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PURPOSE: To determine whether individuals with subjective cognitive decline (SCD) have changes in whole-brain network characteristics and intracerebral node characteristics in the structural network, and whether there is a difference between SCD with and without Apolipoprotein E4 (APOEε4). METHODS: This cross-sectional study included 36 individuals without SCD without APOEε4 (healthy control, HC group), 21 individuals with SCD with APOEε4 (APOEε4+ group), and 33 individuals with SCD without APOEε4 (APOEε4- group). The white matter structural network was constructed using the fractional anisotropy (FA) based deterministic fiber tracking method. Graph theory was used to analyze the whole-brain network characteristics and intracerebral node characteristics of the three groups. RESULTS: Regarding the whole-brain network characteristics, all three groups exhibited small-worldness in their structural networks. The clustering coefficient (Cp) and local efficiency (Eloc) in the APOEε4+ and APOEε4- groups were significantly lower than in the HC group (p < 0.05), but no significant difference in Cp or Eloc was observed between the APOEε4+ and APOEε4- groups. Regarding intracerebral node characteristics, there were significant differences in some brain regions, mainly the default mode network (DMN), the occipital lobe, the temporal lobe, and subcortical regions. The change in intracerebral node characteristics was different between the APOEε4+ group and the APOEε4- group. CONCLUSIONS: Individuals with SCD demonstrate changes in whole-brain network characteristics and intracerebral node characteristics in the structural network. Moreover, differences exist between APOEε4+ and APOEε4- individuals.
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Apolipoproteína E4 , Disfunción Cognitiva , Red Nerviosa , Sustancia Blanca , Humanos , Apolipoproteína E4/genética , Sustancia Blanca/diagnóstico por imagen , Sustancia Blanca/patología , Masculino , Femenino , Disfunción Cognitiva/diagnóstico por imagen , Disfunción Cognitiva/fisiopatología , Disfunción Cognitiva/patología , Estudios Transversales , Anciano , Persona de Mediana Edad , Red Nerviosa/diagnóstico por imagen , Red Nerviosa/patología , Red Nerviosa/fisiopatología , Imagen de Difusión Tensora , Autoevaluación DiagnósticaRESUMEN
Background: 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. Methods: In the current study, we analyzed the relationship of FN1 SNP rs140926439, APOEε4, and AD in the UK Biobank cohort. Results: 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). Conclusion: 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.
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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. OBJECTIVES: 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.
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Diabetes Mellitus , Inhibidores de Hidroximetilglutaril-CoA Reductasas , Anciano , Humanos , Alelos , Apolipoproteínas E/genética , Proteína C-Reactiva/metabolismo , Diabetes Mellitus/genética , Inhibidores de Hidroximetilglutaril-CoA Reductasas/uso terapéutico , Obesidad/genéticaRESUMEN
BACKGROUND: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.
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Enfermedad de Alzheimer , Disfunción Cognitiva , Humanos , Enfermedad de Alzheimer/líquido cefalorraquídeo , Péptidos beta-Amiloides/líquido cefalorraquídeo , Apolipoproteína E4/líquido cefalorraquídeo , Apolipoproteínas E/genética , Biomarcadores/líquido cefalorraquídeo , Disfunción Cognitiva/líquido cefalorraquídeo , Proteínas de Neurofilamentos , Isoformas de Proteínas , Proteínas tau/líquido cefalorraquídeo , Negro o Afroamericano , BlancoRESUMEN
The occurrence and development of cognitive impairment, the early stage of AD, may be affected both by factors of environmental (aluminum exposure) and genetic (ApoEε4 gene). But whether there is an interaction between the two factors on cognitive function is still unknown. To explore the interaction between the two factors on cognitive function of in-service workers. A total of 1121 in-service workers in a large aluminum factory were investigated in Shanxi Province. Cognitive function was assessed by the Mini-mental State Examination (MMSE), the clock-drawing test (CDT), the Digit Span Test (DST, including DSFT and DSBT), the fuld object memory evaluation (FOM), and the verbal fluency task (VFT). The plasma-Al (p-Al) concentrations were measured by inductively coupled plasma-mass spectrometry (ICP-MS) as an internal exposure indicator, and the participants were divided into four Al exposure groups according to the quartile of p-Al concentrations, namely Q1, Q2, Q3, and Q4. ApoE genotype was determined by Ligase Detection Reaction (LDR). The multiplicative model was fitted using non-conditional logistic regression and additive model was fitted using crossover analysis to analyze the interaction between p-Al concentrations and the ApoEε4 gene. Finally, a dose-response relationship between p-Al concentrations and cognitive impairment was observed, with the p-Al concentrations increased, cognitive function performance gradually becomes worse (Ptrendï¼0.05), and the risk of cognitive impairment gradually increases (Ptrendï¼0.05), mainly in executive/visuospatial impairment, auditory memory impairment (particularly the working memory impairment). And ApoEε4 gene may be a risk factor for cognitive impairment, while no association between the ApoEε2 gene and cognitive impairment is observed. Additionally, an additive but no multiplicative interaction between p-Al concentrations and ApoEε4 gene is observed, and when the two factors work together, the risk of cognitive impairment further increased, of which 44.2% can be attributed to the interaction effect.
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Aluminio , Disfunción Cognitiva , Humanos , Aluminio/toxicidad , Cognición , Disfunción Cognitiva/inducido químicamente , Disfunción Cognitiva/genética , Genotipo , Pruebas Neuropsicológicas , Apolipoproteína E4/genéticaRESUMEN
Background: 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. Materials and Methods: 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. Results: (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. Conclusion: 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.
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[This corrects the article DOI: 10.3389/fnins.2021.677823.].
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BACKGROUND AND PURPOSE: Sleep characteristics, including taking a nap and sleep apnea, have been proven to have effects on cognitive function, and apolipoprotein E polymorphism ε4 (APOEε4) has been confirmed to be a risk factor for mild cognitive impairment (MCI), but epidemiological studies linking sleep characteristics and APOEε4 are scarce. We aimed to explore the longitudinal association between sleep characteristics and MCI in an overall cohort, in APOEε4 carriers and in APOEε4 non-carriers. METHODS: We included 3053 older adults from the Tianjin Elderly Nutrition and Cognition Cohort (TENCC) study, recruited from March 2018 to June 2019, and followed up from March 2021 to June 2021. All participants underwent detailed neuropsychological evaluation that allowed psychometric MCI classification. Information on self-reported sleep characteristics was gathered via face-to-face interviews. Crude and multivariable-adjusted hazard ratios (HRs) and 95% confidence intervals (CIs) were estimated using Cox proportional hazard regression models. RESULTS: In the multivariable-adjusted models, taking a nap at noon was associated with decreased risk of MCI in all participants (yes vs. no: HR 0.723, 95% CI 0.592, 0.883) and in APOEε4 non-carriers (yes vs. no: HR 0.719, 95% CI 0.576, 0.897). Sleep apnea was associated with increased risk of MCI in all participants (vs. good: HR 2.213, 95% CI 1.171, 4.180) and in APOEε4 non-carriers (vs. good: HR 2.217, 95% CI 1.085, 4.529). CONCLUSIONS: This study suggests that taking a nap at noon might be a potential protective factor against development of MCI in APOEε4 non-carriers, and sleep apnea might be associated with increased incidence of MCI in APOEε4 non-carriers.
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Disfunción Cognitiva , Síndromes de la Apnea del Sueño , Anciano , Apolipoproteína E4/genética , Disfunción Cognitiva/epidemiología , Disfunción Cognitiva/genética , Estudios de Cohortes , Humanos , Pruebas Neuropsicológicas , Estudios Prospectivos , Sueño/genéticaRESUMEN
PURPOSE: Subjective cognitive decline (SCD) is the earliest symptom stage of Alzheimer's disease (AD), and the APOEε4 allele is the strongest genetic risk factor for sporadic AD. Based on graph theory, the resting state functional connectivity (rsFC) in SCD patients with APOEε4 was studied to explore the effect of APOEε4 on the rsFC network properties of SCD patients. PATIENTS AND METHODS: This cross-sectional study included MRI image data from 19 SCD patients with APOEε4 (SCD+), 29 SCD patients without APOEε4 (SCD-), and 30 normal control (NC-) individuals without APOEε4. We generated a binary matrix based on anatomical automatic labeling (AAL) 90 atlas to construct the functional network. We then calculated the whole brain network characteristics and intracerebral node characteristics by graph theory. RESULTS: For the whole brain network characteristics, all three groups showed small-worldness. The SCD+ group had increased compensatory information transfer speed and enhanced integration capability. This group also had high heterogeneity for intracerebral node characteristics, mainly in the default mode network, left superior occipital gyrus, and bilateral putamen. CONCLUSION: APOEε4 effects the functional brain network in patients with SCD and may be a potential indicator for the identification of SCD.
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BACKGROUND: 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. METHODS: 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). RESULTS: 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). CONCLUSION: 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.
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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. AIM: 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). CONCLUSION: Diagnosis of MetS and ApoEε4 carrier status were persistently associated with cognitive dysfunction among an elderly population in China.
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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 Aß deposition, aluminum exposure can lead to abnormal phosphorylated tau and Aß 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⯵M AlCl3), the medium dose group (400⯵M AlCl3), the high dose group (800⯵M AlCl3), empty plasmid group, ApoEε4 group and 400⯵M AlCl3+ApoEε4 group. The cell viability was determined by CCK-8 kit after transfection for 48â¯h.The contents of total tau proteins, tau-181, tau-231, tau-262, tau-396 and Aß42, 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 Aß 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 Aß 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 Aß in the cells treated with AlCl3 plus ApoEε4 were significantly higher than those in other groups (pâ¯<â¯0.05). Moreover, analyzing data based on the factorial design, there was existed an interaction between AlCl3 and ApoEε4 (pâ¯<â¯0.05). CONCLUSION: 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 Aß increases. In the presence of both Al and ApoEε4 genes, the two factors interact with each other and show a synergistic effect.
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Cloruro de Aluminio/farmacología , Péptidos beta-Amiloides/antagonistas & inhibidores , Apolipoproteína E4/metabolismo , Proteínas tau/metabolismo , Péptidos beta-Amiloides/metabolismo , Apolipoproteína E4/genética , Supervivencia Celular/efectos de los fármacos , Humanos , Fosforilación/efectos de los fármacos , Células Tumorales CultivadasRESUMEN
INTRODUCTION: 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. METHODS: 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. RESULTS: 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. DISCUSSION: 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.
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Enfermedad de Alzheimer/genética , Precursor de Proteína beta-Amiloide/genética , Pueblo Asiatico , Linaje , Presenilina-1/genética , Presenilina-2/genética , Anciano , Alelos , China , Femenino , Humanos , Masculino , Mutación MissenseRESUMEN
BACKGROUND: The apolipoprotein E ε4 gene variant (APOEε4) confers considerable risk for dementia and affects neuroinflammation, brain metabolism, and synaptic function. The kynurenine pathway (KP) gives rise to neuroactive metabolites, which have inflammatory, redox, and excitotoxic effects in the brain. AIM: To assess whether the presence of at least one APOEε4 allele modifies the association between kynurenines and the cognitive prognosis. METHODS: A total of 152 patients with sera for metabolite measurements and APOE genotype were included from the Dementia Study of Western Norway. The participants had mild Alzheimer disease and Lewy body dementia. Apolipoprotein E ε4 gene variant allele status was classified as one or more ε4 versus any other. Mini-Mental State Examination (MMSE) was measured at baseline and for 5 consecutive years. Mann-Whitney U tests and linear mixed-effects models were used for statistical analysis. RESULTS: There were no significant differences in serum concentrations of tryptophan and kynurenine according to the presence or absence of APOEε4. High serum concentrations of kynurenic acid, quinolinic acid, and picolinic acid, and a higher kynurenine-to-tryptophan ratio, were all associated with more cognitive decline in patients without APOEε4 compared to those with the APOEε4 allele (P-value of the interactions < .05). CONCLUSIONS: Kynurenic acid, quinolinic acid, picolinic acid, and the kynurenine-to-tryptophan ratio were associated with a significant increase in cognitive decline when the APOEε4 variant was absent, whereas there was a relatively less decline when the APOEε4 variant was present.
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INTRODUCTION: We aimed to examine the contribution of subjective cognitive decline (SCD) to reduce the number of ß-amyloid (Aß) positron emission tomography scans required for recruiting Aß+ clinically normal individuals in clinical trials. METHODS: Three independent cohorts (890 clinically normal: 72 yrs ± 6.7; Female: 43.4%; SCD+: 24%; apolipoprotein E [APOE] ε4+: 28.5%; Aß+: 32%) were used. SCD was dichotomized from one question. Using logistic regression, we classified Aß+ using the SCD dichotomy, APOEε4, sex, and age. RESULTS: SCD increased odds of Aß+ by 1.58 relative to non-SCD. Female APOEε4 carriers with SCD exhibited higher odds of Aß+ (OR = 3.34), whereas male carriers with SCD showed a weaker, opposing effect (OR = 0.37). SCD endorsement reduces the number of Aß positron emission tomography scans to recruit Aß+ individuals by 13% and by 9% if APOEε4 status is known. CONCLUSION: SCD helps to classify those with high Aß, even beyond the substantial effect of APOE genotype. Collecting SCD is a feasible method for targeting recruitment for those likely on the AD trajectory.
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BACKGROUND: Alzheimer's disease (AD), the most common cause of dementia, is evolving to become a threatening epidemy of the 21st century. Only 21% of the predicted number of AD patients in Macedonia have been diagnosed and treated, which means that almost 80% are underdiagnosed or misdiagnosed. Apolipoprotein E gene (APOE) is recognised as the strongest genetic risk factor for sporadic AD. Whether and when Alzheimer's disease develops, depends on the very complex interaction between genetic and modifiable risk factors. It has been known that vascular factors like hypertension, diabetes mellitus, hypercholesterolemia and obesity increase the risk of developing both AD, vascular dementia and mixed AD and vascular pathology. AIM: This study aims to evaluate the influence of APOEε4 allele presence and modifiable vascular risk factors (hypertension, diabetes mellitus and dyslipidemia) as prognostic and risk factors for AD and their influence on the age of onset of AD symptoms among 144 AD patients from Macedonia. MATERIAL AND METHODS: Study group of a total of 144 patients diagnosed with AD was evaluated. APOE genotyping was performed using APOE haplotype-specific sequence specific-primer (SSP)-PCR (Polymerase Chain Reaction) methodology. The non-standardized questionnaire was used to obtain information about demographics, lifestyle and modifiable risk factors that could influence disease onset and phenotype. RESULTS: Statistically significant association was found between the presences of APOEε4 allele in AD group versus controls. The presence of APOEε4 allele increases the risk of developing AD in a 3-fold manner. The average age of disease onset in the ε4 carrier group was 67.2 ± 8.3 and in the ε4 non-carrier group 69.7 ± 9.4. This confirms that the presence of APOEε4 allele shifts towards earlier disease onset, though the difference is not statistically significant. Out of the vascular risk factors, only hypertension was significantly associated with earlier AD onset. Out of total 144 patients, in 22.9% the first symptom onset was before the age of 65, that can be considered as early onset Alzheimer's Disease (EOAD), which is much higher than 5% for EOAD as most of the studies report. CONCLUSIONS: The average age of disease onset of 68.4 years could be considered earlier than the average age of AD onset worldwide. Out of all the vascular risk factors analysed in this study, only hypertension and dyslipidemia were found to significantly increase the risk for developing AD and only the presence of hypertension influences the age of onset, shifting towards earlier disease onset. Public awareness campaigns should be organised to influence general population knowledge about Alzheimer's disease, early recognition and the influence of modifiable vascular risk factors.
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INTRODUCTION: 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). DISCUSSION: The present findings suggest that the APOEε4 allele and other AD genetic risk factors might potentiate the risk of HSV1-associated AD.
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Accumulating evidence demonstrating higher cerebrospinal fluid (CSF) α-synuclein (αSyn) levels and αSyn pathology in the brains of Alzheimer's disease (AD) patients suggests that αSyn is involved in the pathophysiology of AD. To investigate whether αSyn could be related to specific aspects of the pathophysiology present in both sporadic and familial disease, we quantified CSF levels of αSyn and assessed links to various disease parameters in a longitudinally followed cohort (n = 136) including patients with sporadic mild cognitive impairment (MCI) and AD, and in a cross-sectional sample from the Dominantly Inherited Alzheimer's Network (n = 142) including participants carrying autosomal dominant AD (ADAD) gene mutations and their non-mutation carrying family members.Our results show that sporadic MCI patients that developed AD over a period of two years exhibited higher baseline αSyn levels (p = 0.03), which inversely correlated to their Mini-Mental State Examination scores, compared to cognitively normal controls (p = 0.02). In the same patients, there was a dose-dependent positive association between CSF αSyn and the APOEε4 allele. Further, CSF αSyn levels were higher in symptomatic ADAD mutation carriers versus non-mutation carriers (p = 0.03), and positively correlated to the estimated years from symptom onset (p = 0.05) across all mutation carriers. In asymptomatic (Clinical Dementia Rating < 0.5) PET amyloid-positive ADAD mutation carriers CSF αSyn was positively correlated to 11C-Pittsburgh Compound-B (PiB) retention in several brain regions including the posterior cingulate, superior temporal and frontal cortical areas. Importantly, APOEε4-positive ADAD mutation carriers exhibited an association between CSF αSyn levels and mean cortical PiB retention (p = 0.032). In both the sporadic AD and ADAD cohorts we found several associations predominantly between CSF levels of αSyn, tau and amyloid-ß1-40.Our results suggest that higher CSF αSyn levels are linked to AD pathophysiology at the early stages of disease development and to the onset of cognitive symptoms in both sporadic and autosomal dominant AD. We conclude that APOEε4 may promote the processes driven by αSyn, which in turn may reflect on molecular mechanisms linked to the asymptomatic build-up of amyloid plaque burden in brain regions involved in the early stages of AD development.
Asunto(s)
Enfermedad de Alzheimer/líquido cefalorraquídeo , Disfunción Cognitiva/líquido cefalorraquídeo , alfa-Sinucleína/líquido cefalorraquídeo , Anciano , Enfermedad de Alzheimer/diagnóstico por imagen , Enfermedad de Alzheimer/genética , Péptidos beta-Amiloides/líquido cefalorraquídeo , Precursor de Proteína beta-Amiloide/líquido cefalorraquídeo , Precursor de Proteína beta-Amiloide/genética , Compuestos de Anilina/farmacocinética , Apolipoproteínas E/genética , Encéfalo/diagnóstico por imagen , Encéfalo/efectos de los fármacos , Encéfalo/metabolismo , Disfunción Cognitiva/diagnóstico por imagen , Disfunción Cognitiva/genética , Estudios de Cohortes , Estudios Transversales , Femenino , Humanos , Procesamiento de Imagen Asistido por Computador , Imagen por Resonancia Magnética , Masculino , Persona de Mediana Edad , Mutación/genética , Fragmentos de Péptidos/líquido cefalorraquídeo , Tomografía de Emisión de Positrones , Curva ROC , Estadísticas no Paramétricas , Tiazoles/farmacocinética , Proteínas tau/líquido cefalorraquídeoRESUMEN
Neuro-inflammatory processes that contribute to development of Alzheimer's are evident early in the latent prodromal phase and worsen during the course of the disease. Despite substantial mechanistic and clinical evidence of inflammation, therapeutic approaches targeting inflammation have failed to alter the course of the disease. Disparate results from epidemiological and clinical trials targeting inflammation, highlight the complexity of the inflammatory process. Herein we review the dynamics of the inflammatory process across aging, midlife endocrine transitions, and the APOEε4 genotype and their contribution to progression of Alzheimer's disease (AD). We discuss the chronic inflammatory processes that are activated during midlife chronological and endocrine aging, which ultimately limit the clearance capacity of microglia and lead to immune senescence. Aging, menopause, and APOEε4 combine the three hits of a compromised bioenergetic system of menopause with the chronic low grade innate inflammation of aging with the APOEε4 dyslipidemia and adaptive immune response. The inflammatory immune response is the unifying factor that bridges across each of the risk factors for AD. Immune system regulators that are specific to stage of disease and inflammatory phenotype would provide a therapeutic strategy to disconnect the bridge that drives disease. Outcomes of this analysis provide plausible mechanisms underlying failed clinical trials of anti-inflammatory agents in Alzheimer's patients. Further, they highlight the need for stratifying AD clinical trial cohorts based on inflammatory phenotype. Combination therapies that include targeted use of anti-inflammatory agent's specific to the immune phenotype are considered.
RESUMEN
A single copy of klotho allele KL-VS is associated with longevity, better health, increased cognition, and bigger regional brain volume. However, its longitudinal effects on cognition and brain volumes, both global and regional, in late life are unclear. In this study we show that, relative to noncarriers, KL-VS heterozygotes had (1) shorter survival; (2) smaller white matter volumes; (3) slower cognitive decline; and (4) greater right frontal lobe volumes. The KL-VS heterozygote survival and white matter volume disadvantages were unexpected. A possible explanation for these results in the context of the literature is a potential interaction between the environment and/or age of the participants, leading to a heterozygote disadvantage. The longitudinal cognitive trajectories indicate that heterozygotes would have an advantage in very late life. Collectively these results suggest that the genotype-survival advantage of the KL-VS allele is age-dependent and possibly mediated through differential cognition and brain volume.