UNASSIGNED: A protective genetic variant in the fibronectin FN1 gene reduces the odds of developing AD by up to 70%. This variant, rs140926439, seems to prevent the buildup of excess fibronectin at the blood brain barrier. Increased fibronectin levels are typically observed in people with Alzheimer\'s Disease (AD), but the protective variant appears to counteract its effects.
UNASSIGNED: In the current study, we analyzed the relationship of FN1 SNP rs140926439, APOEε4, and AD in the UK Biobank cohort.
UNASSIGNED: When rs140926439 was absent, 0.10% of APOEε2/3 carriers had AD while 0.40% of APOEε4 carriers or homozygotes had AD. This difference was significant (p < 0.001, 2 tail Fisher exact test). When rs140926439 was present, 0.10% of APOEε2/3 carriers had AD while 0.10% of APOEε4 carriers or homozygotes had AD. This difference was insignificant (p = 1). To examine the overall relationship of rs140926439 and APOE isoform to AD, we used the univariate general linear model, AD (present or absent) dependent variable, rs140926439 (present or absent) and APOE isoform (APOEε2/3 or APOEε4 carrier or homozygote) as fixed factors. The effect of rs140926439 was significant (p = 0.030). The effect of APOE isoform was significant (p = 0.034). There was also a significant interaction between rs140926439 and APOE isoform (p = 0.030).
UNASSIGNED: Fibronectin is an adhesive molecule that is essential to wound healing, especially to the production of extracellular matrix and reepithelialization. Some cases of AD may be due to the initiation of the brain wound healing process, often in the absence of any actual wound. NSAIDS may reduce risk of AD because they potently inhibit wound healing. FN1 appears to be a key player in AD, and its protective variant could offer insights into potential therapeutic targets. However, further research is needed to fully understand the intricate mechanisms underlying AD and to develop effective treatments.

BACKGROUND: C-reactive protein (CRP) is lower in patients who carry the apolipoprotein E epsilon 4 allele variant (APOEε4) of the APOE gene. This could however be explained by other factors observed in APOEε4 carriers, such as lower body mass index (BMI), possibly less diabetes and more use of statins, all associated with CRP concentrations.
OBJECTIVE: To assess the association between CRP and APOEε4 stratified by BMI, statin use and diabetes.
METHODS: We included 2700 community-dwelling older adults from the Hordaland health study with genotyping of the APOE gene by a one-step polymerase chain reaction and CRP measured using immuno-MALDI-TOF MS. Differences in CRP concentrations by APOE (ε4 vs no ε4) were assessed using the Mann-Whitney U tests, also stratified by statin use, diabetes and BMI categories. Finally, we performed linear regression with log (CRP) as the outcome and APOEε4 together with statin use, diabetes, BMI and their respective interactions.
RESULTS: CRP was higher in APOEε4 carriers irrespective of BMI, diabetes and statin use. In APOEε4 non-carriers, CRP was elevated with diabetes and obesity as expected. However, this was attenuated or even reversed in APOEε4 carriers. Such differences were not observed for statin use.
CONCLUSIONS: Statin use, obesity or diabetes did not confound the known association between the APOEε4 allele and lower CRP. Our data suggest that CRP is less responsive to inflammatory cues involved in diabetes and obesity in APOEε4 carriers. Epidemiological studies should take note of these relationships, as CRP, APOEε4, diabetes and obesity are both linked to neurodegenerative and cardiovascular disease.

The APOEε4-promoted risk of Alzheimer\'s disease (AD) is lower in Black/African-Americans (B/AAs), compared to non-Hispanic whites (NHWs). Previous studies reported lower plasma apolipoprotein E (apoE) levels in NHW APOEε4-carriers compared to non-carriers, and low plasma apoE levels were directly associated with an increased risk of AD and all dementia. We further showed that APOEε3/ε3 AD patients exhibited reduced plasma apoE dimers compared to corresponding control subjects. Whether plasma apoE levels and apoE dimer formation differ between races/ethnicities and therefore may help explain AD risk racial disparity remains to be elucidated.
Using mass spectrometry, we determined total plasma apoE and apoE isoform levels in a cohort of B/AAs (n = 58) and NHWs (n = 67) including subjects with normal cognition (B/AA: n = 25, NHW: n = 28), mild cognitive impairment (MCI) (B/AA: n = 24, NHW: n = 24), or AD dementia (B/AA: n = 9, NHW: n = 15). Additionally, we used non-reducing western blot analysis to assess the distribution of plasma apoE into monomers/disulfide-linked dimers. Plasma total apoE, apoE isoform levels, and % apoE monomers/dimers were assessed for correlations with cognition, cerebrospinal fluid (CSF) AD biomarkers, sTREM2, neurofilament light protein (NfL), and plasma lipids.
Plasma apoE was predominantly monomeric in both racial groups and the monomer/dimer distribution was not affected by disease status, or correlated with CSF AD biomarkers, but associated with plasma lipids. Plasma total apoE levels were not related to disease status and only in the NHW subjects we observed lower plasma apoE levels in the APOEε4/ε4-carriers. Total plasma apoE levels were 13% higher in B/AA compared to NHW APOEε4/ε4 subjects and associated with plasma high-density lipoprotein (HDL) in NHW subjects but with low-density lipoprotein levels (LDL) in the B/AA subjects. Higher plasma apoE4 levels, exclusively in APOEε3/ε4 B/AA subjects, were linked to higher plasma total cholesterol and LDL levels. In the controls, NHWs and B/AAs exhibited opposite associations between plasma apoE and CSF t-tau.
The previously reported lower APOEε4-promoted risk of AD in B/AA subjects may be associated with differences in plasma apoE levels and lipoprotein association. Whether differences in plasma apoE levels between races/ethnicities result from altered APOEε4 expression or turnover, needs further elucidation.

UNASSIGNED: Sex is an important factor in studying the relationship between the APOE gene, lipid profiles, and AD. However, few studies have focused on the effect of sex on lipids in AD and normal controls with different APOE genes.
UNASSIGNED: A total of 549 participants, including 298 AD patients and 251 body mass index (BMI)-matched healthy controls (HCs), were enrolled. Lipid profiles and APOE genes in both AD patients and HCs were determined.
UNASSIGNED: (1) TC and LDL were higher in AD patients than in HCs, only in APOEε4 carrying populations, but not in non-carrying populations. (2) TC and LDL were higher in APOEε4 allele carriers than in non-carriers, only in AD populations, but not in HCs. (3) The TC of APOEε2 carriers was lower than that of non-carriers in the male AD population, but not in the female AD population, female HCs, and male HCs. (4) The increased LDL level may increase the risk of AD in female people carrying APOEε4.
UNASSIGNED: The TC and LDL levels of APOEε4 carriers were higher than those of non-carriers, and the effect was more significant in the female AD population. The TC levels in APOEε2 carriers were lower than those in non-carriers, which was more significant in the male AD population.

[This corrects the article DOI: 10.3389/fnins.2021.677823.].

UNASSIGNED: There is evidence that the T allele of rs405509 located in the apolipoprotein E (APOE) promotor region is a risk factor for Alzheimer\'s disease (AD). However, the effect of the T/T allele on brain function in non-demented aging is still unclear.
UNASSIGNED: We analyzed the effects of the rs405509 T/T allele on cognitive performances using multiple neuropsychological tests and local brain function using resting-state functional magnetic resonance imaging (rs-fMRI).
UNASSIGNED: Significant differences were found between T/T carriers and G allele carriers on general cognitive status, memory, and attention (p < 0.05). Rs-fMRI analyses demonstrated decreased amplitude of low frequency fluctuation (ALFF) in the right middle frontal gyrus, decreased percent amplitude of fluctuation (PerAF) in the right middle frontal gyrus, increased regional homogeneity (ReHo) in the right cerebellar tonsil and decreased ReHo in the right putamen, and decreased degree centrality (DC) in the left middle frontal gyrus (p < 0.05, corrected). Furthermore, significant correlations were found between cognitive performance and these neuroimaging changes (p < 0.05).
UNASSIGNED: These findings suggest that T/T allele may serve as an independent risk factor that can influence brain function in different regions in non-demented aging.

BACKGROUND: Metabolic syndrome (MetS) is related to poor cognitive function. However, the results of previous studies were inconsistent, and whether the ApoEε4 allele modifies the association remains unclear.
OBJECTIVE: To elucidate the relationships among MetS, ApoEε4, and cognitive dysfunction in an elderly population in China.
METHODS: One hundred elderly patients with MetS and 102 age- and gender-matched controls were included in the study. Baseline clinical characteristics and biochemical index for glucose and lipid metabolism were obtained. The distribution of ApoEε4 was assessed with PCR restriction fragment length polymorphism analysis. Cognitive function was evaluated by mini-mental status examination at the 1-year follow-up examination.
RESULTS: Compared with controls, MetS patients had worse cognitive function and decreased ability to participate in activities of daily life (P = 0.001 and 0.046, respectively). Patients with cognitive dysfunction had higher prevalence of MetS (62.1% vs 36.4%, P < 0.001) and were more likely to carry the ApoEε4 allele (22.3% vs 10.1%, P = 0.019). Multivariate logistic regression analyses showed that diagnosis with MetS, severe insulin resistance, status as an ApoEε4 carrier, higher systolic blood pressure, and larger waist circumference were risk factors for cognitive dysfunction (P < 0.05). Repeated-measures analysis of variance, performed with data collected at the 1-year follow-up, revealed continuous influences of MetS and ApoEε4 on the deterioration of cognitive function (time × team, P < 0.001 for both).
CONCLUSIONS: Diagnosis of MetS and ApoEε4 carrier status were persistently associated with cognitive dysfunction among an elderly population in China.

BACKGROUND: Aluminum is an environmental neurotoxin widely exposed to animals and humans. Studies have shown that Alzheimer\'s disease (AD) is characterized by abnormally phosphorylated tau and Aβ deposition, aluminum exposure can lead to abnormal phosphorylated tau and Aβ deposition. Numerous epidemiological data and studies have confirmed that ApoEε4 is a risk factor for AD. However, whether there is an interaction effect between aluminum and ApoEε4 has yet to be verified.
METHODS: SH-SY5Y cells were exposed with AlCl3 and transfected with ApoEε4 respectively. The experimental groups included the blank control group, the low dose group (200 μM AlCl3), the medium dose group (400 μM AlCl3), the high dose group (800 μM AlCl3), empty plasmid group, ApoEε4 group and 400 μM AlCl3+ApoEε4 group. The cell viability was determined by CCK-8 kit after transfection for 48 h.The contents of total tau proteins, tau-181, tau-231, tau-262, tau-396 and Aβ42, were determined by ELISA kit. The interaction between AlCl3 and ApoEε4 was analyzed by factorial design.
RESULTS: With the increase of aluminum exposure, SH-SY5Y cell viability decreased, and the expression of the total tau, tau-181, tau-231, tau-262, tau-396 and Aβ content increased. The viability of cells transfected with ApoEε4 is significantly lower than control group, and the expressions of total tau, tau-181, tau-231, tau-262, tau-396 and Aβ in ApoEε4 transfected cells were significantly higher than control group. The viability of cells treated with AlCl3 plus ApoEε4 was lower than those treated with, either AlCl3, or ApoEε4. The expression of total tau, tau-181, tau-231, tau-262, tau-396 and Aβ in the cells treated with AlCl3 plus ApoEε4 were significantly higher than those in other groups (p < 0.05). Moreover, analyzing data based on the factorial design, there was existed an interaction between AlCl3 and ApoEε4 (p < 0.05).
CONCLUSIONS: Al and ApoEε4 gene can cause morphological changes of SH-SY5Y cells, reduce cell activity, and have obvious cytotoxic effects, and increase the phosphorylation levels of tau and the deposition of Aβ increases. In the presence of both Al and ApoEε4 genes, the two factors interact with each other and show a synergistic effect.

BACKGROUND: Herpes simplex virus type 1 (HSV1) in combination with genetic susceptibility has previously been implicated in Alzheimer\'s disease (AD) pathogenesis.
METHODS: Plasma from 360 AD cases, obtained on average 9.6 years before diagnosis, and their age- and sex-matched controls, were analyzed for anti-HSV1 immunoglobulin (Ig) G with enzyme-linked immunosorbent assays (ELISAs). A POE genotype and nine other selected risk genes for AD were extracted from a genome-wide association study analysis by deCODE genetics, Reykjavik, Iceland.
RESULTS: The interaction between APOEε4 heterozygosity (APOEε2/ε4 or ε3/ε4) and anti-HSV1 IgG carriage increased the risk of AD (OR 4.55, P = .02). A genetic risk score based on the nine AD risk genes also interacted with anti-HSV1 IgG for the risk of developing AD (OR 2.35, P = .01).
CONCLUSIONS: The present findings suggest that the APOEε4 allele and other AD genetic risk factors might potentiate the risk of HSV1-associated AD.

The PSENs/APP mutation distribution in Chinese patients with familial Alzheimer\'s disease (FAD) remains unclear. We aimed to analyze the genetic features of Chinese FAD pedigrees with and without PSENs/APP mutations.
In total, 1330 patients with Alzheimer\'s disease (AD) or mild cognitive impairment in 404 pedigrees were enrolled from the Chinese Familial Alzheimer\'s Disease Network. PSENs/APP mutations and APOE frequencies were determined.
In total, 13.12% of pedigrees carried PSENs/APP missense mutations, 3.71% carried PSENs/APP synonymous/untranslated region variants, and 83.17% did not carry PSENs/APP mutations. Eleven missense mutations were first identified. In patients without PSENs/APP mutations, 44.31% carried one APOEε4 allele, and 14.85% two APOEε4 alleles.
The new PSENs/APP mutations indicate heterogeneity in AD pathogenesis between Chinese and other ethnic groups. The low mutation rate suggests the involvement of other genes/factors in Chinese FAD. APOEε4 might be a major gene for some FAD without PSENs/APP mutations.