. We found that in primary hypertension patients, the genotype frequency of epsilon3/4 and epsilon4/4 were significantly higher in the cognitive impairment group than that in the cognitive normal group. The allele frequency of e4 is obviously higher in the cognitive impairment group than that in the cognitive normal group. Age and epsilon4/4 genetype were positively correlated with hypertensive-cognitive impairment, while cultural level was negtively correlated with it. ApoEepsilon4 allele and age might be risk factors for the cognitive impairment in hypertensive patients. The epsilon4 homozygote (epsilon4/4) might be an important influencing factor for the progression of cognitive impairment.
Adult ; Aged ; Aged, 80 and over ; Alleles ; Apolipoprotein E4 ; genetics ; Cognition ; physiology ; Cognition Disorders ; etiology ; Female ; Genotype ; Humans ; Hypertension ; complications ; genetics ; physiopathology ; Male ; Middle Aged ; Polymerase Chain Reaction ; methods ; Polymorphism, Genetic ; Polymorphism, Restriction Fragment Length ; Risk Factors