Effect Of APOE E4 Allele Research Articles

Effect of APOE e4 allele on age‐related brain FDG‐PET uptake in older individuals at risk of dementia

AbstractBackgroundIn Alzheimer’s Disease (AD) patients, accumulating evidence suggests that the APOE‐e4 allele drives amyloid and tau pathology and decreases brain glucose metabolism. Similarly, in older healthy subjects, APOE‐e4 has been linked to brain hypometabolism. However, there are scarce clinical studies concerning the effect of APOE e4 and the age‐related cerebral glucose metabolism patterns of older individuals at‐risk for dementia.ObjectiveThis exploratory analysis aims to study the impact of carriage of the APOE‐e4 allele on age‐related brain glucose metabolism patterns of older individuals at‐risk for dementia.Method54 community‐dwelling older adults aged 60‐80 years with increased risk for AD due to cardiometabolic disorders (CMD, n = 32) or mild cognitive impairment (MCI, n = 22) who participated in a clinical trial. APOE genotyping was performed to identify carriers of the APOE‐e4 allele. 18F‐Fluoro‐2‐deoxy‐D‐glucose‐positron emission tomography/computed tomography (18F‐FDG PET/CT) was conducted and mean 18F‐FDG uptakes in brain regions of interest (ROI) from the atlas of anatomical labeling were obtained.Group differences by diagnosis (CMD,MCI) and APOE‐e4 status were examined using independent samples T‐tests. Linear regression models were conducted to evaluate the effect of age over mean 18F‐FDG uptake in each ROI. Age*APOE‐e4 interactions were examined, and the models were adjusted for diagnosis subgroup and gender effects. Adjusted models were corrected for multiple testing using the False Discovery Ratio (FDR).ResultMean 18F‐FDG uptake at each ROI was comparable between diagnosis and APOE‐e4 allele status groups. After correcting adjusted models for multiple testing, significant Age*APOE‐e4 interactions were found at the right inferior occipital gyrus (β ‐0.13, 95% CI ‐0.25 – 0.02, p = 0.035, FDR = 0.039), right paracentral lobule (β ‐0.14, 95% CI ‐0.25 – ‐0.03, p = 0.016, FDR = 0.024), and left superior parietal gyrus (β ‐0.11, 95% CI ‐0.20 – ‐0.02, p = 0.014, FDR = 0.021).ConclusionIn older individuals at risk of dementia, carriage of the APOE‐e4 allele was associated with an increased age‐related reduction in mean 18F‐FDG uptake in the right inferior occipital gyrus, right paracentral lobule, and left superior parietal gyrus. Knowledge of age‐ and APOE‐e4 allele‐related cerebral metabolic changes is critical to correctly interpreting brain 18F‐FDG PET/CT findings.

Effect of APOE4 Allele and Gender on the Rate of Atrophy in the Hippocampus, Entorhinal Cortex, and Fusiform Gyrus in Alzheimer's Disease.

The hippocampus, entorhinal cortex, and fusiform gyrus are brain areas that deteriorate during early-stage Alzheimer's disease (AD). The ApoE4 allele has been identified as a risk factor for AD development, is linked to an increase in the aggregation of amyloid ß (Aß) plaques in the brain, and is responsible for atrophy of the hippocampal area. However, to our knowledge, the rate of deterioration over time in individuals with AD, with or without the ApoE4 allele, has not been investigated. In this study, we, for the first time, analyze atrophy in these brain structures in AD patients with and without the ApoE4 using the Alzheimer's Disease Neuroimaging Initiative (ADNI) dataset. It was found that the rate of decrease in the volume of these brain areas over 12 months was related to the presence of ApoE4. Further, we found that neural atrophy was not different for female and male patients, unlike prior studies, suggesting that the presence of ApoE4 is not linked to the gender difference in AD. Our results confirm and extend previous findings, showing that the ApoE4 allele gradually impacts brain regions impacted by AD.

APOE4 Allele, Sex, and Dementia Risk in Parkinson's Disease: Lessons From a Longitudinal Cohort.

The effect of APOE4 allele on dementia risk is well established in Alzheimer's disease and Parkinson's disease (PD). However, it is unknown if sex modifies this relationship. We sought to determine the effect of sex on the relationship between APOE4 status and incident cognitive decline in PD. Data from the prospectively collected longitudinal National Alzheimer's Coordinating Center (NACC) Uniform Data Set (UDS) and Neuropathology Data Set (NDS) were analyzed. The NACC develops and maintains data from approximately 29 National Institutes of Aging-funded Alzheimer's Disease Research Centers. Further details may be found at the NACC web site (www.alz.washington.edu). The visit at which diagnosis of PD was made was termed the baseline visit. All patients with a PD diagnosis but without dementia at the baseline visit were included in the analyses. Presence of APOE4 allele was associated with higher odds (OR = 7.4; P < .001) of subsequent diagnosis of dementia and with a faster time to developing dementia (P = .04). Those with APOE4 allele were more likely to have neuropathology associated with Alzheimer's disease than those without APOE4 allele. We did not find any difference by sex. There were no differences between Lewy body pathology or neuron loss in the substantia nigra between the 2 groups. Sex was not associated with dementia risk in PD (OR = 0.53, P = .15) or with the time to dementia onset (P = .22). Sex did not modify the relationship between the APOE4 allele and dementia onset in PD patients (P = .12). APOE4 allele status in PD may be a predictor of cognitive decline in PD but does not appear to be modified by sex.

Apolipoprotein E ε4 Allele was Associated With Nonlesional Mesial Temporal Lobe Epilepsy in Han Chinese Population.

Apolipoprotein E (APOE) gene has been implicated as one of the genes susceptible to temporal lobe epilepsy (TLE), but the association is inconsistent. We carried out a study to investigate the association of APOEε4 allele with a subtype of TLE-nonlesional mesial temporal lobe epilepsy (NLMTLE) in Han Chinese people.The study consisted of total 308 NLMTLE patients and 302 controls in Han Chinese. The APOE polymorphisms were genotyped using polymerase chain reaction (PCR) DNA sequencing. We compared the frequency of APOEε4 allele and carrying status between NLMTLE patients and control subjects to test for the association of APOEε4 allele with NLMTLE clinical status.Carrying status of APOEε4 allele was significantly associated with the risk of NLMTLE. No effect of APOEε4 allele was found on the age of onset, duration of epilepsy, or frequency of seizure. Moreover, there was no association between APOEε4 allele and hippocampal sclerosis (HS) or febrile convulsion (FC) history.Our study provided an evidence that APOEε4 allele was a possible risk factor for NLMTLE, and further study with a larger sample is needed to warrant this finding.

Genetic variation in caspase-1 as predictor of accelerated progression from mild cognitive impairment to Alzheimer’s disease

There has been a lot of interest in the detection of predictors of conversion from mild cognitive impairment (MCI) to Alzheimer’s disease (AD) using neuroimaging methods, CSF biomarkers and cognitive tests [2]. Despite the many genetic studies of AD, there has been little research directed toward determining the influence of genetic variation on progression from MCI to AD [1, 4]. Variation in the caspase-1 (CASP1) gene has been evaluated in both cognitive function in elderly individuals with normal cognition [5] and in predisposition to AD [6], but no previous study has specifically explored the association between genetic variation in CASP1 and progression from MCI to AD. As a primary goal in this study, we investigate APOE e4 allele and CASP1 (rs580253) polymorphisms in order to predict MCI individuals likely to convert to AD in a relatively short follow-up period. Between 2007 and 2009, we examined 84 consecutive patients who attended the Department of Neurology of University Hospital ‘‘Marques de Valdecilla’’ (Santander, Spain) and that fulfilled the Petersen criteria for amnestic MCI [3]. Patients with MCI were longitudinally assessed at 6-month intervals (mean duration of follow-up 26.5 months; SD 8.1; range 7–37 months). According to their Clinical Dementia Rating (CDR) scores during the follow-up period, 50 MCI patients whose global CDR score changed from CDR = 0.5 to CDR = 1 were diagnosed as MCI-converters to AD (70% women; mean age 76.3 years; SD 5.7; range 60–85 years), and two additional MCI patients converted to dementia with Lewy bodies and vascular dementia, respectively; 32 MCI whose global CDR score remained stable were classified as MCI-nonconverters to AD (63% women; mean age 74.8 years; SD 7.0; range 60–86 years). Except one MCI-converter to AD patient with a minimal follow-up period of 7 months, the rest of our patients were followed up for at least 1 year to avoid the risk to label as MCI-non-converter to AD subjects who will develop dementia over time. We selected the CASP1 gene (rs580253) polymorphism that had been previously related to cognitive function [5]. Blood samples were taken after written informed consent had been obtained from the subjects or their representatives. The study was approved by the ethical committee of the University Hospital ‘‘Marques de Valdecilla’’. Kaplan–Meier curves and Cox regression model (including APOE status, age and gender) were used to assess whether timeto-conversion was associated with CASP1 (rs580253) polymorphism. Kaplan–Meier survival analysis (Fig. 1), shows the effect of APOE e4 allele and CASP1 (rs580253) T allele on the time-to-conversion to AD in patients with MCI. Survival function estimates did not differ significantly between APOE e4 allele carriers and non-carriers. Conversely, the mean time of conversion from MCI to AD was 25.2 months (SD 9.1) in people with CASP1 (rs580253) T allele (CT and TT genotypes) versus 31.7 months (SD 7.4) in CASP1 (rs580253) T allele non-carriers (CC genotype); thus, CASP1 (rs580253) T allele accelerated the progression from MCI to AD by an average of 6.5 months (P = 0.009). The risk factors of conversion from MCI to AD were analyzed simultaneously with a multivariate Cox A. Pozueta J. L. Vazquez-Higuera P. Sanchez-Juan E. Rodriguez-Rodriguez C. Sanchez-Quintana I. Mateo J. Berciano O. Combarros (&) Neurology Service and CIBERNED, University Hospital ‘‘Marques de Valdecilla’’ (University of Cantabria), 39008 Santander, Spain e-mail: combarro@unican.es

Kidney function is associated with the rate of cognitive decline in the elderly

We tested the hypothesis that impaired kidney function in the elderly is associated with a more rapid rate of cognitive decline. Baseline serum was used to calculate estimated glomerular filtration rate (eGFR), using the Modification of Diet in Renal Disease formula, for 886 elderly without dementia participating in the Rush Memory and Aging Project, a prospective, observational cohort study. Kidney function was also dichotomized into impairment or no impairment based on eGFR < or >or=60 mL/min/1.73 m(2). Structured cognitive testing was performed at baseline and at annual evaluations, using a battery of 19 cognitive tests summarized into global cognition and 5 cognitive domains. In mixed-effects models adjusted for age, sex, and education, a lower eGFR at baseline was associated with a more rapid rate of cognitive decline (estimate 0.0008, SE <0.001, p = 0.017). The increased rate of cognitive decline associated with a 15-mL/min/1.73 m(2) lower eGFR at baseline (approximately 1 SD) was similar to the effect of being 3 years older at baseline. Impaired kidney function at baseline was associated with a more rapid rate of cognitive decline (estimate -0.028, SE <0.009, p = 0.003). The increased rate of cognitive decline associated with impaired kidney function at baseline was approximately 75% the effect of ApoE4 allele on the rate of cognitive decline. Baseline kidney function was associated with declines in semantic memory, episodic memory, and working memory but not visuospatial abilities or perceptual speed. Impaired kidney function is associated with a more rapid rate of cognitive decline in old age.