Sex differences in the association of the apolipoprotein E epsilon 4 allele with incidence of dementia,cognitive impairment,and decline

We examined longitudinal associations between the apolipoprotein E ε4 allele (ApoE4⁺ status) and several cognitive outcomes and tested effect modification by sex. Data on 644 non-Hispanic Caucasian adults, from the Baltimore Longitudinal Study of Aging (BLSA) were used. Dementia onset, cognitive impairment and decline were assessed longitudinally. After 27.5 years median follow-up, 113 participants developed dementia. ApoE4⁺ predicted dementia significantly (hazard ratio [HR] = 2.89; 95% confidence interval [CI], 1.93–4.33), with nonsignificant sex differences. Taking all time points for predicting cognition, women had significantly stronger positive associations than men between ApoE4⁺ status and impairment or decline on the California Verbal Learning Test (CVLT; delayed recall and List A total recall) and on Verbal Fluency Test-Categories. This ApoE4 × sex interaction remained significant with Bonferroni correction only for CVLT-delayed recall. Taking time points prior to dementia for cognitive predictions, the positive association between impairment in CVLT-delayed recall and ApoE4⁺ status remained stronger among women, though only before Bonferroni correction. While ApoE4+ status appears to be a sex neutral risk factor for dementia, its association with verbal memory and learning decline and impairment was stronger among women.     

Increased levels of CSF phosphorylated tau in apolipoprotein E epsilon4 carriers with mild cognitive impairment

We investigated the correlation between the apolipoprotein E varepsilon4 allele (apoE epsilon4) carrier status, a major risk factor of Alzheimer's disease (AD), and levels of tau protein phosphorylated at threonine 231 (P-tau(231P)) in cerebrospinal fluid (CSF) in predementia and clinical stages of AD and healthy controls (HC). Thirty-one subjects with mild cognitive impairment (MCI) who had converted to AD during follow-up were included, as well as 71 AD patients, and 29 HC subjects. In MCI, but not in AD and HC, CSF P-tau(231P) levels were significantly higher in apoE epsilon4 carriers compared to non-carriers (p<0.001). Controlling for disease duration, the apoE epsilon4 effect on P-tau(231P) remained significant. Our study indicates that the apoE epsilon4 carrier status should be considered when CSF P-tau(231P) is evaluated as biomarker candidate of AD in MCI subjects.     

Influence of the apolipoprotein E epsilon4 allele on human embryonic development

Human apolipoprotein E (apoE) exists in three major isoforms encoded by distinct alleles (APOE epsilon2, epsilon3 and epsilon4) and has important functions in nerve development and repair. Inheritance of the 4 allele is a major risk factor for the development of Alzheimer's disease. To investigate the role of APOE polymorphisms in embryonic development, we analyzed the APOE genotypes of 81 spontaneously aborted embryos and 110 adult controls using a solid-phase minisequencing technique. The epsilon4 allele was significantly less frequent in the spontaneous abortion group than in the control group (P=0.009), while the frequency of epsilon3 was significantly increased (P=0.005), suggesting that epsilon4 may have protective effects during embryogenesis. These protective effects might counterbalance the deleterious age-related effects of the epsilon4 allele in natural selection.     

Accelerated age-related cortical thinning in healthy carriers of apolipoprotein E epsilon 4

Effects of APOE genotype on age-related slopes of cortical thinning was estimated by measuring the thickness of the cerebral cortex on a point-by-point basis across the cortical mantle in 96 healthy non-demented volunteers aged 48-75 years. Fifty nine were APOE epsilon 4- (no epsilon 4 allele) and 37 were epsilon 4+ (1 or 2 epsilon 4 alleles). The genotype groups had similar age, sex and IQ. Two T(1)-weighted MP-RAGE sequences were averaged for each participant to yield images with high signal-to-noise ratio, and quantified using semi-automated analysis tools. epsilon 4 carriers had thicker cortex than non-carriers in several frontal and temporal areas in both hemispheres, but showed a steeper age-related decline in adjacent areas. Upon comparison of the epsilon 4-specific age-related thinning with previously published patterns of thinning in normal aging and Alzheimer's disease (AD), we conclude that APOE epsilon 4 may function to accelerate thinning in areas found to decline in aging (medial prefrontal and pericentral cortex), but also to initiate thinning in areas associated with AD and amyloid-beta aggregation (occipitotemporal and basal temporal cortex).     

The association between delirium and the apolipoprotein E epsilon4 allele in the elderly

OBJECTIVE: As not all patients with similar risk factors and eliciting conditions develop delirium; it may be hypothesized that genetic variation may play a role in the risk of delirium. On the basis of the relationship between dementia, respectively reduced cholinergic activity, and the APOE epsilon4-allele, and the similarities between dementia and delirium in reduced cholinergic activity, the APOE epsilon4-allele is a rational candidate-gene for delirium. This study examined the association between APOE epsilon4-allele and delirium in elderly patients. METHODS: Acutely admitted patients to the Department of Medicine of 65 years and over were included during a 27-month time period. Delirium was scored by the confusion assessment method. Cognitive impairment was diagnosed by Mini Mental State Examination and informant questionnaire on cognitive decline. Genotyping was done with matrix-assisted laser-desorption/ionization time-of flight mass spectrometry. RESULTS: Of 415 included patients, a random sample of 264 patients was genotyped for APOE. The patients who met the criteria for delirium (35%) were significantly older and more frequently had preexisting functional and cognitive impairment. APOE genotype was borderline significantly associated with cognitive impairment in patients below 75 years (P=0.057). The odds ratio for carriers of an APOE epsilon4-allele compared with patients without an APOE epsilon4-allele for developing delirium was 1.17 (95% confidence interval (CI): 0.49-2.78) in the cognitively intact patients and 0.42 (95% CI: 0.14-1.30) in the cognitively impaired patients. No relation existed between the total number of APOE epsilon4-alleles and the different delirium subtypes (P=0.12). CONCLUSIONS: We found no convincing evidence that carriers of the APOE epsilon4-allele have a higher risk of delirium.     

Similar promotion of Abeta1-42 fibrillogenesis by native apolipoprotein E epsilon3 and epsilon4 isoforms

The apolipoprotein E epsilon4 allele contributes to the genetic susceptibility underlying a large proportion (~40-60%) of typical, sporadic Alzheimer disease. Apolipoprotein E deficient mice made transgenic for human apolipoprotein E epsilon4 accumulate excess cerebral amyloid when compared to similarly prepared mice expressing human apolipoprotein E epsilon3. Therefore, it is important to search for relevant interactions(s) between apolipoprotein E epsilon4 and Abeta in order to clarify the biological role for apolipoprotein E epsilon4 in Alzheimer disease. Using a thioflavine T (ThT)-based assay, we have investigated the effects of native human apolipoprotein E isoforms on the kinetics of Abeta fibrillogenesis. No obvious profibrillogenic activity was detected in Abeta1-40-based assays of any native apolipoprotein E isoform. However, when ThT assays were repeated using Abeta1-42, modest, but statistically significant, profibrillogenic activity was detected in both apolipoprotein E epsilon3- and apolipoprotein E epsilon4-containing media and was similar in magnitude for the two isoforms. These data demonstrate that native apolipoprotein E possesses "pathological chaperone"-type activity for Abeta: in other words, the data indicate that a chaperone-like misfolding reaction can occur between native apolipoprotein E and Abeta. However, the equipotent activities of the apolipoprotein E epsilon3 and epsilon4 isoforms suggests the possibility that either extended co-incubation of apolipoprotein E and Abeta, or, perhaps, the inclusion in the reaction of other fibrillogenesis-modulation co-factors (such as metal ions, or inflammatory mediators such as reactive oxygen species, alpha2-macroglobulin, apolipoprotein J, etc.) may be required for modeling in vitro the apolipoprotein E-isoform-specific-regulation of extracellular Abeta accumulation that occurs in vivo. Alternatively, other events, such as differential apolipoprotein E-isoform-mediated clearance of Abeta or of apolipoprotein E/Abeta complexes may underlie apolipoprotein E-isoform-dependent Abeta accumulation.     

Effect of apolipoprotein E allele epsilon4 on the initial phase of amyloid beta-protein accumulation in the human brain

Deposition of amyloid ss-protein (Ass), a hallmark of Alzheimer's disease, occurs to some extent in the brains of most elderly individuals. We sought to learn when Ass deposition begins and how deposition is affected by apolipoprotein E allele epsilon4, a strong risk factor for late-onset Alzheimer's disease. Using an improved extraction protocol and specific enzyme-linked immunosorbent assay, we quantified the levels of Ass40 and Ass42 in the insoluble fractions of brains from 105 autopsy cases, aged 22 to 81 years at death, who showed no signs of dementia. Ass40 and Ass42 were detected in the insoluble fractions from all of the brains examined; low levels were even found in the brains of patients as young as 20 to 30 years of age. The incidence of significant Ass accumulation increased age-dependently, with Ass42 levels beginning to rise steeply in some patients in their late 40's, accompanied by much smaller increases in Ass40 levels. The presence of the apolipoprotein E epsilon4 allele was found to significantly enhance the accumulation of Ass42 and, to a lesser extent, that of Ass40. These findings strongly suggest that the presence of epsilon4 allele results in an earlier onset of Ass42 accumulation in the brain.     

Independent effects of the -219 G>T and epsilon 2/ epsilon 3/ epsilon 4 polymorphisms in the apolipoprotein E gene on coronary artery disease: the Southampton Atherosclerosis Study

A number of studies have shown that coronary artery disease severity is associated with the epsilon 2/ epsilon 3/ epsilon 4 polymorphism in the coding region of the apolipoprotein E gene. In this study, we investigated whether the severity of the disease was also influenced by a functional polymorphism (-219 G>T) in the promoter of the gene, and if so, whether the effects of the two polymorphisms were independent. A cohort of 1170 patients with angiographically documented coronary artery disease were genotyped for the two polymorphisms. The frequency of the epsilon 4 allele of the epsilon 2/ epsilon 3/ epsilon 4 polymorphism increased linearly with increasing number of diseased vessels, so did the -219T allele of the -219 G>T polymorphism. In the sample as a whole, logistic regression analyses indicated that compared with the G/G genotype, the T/T genotype conferred an odds ratio of 1.598 (95% CI=1.161-2.201, P=0.004) in favor of increased disease severity, and the relationship remained significant after adjustment for epsilon 2/ epsilon 3/ epsilon 4 polymorphism genotypes, plasma cholesterol and triglyceride levels, and other risk factors. The effect of the T/T genotype on disease severity was more significant in patients who did not carry the epsilon 4 allele (OR=1.510, 95% CI=1.028-2.221) than in epsilon 4 allele carriers (OR=1.303, 95% CI=0.619-2.742). There was considerable linkage disequilibrium between the two polymorphisms (rho=0.9, P<0.001). Logistic regression analysis showed that the -219T- epsilon 4 haplotype conferred an odds ratio of 1.488 (95% CI=1.133-1.954). These findings suggest that the -219 G>T and epsilon 2/ epsilon 3/ epsilon 4 polymorphisms, which may affect respectively the quantity and quality of apoE, have independent and possibly additive effects on coronary artery disease severity.     

No synergistic effect between -850 tumor necrosis factor-alpha promoter polymorphism and apolipoprotein E epsilon 4 allele in Alzheimer's disease

The eukaryotic initiation factor-2B (eIF-2B) can regulate translation and protein synthesis. We used Western blot analysis to quantify the protein level of the catalytic epsilon (epsilon) subunit of eIF-2B in brains of rats fed lithium chloride (LiCl) for 6 weeks so as to produce a brain lithium concentration that is therapeutically effective in bipolar disorder. The ratio of eIF-2B (epsilon) to actin protein was significantly reduced (P<0.01) in LiCl-fed rats, 0.86+/-0.06 (SE) compared to 1.2+/-0.07 in control rats. These results suggest that a therapeutic level of lithium may downregulate the synthesis of proteins whose translation depends on eIF-2B.     

Regulatory region single nucleotide polymorphisms of the apolipoprotein E gene and the rate of cognitive decline in Alzheimer's disease

The aim of this study was to investigate whether single nucleotide polymorphisms (SNPs) in the regulatory regions of the apolipoprotein E (APOE) gene modify the well-established epsilon4-associated risk for Alzheimer's disease (AD). Sequencing of the APOE gene regulatory regions revealed four previously reported promoter SNPs and one novel SNP in the previously described macrophage enhancer (ME.1). In addition, we also studied the two classic allelic missense SNPs that define epsilon2/epsilon3/epsilon4 status in a case-control association study. Analysis of pair-wise linkage disequilibrium (LD) of the five regulatory region SNPs with classic APOE SNPs revealed a previously unreported 7 kb LD block covering the entire APOE gene, part of the promoter and 3' enhancer region. We report here that in a case-control association study (N=719) of the seven SNPs, the genotype at codon 112 captures all the information required to assess disease risk. To explore correlations with quantitative traits, 169 patients were studied in whom rates of cognitive decline were available. In addition to the epsilon4 allele, two regulatory region SNPs were associated with the rate of cognitive decline in AD patients. This study highlights the effect of APOE gene variation on risk of AD and rate of cognitive decline and demonstrates that a single SNP, which confers epsilon4 status, captures all of the risk of developing AD but two SNPs in the regulatory region may affect the rate of cognitive decline in AD patients.     

The effects of metabolic syndrome and apolipoprotein E4 on cognitive event-related potentials

To reduce the care burden of dementia, identifying whether the combined effect of metabolic syndrome and ?4 increases the risk of cognitive decline needs to be determined. Using the Cognitive Abilities Screening Instrument (CASI), 145 mentally healthy middle-aged and older adults were recruited to investigate the influence of metabolic syndrome and ?4 on cognitive event-related potentials (ERPs). The results showed no difference in CASI scores, N100 and P300 measurements and ?4 carrier percentage between participants with and without metabolic syndrome. The ?4 carriers displayed a significant decrease in P300 amplitude, although the CASI scores and N100 component showed no difference. We conclude that metabolic syndrome exerts little effect on N100 and P300 measurements, and that ?4 carrier is an independent predictor of low P300 amplitude.     

Beneficial effect of ovocystatin on the cognitive decline in APP/PS1 transgenic mice

PurposeCystatin C plays an important role in the course of neurodegenerative diseases and has a beneficial effect through inhibiting cysteine proteases and amyloid-β aggregation. It also induces proliferation and autophagy. Cystatin isolated from chicken egg white, called ovocystatin, has been widely used in the medical and pharmaceutical research due to its structural and biological similarities to human cystatin C. The aim of this study was to assess the effect of administering ovocystatin on the development of dementia-specific cognitive deficits in APP/PS1 transgenic mice.Materials/methodsThe study was conducted on transgenic B6C3-Tg(APPswe,PSEN1dE9)85Dbo/Mmjax mice. Ovocystatin was administered to four-month-old transgenic (AD) and wild type (NCAR) mice in drinking water for 24 weeks (at a dose of 40 and 4 μg/ mouse). The locomotor activity and cognitive functions were determined using an actimeter and the Morris water maze test, respectively.ResultsThe results of the study indicate that ovocystatin has a beneficial effect on the cognitive functions in APP/PS1 transgenic mice. The strongest effects of ovocystatin were found in the group of AD mice, where ovocystatin was administered in drinking water at a dose of 40 μg/mouse (p < 0.05). Mice from the AD group swam statistically significantly further in the target zone during the trial in the Morris water maze compared to the AD (vehiculum) group (p < 0.05).ConclusionsThe obtained results encourage further research into the protective effect, which may be used as an adjuvant in the treatment of deteriorating cognitive functions.     

Age-related cognitive decline during normal aging: the complex effect of education.

The purpose of this study was to further analyze the effects of education on cognitive decline during normal aging. An 806-subject sample was taken from five different Mexican regions. Participants ranged in age from 16 to 85 years. Subjects were grouped into four educational levels: illiterate, 1-4, 5-9, and 10 or more years of education, and four age ranges: 16-30, 31-50, 51-65, and 66-85 years. A brief neuropsychological test battery (NEUROPSI), standardized and normalized in Spanish, was administered. The NEUROPSI test battery includes assessment of orientation, attention, memory, language, visuoperceptual abilities, motor skills, and executive functions. In general, test scores were strongly associated with level of educational, and differences among age groups were smaller than differences among education groups. However, there was an interaction between age and education such as that among illiterate individuals scores of participants 31-50 years old were higher than scores of participants 16-30 years old for over 50% of the tests. Different patterns of interaction among educational groups were distinguished. It was concluded that: (a) The course of life-span changes in cognition are affected by education. Among individuals with a low level of education, best neuropsychological test performance is observed at an older age than among higher-educated subjects; and (b) there is not a single relationship between age-related cognitive decline and education, but different patterns may be found, depending upon the specific cognitive domain.     

Dose dependent effect of APOE epsilon4 on behavioral symptoms in frontal lobe dementia

To determine whether apolipoprotein alleles (APOE) influence behavioral and psychological signs and symptoms of dementia (BPSD), we initiated a prospective, longitudinal study. Patients with Alzheimer's disease (AD) (N=186), frontotemporal dementia (FTD) (N=29), mixed dementia (MXD) (N=28), dementia with Lewy bodies (DLB) (N=11) and Parkinson's disease dementia (PDD) (N=7) were included. Blood was collected for DNA extraction and APOE genotyping. Behavioral assessments were performed at baseline and semi-annually thereafter, using behavioral assessment scales (Middelheim frontality score, behavioral pathology in Alzheimer's disease rating scale (Behave-AD)). In FTD patients, we identified dose dependent effects of APOE epsilon4 on the Behave-AD total and cluster aggressiveness scores. APOE epsilon2 was associated with a higher score on the Behave-AD cluster delusions in PDD/DLB patients. No APOE effects on frequency or severity of BPSD in AD and MXD patients were found. In conclusion, APOE has disease-specific effects on BPSD in FTD and PDD/DLB patients, given the reported associations of APOE epsilon4 with aggression (FTD) and of APOE epsilon2 with delusions (PDD/DLB).     

Interaction between matrix metalloproteinase 3 and the epsilon4 allele of apolipoprotein E increases the risk of Alzheimer's disease in Finns

Polymorphisms affecting the expression of matrix metalloproteinases (MMPs), i.e. proteolytic enzymes that degrade intercellular material, have been found at position -1607 (1G/2G) in MMP1 and at -1171 (5A/6A) in MMP3. Interestingly, elevated levels of MMP1 and MMP3 have been observed in the brains of Alzheimer's disease (AD) patients and those of tissue inhibitors of MMPs in the cerebrospinal fluid of AD and Parkinson's disease (PD) patients, suggesting a role for MMPs in these disorders. The aim was to investigate a possible association between the afore-mentioned MMP1 and MMP3 polymorphisms and the risk of developing AD or PD. The polymorphisms were genotyped in 97 AD, 52 PD and 101 control patients. We found an interaction between MMP3*5A and APOE 4 alleles (P < 0.0001) which increases the risk of AD (OR: 23.7, 95% CI: 5.8-144.9, P < 0.0001) compared to those who possess neither MMP3*5A nor APOE 4. In conclusion, our finding suggests that the MMP3 gene, especially together with APOE 4, may contribute to the development of AD.     

Education modifies the relation of vascular pathology to cognitive function: cognitive reserve in cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy

A clinical impact of cognitive reserve (CR) has been demonstrated in Alzheimer's disease, whereas its role in vascular cognitive impairment (VCI) is largely unknown. In this study, we investigated the impact of CR in patients with cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), a genetic variant of pure VCI. A total of 247 NOTCH3 mutation carriers from a two-center study were investigated using detailed neuropsychological and neuroimaging protocols. CR was operationalized as years of formal education. Brain pathology was assessed by MRI using normalized brain volume and lacunar lesion volume as proxies. Multivariate analyses were done for each structural measure with scores of processing speed, executive function, and memory as dependent variables. Additional linear regression models were conducted with interaction terms for education × brain volume and education × lacunar lesion volume. Education had an independent impact on cognitive performance in subjects with mild and moderate degrees of brain pathology, whereas there was no significant influence of education on cognition in patients with severe MRI changes. This interaction was found for processing speed, the cognitive domain most impaired in our patients. Our findings demonstrate an interaction of education and brain pathology in regard to cognitive impairment: the effect of education seems most pronounced in early disease stages but may ultimately be overwhelmed by the pathological changes. The results extend the concept of CR to VCI.     

Association between apolipoprotein E epsilon4 and neuropsychiatric symptoms during interferon alpha treatment for chronic hepatitis C

Neuropsychiatric complications are common in patients with chronic hepatitis C undergoing treatment with interferon alpha. These side effects include alterations of mood, cognition, and neuroendocrine function and are unpredictable. In a number of neurological disorders characterized by neuropsychiatric symptoms and cognitive dysfunction, inheritance of an apolipoprotein E (APOE) epsilon4 allele is associated with adverse neuropsychiatric outcomes. The authors present evidence that the APOE genotype may influence a patient's neuropsychiatric response to interferon alpha treatment. The inheritance of APOE genotypes was examined in 110 patients with chronic hepatitis C treated with interferon alpha. A retrospective investigation was conducted by assessing the rates of psychiatric referral and neuropsychiatric symptoms experienced during treatment along with other complaints indicating psychological distress. A highly statistically significant association was seen between APOE genotypes and interferon-induced neuropsychiatric symptoms. Patients with an epsilon4 allele were more likely to be referred to a psychiatrist and had more neuropsychiatric symptoms during antiviral treatment than those without an epsilon4 allele. Additionally, patients with an epsilon4 allele were more likely to experience irritability or anger and anxiety or other mood symptoms. These data demonstrate that an individual's APOE genotype may influence the neuropsychiatric response to antiviral therapy with interferon alpha. Prospective studies evaluating the importance of APOE in susceptibility to interferon alpha-induced neuropsychiatric complications are needed. Moreover, pathways involving APOE should be considered in understanding the pathophysiology of interferon alpha-induced neuropsychiatric complications.     

The role of extracerebral cholesterol homeostasis and ApoE e4 in cognitive decline

We examined the associations between extracerebral markers of cholesterol homeostasis and cognitive decline over 6 years of follow-up, and studied the modifying effect of apolipoprotein E (ApoE) e4. Data were collected in the Longitudinal Aging Study Amsterdam (n = 967, with longitudinal data on cognition, ages ≥ 65 years) and analyzed using linear mixed models. General cognition (Mini-Mental State Examination; MMSE), memory (Auditory Verbal Learning Test), and information processing speed (Coding task) were measured. The results show that ApoE e4 was a significant effect modifier. Significant associations were found only in ApoE e4 noncarriers (n = 718). We found a nonlinear negative association between the ratio of lanosterol to cholesterol (≤ 189.96 ng/mg), a marker for cholesterol synthesis, and general cognition. Lower cholesterol absorption, i.e., lower ratios of campesterol and sitosterol to cholesterol, as well as a higher rate of cholesterol synthesis relative to absorption were associated with lower information processing speed. In ApoE e4 carriers, the negative association between the ratio of campesterol to cholesterol and memory reached borderline significance. Future research should focus on the interaction between (disturbed) cholesterol homeostasis and ApoE e4 status with respect to dementia.