Effect Of E4 Research Articles

Sex and APOE ε4 carrier effects on atrophy, amyloid PET, and tau PET burden in early-onset Alzheimer's disease.

We used sex and apolipoprotein E ε4 (APOE ε4) carrier status as predictors of pathologic burden in early-onset Alzheimer's disease (EOAD). We included baseline data from 77 cognitively normal (CN), 230 EOAD, and 70 EO non-Alzheimer's disease (EOnonAD) participants from the Longitudinal Early-Onset Alzheimer's Disease Study (LEADS). We stratified each diagnostic group by males and females, then further subdivided each sex by APOE ε4 carrier status and compared imaging biomarkers in each stratification. Voxel-wise multiple linear regressions yielded statistical brain maps of gray matter density, amyloid, and tau PET burden. EOAD females had greater amyloid and tau PET burdens than males. EOAD female APOE ε4 non-carriers had greater amyloid PET burdens and greater gray matter atrophy than female ε4 carriers. EOnonAD female ε4 non-carriers also had greater gray matter atrophy than female ε4 carriers. The effects of sex and APOE ε4 must be considered when studying these populations. Novel analysis examining the effects of biological sex and apolipoprotein E ε4 (APOEε4) carrier status on neuroimaging biomarkers among early-onset Alzheimer's disease (EOAD), early-onset non-AD (EOnonAD), and cognitively normal (CN) participants. Female sex is associated with greater pathology burden in the EOAD cohort compared to male sex. The effect of APOE ε4 carrier status on pathology burden was the most impactful in females across all cohorts.

A haptoglobin (HP) structural variant alters the effect of APOE alleles on Alzheimer's disease.

Haptoglobin (HP) is an antioxidant of apolipoprotein E (APOE), and previous reports have shown HP binds with APOE and amyloid beta (Aβ) to aid its clearance. A common structural variant of the HP gene distinguishes it into two alleles: HP1 and HP2. HP genotypes were imputed in 29 cohorts from the Alzheimer's Disease Genetics Consortium (N=20,512). Associations between the HP polymorphism and Alzheimer's disease (AD) risk and age of onset through APOE interactions were investigated using regression models. The HP polymorphism significantly impacts AD risk in European-descent individuals (and in meta-analysis with African-descent individuals) by modifying both the protective effect of APOE ε2 and the detrimental effect of APOE ε4. The effect is particularly significant among APOE ε4 carriers. The effect modification of APOE by HP suggests adjustment and/or stratification by HP genotype is warranted when APOE risk is considered. Our findings also provided directions for further investigations on potential mechanisms behind this association.

Independent role of Alzheimer's disease genetics and C-reactive protein on cognitive ability in aging

Apolipoprotein E (APOE) ε4, the strongest genetic risk factor for late onset Alzheimer's disease (LOAD), has been associated with cognitive decline independent from AD pathology, but the role for other LOAD risk genes in normal cognitive aging is less studied. We examined the effect of APOE ε4 and several different polygenic risk scores (PRS) for LOAD on cognitive level and decline in aging, using longitudinal data from the UK Biobank. While PRS-LOAD including all variants (except APOE) predicted cognitive level, APOE ε4 and PRS-LOAD based on 17 non-APOE gene variants with strong association to AD (p < 5e-8) predicted age-related decline in verbal numeric reasoning. The effect on decline were partly driven by 4 variants involved in the immune system. Those variants also predicted serum levels of the inflammatory marker C-reactive protein (CRP), but CRP did not mediate the effect on decline. Those findings suggest genetic variations in immune functions play a role in aspects of cognitive aging that may be independent of LOAD pathology as well as systemic inflammation measured by CRP.

APOE ε4 is associated with earlier symptom onset in LOAD but later symptom onset in EOAD.

We studied the effect of apolipoprotein E (APOE) ε4 status and sex on age of symptom onset (AO) in early- (EO) and late- (LO) onset Alzheimer's disease (AD). A total of 998 EOAD and 2562 LOAD participants from the National Alzheimer's Coordinating Center (NACC) were included. We used analysis of variance to examine AO differences between sexes and APOE genotypes and the effect of APOE ε4, sex, and their interaction on AO in EOAD and LOAD, separately. APOE ε4 carriers in LOAD had younger AO and in EOAD had older AO. Female EOAD APOE ε4 carriers had older AO compared to non-carriers (P<0.0001). There was no difference for males. Both male and female LOAD APOE ε4 carriers had younger AO relative to non-carriers (P<0.0001). The observed earlier AO in EOAD APOE ε4 non-carriers relative to carriers, particularly in females, suggests the presence of additional AD risk variants.

Interactive association of posttraumatic stress disorder, apolipoprotein ε4 genotype, and age on cognitive functioning.

The ε4 allele of the apolipoprotein (APOE) gene and posttraumatic stress disorder (PTSD) are associated with cognitive deficits. Both associations may vary depending on age. No previous study has examined a possible three-way interaction between APOE ε4, PTSD, and age on cognitive functioning. Data were analyzed from 1244 European-American U.S. military veterans who participated in the 2011 National Health and Resilience in Veterans Study (NHRVS). Analyses of covariance were used to examine the main effects and interactions of APOE ε4, PTSD, and age on learning/working memory (LWM) and attention/psychomotor (APM) performance. A significant three-way interaction between APOE ε4, PTSD, and age on the LWM composite (ηp 2 =0.011) was observed such that the main effect of APOE ε4 on LWM was only significant for older participants with PTSD. A significant two-way interaction between PTSD and age on the APM composite (ηp 2 =0.011) was observed such that the main effect of PTSD on APM was only significant in older participants. Older APOE ε4 carriers with probable PTSD showed poorer LWM performance relative to other groups. Aging-related associations on APM performance were most pronounced in veterans with PTSD. These data are preliminary evidence that identification and treatment of PTSD may be beneficial for individuals at risk for age-related cognitive impairment.

APOE ε4 status and plasma p-tau181 interact to influence cognitive performance among non-demented older adults

ObjectiveIn this study, we aimed to investigate the relationships among plasma p-tau181, APOE ε4, and cognitive performance in non-demented elderly individuals. MethodsWe used individuals (n = 630) with cognitive normal (CN, n = 182) and mild cognitive impairment (MCI, n = 448). Multiple linear regression models were performed to test the effects of APOE ε4 × plasma p-tau181 interaction on MMSE, CDR-SOB, ADAS-cog13, and RAVLT immediate recall. All models adjusted for age, sex, and education. ResultsIn total, our study comprised 630 samples including 364 APOE ε4 non-carriers and 266 APOE ε4 carriers. In APOE ε4 carriers, plasma p-tau181 was significantly associated with MMSE (B = −0.04, p = 0.003), ADAS-Cog13 (B [unstandardized coefficient] = 0.21, p < 0.001), CDR-SB (B = 0.02, p = 0.003) and RAVLT immediate recall ((B = −0.17, p = 0.035). After correcting for Aβ status and diagnosis, the interaction between APOE ε4 and plasma p-tau181 was significant or marginally significant associations for RAVLT immediate recall (p = 0.076), MMSE (p = 0.011), CDR (p = 0.008), and ADAS-Cog13 (p < 0.001). ConclusionsOur findings suggested that plasma p-tau181 levels predicted cognitive performance among non-demented older adults, but only in the APOE ε4 carriers.

Effect of APOE ε4 genotype on amyloid-β, glucose metabolism, and gray matter volume in cognitively normal individuals and amnestic mild cognitive impairment.

The presence of apolipoprotein E ε4 (APOE ε4) is associated with an increased risk of developing Alzheimer disease (AD). The aim of this study was to assess the effects of APOE ε4 on amyloid-β (Aβ) pathology, glucose metabolism, and gray matter (GM) volume and their longitudinal changes in healthy control (HC) and amnestic mild cognitive impairment (aMCI). We included 50 HCs and 109 aMCI patients from the Alzheimer's Disease Neuroimaging Initiative phase 2/GO based on availability of baseline T1-weighted magnetic resonance imaging, 18 F-florbetapir positron emission tomography (PET), and 18 F-fluorodeoxyglucose (FDG) PET. Of these, 35 HCs and 67 aMCI patients who underwent 24-month scans were included for follow-up study. Voxelwise analysis revealed that APOE ε4 carriers exhibited greater baseline Aβ deposition than APOE ε4 noncarriers in both diagnostic groups. However, there was no significant difference between APOE ε4 noncarriers and APOE ε4 carriers in terms of 18 F-FDG PET standardized uptake value ratio and GM volume. Region of interest-based analysis showed statistically significant greater Aβ deposition in APOE ε4 carriers than APOE ε4 noncarriers only in aMCI patients. Furthermore, APOE ε4 carriers generally exhibited a greater magnitude and spatial extent of longitudinal changes in Aβ deposition than APOE ε4 noncarriers in both diagnostic groups. Our findings suggest a differential effect of APOE ε4 on Aβ pathology, glucose metabolism, and GM volume. Studying APOE ε4-related brain changes with neuroimaging biomarkers in preclinical AD offers an opportunity to further our understanding of the pathophysiology of AD at an early stage.

AD and non-AD mediators of the pathway between the APOE genotype and cognition.

The apolipoprotein E (APOE) genotype is a driver of cognitive decline and dementia. We used causal mediation methods to characterize pathways linking the APOE genotype to late-life cognition through Alzheimer's disease (AD) and non-AD neuropathologies. We analyzed autopsy data from 1671 individuals from the Religious Orders Study, Memory and Aging Project, and Minority Aging Research Study (ROS/MAP/MARS) studies with cognitive assessment within 5 years of death and autopsy measures of AD (amyloid beta (Aβ), neurofibrillary tangles), vascular (athero/arteriolo-sclerosis, micro-infarcts/macro-infarcts), and non-AD neurodegenerative neuropathologies (TAR DNA protein 43 [TDP-43], Lewy bodies, amyloid angiopathy, hippocampal sclerosis). The detrimental effect of APOE ε4 on cognition was mediated by summary measures of AD and non-AD neurodegenerative neuropathologies but not vascular neuropathologies; effects were strongest in individuals with dementia. The protective effect of APOE ε2 was partly mediated by AD neuropathology and stronger in women than in men. The APOE genotype influences cognition and dementia through multiple neuropathological pathways, with implications for different therapeutic strategies targeting people at increased risk for dementia. Both apolipoprotein E (APOE) ε2 and APOE ε4 effects on late-life cognition are mediated by AD neuropathology. The estimated mediated effects of most measures of AD neuropathology were similar. Non-Alzheimer's disease (AD) neurodegenerative pathologies mediate the effect of ε4 independently from AD. Non-AD vascular pathologies did not mediate the effect of the APOE genotype on cognition. The protective effect of APOE ε2 on cognition was stronger in women.

Interactions between the apolipoprotein E4 gene and modifiable risk factors for cognitive impairment: a nationally representative panel study

BackgroundFew studies using rigorous clinical diagnosis have considered whether associations with cognitive decline are potentiated by interactions between genetic and modifiable risk factors. Given the increasing burden of cognitive impairment (CI) and dementia, we assessed whether Apolipoprotein E ε4 (APOE4) genotype status modifies the association between incident CI and key modifiable risk factors .MethodsOlder adults (70+) in the US were included. APOE4 status was genotyped. Risk factors for CI were self-reported. Cognitive status (normal, CI, or dementia) was assigned by clinical consensus panel. In eight separate Cox proportional hazard models, we assessed for interactions between APOE4 status and other CI risk factors.ResultThe analytical sample included 181 participants (mean age 77.7 years; 45.9% male). APOE4 was independently associated with a greater hazard of CI in each model (Hazard Ratios [HR] between 1.81–2.66, p < 0.05) except the model evaluating educational attainment (HR 1.65, p = 0.40). The joint effects of APOE4 and high school education or less (HR 2.25, 95% CI: 1.40–3.60, p < 0.001), hypertension (HR 2.46, 95% CI: 1.28–4.73, p = 0.007), elevated depressive symptoms (HR 5.09, 95% CI: 2.59–10.02, p < 0.001), hearing loss (HR 3.44, 95% CI: 1.87–6.33, p < 0.0001), vision impairment (HR 5.14, 95% CI: 2.31–11.43, p < 0.001), smoking (HR 2.35, 95% CI: 1.24–4.47, p = 0.009), or obesity (HR 3.80, 95% CI: 2.11–6.85, p < 0.001) were associated with the hazard of incident CIND (compared to no genetic or modifiable risk factor) in separate models. The joint effect of Apolipoprotein ε4 and type 2 diabetes was not associated with CIND (HR 1.58, 95% CI: 0.67–2.48, p = 0.44).DiscussionThe combination of APOE4 and selected modifiable risk factors conveys a stronger association with incident CI than either type of risk factor alone.

The cross‐sectional association between APOE ε4 and cognition in midlife: Baseline data analysis of the Physical Activity and Alzheimer’s Disease study ‐ II

AbstractBackgroundCarrying at least one ε4 allele of Apolipoprotein E (APOE ε4) is a strong genetic risk factor for cognitive decline in late life. However, how APOE ε4 is associated with cognition in midlife (to what extent and in which domains) remains unspecified. We investigated the association between APOE ε4 carrier status and various domains of memory and executive function in healthy, sedentary adults in midlife.MethodA subset of 91 participants (M age = 57±6 years; 86.8% females; 33 carriers and 58 non‐carriers of APOE ε4) from a larger study (PAAD‐II, NCT03876314) were included for analyses. At baseline, participants provided a passive drool saliva sample to determine APOE ε4 carrier status and completed a comprehensive cognitive assessment. Composite scores for auditory verbal learning, visuospatial memory, associative memory, story memory, mnemonic discrimination, working memory, inhibitory control, and fluid intelligence were computed. Analyses of covariance tested the effects of APOE ε4 on the composite scores with demographic factors as covariates.ResultSignificant effects of APOE ε4 on auditory verbal learning [F(1, 82) = 4.8, p&lt;0.05] and fluid intelligence [F(1, 73) = 5.155, p&lt;0.05] were found after controlling for the effects of age, race, education, and gender. APOE ε4 carriers’ z‐scores for auditory verbal learning (‐0.202±0.208) were lower than non‐carriers (0.164±0.104), and the same was found for fluid intelligence (carriers: ‐0.218±0.183; non‐carriers: 0.145±0.139). APOE ε4 was unrelated to other composite scores of memory and executive function (p’s&gt;0.5).ConclusionEvidence from longitudinal studies suggests that negative effects of APOE ε4 on cognition are evident at 65–75 years old. We conducted a comprehensive assessment of multiple cognitive domains and demonstrated that APOE ε4 is negatively associated with some cognitive domains in midlife. These findings imply that, although APOE ε4 is a strong risk factor for cognitive decline in late life, its effects on cognitive aging could gradually start in midlife. The small but notable effects of APOE ε4 on comparably intact cognitive function in midlife suggests the potential importance of early preventive interventions (e.g., physical activity, healthy diet) for cognitive preservation in late life, especially in people with higher genetic risk for cognitive decline.

A genetically informed examination of posttraumatic stress disorder and traumatic brain injury’s impact on dementia risk in US Veterans

AbstractBackgroundThe US Veteran population is aging, and Veterans have higher rates of dementia risk factors such posttraumatic stress disorder (PTSD) and traumatic brain injury (TBI). Moreover, some studies have indicated that APOE:ε4 (the largest Alzheimer’s disease genetic risk factor) x TBI interactions could further elevate dementia risk.MethodAlzheimer’s disease and related dementia (ADRD) risk was examined using the electronic medical record and survey‐based phenotypes in the VA Million Veteran Program (MVP) cohort. We examined the impact of TBI (survey‐based), PTSD (medical record and survey‐based), and APOE:ε4 on ADRD risk in a European‐descent cohort (EUR, n=11,112 ADRD cases; 170,361 controls) and an African American cohort (AA, n=1,443 ADRD cases; 16,191 controls).ResultPTSD, TBI, and ε4 were associated with ADRD in both cohorts (p&lt;10‐9). In EUR, logistic models indicated dementia risk associated with TBI (OR=1.96) was approximately that of ε4 (OR=2.05), while the PTSD‐associated risk was slightly higher (OR=2.18). In AA, the effect of PTSD and ε4 were similar (OR=1.73 and 1.69 respectively), while the effect of TBI was higher (OR=2.69). GxE analyses yielded a modest but significant PTSD x ε4 interaction term in EUR (OR=0.84, p=0.0046). As multiplicative (logistic) interactions can be difficult to interpret, we calculated the risk curves predicted by the models (Figure 1) and relative excess risk due to interaction (RERI), which measures additive‐scale interactions. Modest but significant positive RERIs were observed for PTSD x APOE (EUR, RERI=1.28) and TBI x APOE (EUR and AA, RERI=0.86 and 1.45 respectively), indicating that risk of ADRD in terms of raw percentage associated with PTSD/TBI case status increases as ε4 dosage increases. For example, age 80 risk of ADRD associated with PTSD (PTSD case ADRD% – control ADRD%) in EUR is predicted to be 5.70% for those with one copy of ε4 and 11.19% for two copies of ε4.ConclusionAlthough the mechanisms have yet to be elucidated, PTSD, TBI, and genetic risk are strongly associated with dementia in Veterans. Veterans with PTSD and TBI have increased risk for ADRD and require monitoring for early detection of cognitive decline which can precede dementia onset.

Role of APOE ε gene in cognitive performance among cognitively healthy participants of TLSA cohort

AbstractBackgroundAPOE ε4 is a major genetic risk factor for Alzheimer’s Disease (AD), however, effect of APOE ε4 on cognitive decline is not well understood. TATA Longitudinal Study of Aging (TLSA) is a longitudinal study in healthy aging individuals in Bangalore, India.MethodWe analyzed the performance on global cognition, processing speed, working memory, auditory attention, verbal short‐term memory, and visuospatial skills, to ascertain between APOE ε4 carriers and non‐carriers among healthy participants of TLSA.ResultGeneralized linear models were constructed which showed that APOE ε4 carriers showed a faster cognitive decline in auditory attention and verbal short‐term memory as measured by digit forward test (B = ‐0.79; p = 0.001) compared to non‐carriers at two years of follow up. The presence of APOE ε4 allele didn’t affect the rate of cognitive decline on other cognitive domains.ConclusionThe presence of specific cognitive deficits in APOE ε4 carriers could potentially be a composite biomarker for early cognitive decline in people carrying this allele.

Mid‐to‐Late Life Healthy Lifestyle Modifies Genetic Risk for Longitudinal Cognitive Aging among Asymptomatic Individuals from the Wisconsin Registry for Alzheimer’s Prevention

AbstractBackgroundGenetic and lifestyle factors contribute to an individual’s risk for developing Alzheimer’s disease (AD). A better understanding of interactions between these factors may help design targeted interventions. In this study, we investigated whether number of long‐term healthy lifestyles modified the effect of genetic predisposition to AD on cognitive decline during the preclinical stage of AD.MethodsWe evaluated longitudinal associations of cognitive aging with a healthy lifestyle composite score, which included physical activity, diet, smoking, cognitive activity, and alcohol consumption, and the interaction of the healthy lifestyle composite score with APOE ε4 carrier status and a non‐APOE polygenic risk score (PRS) in a sample of 848 individuals from the Wisconsin Registry for Alzheimer’s Prevention (Table 1). The primary outcome was a multi‐domain cognitive composite (PACC3); secondary outcomes were immediate/delayed memory and executive function composites. We fitted all analyses using a linear mixed effects model and adjusted for within‐individual and within‐family correlation.ResultsFavorable lifestyles can marginally modify the age dependent influence of APOE on PACC3 (p = 0.1) and executive function (p = 0.14), and significantly mitigate the adverse effect of APOE ε4 on delayed recall as people aging (p &lt; 0.01, Figure 1). However, we observed no statistically significant interactions between non‐APOE PRS, combined lifestyle factors, and age for all the assessed cognitive outcomes (Figure 2). When we further stratify the sample by the APOE ε4 carrier status, we found the interaction between non‐APOE PRS, age, and healthy lifestyle is statistically significant for PACC3 (p = 0.02) and delayed recall (p &lt; 0.01) and marginally significant for immediate learning (p = 0.06) among APOE ε4 carriers (Figure 3). Among APOE ε4 noncarriers, combined lifestyle factors can only modify the age‐dependent adverse genetic influence of non‐APOE PRS on PACC3 (p = 0.01), but the protective effect is more evident at a younger age (Figure 4). These results are robust to multiple sensitivity analyses.ConclusionA favorable lifestyle can mitigate the genetic risk caused by both APOE ε4 and non‐APOE PRS, but the protective effect against non‐APOE PRS is more evident among APOE ε4 carriers.

Impact of Amyloid Pathology in Mild Cognitive Impairment Subjects: The Longitudinal Cognition and Surface Morphometry Data

The amyloid framework forms the central medical theory related to Alzheimer disease (AD), and the in vivo demonstration of amyloid positivity is essential for diagnosing AD. On the basis of a longitudinal cohort design, the study investigated clinical progressive patterns by obtaining cognitive and structural measurements from a group of patients with amnestic mild cognitive impairment (MCI); the measurements were classified by the positivity (Aβ+) or absence (Aβ-) of the amyloid biomarker. We enrolled 185 patients (64 controls, 121 patients with MCI). The patients with MCI were classified into two groups on the basis of their [18F]flubetaben or [18F]florbetapir amyloid positron-emission tomography scan (Aβ+ vs. Aβ-, 67 vs. 54 patients) results. Data from annual cognitive measurements and three-dimensional T1 magnetic resonance imaging scans were used for between-group comparisons. To obtain longitudinal cognitive test scores, generalized estimating equations were applied. A linear mixed effects model was used to compare the time effect of cortical thickness degeneration. The cognitive decline trajectory of the Aβ+ group was obvious, whereas the Aβ- and control groups did not exhibit a noticeable decline over time. The group effects of cortical thickness indicated decreased entorhinal cortex in the Aβ+ group and supramarginal gyrus in the Aβ- group. The topology of neurodegeneration in the Aβ- group was emphasized in posterior cortical regions. A comparison of the changes in the Aβ+ and Aβ- groups over time revealed a higher rate of cortical thickness decline in the Aβ+ group than in the Aβ- group in the default mode network. The Aβ+ and Aβ- groups experienced different APOE ε4 effects. For cortical-cognitive correlations, the regions associated with cognitive decline in the Aβ+ group were mainly localized in the perisylvian and anterior cingulate regions. By contrast, the degenerative topography of Aβ- MCI was scattered. The memory learning curves, cognitive decline patterns, and cortical degeneration topographies of the two MCI groups were revealed to be different, suggesting a difference in pathophysiology. Longitudinal analysis may help to differentiate between these two MCI groups if biomarker access is unavailable in clinical settings.

APOE ε4 carrier status and sex differentiate rates of cognitive decline in early- and late-onset Alzheimer's disease.

We studied the effect of apolipoprotein E (APOE) ε4 status and sex on rates of cognitive decline in early- (EO) and late- (LO) onset Alzheimer's disease (AD). We ran mixed-effects models with longitudinal cognitive measures as dependent variables, and sex, APOE ε4 carrier status, and interaction terms as predictor variables in 998 EOAD and 2562 LOAD participants from the National Alzheimer's Coordinating Center. APOE ε4 carriers showed accelerated cognitive decline relative to non-carriers in both EOAD and LOAD, although the patterns of specific cognitive domains that were affected differed. Female participants showed accelerated cognitive decline relative to male participants in EOAD only. The effect of APOE ε4 was greater in EOAD for executive functioning (p<0.0001) and greater in LOAD for language (p<0.0001). We found APOE ε4 effects on cognitive decline in both EOAD and LOAD and female sex in EOAD only. The specific patterns and magnitude of decline are distinct between the two disease variants. Apolipoprotein E (APOE) ε4 carrier status and sex differentiate rates of cognitive decline in early-onset (EO) and late-onset (LO) Alzheimer's disease (AD). APOE ε4 in EOAD accelerated decline in memory, executive, and processing speed domains. Female sex in EOAD accelerated decline in language, memory, and global cognition. The effect of APOE ε4 was stronger for language in LOAD and for executive function in EOAD. Sex effects on language and executive function decline differed between EOAD and LOAD.

The Impact of Anticholinergic Use for Overactive Bladder on Cognitive Changes in Adults with Normal Cognition, Mild Cognitive Impairment, or Dementia

BackgroundFew studies have addressed whether anticholinergic (AC) medications for overactive bladder (OAB) cause cognitive decline in individuals with existing cognitive impairment, and whether the APOE ε4 gene increases this risk. ObjectiveTo determine whether OAB AC use is associated with a clinically relevant change in cognitive measures among adults with normal and abnormal cognition. Design, setting, and participantsThis was a retrospective cohort study using data from the National Alzheimer’s Coordinating Center. Patients were enrolled at specialized centers in the USA between 2005 and 2019. Patients with existing OAB AC use, missing APOE ε4 status, and confounding neurologic diagnoses were excluded. New users of an OAB AC were matched 1:1 to patients not taking an OAB AC using propensity scores. InterventionNew use of oxybutynin, tolterodine, solifenacin, trospium, darifenacin, or fesoterodine. Outcome measurements and statistical analysisThe outcome was a change in cognitive function, measured as a ≥1-point increase on the Clinical Dementia Rating (CDR) instrument or a ≥3-point decrease on the Mini-Mental State Examination (MMSE). Conditional logistic regression with odds ratios (ORs) was conducted. We also tested for APOE ε4 effect modification. Results and limitationsAmong 18 835 eligible patients, 782 matched pairs were identified. The most common OAB ACs were oxybutynin (38%) and tolterodine (23%). There was no significant increase in the risk of a clinically relevant cognitive decline among OAB AC users (CDR: OR 1.38, 95% confidence interval [CI] 0.93–2.05; p = 0.11, MMSE: OR 1.06, 95% CI 0.79–1.43; p = 0.70). There was no significant interaction between APOE ε4 status and OAB AC use for the CDR (p = 0.38) or MMSE (p = 0.95) outcomes. Users of oxybutynin or tolterodine had numerically higher odds of a change on the CDR test (OR 1.65, 95% CI 0.98–2.77) that was close to statistical significance (p = 0.06). Limitations include the inability to determine medication dose or duration, and residual confounding. ConclusionsOAB AC use was not associated with a significant change in cognitive function among individuals with normal and abnormal cognition. Further research is necessary to determine if oxybutynin and tolterodine are significantly more likely to cause cognitive decline. Patient summaryUse of a specific class of overactive bladder medication was not associated with negative changes in brain function among patients with either normal or abnormal function. A genetic risk factor for Alzheimer’s disease did not predispose individuals to cognitive decline when taking these drugs. Two of the drugs (oxybutynin and tolterodine) may lead to a higher risk of cognitive decline in comparison to other drugs, and this needs further research.

The impact of APOE and smoking history on cognitive function in older, long-term breast cancer survivors.

This study aims to determine whether older breast cancer survivors score lower on neuropsychological tests compared to matched non-cancer controls and to test the hypotheses that survivors who were APOE ε4 carriers would have the lowest cognitive performance but that smoking history would decrease the negative effect of ε4 on cognition. Female breast cancer survivors who had been diagnosed and treated at age 60 or older and were 5-15-year survivors (N = 328) and age and education matched non-cancer controls (N = 162) were assessed at enrollment and at 8-, 16-, and 24-month follow-ups with standard neuropsychological and psychological assessments. Blood for APOE genotyping was collected, and smoking history was assessed at enrollment. Participants were purposely recruited so that approximately 50% had a history of treatment with chemotherapy or no chemotherapy and approximately 50% had a smoking history. After adjusting for age, cognitive reserve, depression, and fatigue, breast cancer survivors scored significantly lower on all domains of cognitive function. A significant two-way interaction demonstrated that the negative effect of ε4 on cognitive performance was stronger among survivors. A significant three-way interaction supported the hypothesis that smoking history had a protective effect on cognitive function in ε4 carriers that was more pronounced in the controls than the survivors. The results support the long-term cognitive impact of breast cancer diagnosis and treatments on older, disease-free survivors, particularly for ε4 carriers. The results also emphasize the importance of assessing smoking history when examining APOE and cognition and are an example of the complex interactions of age, genetics, health behaviors, and disease history in determining cognitive function. These results help explain why only a subset of breast cancer survivors appear to be vulnerable to cognitive problems.

A locus at 19q13.31 significantly reduces the ApoE ε4 risk for Alzheimer's Disease in African Ancestry.

African descent populations have a lower Alzheimer disease risk from ApoE ε4 compared to other populations. Ancestry analysis showed that the difference in risk between African and European populations lies in the ancestral genomic background surrounding the ApoE locus (local ancestry). Identifying the mechanism(s) of this protection could lead to greater insight into the etiology of Alzheimer disease and more personalized therapeutic intervention. Our objective is to follow up the local ancestry finding and identify the genetic variants that drive this risk difference and result in a lower risk for developing Alzheimer disease in African ancestry populations. We performed association analyses using a logistic regression model with the ApoE ε4 allele as an interaction term and adjusted for genome-wide ancestry, age, and sex. Discovery analysis included imputed SNP data of 1,850 Alzheimer disease and 4,331 cognitively intact African American individuals. We performed replication analyses on 63 whole genome sequenced Alzheimer disease and 648 cognitively intact Ibadan individuals. Additionally, we reproduced results using whole-genome sequencing of 273 Alzheimer disease and 275 cognitively intact admixed Puerto Rican individuals. A further comparison was done with SNP imputation from an additional 8,463 Alzheimer disease and 11,365 cognitively intact non-Hispanic White individuals. We identified a significant interaction between the ApoE ε4 allele and the SNP rs10423769_A allele, (β = -0.54,SE = 0.12,p-value = 7.50x10-6) in the discovery data set, and replicated this finding in Ibadan (β = -1.32,SE = 0.52,p-value = 1.15x10-2) and Puerto Rican (β = -1.27,SE = 0.64,p-value = 4.91x10-2) individuals. The non-Hispanic Whites analyses showed an interaction trending in the “protective” direction but failing to pass a 0.05 significance threshold (β = -1.51,SE = 0.84,p-value = 7.26x10-2). The presence of the rs10423769_A allele reduces the odds ratio for Alzheimer disease risk from 7.2 for ApoE ε4/ε4 carriers lacking the A allele to 2.1 for ApoE ε4/ε4 carriers with at least one A allele. This locus is located approximately 2 mB upstream of the ApoE locus, in a large cluster of pregnancy specific beta-1 glycoproteins on chromosome 19 and lies within a long noncoding RNA, ENSG00000282943.This study identified a new African-ancestry specific locus that reduces the risk effect of ApoE ε4 for developing Alzheimer disease. The mechanism of the interaction with ApoEε4 is not known but suggests a novel mechanism for reducing the risk for ε4 carriers opening the possibility for potential ancestry-specific therapeutic intervention.

APOE ε4 and late-life cognition: mediation by structural brain imaging markers.

The apolipoprotein E allele 4 (APOE-ε4) is established as a major genetic risk factor for cognitive decline and late-onset Alzheimer's disease. Accumulating evidence has linked ε4 carriership to abnormal structural brain changes across the adult lifespan. To better understand the underlying causal mechanisms, we investigated the extent to which the effect of the ε4 allele on cognition is mediated by structural brain imaging markers in the population-based Age, Gene/Environment Susceptibility-Reykjavik Study (AGES-Reykjavik). This study included 4527 participants (aged 76.3 ± 5.4 at baseline) who underwent the brain magnetic resonance imaging assessment (of brain tissue volumes, white matter lesion volume, subcortical and cortical infarcts, and cerebral microbleeds) and a battery of neuropsychological tests at baseline. Causal mediation analysis was used to quantify the mediation of the ε4 effect on cognition by these MRI markers, both individually and jointly. We observed that about 9% of the total effect of ε4 carriership on cognition was mediated by white matter lesion volume. This proportion increased to 25% when total brain tissue volume was jointly considered with white matter lesion volume. In analyses separating ε4 homozygotes from ε4 heterozygotes, the effect on global cognition of specifically ε4 homozygosity appeared to be partially mediated by cerebral microbleeds, particularly lobar microbleeds. There was no evidence of mediation of the ε4 effect by cortical or subcortical infarcts. This study shows that the ε4 effect on cognition is partly mediated by white matter lesion volume and total brain tissue volume. These findings suggest the joint role of cerebral small vessel disease and neurodegeneration in the ε4-cognition relationship.

The Effect of APOE ɛ4 on the Functional Connectivity in Frontoparietal Network in Hypertensive Patients.

Allele 4 of the apolipoprotein E gene (APOE ε4) and hypertension are considered risk factors for Alzheimer’s Disease (AD). The detection of differences in cognitive function and brain networks between hypertensive patients who are APOE ε4 carriers and non-carriers may help in understanding how hypertension and risk genes cumulatively impair brain function, which could provide critical insights into the genetic mechanism by which hypertension serves as a potential risk factor for cognitive decline and even AD. Using behavioral data from 233 elderly hypertensive patients and neuroimaging data from 38 of them from Beijing, China; the study aimed to assess the effects of APOE ε4 on cognition and to explore related changes in functional connectivity. Cognitively, the patients with APOE ε4 showed decreased executive function, memory and language. In the MRI sub-cohort, the frontoparietal networks in the APOE ε4 carrier group exhibited an altered pattern, mainly in the left precentral regions, inferior frontal lobe and angular gyrus. More importantly, the decline of cognitive function was correlated with abnormal FC in the left precentral regions in APOE ε4 carriers. APOE ε4 aggravated the dysfunction in frontal and parietal regions in hypertensive patients. This highlights the importance of brain protection in hypertensive patients, especially those with a genetic risk of AD.