APOE Ε4 Noncarriers Research Articles

Polygenic risk scores for Alzheimer's disease predict MMSE decline in APOE4 carriers and noncarriers and the impact of sample overlap with GWAS summary statistics.

Heterogeneity in the progression of cognitive impairment, which is common in sporadic Alzheimer's disease (AD) trials, is especially challenging to predict in pre-symptomatic populations, and has a negative impact on clinical trial power. Heritability of AD extends beyond the APOE genotype, with multiple common genetic variants identified in large genome wide association studies (GWAS). Incorporating APOE and additional genetic variants into models has the potential to improve the prediction of disease progression. The limited volume of genetic cohorts in AD and the sample overlap in GWAS summary statistics poses some concern for polygenic risk score (PRS) overfitting. A PRS was calculated using genome-wide association study (GWAS) summary statistics for clinical AD diagnosis. PRS derived from this GWAS study was computed for participants drawn from two aging studies. Logistic regression models assessed the association between PRS and Mini Mental State Exam (MMSE) decline covarying for age, sex, education, APOE-ε4, and baseline MMSE score. Age and sex interactions with PRS were also assessed. Samples assumed to be used in the GWAS calculations were then removed from the test set and the impact to performance was analyzed. Participants in the training and test set showed similar baseline ages, years of education and baseline MMSE scores in the whole sample and after stratification by APOE4 carrier status. The PRS model was a significant predictor of MMSE decline, as well as in APOE4 carriers and noncarriers. Model performance was compared to the test set excluding the GWAS overlap samples and no significant difference was observed. The proposed model including PRS explains heterogeneity in cognitive decline above and beyond the APOE4 allele. Testing the model in a dataset excluding GWAS overlap samples did not result in a significant difference in performance and potential overfitting does not appear to be an impact. Utilization of demographic and genomic factors beyond APOE in PRS models could enhance clinical trial recruitment and stratification strategies for trial analyses, such that APOE4 carriers are selected for probable cognitive decline, in addition to APOE3 carriers that are high on polygenic risk.

Higher inflammation levels in cognitively normal older adults are associated with conversion to mild cognitive impairment and Alzheimer's disease.

There is growing evidence that Alzheimer's disease (AD) pathogenesis interacts with immunological mechanisms in the brain. CSF and blood inflammatory markers of the NF-κß pathway, a key transcriptional regulator of inflammation involved in learning and memory, are elevated in cognitively normal older adults and those with early MCI. However, few studies have examined whether elevated inflammation predicts clinical conversion in cognitively normal older adults. Our study aimed to investigate the relationship between levels of TNF-α, canonical trigger of NF-κß pathway and IL-9, a cytokine whose expression is driven by NF-κß, and clinical conversion status. 295 older adult participants (118 males, mean age+SE=74.87+6.75, 124 APOE4 carriers) from ADNI were selected based on having available baseline CSF values and diagnoses for at least two timepoints. Cox proportional-hazard models were used to test the association between baseline inflammatory markers and clinical conversion from cognitively normal to MCI or AD. Baseline age, sex, and APOE4 status were included as covariates. Additional analyses explored the modifying role of APOE4 on the relationship between CSF values and conversion. Higher levels of TNF-α were associated with greater conversion from cognitively normal (CN) to MCI (Hazard ratio (HR): 1.31, confidence interval (CI): 1.07, 1.59, p<0.01), and from CN and MCI to AD (HR: 1.13, CI: 1.01, 1.21, p =0.02), suggesting those who were cognitively normal with elevated TNF-α levels had a 31% increased risk of conversion to MCI relative to those with lower TNF-α levels. Higher IL-9 was associated with a 37% increased risk of conversion to MCI (HR: 1.37, CI: 1.02, 1.84, p=0.04). Additionally, an APOE4-to-IL-9 interaction was observed (HR: 2.46, CI: (1.34, 4.52), p<0.01), such that APOE4 carriers with higher IL-9 levels were at greater risk for conversion than APOE4 non-carriers (Fig 1). In cognitively normal older adults, higher levels of inflammatory markers TNF-α and IL-9 are associated with greater conversion to MCI and AD. This relationship is exacerbated in APOE4 carriers. Together, this suggests that early elevated inflammation levels are associated with subsequent cognitive decline and dementia risk and may be an earlier indicator of future conversion to MCI or AD.

Peripheral inflammation and AD-related hippocampal neurodegeneration in prodromal AD patients.

Alzheimer's disease (AD) is a neurodegenerative disorder characterized by the presence of beta-amyloid (Aβ42) and phosphorylated tau (P-tau) deposits in the brain, neurodegeneration in specific brain regions, and inflammation. This study aimed at investigating the association of periferal inflammatory signaling with brain structural alterations in MCI patients with or without AD pathology. Study population: 89 consecutive enrolled amnestic MCI patients. AD pathology definition: based on baseline CSF Aβ42/P-tau level as well as APOE genotype (positivity defined as Aβ42/P-tau ratio<7.8 for APOE4 non-carriers, <15.2 for carriers). MRI processing: volumes of the hippocampus and its subfields were extracted with Freesurfer (version 7). Cytokine expression: pro- (IL6, IL8, IL1beta, TNF-alpha, NLRP3) and anti- (IL10) inflammatory molecules were measured by Real Time PCR Assay. Subjects provided written informed consent, validated by the local ethics commitee RESULT: As expected, MCI patients with AD pathology had lower volume in the presubiculum (p=.007), subiculum (p=.030) and CA1 (p=.028) than negative patients. Moreover, positive patients showed lower expression of IL-10 (p=.033) as well as higher expression of NLRP3 (p=.050) and IL-8 (p=.037). Correlation analyses in all MCI patients revealed a negative association between IL10 levels and ADAScog13 (r=-0.27, p=0.01) and P-tau (r=-0.22, p=0.04), and a positive association with CSF Aβ42 (r=0.22, p=0.037), hippocampal volume (r=0.23, p=0.03), temporal lobe (r=0.38, p=0.0004) and precuneus thicknesses (r=0.37 p=0.0006), consistent with a protective effect of IL10 in AD pathology. More analysis are ongoing on the effect of cytokines on different rates of atrophy of brain subfields. Higher expression of anti-inflammatory factors are associated to a lower hippocampal neurodegeneration and better clinical and pathophysiological outcome in prodromal AD patients. These preliminary results suggest that non-invasive peripheral inflammatory biomarkers could represent possible biomarkers to support the early diagnosis of AD.

Perioperative neurocognitive and functional neuroimaging trajectories in older APOE4 carriers compared with non-carriers: secondary analysis of a prospective cohort study

BackgroundCognitive dysfunction after surgery is a major issue in older adults. Here, we determined the effect of APOE4 on perioperative neurocognitive function in older patients. MethodsWe enrolled 140 English-speaking patients ≥60 yr old scheduled for noncardiac surgery under general anaesthesia in an observational cohort study, of whom 52 underwent neuroimaging. We measured cognition; Aβ, tau, p-tau levels in CSF; and resting-state intrinsic functional connectivity in six Alzheimer's disease-risk regions before and 6 weeks after surgery. ResultsThere were no significant APOE4-related differences in cognition or CSF biomarkers, except APOE4 carriers had lower CSF Aβ levels than non-carriers (preoperative median CSF Aβ [median absolute deviation], APOE4 305 pg ml−1 [65] vs 378 pg ml−1 [38], respectively; P=0.001). Controlling for age, APOE4 carriers had significantly greater preoperative functional connectivity than non-carriers between several brain regions implicated in Alzheimer's disease, including between the left posterior cingulate cortex and left angular gyrus (β [95% confidence interval, CI], 0.218 [0.137–0.230]; PFWE=0.016). APOE4 carriers, but not non-carriers, experienced significant connectivity decreases from before to 6 weeks after surgery between several brain regions including between the left posterior cingulate cortex and left angular gyrus (β [95% CI], –0.196 [–0.256 to –0.136]; PFWE=0.001). Most preoperative and postoperative functional connectivity differences did not change after controlling for preoperative CSF Aβ levels. ConclusionsPostoperative change trajectories for cognition and CSF Aβ, tau or p-tau levels did not differ between community dwelling older APOE4 carriers and non-carriers. APOE4 carriers showed greater preoperative functional connectivity and greater postoperative decreases in functional connectivity in key Alzheimer's disease-risk regions, which occur via Aβ-independent mechanisms.

Apolipoprotein E4 increases the risk of depression recurrence

BackgroundPossession of the ε4 allele of apolipoprotein E (APOE4) is related to the incidence of depression in old age. We investigated whether the presence of APOE4 is also associated with subsequent depression recurrence in a wide range of age groups. MethodsAltogether, 163 patients with major depressive disorder (MDD) after remission were recruited between August 2004 and March 2016 and followed up prospectively. The patients were divided into two groups: APOE4 carriers and non-carriers. We compared the time to recurrence of depression between the two groups. Kaplan–Meier survival curves, log-rank test for trend for survivor functions, and Cox proportional hazard ratio estimates for a multivariate model were conducted to examine the effect of the APOE4 allele on risk of a depression recurrence. ResultsCumulative probability of developing a depression recurrence was higher in APOE4 carriers than non-carriers. Presence of an APOE4 allele remained significantly associated with the incidence of depression recurrence. LimitationsAll patients were treated with one or two different antidepressants, which may have had different effects on patients with MDD. Second, participants in the present study comprised patients with both first and multiple episodes of MDD. Third, we did not have the statistical power to perform a stratified analysis in consideration of heterozygous or homozygous genotypes of APOE4. ConclusionPossession of an APOE4 allele may increase the risk of depression recurrence.

Predictability of polygenic risk score for progression to dementia and its interaction with APOE \u03b54 in mild cognitive impairment

BackgroundThe combinatorial effect of multiple genetic factors calculated as a polygenic risk score (PRS) has been studied to predict disease progression to Alzheimer’s disease (AD) from mild cognitive impairment (MCI). Previous studies have investigated the performance of PRS in the prediction of disease progression to AD by including and excluding single nucleotide polymorphisms within the region surrounding the APOE gene. These studies may have missed the APOE genotype-specific predictability of PRS for disease progression to AD.MethodsWe analyzed 732 MCI from the Alzheimer’s Disease Neuroimaging Initiative cohort, including those who progressed to AD within 5 years post-baseline (n = 270) and remained stable as MCI (n = 462). The predictability of PRS including and excluding the APOE region (PRS+APOE and PRS−APOE) on the conversion to AD and its interaction with the APOE ε4 carrier status were assessed using Cox regression analyses.ResultsPRS+APOE (hazard ratio [HR] 1.468, 95% CI 1.335–1.615) and PRS−APOE (HR 1.293, 95% CI 1.157–1.445) were both associated with a significantly increased risk of MCI progression to dementia. The interaction between PRS+APOE and APOE ε4 carrier status was significant with a P-value of 0.0378. The association of PRSs with the progression risk was stronger in APOE ε4 non-carriers (PRS+APOE: HR 1.710, 95% CI 1.244–2.351; PRS−APOE: HR 1.429, 95% CI 1.182–1.728) than in APOE ε4 carriers (PRS+APOE: HR 1.167, 95% CI 1.005–1.355; PRS−APOE: HR 1.172, 95% CI 1.020–1.346).ConclusionsPRS could predict the conversion of MCI to dementia with a stronger association in APOE ε4 non-carriers than APOE ε4 carriers. This indicates PRS as a potential genetic predictor particularly for MCI with no APOE ε4 alleles.

Herpes simplex virus, early neuroimaging markers and incidence of Alzheimer\u2019s disease

While previous studies suggest the implication of herpes simplex virus (HSV) in the onset of Alzheimer’s disease (AD), no study has investigated its association with early neuroimaging markers of AD. In the Three-City and the AMI cohorts, the associations between HSV infection and (i) hippocampal volume (n = 349), (ii) white matter alterations in the parahippocampal cingulum and fornix using diffusion tensor imaging (n = 260), and (iii) incidence of AD (n = 1599) were assessed according to APOE4 status. Regardless of APOE4 status, infected subjects presented (i) significantly more microstructural alterations of the parahippocampal cingulum and fornix, (ii) lower hippocampal volumes only when their anti-HSV IgG level was in the highest tercile—reflecting possibly more frequent reactivations of the virus (p = 0.03 for subjects with a high anti-HSV IgG level while there was no association for all infected subjects, p = 0.19), and (iii) had no increased risk of developing AD. Nevertheless, among APOE4 carriers, infected subjects presented lower hippocampal volumes, although not significant (p = 0.09), and a two or three times higher risk of developing AD (adjusted Hazard ratio (aHR) = 2.72 [1.07–6.91] p = 0.04 for infected subjects and aHR = 3.87 [1.45–10.28] p = 0.007 for infected subjects with an anti-HSV IgG level in the highest tercile) while no association was found among APOE4 noncarriers. Our findings support an association between HSV infection and AD and a potential interaction between HSV status and APOE4. This reinforces the need to further investigate the infectious hypothesis of AD, especially the associated susceptibility factors and the possibility of preventive treatments.

Interaction Between APOE Genotype and Diabetes in Longevity.

While both apolipoprotein E (APOE) genotype and diabetes affect longevity as well as Alzheimer's disease, their relationship remains to be elucidated. The current study investigated the potential interaction between diabetes and APOE for lifespan and their relationship with cognitive status. We reviewed the National Alzheimer's Coordinating Center (NACC) dataset, which documents longitudinally clinical records of 24,967 individuals with APOE genotype and diabetic status. Diabetes was associated with shorter lifespan in APOE3 carriers (n = 12,415, HR = 1.29, 95%CI = 1.17-1.42, p < 0.001) and APOE2 carriers (n = 2,390, HR = 1.37, 95%CI = 1.10-1.69, p = 0.016), while such associations were weaker and not significant in APOE4 carriers (n = 9,490, HR = 1.11, 95%CI = 0.99-1.24, p = 0.162). As there is a significant interactive effect of cognitive status and diabetes on lifespan (p < 0.001), we stratified subjects by cognitive status and observed persistent APOE-dependent harmful effects of diabetes in nondemented individuals but not demented individuals. Notably, questionnaire-based activity status, with which we previously observed an association between APOE genotype and longevity, was also significantly affected by diabetes only in non-APOE4 carriers. The effects of diabetes on longevity vary among APOE genotype. These effects are observed in nondemented individuals and are potentially associated with activity status during their lifespan.

APOE Genotype and Alzheimer's Disease: The Influence of Lifestyle and Environmental Factors.

Alzheimer's disease (AD) is the most common neurodegenerative disorder with obscure pathogenesis and no disease-modifying therapy to date. AD is multifactorial disease that develops from the complex interplay of genetic factors and environmental exposures. The E4 allele of the gene encoding apolipoprotein E (APOE) is the most common genetic risk factor for AD, whereas the E2 allele acts in a protective manner. A growing amount of epidemiological evidence suggests that several lifestyle habits and environmental factors may interact with APOE alleles to synergistically affect the risk of AD development. Among them, physical exercise, dietary habits including fat intake and ketogenic diet, higher education, traumatic brain injury, cigarette smoking, coffee consumption, alcohol intake, and exposure to pesticides and sunlight have gained increasing attention. Although the current evidence is inconsistent, it seems that younger APOE4 carriers in preclinical stages may benefit mostly from preventive lifestyle interventions, whereas older APOE4 noncarriers with dementia may show the most pronounced effects. The large discrepancies between the epidemiological studies may be attributed to differences in the sample sizes, the demographic characteristics of the participants, including age and sex, the methodological design, and potential related exposures and comorbidities as possible cofounding factors. In this Review, we aim to discuss available evidence of the prominent APOE genotype-environment interactions in regard to cognitive decline with a focus on AD, providing an overview of the current landscape in this field and suggesting future directions.

The Effects of rs405509 on APOEε4 Non-carriers in Non-demented Aging.

BackgroundThere is evidence that the T allele of rs405509 located in the apolipoprotein E (APOE) promotor region is a risk factor for Alzheimer’s disease (AD). However, the effect of the T/T allele on brain function in non-demented aging is still unclear.MethodsWe analyzed the effects of the rs405509 T/T allele on cognitive performances using multiple neuropsychological tests and local brain function using resting-state functional magnetic resonance imaging (rs-fMRI).ResultsSignificant differences were found between T/T carriers and G allele carriers on general cognitive status, memory, and attention (p < 0.05). Rs-fMRI analyses demonstrated decreased amplitude of low frequency fluctuation (ALFF) in the right middle frontal gyrus, decreased percent amplitude of fluctuation (PerAF) in the right middle frontal gyrus, increased regional homogeneity (ReHo) in the right cerebellar tonsil and decreased ReHo in the right putamen, and decreased degree centrality (DC) in the left middle frontal gyrus (p < 0.05, corrected). Furthermore, significant correlations were found between cognitive performance and these neuroimaging changes (p < 0.05).ConclusionThese findings suggest that T/T allele may serve as an independent risk factor that can influence brain function in different regions in non-demented aging.

Progression along data-driven disease timelines is predictive of Alzheimer’s disease in a population-based cohort

Data-driven disease progression models have provided important insight into the timeline of brain changes in AD phenotypes. However, their utility in predicting the progression of pre-symptomatic AD in a population-based setting has not yet been investigated. In this study, we investigated if the disease timelines constructed in a case-controlled setting, with subjects stratified according to APOE status, are generalizable to a population-based cohort, and if progression along these disease timelines is predictive of AD. Seven volumetric biomarkers derived from structural MRI were considered. We estimated APOE-specific disease timelines of changes in these biomarkers using a recently proposed method called co-initialized discriminative event-based modeling (co-init DEBM). This method can also estimate a disease stage for new subjects by calculating their position along the disease timelines. The model was trained and cross-validated on the Alzheimer’s Disease Neuroimaging Initiative (ADNI) dataset, and tested on the population-based Rotterdam Study (RS) cohort. We compared the diagnostic and prognostic value of the disease stage in the two cohorts. Furthermore, we investigated if the rate of change of disease stage in RS participants with longitudinal MRI data was predictive of AD. In ADNI, the estimated disease timeslines for ϵ4 non-carriers and carriers were found to be significantly different from one another (p<0.001). The estimate disease stage along the respective timelines distinguished AD subjects from controls with an AUC of 0.83 in both APOEϵ4 non-carriers and carriers. In the RS cohort, we obtained an AUC of 0.83 and 0.85 in ϵ4 non-carriers and carriers, respectively. Progression along the disease timelines as estimated by the rate of change of disease stage showed a significant difference (p<0.005) for subjects with pre-symptomatic AD as compared to the general aging population in RS. It distinguished pre-symptomatic AD subjects with an AUC of 0.81 in APOEϵ4 non-carriers and 0.88 in carriers, which was better than any individual volumetric biomarker, or its rate of change, could achieve. Our results suggest that co-init DEBM trained on case-controlled data is generalizable to a population-based cohort setting and that progression along the disease timelines is predictive of the development of AD in the general population. We expect that this approach can help to identify at-risk individuals from the general population for targeted clinical trials as well as to provide biomarker based objective assessment in such trials.

Blood Pressure Level Is Associated With Changes in Plasma Aβ1 -40 and Aβ1-42 Levels: A Cross-sectional Study Conducted in the Suburbs of Xi'an, China.

Objectives: Amyloid-β (Aβ) deposition in the brain is the hallmark of Alzheimer’s disease (AD) pathology. Hypertension is a risk factor for AD, but the effects of hypertension on Aβ deposition are not fully determined. Considering peripheral Aβ closely relates to Aβ deposition in the brain, we investigated the relationships between blood pressure (BP) level and plasma Aβ concentrations.Methods: One-thousand and sixty-nine participants (age above 45) from a village in the suburbs of Xi’an, China were enrolled. Questionnaires and validated Chinese versions of the Mini-Mental State Examination (MMSE) were used to collect information about vascular risk factors and assess cognition function. The apolipoprotein E (ApoE) genotype was detected using PCR and sequencing. Plasma Aβ levels were measured using ELISA. The associations between BP and plasma Aβ levels were analyzed by using multivariate linear regression.Results: Plasma Aβ1–40 level was higher in high BP group than that in normal BP group (53.34 ± 8.50 pg/ml vs. 51.98 ± 8.96 pg/ml, P = 0.013), in high SBP group than that in normal SBP group (53.68 ± 8.69 pg/ml vs. 51.88 ± 8.80 pg/ml, P = 0.001) and in high MABP group than that in normal MABP group (54.05 ± 8.78 pg/ml vs. 52.04 ± 8.75 pg/ml, P = 0.001). After controlling for the confounding factors, SBP (b = 0.078, P < 0.001), DBP (b = 0.090, P = 0.008) and MABP (b = 0.104, P < 0.001) correlated with plasma Aβ1–40 level positively in ApoE ε4 non-carriers, but not ApoE ε4 carriers.Conclusions: Elevated BP levels were associated with increased plasma Aβ1–40 levels in middle-aged and elderly ApoE ε4 non-carriers.

Evidence of cerebral hemodynamic dysregulation in middle-aged APOE ε4 carriers: The PREVENT-Dementia study

Accumulating evidence suggests vascular dysregulation in preclinical Alzheimer’s disease. In this study, cerebral hemodynamics and their coupling with cognition in middle-aged apolipoprotein ε4 carriers (APOEε4+) were investigated. Longitudinal 3 T T1-weighted and arterial spin labelling MRI data from 158 participants (40–59 years old) in the PREVENT-Dementia study were analysed (125 two-year follow-up). Cognition was evaluated using the COGNITO battery. Cerebral blood flow (CBF) and cerebrovascular resistance index (CVRi) were quantified for the flow territories of the anterior, middle and posterior cerebral arteries. CBF was corrected for underlying atrophy and individual hematocrit. Hemodynamic measures were the dependent variables in linear regression models, with age, sex, years of education and APOEε4 carriership as predictors. Further analyses were conducted with cognitive outcomes as dependent variables, using the same model as before with additional APOEε4 × hemodynamics interactions. At baseline, APOEε4+ showed increased CBF and decreased CVRi compared to non-carriers in the anterior and middle cerebral arteries, suggestive of potential vasodilation. Hemodynamic changes were similar between groups. Interaction analysis revealed positive associations between CBF changes and performance changes in delayed recall (for APOEε4 non-carriers) and verbal fluency (for APOEε4 carriers) cognitive tests. These observations are consistent with neurovascular dysregulation in middle-aged APOEε4+.

Behavioural effects of the ACE insertion/deletion polymorphism in Alzheimer’s disease depend upon stratification according to APOE-ϵ4 carrier status

ABSTRACT Introduction: The inherited risk of late-onset Alzheimer’s disease (AD) is genetically determined. We aimed to examine associations of genetic variants of APOE and ACE with age at AD onset and with neuropsychiatric symptoms according to each dementia stage. Methods: Consecutive outpatients with AD were assessed for demographic features, Clinical Dementia Rating scores, and the 10-item Neuropsychiatric Inventory, and genotyped for rs7412 and rs429358 (APOE haplotypes, Real-Time Polymerase Chain Reactions), and the ACE insertion/deletion polymorphism (Polymerase Chain Reactions). Combined genetic variants of APOE and ACE were associated with age at dementia onset, and with neuropsychiatric symptoms in each dementia stage (adjusted for sex and age at dementia onset). Results: Over two-thirds of the 238 patients were women, whereas the mean age at dementia onset was 73.82 ± 6.2 years-old. APOE-ϵ4/ϵ4 carriers had earlier dementia onset (p<.001). The ACE insertion/deletion polymorphism was in Hardy-Weinberg equilibrium (p=.37) but was not associated with age at dementia onset, regardless of APOE-ϵ4 carrier status. The only results that survived corrections for false discovery rates were higher scores of dysphoria for APOE-ϵ4 carriers (n=122) who also carried ACE deletion/deletion (p=.031). No results survived corrections for false discovery rates for APOE-ϵ4 non-carriers (n=116). Conclusions: Though only the APOE-ϵ4/ϵ4 haplotype affected AD onset, effects of the ACE insertion/deletion polymorphism over behavioural features might differ according to APOE-ϵ4 carrier status in genetic associations.

Sex differences in the association between the APOEε4 allele and hearing impairment: A longitudinal memory clinic study

BackgroundThe APOEε4 allele and hearing impairment are risk factors for dementia. Cross-sectional studies have shown controversial findings regarding the relationship between APOEε4 and hearing impairment. These may be explained by reported sex differences in the association between APOEε4 and some Alzheimer's disease biomarkers. We aimed to investigate APOEε4 and hearing impairment in a longitudinal setting considering the modifying effects of sex on APOEε4. MethodsIn total, 1810 subjects with APOE genotype at Ilsan Hospital memory clinics were linked to the longitudinal National Health Insurance Service database with International Statistical Classification of Diseases and Related Health Problems 10th revision (ICD-10) diagnosis codes of hearing impairment. After excluding cases with prevalent hearing impairment and incomplete records, 1092 subjects were analyzed for the period January 2004–July 2019. We used Cox proportional hazard models with or without adjustment for education, hypertension, diabetes, and cognitive function. Effect modification was analyzed by sex stratification and by adding APOEε4 by sex interaction terms. ResultsHearing impairment did not differ between APOEε4 carriers and non-carriers. Sex-stratification analysis with an unadjusted model showed men with APOEε4 developed more hearing impairment than men without (HR 1.90, 95% CI 1.20–3.01), but women did not. The results remained similar in covariate-adjusted models. The interaction between APOEε4 and sex was also significant regardless of adjustment. ConclusionsOur longitudinal analyses suggested male memory clinic visitors with APOEε4 allele were more likely to develop hearing impairment than those without the genotype. This group may benefit more from regular monitoring and preventive measures for hearing impairment.

Small-World Networks and Their Relationship With Hippocampal Glutamine/Glutamate Concentration in Healthy Adults With Varying Genetic Risk for Alzheimer's Disease.

BackgroundApolipoprotein E ɛ4 allele (ApoE4) is the most common gene polymorphism related to Alzheimer's disease (AD). Impaired synaptic dysfunction occurs in ApoE4 carriers before any clinical symptoms. It remains unknown whether ApoE4 status affects the hippocampal neuromodulation, which further influences brain network topology.PurposeTo study the relationship of regional and global network properties by using graph theory analysis and glutamatergic (Glx) neuromodulation in the ApoE isoforms.Study TypeProspective.SubjectsEighty‐four cognitively normal adults (26 ApoE4 and 58 non‐ApoE4 carriers).Field Strength/SequenceGradient‐echo echo‐planar and point resolved spectroscopy sequence at 3 T.AssessmentGlx concentration in bilateral hippocampi were processed with jMRUI (4.0), and graph theory metrics (global: γ, λ, small‐worldness in whole brain; regional: nodal clustering coefficient (C i) and nodal characteristic path length (L i)) in top 20% highly connected hubs of subgroups (low‐risk: non‐ApoE4; high‐risk: APOE4) were calculated and compared.Statistical TestsTwo‐sample t test was used to compare metrics between subgroups. Correlations between regional properties and Glx by Pearson's partial correlation with false discovery rate correction.ResultsSignificant differences (P < 0.05) in C i between subgroups were found in hubs of left inferior frontal, bilateral inferior temporal, and bilateral precentral gyri, right parahippocampus, and bilateral precuneus. In addition, there was a significant correlation between Glx in the left hippocampus and C i in inferior frontal gyrus (r = −0.537, P = 0.024), right inferior temporal (r = −0.478, P = 0.043), right parahippocampus (r = −0.629, P = 0.016), left precentral (r = −0.581, P = 0.022), right precentral (r = −0.651, P = 0.003), left precuneus (r = −0.545, P = 0.024), and right precuneus (r = −0.567, P = 0.022); and L i in left precuneus (r = 0.575, P = 0.032) and right precuneus (r = 0.586, P = 0.032) in the high‐risk group, but not in the low‐risk group.Data ConclusionOur results suggested that healthy ApoE4 carriers exhibit poorer local interconnectivity. Moreover, the close relationship between glutamate and small‐world network properties in ApoE4 carriers might reflect a compensatory response to the impaired network efficiency.Evidence Level2Technical EfficacyStage 3

Association of Life's Simple 7 with incident dementia and its modification by the apolipoprotein E genotype.

There is limited and inconsistent reporting on the association between Life's Simple 7 (LS7) and dementia in the elderly population. Based on the Washington Heights-Inwood Columbia Aging Project (WHICAP), LS7 scores were estimated to assess cardiovascular health status. Associations between LS7 scores and incident dementia were investigated by Cox proportional hazards models. Among 1987 subjects, 291 incident cases of dementia were identified over a median follow-up of 5.84 years. Compared with subjects in the poor cardiovascular health group (scores 0 to 5), those in intermediate (6 to 9) and optimal (10 to 14) groups had lower dementia risk, with the hazard ratio (HR; 95% confidence interval) being 0.74 (0.54 to 1.00) and 0.59 (0.38 to 0.91), respectively. These results were significant in apolipoprotein E genotype ε4 (APOE ε4) allele non-carriers but not in carriers. Higher LS7 scores are protective for dementia, especially among the APOE ε4 noncarriers.

Education, APOE ε4, and Cognition in Individuals with Subjective Cognitive Decline with Worry in the SILCODE Study.

Education could offer a protective effect on cognition in individuals with Subjective Cognitive Decline (SCD), which is considered to be the early stage of Alzheimer's Disease (AD). However, the effect of education on cognition in SCD individuals with SCD-plus features is not clear. The aim of the study was to explore the effect of education on cognition in SCD individuals with SCD-plus features. A total of 234 individuals with SCD were included from the Sino Longitudinal Study on Cognitive Decline (SILCODE). Cognition was assessed across 4 domains (memory, executive, language, and general cognitive functions). Multiple linear regression models were constructed to examine the effect of education on cognitive scores in individuals without worry (n=91) and with worry (n=143). Furthermore, we assessed differences in effects between APOE ε4 noncarriers and APOE ε4 carriers in both groups. Multiple linear regression analysis showed a positive effect of education on memory, executive, and language cognition in individuals without worry and all cognitive domains in individuals with worry. Furthermore, we found a positive effect of education on executive cognition in APOE ε4 noncarriers without worry and language and general cognition in APOE ε4 carriers without worry. Meanwhile, education had a positive effect on all cognitive domains in APOE ε4 noncarriers with worry and executive, language, and general cognition in APOE ε4 carriers with worry. This study indicates that education has the potential to delay or reduce cognitive decline in SCD individuals with SCD-plus features.

Effect of physical exercise on cognitive function in older adults' carriers versus noncarriers of apolipoprotein E4: systematic review and meta-analysis.

The presence of apolipoprotein (Apo) E4 is a genetic risk factor in cognitive impairment. Physical exercise contributes to slowing cognitive impairment in older adults, but little is known about the influence of exercise on ApoE4 carriers and noncarriers. The objective of systematic review is to study the role of physical exercise in older adults’ ApoE4 carriers and noncarriers. A systematic literature search was carried out in five international databases: PubMed, Web of Science, PeDro, Scopus, and SPORTDiscus. A total of nine randomized controlled trials were included with a sample size of 2,025 subjects (901 ApoE4 carriers). The exercise reported a significant improvement on cognitive performance in older adults’ ApoE4 noncarriers (standardized mean difference [SMD]=0.653; 95% confidence interval [CI], 0.29–1.00; chi2=35.36; degrees of freedom [df ]=7; P<0.0001; l 2=80%). It was also reported that a total program duration greater than 50 sessions generated different and significant effects on cognitive performance in older adults’ ApoE4 noncarriers (SMD=0.878; 95% CI, 0.14–1.61; chi2=31.82; df=3; P<0.0001; l 2=91%). The results reported that high intensity generated a differential effect on cognitive performance in older adults’ ApoE4 carriers versus noncarriers (SMD=0.963; 95% CI, 0.25–1.67; chi2=18.11; df=3; P<0.0004; l 2=83%). The effect of physical exercise on cognitive performance in older adults is conditioned by the presence or not of ApoE4.

The Effects of CSF Neurogranin and APOE ε4 on Cognition and Neuropathology in Mild Cognitive Impairment and Alzheimer's Disease.

Cerebrospinal fluid (CSF) measurements of neurogranin (Ng) have emerged as a promising biomarker for cognitive decline in mild cognitive impairment (MCI) and Alzheimer’s disease (AD). The apolipoprotein E ε4 (APOE ε4) allele is by far the most consistent genetic risk factor for AD. However, it is not known whether the pathophysiological roles of Ng in MCI or AD are related to APOEε4. We stratified 250 participants from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) database into cognitively normal (CN) ε4 negative (CN ε4−), CN ε4 positive (CN ε4+), MCI ε4 negative (MCI ε4−), MCI ε4 positive (MCI ε4+), AD ε4 negative (AD ε4−), and AD ε4 positive (AD ε4+). CSF Ng levels were significantly increased in APOE ε4 carriers compared to APOE ε4 non-carriers with MCI. In addition, CSF Ng identified MCI ε4+ versus CN ε4−, but not MCI ε4− versus CN ε4−. Similarly, CSF Ng negatively correlated with Mini-Mental State Examination (MMSE) scores at baseline in the MCI ε4+ group. Our findings support the use of CSF Ng as a biomarker of synaptic pathology for AD. We propose that the roles of CSF Ng in the pathophysiology of MCI may be related to APOE ε4.