APOE E4 Allele Status Research Articles

Impact of work type and APOE-e4 status on cognitive functioning in older women

Prior research indicates that APOE-e4 allele(s) and working without compensation may be independently associated with risk for cognitive decline. This study investigated whether the interaction of type of work (paid versus unpaid) and presence of APOE-e4 allele(s) was associated with cognitive dysfunction in women in mid- and late-life. Participants included 340 females (mean age = 74.7 years) from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) dataset. A two-way ANOVA to assess the simple main effects of type of work and APOE-e4 allele status on cognition as well as their interaction was performed. A two-way ANCOVA including age, education, and marital status as covariates was also conducted. The presence of one or two APOE-e4 allele(s) and unpaid work was associated with greater cognitive dysfunction. A significant interaction effect revealed engagement in paid work, regardless of the presence of APOE-e4 allele(s), was associated with better cognitive functioning. Consistent with prior literature, women who engage in unpaid forms of labor for the majority of their life may be at higher risk for cognitive decline, regardless of presence of APOE-e4 allele(s). Further research is needed to identify the factors related to unpaid labor that may increase risk for cognitive dysfunction.

A novel analytic approach to examine the relationship between APOE4 allele status and CSF complement‐related proteins and signaling pathways

AbstractBackgroundThe mechanisms by which the APOE4 allele contributes to AD risk are unclear. Here, we tested the hypothesis that in cognitively normal adults, APOE4 allele is associated with a decrease in complement‐related proteins and downregulation of complement‐related pathways.MethodUntargeted LC‐MS/MS proteomics was conducted on CSF samples (n = 118) from APOE3/3, APOE3/4 and APOE4/4 individuals over age 60, with groups matched on age and sex. We developed a novel analytic approach (which we term “up/down analysis”) based on the directional consistency of the β‐coefficients from a linear model for the intensities of peptides mapping to a given protein with respect to APOE4 carrier status (APOE4‐/ APOE4+). The analysis involves two steps: 1) The direction of the beta‐coefficient (positive/up or negative/down) for the level of each peptide (the outcome variable) due to APOE4 carrier status was derived from linear regression models adjusting for age, sex, and study. 2) These β‐coefficients were tallied for all peptides from a given protein (i.e. number of positive/up versus negative/down β‐coefficients). We then tested the probability under a binomial distribution that the distribution of up versus down peptides from each protein would be as, or more extreme than what we found, with a = 0.05. Pathway enrichment analysis (using p‐values from binomial tests) was conducted using GAGE and functional annotations based on KEGG. We used Benjamini‐Hochberg for multiple comparison correction.ResultWe found 158 proteins for which the direction of peptide intensity was consistently up (+β‐coefficient) or down (‐β‐coefficient) with respect to APOE4 status beyond what would be expected by chance. Of these 158 proteins, 37 were from the complement pathway. Pathway enrichment analysis further supports the role of the complement system; as the top differentially expressed pathway (FDR <0.05) was related to complement signaling.ConclusionOur results suggest that APOE4 carriers have lower CSF levels of key complement cascade proteins, which has previously been viewed as an indicator of complement activation. These results may provide insights into the mechanisms by which APOE4 and associated complement‐related proteins and signaling pathways ultimately contribute to increased AD risk.

76 Baseline Frontoparietal Gray Matter Volume Predicts Executive Function Performance at 24-Months in Early and Late Mild Cognitive Impairment

Objective:To examine the relationships between baseline gray matter volumes, diagnostic status, and executive function performance at 24-month follow-up, and the relative importance of predictors of executive function in a cohort of non-demented older adults.Participants and Methods:The study sample included 147 participants from the Alzheimer’s Disease Neuroimaging Initiative (mean age = 70.6, SD = 6.4; mean education = 17 years, SD = 2.4). At baseline, 49 participants were diagnosed as cognitively normal (CN), 60 as early mild cognitive impairment (EMCI), and 38 as late mild cognitive impairment (LMCI). Magnetic resonance imaging (MRI) data were collected at baseline. A composite score of executive function and FreeSurfer-derived gray matter regions-of-interest (ROI; whole brain, superior frontal gyrus, middle frontal gyrus, inferior frontal gyrus, orbitofrontal cortex, anterior cingulate cortex, superior parietal lobule, inferior parietal lobule, hippocampus) were examined. Hierarchical linear regression models were employed to assess whether brain volume predicted executive function at 24-month follow-up and interaction effects between baseline ROI volume and diagnostic status. Age, gender, education, Mini-Mental State Examination scores, and APOE-e4 allele status were included as control variables in each model. Relative importance metrics, which quantifies an individual regressor’s contribution to a multiple regression model, were computed using the Lindemen, Merenda, and Gold (lmg) method to assess the relative contribution of each variable in predicting executive function performance.Results:Across all participants, baseline gray matter ROI volume accounted for a significant amount of variance in executive function at 24-months after accounting for control variables. Specifically, anterior cingulate cortex and superior parietal lobule accounted for an additional 7% and 6% of variance in executive function at 24-months. Significant brain region X diagnostic status interaction effects were observed in executive function performance at 24-months. Relative importance metrics within each group indicated that age is the most important predictor of executive function at 24-months for CN, anterior cingulate cortex is most important for EMCI, and Mini-Mental Examination score is most important for LMCI.Conclusions:Our findings implicate frontoparietal gray matter regions as significant predictors of executive function performance at 24-months, and that this relationship is moderated by diagnostic status. Our results indicate that the value of specific variables to predict executive function performance varies based on diagnostic status. Specifically, anterior cingulate cortex was a significant predictor of executive function performance across all participants and was the most important variable in predicting performance in the earliest stage of mild cognitive impairment. These results support previous studies examining gray matter correlates of executive function and extend the literature by exploring predictors of executive function in early and late stages of mild cognitive impairment.

Cross‐sectional and longitudinal associations of plasma makers of amyloid and tau pathology and neurodegeneration with gait speed

AbstractBackgroundHigher brain amyloid PET is associated with slower gait speed and has been hypothesized to play a role in age‐related mobility decline. With the development of blood‐based biomarkers of Alzheimer’s disease pathology, we examined whether plasma levels of amyloid‐beta (Aβ)40, Aβ42, the Aβ42/Aβ40 ratio, phosphorylated tau 181 (p‐tau181) and 217 (p‐tau217), total tau, and neurofilament light chain (NfL) were associated with gait speed.MethodThis study included 779 cognitively unimpaired participants (median age 75, 54.8% male, median follow‐up 6.8 years) in the Mayo Clinic Study of Aging with concurrent measurement of plasma biomarkers and gait speed. Individuals with chronic kidney disease or a history of stroke were excluded. The plasma markers (pg/mL) were measured on the Quanterix Simoa® HD‐1 analyzer (total tau, Aβ42, Aβ40, NfL) and the Meso Scale Discovery platform (p‐tau181, p‐tau217). Gait speed (m/s) was obtained by timing a self‐paced walk across 25 ft using a stopwatch. Linear mixed effects models, with subject‐specific intercepts and slopes for time since baseline, with z‐scored baseline plasma markers were used to predict cross‐sectional and longitudinal gait speed. All models adjusted for baseline age and sex.ResultAt baseline, higher Aβ42 [Beta = ‐0.019; 95%CI = (‐0.035, ‐0.004)], total‐tau [‐0.026; (‐0.041, ‐0.011)], and p‐tau181 [‐0.021; (‐0.036, ‐0.006)] were associated with slower gait speed. Gait speed decreased, on average, by about 0.015 m/s annually for those in this study. Each one standard deviation (SD) increase in baseline level of plasma Aβ40 [‐0.005; (‐0.007, ‐0.002)], NfL [‐0.006; (‐0.009, ‐0.004)], and p‐tau217 [‐0.004; (‐0.007, ‐0.001)] accelerated this decline over time. In contrast, each one SD increase in Aβ42/Aβ40 ratio [0.003; (0.001, 0.006)] mitigated decline. Additional analyses adjusting for Charlson comorbidity index, Beck Depression Inventory, body mass index, and APOE E4 allele status gave similar results.ConclusionBoth cross‐sectional and longitudinal associations of plasma markers of amyloid and tau pathology and neurodegeneration with gait speed among cognitively unimpaired individuals were present. Therefore, not only are these markers of cognitive changes, they are also related to motor changes such as those affecting gait speed.

A glycan epitope correlates with tau in serum and predicts progression to Alzheimer's disease in combination with APOE4 allele status.

There is an urgent need for novel blood biomarkers for the detection of Alzheimer's disease (AD). We previously showed that levels of the bisecting N-acetylglucosamine glycan epitope was elevated in cerebrospinal fluid in AD. However, its diagnostic value in blood is unknown. We analyzed blood levels of bisecting N-acetylglucosamine and total tau in a retrospective cohort of 233 individuals. Progression to AD was compared between the groups using Cox regression. The predictive value of the biomarkers was determined by logistic regression. Bisecting N-acetylglucosamine correlated with tau levels (p<0.0001). Individuals with an intermediate tau/bisecting N-acetylglucosamine ratio had elevated AD risk (hazard ratio=2.06, 95% confidence interval [CI]: 1.18-3.6). Moreover, a combined model including tau/bisecting N-acetylglucosamine ratio, apolipoprotein E (APOE) ε4 status, and Mini-Mental State Examination score predicted future AD (area under the curve = 0.81, 95% CI: 0.68-0.93). Bisecting N-acetylglucosamine in combination with tau is a valuable blood biomarker for predicting AD.

Unique contributions of brain amyloid load and APOE4 Status to Regional Brain Volume

AbstractBackgroundBrain amyloid and tau, and volumetric atrophy on MRI, are defining features of AD (Jack et al., 2018). Despite growing interest in these component processes, their relationship is still poorly understood.We evaluated the unique contributions of APOE4 allele (E4+/E4−) and brain amyloid (Aβ) status (Amy+/Amy−) to brain volume in the elderly to identify associations with neurodegeneration in regions vulnerable to Alzheimer’s disease (AD).MethodAccelerated 3T T1‐weighted brain MRI scans (N=1,353) obtained at screening for three distinct phases of ADNI with available information on APOE status and/or Amyloid positive/negative status were identified for the following subjects: 561 healthy controls (CN) (age: 71.8±6.3 y, 330F/231M), 599 MCI (mild cognitive impairment; age: 71.9 ± 7.5 y, 264 F/335 M), and 193 AD (age: 74.4±8.2 y, 79 F/114 M). Amyloid status was based on standardized cut‐off values in amyloid sensitive PET scans (Royse et al., 2021).We applied unbiased tensor‐based morphometry (TBM; Leow et al., 2009; Hua et al., 2011) to each scan to measure relative volume differences between each subject and a common minimal deformation template (MDT), resulting in 3D Jacobian maps to represent relative expansion or contraction at each brain voxel.At each voxel, a linear regression model was fit to relate regional brain volumes to amyloid status, and APOE4, after adjusting for covariates. P‐value maps were generated to visualize the pattern of voxel‐wise model contributions and statistical significance while enforcing a standard 5% false discovery rate (FDR) correction for multiple statistical comparisons across the brain (Benjamini et al., 1995).ResultAmyloid positive status was associated with significantly lower regional volume in the temporal lobes and higher volume in the ventricles, i.e., ventricular expansion. APOE4 positive status was associated with lower volume in the temporal lobes (see Fig. 1). ConclusionThe highly localized effects of APOE4 status and amyloid load on brain volumes are consistent with greatest effects of AD pathologic processes in the temporal lobes and similar associations found for Amy+ and E4+ status with cortical thinning (Li et al. (2017).Continued analysis of longitudinal ADNI data will offer further insight into effects of amyloid and APOE4 allele status on atrophy estimates.

The association between long‐term PM2.5 exposure and late‐life amyloid burden in the Atherosclerosis Risk in Communities (ARIC) study cohort

AbstractBackgroundA number of studies show an association between long‐term exposure to ambient particulate matter ≤ 2.5 um (PM2.5) and late‐life cognitive impairment. Mechanistic models suggest that PM2.5 may influence cognitive health through promotion of Alzheimer’s disease, which is characterized by brain amyloid accumulation. However, the association between long‐term PM2.5 exposure and brain amyloid deposition remains poorly characterized in epidemiological studies.MethodWe used data from the Atherosclerosis Risk in Communities (ARIC) study cohort. We used a chemical transport model with data fusion to estimate mean PM2.5 concentrations (ug/m3) in 36‐, 12‐, 4‐, and 1‐km grid cells in ARIC study areas. We linked the concentrations to geocoded participant addresses and calculated mean PM2.5 concentrations from 2000 to 2007. We estimated amyloid deposition using florbetapir amyloid positron emission tomography (PET) scans in 346 ARIC‐PET participants with normal cognition or mild cognitive impairment in 2011‐2014. We defined amyloid positivity as a global cortical standardized uptake value ratio (SUVR) ≥ the sample median of 1.2. We used logistic regression models to quantify the association between amyloid positivity and mean 2000‐2007 PM2.5 concentration after adjusting for potential confounders. We additionally explored effect measure modification by APOE e4 allele status and tested whether effect estimates were consistent using alternate PM2.5 exposure methods.ResultAfter restricting to participants with non‐missing exposure and confounder data and excluding one participant with dementia, the analytic sample included 279 participants. At the time of amyloid‐PET scans, their mean age was 78 years, 56% were female, 42% were Black, and 26% had mild cognitive impairment. After adjusting for age, sex, education, and race‐study center, we found no significant association between brain amyloid positivity and long‐term mean PM2.5 exposure. We also found no evidence of effect measure modification by APOE e4 allele status. Results were consistent when we used alternate PM2.5 estimation methods.ConclusionOur findings suggest that ambient PM2.5 may induce neurotoxic effects through non‐amyloid, potentially vascular pathways, though we note the small sample size may have made us underpowered to detect a significant association.

Different associations of varying types of Vitamin E and cognitive function in older adults with or without APOE Ɛ4 allele

AbstractBackgroundDifferent forms of vitamin E may have a different association with cognitive function, which might vary by the APOE E4 allele status. We aim to examine vitamin E from different sources and in varying forms and their relation to cognitive decline among those with and without the APOE E4 allele.MethodsWe included 2,014 participants from the Chicago Health and Aging Project (62% African Americans, 63% female). Global cognition was assessed using a composite score of episodic memory, perceptual speed, and the MMSE. Diet was assessed by a 139‐item FFQ. APOE genotype was assessed by hME Sequenom mass‐array platform. Mixed models were adjusted for age, sex, education, smoking status, calorie intake, alcohol consumption, use of supplements, time since baseline, and the interaction term of time with each covariate.ResultsA higher dietary vitamin E was associated with slower cognitive decline. Those in the highest quintile of dietary vitamin E intake had 28% slower cognitive decline than the lowest quintile (β = 0.014, p = 0.02). A higher intake of dietary αlpha‐tocopherol was associated with slower cognitive decline in participants with APOE E4 allele, but not among those without. In participants with APOE E4 allele and in the highest quintile of alpha‐tocopherol intake had a 16.4% slower rate of global cognitive decline than those in the lowest quintile (β = 0.015, p = 0.0015). A higher intake of delta‐tocopherol was associated with a slower decline in individuals without the APOE E4 allele only. Among those without the APOE E4 allele and in the highest quintile, the rate of global cognitive decline was slower by 22% than the lowest quintile (β = 0.012, p = 0.0014). We found no significant associations between beta‐ and gamma‐tocopherol intakes and cognitive decline among those with and without the APOE E4 allele.ConclusionOur study found a positive association of alpha‐tocopherol with cognitive decline among those with the APOE E4 allele and delta‐tocopherol with the decline in those without the APOE E4 allele. Our findings suggest that different forms of vitamin E might have a different association with cognitive decline in older adults depending on their APOE E4 allele status.

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.

Misappraisal of sleep quality is associated with lower cognitive functioning

AbstractBackgroundSelf‐reported sleep quality often does not strongly correlate with objective measurements of sleep, and thus, other factors such as cognitive ability might contribute in the self‐awareness of one’s own sleep. Although sleep disturbances are increasingly recognized as risk factor for dementia, individuals with lower cognitive performance might present with an impaired ability to appropriately report their sleep, reducing the importance of self‐reported data. The purpose of this study was to evaluate whether misappraisal of sleep consolidation and quality was associated with poorer cognitive performance.MethodWe studied 265 participants (58.0±8.9 years, 50.2 % men) in the Framingham Heart Study Offspring Cohort who had an overnight in‐home polysomnography and neuropsychological testing 3.5 years later on average. Self‐reported sleep quality regarding the night of the polysomnography was compared to objective sleep efficiency (cut‐off at 85%). Four groups were created representing those with consistent appraisal of good sleep (n=75, good self‐reported and objective sleep); consistent appraisal of poor sleep (n=72, poor self‐reported and objective sleep); misappraisal of poor sleep (n=41, good self‐reported sleep but poor objective sleep); misappraisal of good sleep (n=77, poor self‐reported sleep but good objective sleep). We evaluated global cognition (composite score), verbal memory (Logical Memory immediate and delayed recall), executive function (Trail Making Test B minus A) and visual organization (Hooper Visual Organization Test). Models were adjusted for age, sex, education, time between polysomnography and neuropsychology, APOE4 allele status, body mass index, sleeping pills, depression, and stroke risk.ResultParticipants that misappraised poor sleep, i.e., reported good sleep quality but had lower sleep efficiency, had lower global cognitive performance (β±SE=‐0.34±0.17; p=0.047), worse immediate verbal memory recall (‐1.39±0.67; p=0.039) and poorer executive functioning (‐0.16±0.05; p=0.003) compared to participants with consistent appraisal of good sleep. No other between‐group differences were observed.ConclusionIndividuals with misappraisal of poor sleep had poorer cognitive performance than individuals with consistent appraisal of good sleep. This type of sleep misappraisal could be occurring when cognitive functions are declining and self‐awareness is impaired. Further studies comparing self‐report to objective measures of sleep are required in patients in preclinical stages of dementia and with cognitive impairment.

MRI markers of accelerated brain aging and misappraisal of sleep depth

AbstractBackgroundSlow‐wave sleep (SWS) is the deepest sleep stage, and has been linked to many important physiological functions, including the cerebral metabolic clearance of toxins associated with Alzheimer’s disease. SWS loss might correlate with accelerated brain aging. However, older individuals and people with cognitive impairment have an impaired ability to appraise their sleep, suggesting that accelerated brain aging might affect how sleep depth is perceived. The purpose of this study was to evaluate whether misappraisal of sleep depth was associated with MRI markers of accelerated brain aging.MethodWe studied 242 participants (mean: 62.0±8.7 years) participants in the Framingham Heart Study Offspring Cohort that were evaluated with an overnight in‐home polysomnography and an MRI 3.4 years later on average. Self‐reported sleep depth (whether sleep was light or deep) on the night of the polysomnography was compared to objective SWS (percent of total sleep spent in SWS, separated by the median). Four groups were created: 36% of the sample had consistent appraisal of deep sleep; 12% of the sample had consistent appraisal of light sleep; 36% misappraised their light sleep as deep; and 16% misappraised their deep sleep as light. We evaluated total brain volume, cortical gray matter volume, and subcortical gray matter volume on MRI. A first set of models were adjusted for age, sex, time between MRI and neuropsychology; a second set of models were additionally adjusted for APOE4 allele status, body mass index, sleeping pills, depression, and stroke risk.ResultParticipants who misappraised light sleep, i.e., reported deep sleep but had lower SWS, had lower cortical gray matter volume (model 1: β±SE=‐0.62±0.26, p=0.018; model 2: ‐0.56±0.27, p=0.036) compared to those that reported deep sleep with higher SWS. We also observed a trend for lower subcortical gray matter volume in the same group (model 1:β±SE=‐0.09±0.05, p=0.084). No other between‐group differences were observed.ConclusionParticipants with lower SWS that reported their sleep as deep displayed lower cortical volume. Accelerated brain aging might affect the ability to appropriately perceived sleep depth, which could be occurring in preclinical stages of dementia. Relying on self‐report sleep depth may introduce systematic misclassification.

Apolipoprotein E e4 allele status and later-life depression in the Lothian Birth Cohort 1936.

Previous results have been mixed regarding the role of the apolipoprotein E e4 (APOE e4) allele in later-life depression: some studies note that carriers experience greater symptoms and increased risk while others find no such association. However, there are few prospective, population-based studies of the APOE e4-depression association and fewer that examine depressive symptom trajectory and depression risk longitudinally. We examined the association between APOE e4 allele status and longitudinal change in depressive symptoms and depression risk in later-life, over a 12-year follow-up period. We used data from 690 participants of the Lothian Birth Cohort 1936 who took part in the Scottish Mental Survey 1947 (aged 11) and were followed-up in later-life over five waves from 2004 to 2019 (aged 70-82). We used APOE e4 allele status to predict longitudinal change in depressive symptom scores and risk of depression (defined by a symptom score threshold or use of depression-related medication). Models were adjusted for sex, childhood cognitive ability, childhood social class, education, adult social class, smoking status and functional limitations at baseline. Depressive symptom scores increased with age. Once adjusted for covariates, APOE e4 allele status did not significantly predict symptom score trajectories or depression risk. Greater functional limitations at baseline significantly predicted poorer symptom score trajectories and increased depression risk (defined by medications). APOE e4 allele status did not significantly moderate the contribution of sex, education or functional limitations. There was no evidence that APOE e4 carriers experience an increased risk for later-life depression.

Gene Network Analysis Reveals Association between Somatic Loss of Y and Genes Involved in Hemostasis

Background and Hypothesis: &#x0D; Somatic loss of the Y chromosome (LOY) is associated with diagnoses of various cancers, Alzheimer’s disease, and cardiovascular events. In the case of cardiovascular disorders, no mechanistic link to LOY has been elucidated. To explore this relationship, we utilized Weighted Gene Co-Expression Analysis (WGCNA), a powerful technique that can reveal associations between modules of co-expressed genes and clinical traits. We hypothesized WGCNA would reveal a module that illuminates the relationship between LOY and cardiovascular disease. &#x0D; &#x0D; Methods: &#x0D; Information about 403 male participants was obtained from Alzheimer’s Disease Neuroimaging Initiative (ADNI), including Genome Wide Association Study (GWAS), microarray, and patient demographic data. GWAS data was obtained from each participant within one year of collecting gene expression data. Using GWAS data for each participant, a median log R ratio was calculated for probes in the male specific region of the Y (MSY), which showed detectable LOY in 16 participants. Microarray data was used for WGCNA. Genes with correlated expression levels were organized into modules which were tested for associations with age, Alzheimer’s disease status, APOE-e4 allele status, and LOY. Ensembl IDs were used to investigate Gene Ontology (GO) enrichment in the GO database. &#x0D; &#x0D; Results: &#x0D; One module was associated with LOY (p=0.001). GO enrichment revealed significant representation of 47 GO terms within this module. Highly enriched GO terms included “platelet aggregation” (FDR = 8.05 x 10-6), “blood coagulation, fibrin clot formation” (FDR= 0.0328), “regulation of megakaryocyte differentiation” (FDR=3.01 x 10-5), and other terms related to the vascular response to injury. &#x0D; &#x0D; Potential Impact: &#x0D; WGNCA revealed a module associated with LOY that is related to vascular injury response. While LOY is associated with cardiovascular events, more work is needed to explore its association with biomarkers for cardiovascular disease. Our findings warrant more investigation into the relationship between LOY and cardiovascular dysfunction in males.

Role of apolipoprotein ε4 allele as a predictor in the course and outcome in patients with subcortical vascular dementia

AbstractBackgroundVascular dementia (VaD) is the second most common dementia in elderly and the major contributor being Cerebral Small Vessel Disease (SVD) which has radiological manifestations of White Matter Hyperintensities(WMH), Cerebral Microbleeds and Lacunar infarcts. This study looks into the role of clinico‐demographic profile, genetic factors in terms of Apo E4 status and neuropsychological characteristics in predicting the course and outcome in patients with Subcortical VaD.MethodA prospective cohort study involving 202 patients who were followed up at baseline and subsequently after 1 and 2 years’ time intervals following informed consent and IEC approval with attempt to understand the role of APOE4 positive status as a predictor for cognitive decline. Comparison of Neuropsychological test performance with ANOVA, regression analysis and survival analysis by plotting Kaplan Meier’s curve was done using SPSS v.21.ResultThe major risk factor identified was Hypertension in 92% followed by smoking in 76% and low socioeconomic status in 56% patients. 35.7% of the population had an APO E4 allele positivity. Regression analysis done showed APO E4 positive status as a significant independent predictor of poorer performance in neuropsychological test scores across time periods. However, survival analysis utilizing Kaplan Meir’s plot showed that unlike smoking and WMH (Odds ratio : 2.62) which increased mortality rates more than twofold, APO E4 did not contribute to increased mortality.ConclusionThis study comprehensively looks into the role of APO E4 in VaD and identifies need for prevention of modifiable risk factors like smoking, hypertension, low SES, poor cognitive reserves and WMH which predicts cognitive decline in subcortical VaD and lead to early mortality in patients with VaD. Positive APO E4 allele status significantly affects performance in cognitive assessments but does not appear to predict mortality and hence risk modification needs to be tailored in patients with VaD.

Cognitive decline in older adults with epilepsy: The Cardiovascular Health Study.

Cognitive decline is a major concern for older adults with epilepsy. Whether and how much faster older adults with epilepsy experience cognitive decline beyond expected age-related cognitive change remain unclear. We sought to estimate and compare rates of cognitive decline in older adults with and without epilepsy. The Cardiovascular Health Study is a population-based longitudinal cohort study of 5888 US adults aged 65+. Cognitive function was assessed annually with Modified Mini-Mental State Exam (3MS) and Digit Symbol Substitution Test (DSST). We used linear mixed models to estimate average rates of decline in 3MS and DSST scores by epilepsy status (prevalent, incident, or no epilepsy), adjusted for risk factors associated with cognitive decline. The rate of decline in 3MS was significantly faster in prevalent epilepsy (P<.001) and after incident epilepsy (P=.002) compared with no epilepsy. Prevalent epilepsy and apolipoprotein E gene (APOE) ε4 (ApoE4) had a synergistic interaction, whereby prevalent epilepsy and ApoE4 together were associated with 1.51 points faster annual decline in 3MS than would be expected if prevalent epilepsy and ApoE4 did not interact (P<.001). Older adults with prevalent epilepsy had a significantly lower initial DSST score and faster rate of decline compared to those with no epilepsy (P<.001). Faster decline in global cognitive ability seen in this study validates concerns of patients. ApoE4 allele status was an effect modifier of the relationship between cognitive decline and prevalent epilepsy. Further research is warranted to explore biological mechanisms and possible interventions to mitigate cognitive decline.

Abstract MP39: Association of MIND Diet Adherence With Brain Volume, Silent Brain Infarcts and Brain Atrophy in the Framingham Heart Study

Objective: Adherence to the Mediterranean- DASH for Neurodegenerative Delay (MIND) diet has previously been associated with cognitive decline and dementia. To our knowledge, no prior study has investigated the association between the MIND diet and measures of brain volume, silent brain infarcts (SBIs) or brain atrophy. Methods: We aimed to evaluate, cross-sectionally and longitudinally, whether consumption of a diet consist with the MIND diet was associated with larger brain volumes, fewer SBIs and fewer atrophy in the community-based Framinham Heart Study. We included 1,904 participants (mean age 69 (SD, 9)) who completed a brain MRI and a validated food frequency questionnaire (FFQ). The MIND diet consists of 10 healthy and five unhealthy components (range: 0-15). A cumulative MIND diet score was calculated by averaging across three FFQs (exams 5 (1991-1995), 6 (1995-1998), and 7 (1998-2001)). From the total study population, 86 % completed all three FFQs. Brain MRI was performed proximal to exam 7 and again after a mean of 7 years (SD, 1.1) (n=1,317). Total brain volume (TBV), hippocampal volume (HPV), white matter hyperintensity volume (WMHV), expressed as a percentage of total cranial volume, and presence of SBIs were assessed from MRI scans. We used multivariable linear (TBV, HPV and WMHV) and logistic (SBIs) regressions for the cross-sectional analyses, and we analyzed the annualized change of TBV and HPV as atrophy measures using multivariable linear regression. Results: In cross-sectional analyses, higher MIND diet scores were significantly associated with larger TBV (β±SE, +0.09±0.04; p=0.03) after adjustment for basic demographic factors, total daily energy intake, and APOE e4 allele status, but was not associated with HPV (+0.001±0.001; p=0.09), WMHV (-0.01±0.01; p=0.27), SBIs (OR (95%CI), +1.01, 0.92:1.10; p=0.61) or atrophy (TBV, -0.001±0.01; p=0.88; HPV, -0.0003±0.001; p=0.62). After additional adjustments for cardiovascular risk factors the association with TBV was attenuated (+0.05±0.04; p=0.17). Significant interactions were observed for HPV by APOE ε4 status and BMI in the basic model. After stratification by APOE ε4 status, higher MIND diet scores were significantly associated with higher HPV among APOE ε4 non-carriers (+0.002±0.001; p=0.01) but not carriers (n=412). After stratification by BMI, higher adherence to the MIND diet was associated with larger HPV among participants with a BMI above 25 (+0.002±0.001; p=0.01), but not among participants with a BMI below 25. Conclusions: Higher adherence to the MIND diet was not independently associated with brain volume measures, SBIs or brain atrophy in our community cohort as the associations appeared to be mediated by cardiovascular risk factors. In addition, we observed that adherence to the diet was associated with larger brain volume measures in sub groups. Replication is needed to confirm our findings.

Current versus lifetime depression, APOE variation, and their interaction on cognitive performance in younger and older adults.

An interaction effect of depressive symptoms and APOE e4 allele status on cognitive decline has been shown in old age: e4 allele carriers with more depressive symptoms have faster cognitive decline than those with either depression or the e4 allele. We test this interaction effect on four cognitive domains, using a clinical depression measure comparing current versus lifetime depression. 14,379 individuals aged 18 to 59 years, and 3944 individuals aged 60 to 94 years from the Generation Scotland: Scottish Family Health Study participated. Linear-mixed models-accounting for participant relatedness and demographic and health indices-tested for effects of depression and APOE on cognitive abilities. There was no interaction between depression and APOE on cognition (p > .05). Current depression was associated with poorer speed (in both groups) and memory (18- to 59-year-olds); differences ranged from 0.01 to 0.03 standard deviation [SD]. For lifetime depression, cognitive performance was lower for digit symbol in younger adults, but higher for vocabulary in both younger (0.03 SD) and older (0.05 SD) adults. A negative effect of the APOE e4 allele on speed and memory was found in the group 60 years and older (effect sizes of 0.04 SD). The absence of a depression by APOE interaction on cognitive abilities suggests that these synergistic effects only operate at the level of cognitive decline. This implies that it is those biological pathways especially affected by aging that become compromised further by the combined presence of depression and APOE e4 in an individual.

When Mars Versus Venus is Not a Cliché: Gender Differences in the Neurobiology of Alzheimer's Disease.

OPINION article Front. Neurol., 12 January 2015Sec. Neurodegeneration https://doi.org/10.3389/fneur.2014.00288

Apolipoprotein E Allele and Hearing Thresholds in Older Adults.

Whether apolipoprotein E (APOE) E4 allele status which is associated with an increased risk of cognitive decline is also associated with hearing impairment is unknown. We studied 1833 men and women enrolled in the Health, Aging and Body Composition study. Regression models adjusted for demographic and cardiovascular risk factors were used to assess the cross-sectional association of APOE-E4 status with individual pure tone hearing thresholds and the 4-frequency pure tone average (0.5-4 kHz) in the better hearing ear. Compared to participants with no APOE-E4 alleles, participants with 1 allele had better thresholds at 4.0 kHz (β = -2.72 dB, P = .013) and 8.0 kHz (β = -3.05 kHz, P = .006), and participants with 2 alleles had better hearing thresholds at 1.0 kHz (β = -8.56 dB, P = .021). Our results suggest that APOE-E4 allele status may be marginally associated with better hearing thresholds in older adults.

Clinical and pathologic presentation in Parkinson's disease by apolipoprotein e4 allele status

BackgroundApolipoprotein (APOE) e4 allele status has been linked to clinical presentation and progression in Alzheimer's disease; however, evidence for a role of APOE e4 in Parkinson's disease (PD) remains largely inconclusive. In this analysis we explored potential significant associations between APOE e4 allele status and characteristics of clinical presentation in patients with PD. MethodsData came from 424 subjects evaluated using the Uniform Data Set (UDS) assessment collected by the National Alzheimer's Coordinating Center. Subjects had a known year of diagnosis of PD and experienced change in motor function prior to any change in cognition. Linear and logistic regression were used to model the association between APOE e4 carrier status and clinical characteristics including measures of cognitive decline and motor and neuropsychiatric symptoms. Amyloid burden was also evaluated for a subset of patients who died and consented to autopsy. ResultsOdds of dementia were higher in APOE e4 carriers (OR = 5.15), and, on average, APOE e4 carriers scored two points worse on tests of episodic memory and the Clinical Dementia Rating Sum of Boxes assessment. There was little evidence to support an association between e4 carrier status and severity of motor features, and, of the four neuropsychiatric symptoms evaluated, only presence of hallucinations was significantly associated with APOE e4 carrier status (OR = 5.29). Neuropathology data revealed higher frequencies of neuritic and diffuse amyloid plaques in APOE e4 carriers compared to non-carriers. ConclusionsAPOE e4 allele status is associated with dementia and severity of Alzheimer's disease pathologic features in PD.