Presence Of APOE-ε4 Research Articles

Cross-sectional and longitudinal associations between late-life depressive symptoms and cognitive deficits: 20-year follow-up of the Kuakini Honolulu-Asia aging study

ObjectiveTo examine depressed affect, somatic complaints, and positive affect as longitudinal predictors of fluid, crystallized and global cognitive performance in the Kuakini Honolulu-Asia Aging Study (HAAS), a large prospective cohort study of Japanese-American men. MethodsWe assessed 3,088 dementia-free Kuakini-HAAS participants aged 71–93 (77.1 ± 4.2) years at baseline (1991–1993). Depressive symptoms were evaluated by the Center for Epidemiologic Studies Depression (CES-D) Scale. Baseline CES-D depression subscales (depressed and positive affects; somatic complaints) were computed. The Cognitive Abilities Screening Instrument (CASI) measured cognitive performance on a 100-point scale; fluid and crystallized cognitive abilities were derived from CASI factor analysis. Cognition was also evaluated at 4 follow-up examinations over a 20-year period. Multiple regression assessed baseline CES-D subscales as predictors of cognitive change. The baseline covariates analyzed were CASI, age, education, prevalent stroke, APOE ε4 presence, and the longevity-associated FOXO3 genotype. ResultsCross-sectionally, baseline CES-D subscales were related to cognitive measures; e.g., higher depressed affect was associated with lower crystallized ability (β = −0.058, p ≤ 0.01), and somatic complaints were linked to poorer fluid ability (β = −0.045, p ≤ 0.05) and to worse global cognitive function as measured by total CASI score (β = −0.038, p ≤ 0.05). However, depression subscales did not significantly or consistently predict fluid ability, crystallized ability, or global cognitive performance over time. ConclusionPsychological and physical well-being were associated with contemporaneous but not subsequent cognitive functioning. Assessment of depressive symptoms may identify individuals who are likely to benefit from interventions to improve mood and somatic health and thereby maintain or enhance cognition.

Sensitivity of the African neuropsychology battery memory subtests and learning slopes in discriminating APOE 4 and amyloid pathology in adult individuals in the Democratic Republic of Congo.

The current study examined the sensitivity of two memory subtests and their corresponding learning slope metrics derived from the African Neuropsychology Battery (ANB) to detect amyloid pathology and APOEε4 status in adults from Kinshasa, the Democratic Republic of the Congo. 85 participants were classified for the presence of β-amyloid pathology and based on allelic presence of APOEε4 using Simoa. All participants were screened using CSID and AQ, underwent verbal and visuospatial memory testing from ANB, and provided blood samples for plasma Aβ42, Aβ40, and APOE proteotype. Pearson correlation, linear and logistic regression were conducted to compare amyloid pathology and APOEε4 status with derived learning scores, including initial learning, raw learning score, learning over trials, and learning ratio. Our sample included 35 amyloid positive and 44 amyloid negative individuals as well as 42 without and 39 with APOEε4. All ROC AUC ranges for the prediction of amyloid pathology based on learning scores were low, ranging between 0.56-0.70 (95% CI ranging from 0.44-0.82). The sensitivity of all the scores ranged between 54.3-88.6, with some learning metrics demonstrating good sensitivity. Regarding APOEε4 prediction, all AUC values ranged between 0.60-0.69, with all sensitivity measures ranging between 53.8-89.7. There were minimal differences in the AUC values across learning slope metrics, largely due to the lack of ceiling effects in this sample. This study demonstrates that some ANB memory subtests and learning slope metrics can discriminate those that are normal from those with amyloid pathology and those with and without APOEε4, consistent with findings reported in Western populations.

Neuropsychological assessment as a predictor of dementia conversion in Alzheimer’s disease

AbstractBackgroundProgressive cognitive decline is a characteristic of Alzheimer’s disease (AD). Identifying reliable predictors of conversion to dementia in older adults, particularly those with mild cognitive impairment (MCI), is critical for clinicians, patients, and patient families.Method1083 adult participants (Age: M = 73.20, SD = 6.92) were included in this study from the Alzheimer’s Disease Neuroimaging Initiative (ADNI). The average follow up was over 5 years (M = 65.25, SD = 40.16). Cox proportional hazards regression models were implemented to estimate the risk of dementia. Models were built sequentially to examine changes in predictive contributions when including biomarkers and cognitive predictors.Result57% of participants were classified as MCI and 43% as cognitively normal (CN). By the end of study, there is an overall conversion rate of 24% from the participants with cognitive normal and MCI to dementia. Participants with MCI demonstrated significantly higher rates of conversion than those with CN (F(1,258) = 92.51, p < .001, η2 = .26). The initial model indicated greater age (HR = 1.03, p = .004), fewer years of education (HR = 0.95, p < .027), the presence of at least one APOE ε4 gene (HR = 3.23, p < .001), and higher levels of neurofilament light chain (NFL) (HR = 1.28, p < .001) predicted conversion to dementia. A second model indicated higher levels of Ab42 was predictive of lower risk (HR = 0.41, p < .001), whereas higher levels of P‐tau was predictive of greater risk (HR = 1.48, p < .001). APOE ε4 presence and NfL levels remained significant predictors. Finally, composites of memory and executive scores were added. Memory performance at baseline was highly associated with dementia risk (HR = 0.26, p < .001), with poorer performance at baseline predicting greater likelihood of conversion. Similarly, poorer performance on executive functioning tasks was predictive of dementia risk (HR = 0.57, p < .001).ConclusionComposite scores of memory and executive functions are strong predictors of conversion to dementia. Such composites are approximately as predictive as Ab42, and more predictive than demographics, APOE ε4 presence, baseline P‐tau and NFL.

Association of plasma biomarkers with cognitive function in persons with dementia and cognitively healthy in the Democratic Republic of Congo

AbstractBackgroundCross‐sectional and longitudinal measurements of plasma biomarkers of Alzheimer’s disease (AD) in Western countries are being applied in clinical practice, whereas their associations with culturally validated cognitive tests in other settings remain unknown. We aim to examine cross‐sectional association of plasma protein biomarker concentrations and APOE proteotype with cognitive function and explore the discriminative role of these AD biomarkers in such an association.MethodThis is a cross‐sectional retrospective study completed from 2018 to 2022 in the Democratic Republic of Congo (DRC). Subjects were recruited from clinics, hospitals, churches, and across DRC. The study started in January 2018 until December 2022. Data were analyzed from May 2022 to December 2022. The DRC Memory clinic team recruited 1430 individuals 65 years and over. Based on Community Screening Instruments for Dementia (CSID), and Alzheimer’s Questionnaire (AQ), and DSM‐5 diagnostic criteria, participants included 44 individuals classified as major neurocognitive disorder (dementia) and 41 as healthy controls (HC). Subjects underwent cognitive assessment with a validated, culturally‐tailored cognitive battery. AD plasma biomarkers (Aβ42, Aβ40, Aβ42/40, p‐tau 181), APS (derived from Aβ42/40, APOE status, and age), and APOE proteotype were utilized to assess for genetic risk.ResultIndividuals with dementia had significantly lower Aβ42/40 levels, higher APS, and higher APOE ε4 prevalence compared to HC. Linear regressions showed significantly associations between Aβ42/40 and APS with ANT, ALMT, and AVMT scores, while APOE ε4 presence was associated with ANT, ALMT, AVMT, and APT scores. APS showed the highest AUC value (AUC = 0.78, 95% CI: 0.68‐0.88) followed by Aβ42/40 (AUC = 0.75, 95% CI: 0.66‐0.86) and APOE ε4 (AUC = 0.69 (CI 0.57‐0.81) in discriminating dementia from HC.ConclusionSelect AD biomarkers were associated with cognition and differentiated dementia from HC, consistent with extant research. These findings may have implications for the assessment of AD biomarkers in DRC.

Understanding the interplay between APO E polymorphism and cognition in the Italian oldest old: results from the "Mugello study".

Recent data suggest that the deleterious effect on general health and cognition of ε4 allele of Apolipoprotein E (ApoE) observed in the elderly population, may attenuate in extreme aging. This study aimed to describe the ApoE genotype distribution and its relationship with cognition in a group of nonagenarians living in the Mugello area, Italy. Cognition was evaluated using the Mini-Mental-State-Examination (MMSE). DNA was extracted from blood samples to determine ApoE genotyping. Participants were classified into three ApoE groups (ε2, ε3, ε4). Logistic and linear regression models were created, to assess the relationship between ApoE genotype group and dementia diagnosis and cognitive performance, respectively. 169 subjects were included. ApoE ε3 was the most prevalent genotype (76.3%). Dementia prevalence was 26.6% and it was not associated with the presence of ApoE ε4. Participants of ε4 group were significantly more likely to have lower cognitive performances than ε2 and ε3, independently of a dementia diagnosis. Results support that ApoE genotype no longer plays a role in the health condition of the oldest old, however, an interaction is detectable between ApoE polymorphism and cognitive performances at this extreme age.

Disentangling the heterogeneity of brain atrophy in Alzheimer’s Disease

AbstractBackgroundAlzheimer’s disease (AD) is the most common cause of dementia. In AD patients, structural MRI analyses have identified various brain atrophy patterns, which are likely the result of differences in regional pathology distribution and variable presence of co‐pathologies.MethodWe included 496 ADNI participants and applied our robust collaborative clustering approach (RCC) to the MRI scans of the Aβ+ participants. RCC removes noise while simultaneously clustering subjects and features. Group comparisons were performed applying Kruskal‐Wallis analyses for quantitative variables and chi‐square tests for categorical variables (Table 1). Power transformations were used to normalize the distribution of quantitative variable for linear regression analyses. APOE ε4 presence and white matter hyperintensity (WMH) volume were included as predictors. P‐values <0.05 were considered statistically significant.ResultWe identified three distinct atrophy clusters among the Aβ+ participants (Table 1). A “limbic predominant” atrophy cluster showed greater cingulate and right hippocampus, inferior and middle temporal lobe atrophy than the cognitively unremarkable (CU) Aβ‐ reference group (Figure 1). The diffuse atrophy cluster showed greater parieto‐occipital‐temporal atrophy. The “hippocampus sparing” atrophy cluster showed a similar neocortical atrophy pattern except for less atrophy in the temporal lobe. The limbic predominant cluster participants had a higher APOE ε4 prevalence than the hippocampal sparing cluster participants (Table 1, 2). The three clusters had higher baseline ADAS‐Cog13 and flortaucipir SUVR binding in all the Braak staging‐defined areas than the CU Aβ‐ reference group (Table 3). The diffuse atrophy cluster had higher ADAS‐Cog13 scores, florbetapir composite scores, and flortaucipir SUVRs in all the Braak staging‐defined areas than the two other atrophy clusters. The hippocampal sparing atrophy cluster participants were older and had higher WMH volumes than the limbic predominant atrophy cluster and the CU Aβ‐ reference group participants.ConclusionOur clustering method discovered three reproducible atrophy patterns in AD, including typical and atypical presentations. This finding likely reflects different combinations of co‐pathology leading to the development of AD, some of which are captured with MRI. Mainly, WMH contributed to the heterogeneity of AD and the atypical neocortical variant.

Annual stability of the plasma Aß40/42 ratio and associated factors.

The plasma Aß40/42 ratio is a biomarker of brain amyloidosis. However, the threshold difference between amyloid positivity and negativity is only 10-20% and fluctuates with circadian rhythms, aging, and APOE-ε4 during the decades of evolution of Alzheimer's disease. Plasma Aß40 and Aß42 levels in 1472 participants aged between 19 and 93 years in the Iwaki Health Promotion Project for 4 years were statistically analyzed. The means and standard deviations of annual inter-individual coefficients of variation were 5.3 ± 3.2% for Aß40, 7.8 ± 4.6% for Aß42, and 6.4 ± 4.1% for the Aß40/42 ratio. No significant age-dependent changes were observed in inter-individual coefficients of variation. Age-dependent increases in Aβ42 levels were suppressed, whereas those in the Aβ40/42 ratio were enhanced in APOE-ε4 carriers. The change points of Aß42, Aß40, and the Aß40/42 ratio were 36.4, 38.2, and 43.5 years, respectively. In the presence of APOE-ε4, the Aß40/42 ratio increased in middle-aged and elderly subjects while Aβ42 levels decreased in elderly subjects. Individual values for Aß40, Aß42, and the Aß40/42 ratio did not fluctuate annually or in an age-dependent manner. If the plasma Aβ40/42 ratio changes by more than 14.7% (+2 standard deviations) relative to age- and APOE-ε4-adjusted normal annual fluctuations, other biomarkers also need to be examined.

Abstract 13367: APOE ε4 Carriage Associates With Improved Myocardial Performance in Older Age

Introduction: Although APOE ε 4 allele carriage confers a risk of coronary disease, its persistence in human populations might be explained by certain survival advantages (antagonistic pleiotropy) . Hypothesis: Combining data from two British cohorts– the 1946 National Survey of Health and Development (NSHD) and Southall and Brent Revised (SABRE)–we explored whether APOE ε 4 carriage associates with beneficial or unfavorable left ventricular (LV) structural and functional echocardiography parameters in older age. Methods: Based on the presence of APOE ε 4, genotypes were divided into: APOE ε 4 (ε2ε4, ε3ε4, ε 4 ε 4) and non- APOE ε 4 carriers. Echocardiographic data included: LV ejection fraction, E/e’, systolic and diastolic posterior wall and interventricular septal thickness (LVPWT s/d , IVS s/d ), LV mass and the ratio of the LV stroke volume to the LV myocardial volume called myocardial contraction fraction (MCF). Generalized linear models explored associations between APOE ε 4 genotypes as exposures and echocardiographic biomarkers as outcomes. As APOE genotype is a genetic instrumental variable (unconfounded), Model 1 was unadjusted. Model 2 was adjusted for factors associated with the outcome (sex and socio-economic position) to yield more precise estimates; subsequent models were individually adjusted for mediators (body mass index, cardiovascular disease [CVD], high cholesterol and hypertension) to explore mechanistic pathways. Random-effects meta-analyses were performed across the cohorts. Results: 2596 participants were included. Compared to non- APOE ε 4 carriers, APOE ε 4 carriers had similar cardiac phenotypes in terms of EF, E/e’, LVPWT s/d , IVS s/d and LV mass but had a 4% higher MCF (95% confidence interval [CI]: 1–7%, p =0.016) which persisted in Model 2 (95% CI 1–7%, p =0.008) but was attenuated to 3% after adjustment for CVD, diabetes and hypertension (all 95% CI 0–6% all p <0.070). Conclusions: APOE ε 4 carriage associates with improved myocardial performance in older age resulting in greater LV stroke volume generation per 1 mL of myocardium. This potentially favorable cardiac phenotype adds to the growing number of reported survival advantages attributed to APOE ε4 carriage that might collectively explain its persistence in humans.

APOE ε4-dependent effects on the early amyloid pathology in induced neurons of patients with Alzheimer’s disease

BackgroundThe ε4 allele of apolipoprotein E (APOE ε4) is the strongest known genetic risk factor for late-onset Alzheimer’s disease (AD), associated with amyloid pathogenesis. However, it is not clear how APOE ε4 accelerates amyloid-beta (Aβ) deposition during the seeding stage of amyloid development in AD patient neurons.MethodsAD patient induced neurons (iNs) with an APOE ε4 inducible system were prepared from skin fibroblasts of AD patients. Transcriptome analysis was performed using RNA isolated from the AD patient iNs expressing APOE ε4 at amyloid-seeding and amyloid-aggregation stages. Knockdown of IGFBP3 was applied in the iNs to investigate the role of IGFBP3 in the APOE ε4-mediated amyloidosis.ResultsWe optimized amyloid seeding stage in the iNs of AD patients that transiently expressed APOE ε4. Remarkably, we demonstrated that Aβ pathology was aggravated by the induction of APOE ε4 gene expression at the amyloid early-seeding stage in the iNs of AD patients. Moreover, transcriptome analysis in the early-seeding stage revealed that IGFBP3 was functionally important in the molecular pathology of APOE ε4-associated AD.ConclusionsOur findings suggest that the presence of APOE ε4 at the early Aβ-seeding stage in patient iNs is critical for aggravation of sporadic AD pathology. These results provide insights into the importance of APOE ε4 expression for the progression and pathogenesis of sporadic AD.

Development of prediction models for distinguishable cognitive trajectories in patients with amyloid positive mild cognitive impairment

The clinical outcomes of patients with amyloid beta-positive (Aβ+) mild cognitive impairment (MCI) are heterogeneous. We therefore developed prediction models for distinguishable cognitive trajectories in Aβ+ participants with MCI. We included 238 Aβ+ participants with MCI from the Alzheimer's Disease Neuroimaging Initiative to develop a group-based trajectory model and 63 Aβ+ participants with MCI from the Samsung Medical Center for external validation. Three distinguishable classes, slow decliners (18.5%), intermediate decliners (42.9%), and fast decliners (38.7%), were identified. Intermediate decliners were associated with older age, higher AV45 standardized uptake value ratios (SUVR) and lower fluorodeoxyglucose (FDG) SUVR than slow decliners. Fast decliners were associated with older age, presence of APOE ε4, higher AV45 SUVR and lower FDG SUVR than slow decliners. Prediction models of cognitive decline showed good discrimination and calibration capabilities in the development and validation data sets. Our analysis yields novel insights into the cognitive trajectories of Aβ+ patients with MCI, which will facilitate their effective stratification in Aβ-targeted clinical trials.

Genetic Effects of NDUFAF6 rs6982393 and APOE on Alzheimer's Disease in Chinese Rural Elderly: A Cross-Sectional Population-Based Study.

PurposeTo investigate the associations of genotypes of NDUFAF6 rs6982393 and APOE and their combined genotypes with the risk of Alzheimer’s disease (AD) and mild cognitive impairment (MCI) in Chinese rural elderly.MethodsThis cross-sectional population-based study included 5096 older adults (age ≥60 years, 57.1% female). Genotypes of NDUFAF6 rs6982393 and APOE were detected using the multiple-polymerase chain reaction amplification. We diagnosed AD following the criteria of Diagnostic and Statistical Manual of Mental Disorders, the fourth edition and diagnosed MCI following the Petersen’s criteria MCI. Data were analyzed using the logistic regression model.ResultsThe overall prevalence of AD and MCI was 3.57% (95% confidence interval [CI]: 0.040, 0.053) and 22.65% (95% CI: 0.223, 0.247), separately. The TT versus CC/CT genotype of NDUFAF6 rs6982393 was related to a higher risk of AD with the multi-adjusted odds ratio (95% CI) being 1.61 (1.02, 2.54) in the total sample, 3.36 (1.48, 7.60) in those aged 60–69, and 1.24 (0.71, 2.17) in those aged 70 years and above. The interaction between genotype of NDUFAF6 rs6982393 with age groups (60–69 versus ≥70 years) was significant on the risk of AD. The presence of APOE ε4 was not significantly associated with the risk of AD. Carrying both NDUFAF6 TT and APOE ε4 was related to a higher risk of AD with the multi-adjusted odds ratio (95% CI) being 2.69 (1.10, 2.56). In addition, there was no significant association between the above genotypes and MCI.ConclusionIn Chinese rural elderly, the TT versus CT/CC genotype of NDUFAF6 rs6982393 was associated with an increased likelihood of AD; such an association only existed among young-old adults. Carrying both NDUFAF6 rs6982393-TT and APOE ε4 was related to a higher risk of AD. This finding highlights the importance of considering age and combined genotype in studying the genetic profiles of AD.

Predictors of Incident Mild Cognitive Impairment and Its Course in a Diverse Community-Based Population.

Background and ObjectivesTo investigate sociodemographic and medical predictors of incident mild cognitive impairment (MCI) and subsequent course of MCI at follow-up, including sustained MCI diagnosis, classification as cognitively normal, and progression to dementia.MethodsWithin a community-based cohort, diagnoses of MCI were made with a published algorithm. Diagnosis of dementia was based on clinical consensus. Cox regressions estimated hazard ratios of incident MCI associated with several predictors. Modified Poisson regressions estimated relative risks associated with predictors of diagnostic status at follow-up after incidence.ResultsAmong 2,903 cognitively normal participants at baseline, 752 developed MCI over an average of 6.3 (SD 4.5) years (incidence rate 56 per 1,000 person-years). Presence of APOE ε4 and higher medical burden increased risk of incident MCI, while more years of education, more leisure activities, and higher income decreased this risk. Of the incident MCI cases, after an average of 2.4 years of follow-up, 12.9% progressed to dementia, 9.6% declined in functioning and did not meet the algorithmic criteria for MCI but did not meet the clinical criteria for dementia, 29.6% continued to meet MCI criteria, and 47.9% no longer met MCI criteria. Multidomain MCI, presence of APOE ε4, depressive symptoms, and antidepressant use increased the risk of progression to dementia.DiscussionThis community-based study showed that almost half of the individuals with incident MCI diagnoses were classified as cognitively normal at follow-up. Predictors of incident MCI demonstrably differed from those of subsequent MCI course; these findings can refine expectations for cognitive and functional course of those presenting with MCI.

Tau‐load in the lingual gyrus impacts anxiety levels during the COVID‐19 pandemic in participants of longitudinal observational studies in aging

BackgroundBy obtaining a better grasp on the impact of the COVID‐19 pandemic on individuals with cognitive impairment, this knowledge could be used to improve the delivery of information to this particular group. We aimed to assess the relationship between tau deposition and the change in anxiety levels, before and during the pandemic. We hypothesized that since the pandemic, higher tau loads would lower the change in anxiety. Furthermore, we expected these anxiety levels not to be associated with COVID‐19 related stress in participants with cognitive decline.Methods63 participants of the Translational Biomarker of Aging and Dementia (TRIAD) cohort (cognitively healthy, N=38; cognitively impaired, N=25, of which 7 had dementia due to Alzheimer’s disease), were assessed to evaluate their individual change in anxiety levels (GAD‐7). This was done at three different timepoints, of which the latest fell during the COVID‐19 lockdown period. Two rates of change, one before and one during the pandemic, were determined using the following definition: (next timepoint – current timepoint)/time difference. In addition, at the latest timepoint, subjective stress due to COVID‐19 was measured using the Montreal Assessment of Stress related to COVID‐19 (MASC). To assess the levels of tau, standard uptake value ratios (SUVR) from previously obtained [18F]MK‐6240 PET‐scans were used.Results[18F]MK‐6240 tracer binding in the lingual gyrus was negatively associated with the rate of change in GAD‐7 scores after correcting for age, sex, years of education and the presence of APOE ε4, but only in cognitively impaired individuals during the pandemic (fig 1A). In addition, the GAD‐7 score at the latest timepoint was associated with stress related to COVID‐19, but only in cognitively healthy individuals (fig 1B and 1C).ConclusionsThe presence of tau in the lingual gyrus negatively affected the rate of change in GAD‐7 scores during the COVID‐19 pandemic in individuals with cognitive impairment. This could indicate that information pertaining to the pandemic does not reach these individuals in an efficient manner. The missing association between COVID‐19 induced stress and the latest GAD‐7 scores in these individuals is a further indication of this.

Apolipoprotein E genotype, cognitive performance, and dementia among diverse Latin American populations.

APOE-ε4 allele is the most significant genetic risk factor for late-onset Alzheimer disease (AD). The magnitude of the association between the APOE-ε4 allele, AD, and cognitive decline has been shown to be stronger in populations of European descent relative to populations of African descent. However, these associations have been understudied in more admixed populations, including Latin American (LatAm) populations. We examine the associations between APOE-ε4, cognitive performance, and dementia prevalence among a sample of 5,953 older adults from LatAm (Cuba, Dominican Republic [DR], Puerto Rico [PR], and Venezuela) drawn from the 10/66 Dementia Research Group study. We further examine whether global ancestry modifies these associations. Dementia diagnosis was established using the previously validated 10/66 diagnostic algorithm and DSM-IV criteria. Mean age was 72.7 in Venezuela and 75.0 years in Cuba, DR, and PR. Dementia prevalence was lower in Venezuela (6.9%) compared to the Caribbean countries (Cuba=10.6%, PR=11.7%, DR=11.8%). The prevalence of the APOE-ε4 allele was higher in DR compared to PR, Venezuela, and Cuba. Using APOE-ε3 allele as a reference category, presence of APOE-ε4 was significantly associated with increased risk of dementia (OR, 2.33; 95% confidence interval [CI], 1.84, 2.81). We found that APOE-ε4 carriers with a higher African ancestry proportion had slower cognitive decline, although this was not statistically significant. Although we found strong association between APOE-ε4 and increased dementia risk; compared to previous reports in European descent populations the effect of APOE-ε4 is attenuated in Caribbean origin populations. The possibility that African ancestry may mediate the effect of APOE-ε4 will require further confirmation using larger samples.

Cognitive Functioning and Hippocampal Connectivity in Patients With Longstanding Type 1 Diabetes and Apolipoprotein E ε4.

While the apolipoprotein E ε4 allele (ApoE-ε4) is related to cognitive and brain decline in the general population, its effect on the brain in type 1 diabetes mellitus (T1DM) remains unclear. Therefore, the aim was to determine the interaction between ApoE-ε4 and T1DM on cognitive performance and hippocampal structure and connectivity as the brain area most vulnerable to ApoE-ε4 effects in adult patients with T1DM. Blood sampling was performed in 104 patients with T1DM and 49 control subjects for ApoE genotyping, neuropsychology, and neuroimaging to determine hippocampal volume and resting-state connectivity. The interaction between T1DM status and ApoE-ε4 presence was investigated and adjusted for age and mean systolic blood pressure. ApoE genotyping could not be performed for three patients with T1DM. Significant interaction effects, indicating a differential effect of ApoE-ε4 between both groups, were found for overall cognitive functioning and for the subdomains of information processing speed and attention. Additionally, interaction effects were present for right hippocampal connectivity with the right posterior cingulate and supramarginal gyri. Subsequent group analysis showed that patients with T1DM with ApoE-ε4 performed worse on these cognitive domains with increased connectivity, relative to their counterparts without ApoE-ε4. In contrast, no cognitive effects, but decreased connectivity, were observed in control subjects with ApoE-ε4. In patients with T1DM, higher right hippocampus connectivity with the posterior cingulate gyrus was related to poorer overall cognitive functioning. The results may suggest that ApoE-ε4 presence leaves our patients with T1DM more susceptible to cognitive decrements at a younger age, possibly through vascular pathways, warranting further longitudinal studies.

Check your immune privilege: Is there a role for the maternal immune system in the pathogenesis of childhood tics and obsessive-compulsive disorder?

Elevated serum C-reactive protein (CRP) and possessing an APOE ε4 allele are two of the most prominent risk factors for cognitive and neurological dysfunction in older adults, but little is known about the unique or cumulative effects of these risk factors in young-to-middle-aged adults. To further characterize these potential relationships, measures of cognition and microstructural white matter integrity were examined using data from a sample of 329 post-9/11 war veterans that was collected as part of a comprehensive evaluation that included assessment of neuropsychological functioning, MRI scanning, psychiatric diagnoses, health screening, markers of inflammation, and APOE genotypes. Hierarchical linear regression analyses revealed the CRP and APOE ε4 interaction was associated with global cognition (β = -0.633), executive functioning (β = -0.566), and global fractional anisotropy (β = -0.470), such that elevated CRP was associated with worse cognition and white matter integrity in APOE ε4 carriers. Diffusion tensor imaging (DTI) was used to determine if CRP × APOE ε4 presence was associated with regionally specific fractional anisotropy in white matter tracts. Tract-based spatial statistics revealed CRP × APOE ε4 presence was associated with fractional anisotropy in the corpus callosum, right superior longitudinal fasciculus, right posterior corona radiata, as well as the bilateral anterior and superior corona radiatas. This suggests that APOE ε4 carriers may be uniquely vulnerable to the potentially negative impact of elevated systematic inflammation to cognition and microstructural white matter integrity.

Culture Variabilities of Human iPSC-Derived Cerebral Organoids Are a Major Issue for the Modelling of Phenotypes Observed in Alzheimer's Disease.

Apolipoprotein E (APOE) is the most important susceptibility gene for late onset of Alzheimer's disease (AD), with the presence of APOE-ε4 associated with increased risk of developing AD. Here, we reprogrammed human fibroblasts from individuals with different APOE-ε genotypes into induced pluripotent stem cells (iPSCs), and generated isogenic lines with different APOE profiles. Following characterisation of the newly established iPSC lines, we used an unguided/unpatterning differentiation method to generate six-month-old cerebral organoids from all iPSC lines to assess the suitability of this in vitro system to measure APOE, β amyloid, and Tau phosphorylation levels. We identified variabilities in the organoids' cell composition between cell lines, and between batches of differentiation for each cell line. We observed more homogenous cerebral organoids, and similar levels of APOE, β amyloid, and Tau when using the CRISPR-edited APOE isogenic lines, with the exception of one site of Tau phosphorylation which was higher in the APOE-ε4/ε4 organoids. These data describe that pathological hallmarks of AD are observed in cerebral organoids, and that their variation is mainly independent of the APOE-ε status of the cells, but associated with the high variability of cerebral organoid differentiation. It demonstrates that the cell-line-to-cell-line and batch-to-batch variabilities need to be considered when using cerebral organoids.

Amyloid Positivity in the Alzheimer/Subcortical-Vascular Spectrum.

We investigated the frequency of β-amyloid (Aβ) positivity in 9 groups classified according to a combination of 3 different cognition states and 3 distinct levels of white matter hyperintensities (WMH) (minimal, moderate, and severe) and aimed to determine which factors were associated with Aβ after controlling for WMH and vice versa. A total of 1,047 individuals with subjective cognitive decline (SCD, n = 294), mild cognitive impairment (MCI, n = 237), or dementia (n = 516) who underwent Aβ PET scans were recruited from the memory clinic at Samsung Medical Center in Seoul, Korea. We investigated the following: (1) Aβ positivity in the 9 groups, (2) the relationship between Aβ positivity and WMH severity, and (3) clinical and genetic factors independently associated with Aβ or WMH. Aβ positivity increased as the severity of cognitive impairment increased (SCD [15.7%], MCI [43.5%], and dementia [76.2%]), whereas it decreased as the severity of WMH increased (minimal [54.5%], moderate [53.9%], and severe [41.0%]) or the number of lacunes (0 [59.0%], 1-3 [42.0%], and >3 [23.4%]) increased. Aβ positivity was associated with higher education, absence of diabetes, and presence of APOE ε4 after controlling for cognitive and WMH status. Our analysis of Aβ positivity involving a large sample classified according to the stratified cognitive states and WMH severity indicates that Alzheimer and cerebral small vessel diseases lie on a continuum. Our results offer clinicians insightful information about the association among Aβ, WMH, and cognition.

Association between Thyroid Hormones, Apolipoprotein E, and Cognitive Function among Cognitively-Normal Elderly Dwellers.

ObjectiveThe correlation among the thyroid-related hormones, Apolipoprotein E ε4 (APOE ε4) and cognitive function has been reported despite controversial results. This study was designed to investigate this correlation among cognitively-normal elderly dwellers. MethodsThis study assessed 507 cognitively normal individuals aged over 60 who underwent comprehensive hematological and neuropsychological assessments including the quantification of serum free thyroxine and thyroid stimulating hormone (TSH) as well as the Korean version of the Consortium Establish a Registry for Alzheimer’s disease. The Korean version of Geriatric Depression Scale was also employed to evaluate the severity of depression. Age, gender, education, and the presence of APOE ε4 were taken into account as covariates. ResultsThere was a significant positive association between verbal fluency test (VFT), Word List Memory Test (WLMT), and Word List Recall Test (WLRT) score and serum TSH levels (p=0.007, 0.031, and 0.023 respectively). The further analysis adding the interaction between APOE ε4 and TSH level, however, revealed only VFT score was significantly influenced by this interaction (p=0.026). ConclusionLower serum TSH levels had impacts on both semantic memory (VFT) and episodic memory (WLMT, WLRT) among cognitively-normal elderly, whereas the interaction of TSH and APOE ε4 influenced only the task of semantic memory (VFT) in this group.

Exergaming improves functional fitness in MCI patients. Does the APOE genotype moderate the outcome?

Objectives: Mild cognitive impairment could be defined as the condition between healthy aging and dementia. MCI patients seem to retain the neuroplasticity to benefit from Physical Exercise (PE) interventions delaying the progression to dementia. The present study investigates the impact of PE via “Exergaming” on the functional fitness of MCI adults, depending on the presence of the APOEɛ4 allele. Methods: 159 MCI participants were recruited. They were separated to two groups (performing PE or not). The Fullerton Functional Test was used as a primary outcome measure in two-time points (prior to and after PE). Results: The Active group showed more considerable improvement compared to the Passive group in all Fullerton components despite the presence of APOEε4. Discussion: ΡΕ via exergaming has a beneficial functional effect in MCI patients, whether carrying the APOEɛ4 allele or not.