Proteins linking APOE ɛ4 with Alzheimer's disease.

INTRODUCTION: The ɛ4 allele of the apolipoprotein E gene (APOE ɛ4) is the strongest genetic risk factor for Alzheimer's disease (AD), but the mechanisms connecting APOE ɛ4 to AD are not clear. METHODS: Participants (n = 596) were from two clinical-pathological studies. Tissues from dorsolateral prefrontal cortex were examined to identify 8425 proteins. Post mortem pathological assessment used immunohistochemistry to obtain amyloid beta (Aß) load and tau tangle density. RESULTS: In separate models, APOE ɛ4 was associated with 18 proteins, which were associated with Aß and tau tangles. Examining the proteins in a single model identified Netrin-1 and secreted frizzled-related protein 1 (SFRP1) as the two proteins linking APOE ɛ4 with Aß with the largest effect sizes and Netrin-1 and testican-3 linking APOE ɛ4 with tau tangles. DISCUSSION: We identified Netrin-1, SFRP1, and testican-3 as the most promising proteins that link APOE ɛ4 with Aß and tau tangles. HIGHLIGHTS: Of 8425 proteins extracted from prefrontal cortex, 18 were related to APOE ɛ4. The 18 proteins were also related to amyloid beta (Aß) and tau. The 18 proteins were more related to APOE ɛ4 than other AD genetic risk variants. Netrin-1 and secreted frizzled-related protein 1 were the two most promising proteins linking APOE ɛ4 with Aß. Netrin-1 and testican-3 were two most promising proteins linking APOE ɛ4 with tau.

APOE ε4 carriage associates with improved myocardial performance from adolescence to older age.

BACKGROUND: Although APOE ε4 allele carriage confers a risk for coronary artery disease, its persistence in humans might be explained by certain survival advantages (antagonistic pleiotropy). METHODS: Combining data from ~ 37,000 persons from three older age British cohorts (1946 National Survey of Health and Development [NSHD], Southall and Brent Revised [SABRE], and UK Biobank) and one younger age cohort (Avon Longitudinal Study of Parents and Children [ALSPAC]), we explored whether APOE ε4 carriage associates with beneficial or unfavorable left ventricular (LV) structural and functional metrics by echocardiography and cardiovascular magnetic resonance (CMR). RESULTS: Compared to the non-APOE ε4 group, APOE ε4 carriers had similar cardiac phenotypes in terms of LV ejection fraction, E/e', posterior wall and interventricular septal thickness, and LV mass. However, they had improved myocardial performance resulting in greater LV stroke volume generation per 1 mL of myocardium (higher myocardial contraction fraction). In NSHD (n = 1467) and SABRE (n = 1187), ε4 carriers had a 4% higher MCF (95% CI 1-7%, p = 0.016) using echocardiography. Using CMR data, in UK Biobank (n = 32,972), ε4 carriers had a 1% higher MCF 95% (CI 0-1%, p = 0.020) with a dose-response relationship based on the number of ε4 alleles. In addition, UK Biobank ε4 carriers also had more favorable radial and longitudinal strain rates compared to non APOE ε4 carriers. In ALSPAC (n = 1397), APOE ε4 carriers aged < 24 years had a 2% higher MCF (95% CI 0-5%, p = 0.059). CONCLUSIONS: By triangulating results in four independent cohorts, across imaging modalities (echocardiography and CMR), and in ~ 37,000 individuals, our results point towards an association between ε4 carriage and improved cardiac performance in terms of LV MCF. This potentially favorable cardiac phenotype adds to the growing number of reported survival advantages attributed to the pleiotropic effects APOE ε4 carriage that might collectively explain its persistence in human populations.

Examining the relationship between anxiety and regional brain volumes in the National Alzheimer's Coordinating Center uniform, imaging, and biomarker datasets.

Anxiety has been associated with a greater risk of Alzheimer's disease (AD). Existing research has identified structural differences in regional brain tissue in participants with anxiety, but results have been inconsistent. We sought to determine the association between anxiety and regional brain volumes, and the moderation effect of APOE ε4. Using data from participants in the National Alzheimer's Coordinating Center (NACC) Uniform Data Set, with complete imaging (MRI) and biomarker data (n = 1533), multiple linear regression estimated the adjusted effect of anxiety on 30 structural MRI regions. The moderation effect of APOE ε4 on the relation between structural MRI regions and anxiety was assessed as was the moderation effect of cognitive status. False discovery rate was used to adjust for multiple comparisons. After controlling for intracranial volume, age, sex, years of education, race, Hispanic ethnicity, and cognitive status, seven MRI regions demonstrated lower volumes among participants with anxiety: total cerebrum gray matter volume, right hippocampus volume, hippocampal volume (total), right and left frontal lobe cortical gray matter volume, and right and total temporal lobe cortical gray matter volume. Findings suggest that anxiety is associated with significant atrophy in multiple brain regions, with corresponding ventricular enlargement. Future research should investigate if anxiety-related changes to brain morphology contribute to greater AD risk.

Ginseng intake and Alzheimer disease-specific cognition in older adults according to apolipoprotein ε4 allele status.

Background: The probable association among ginseng intake, Alzheimer's disease (AD)-specific cognition, and apolipoprotein ε4 (APOE4) remains poorly investigated. Hence, we examined the association between ginseng intake and AD-specific cognition in older adults under the moderating effect of APOE4 status. Methods: This study enrolled 160 adults aged 65-90 years without dementia. All participants underwent comprehensive dietary and clinical assessments including ginseng intake, AD-related cognition (i.e., delayed episodic memory, as the earliest cognitive change in AD), and non-memory cognition for comparative purposes. Results: Ginseng intake was associated with higher delayed episodic memory, but not non-memory cognition, compared to no ginseng intake. The interaction between ginseng intake and APOE4 status had a significant effect on delayed episodic memory. Subgroup analyses showed that ginseng intake was associated with higher delayed episodic memory in the APOE4-negative but not the APOE4-positive subgroup. The benefits of ginseng intake on delayed episodic memory were prominent in the high duration (≥5 years) and midlife onset (<65 years) groups. Conclusion: Our study of older adults with no dementia suggests that ginseng intake (with high duration and midlife onset) had a beneficial effect on AD-specific cognitive decline, i.e., the delayed episodic memory. In addition, APOE4 status moderates the association between ginseng intake status and AD-specific cognitive decline.

APOE ε4 influences within and between network functional connectivity in posterior cortical atrophy and logopenic progressive aphasia.

INTRODUCTION: Presence of apolipoprotein E (APOE) ε4 has shown greater predisposition to medial temporal involvement in posterior cortical atrophy (PCA) and logopenic progressive aphasia (LPA). Little is known about its influence on memory network connectivity, a network comprised of medial temporal structures. METHODS: Fifty-eight PCA and 82 LPA patients underwent structural and resting state functional magnetic resonance imaging (MRI). Bayesian hierarchical linear models assessed the influence of APOE ε4 on within and between-network connectivity for five networks. RESULTS: APOE ε4 carriers showed reduced memory and language within-network connectivity in LPA and increased salience within-network connectivity in PCA compared to non-carriers. Between-network analysis showed evidence of reduced DMN connectivity in APOE ε4 carriers, with reduced DMN-to-salience and DMN-to-language network connectivity in PCA, and reduced DMN-to-visual network connectivity in LPA. DISCUSSION: The APOE genotype influences brain connectivity, both within and between-networks, in atypical Alzheimer's disease. However, there was evidence that the modulatory effects of APOE differ across phenotype. HIGHLIGHTS: APOE genotype is associated with reductions in within-network connectivity for the memory and language networks in LPA APOE genotype is associated with reductions in language-to-visual connectivity in LPA and PCA APOE genotype has no effect on the memory network in PCA.

APOE ε4 influences medial temporal atrophy and tau deposition in atypical Alzheimer's disease.

INTRODUCTION: Apolipoprotein E (APOE) ε4 is an important genetic risk factor for typical Alzheimer's disease (AD), influencing brain volume and tau burden. Little is known about its influence in atypical presentations of AD. METHODS: An atypical AD cohort of 140 patients diagnosed with either posterior cortical atrophy or logopenic progressive aphasia underwent magnetic resonance imaging and positron emission tomography. Linear mixed effects models were fit to assess the influence of APOE Îµ4 on cross-sectional and longitudinal regional metrics. RESULTS: At baseline, APOE ε4 carriers had smaller hippocampal and amygdala volumes and greater tau standardized uptake volume ratio in the hippocampus and entorhinal cortex compared to non-carriers while longitudinally, APOE ε4 non-carriers showed faster rates of atrophy and tau accumulation in the entorhinal cortex, with faster tau accumulation in the hippocampus. DISCUSSION: APOE ε4 influences patterns of neurodegeneration and tau deposition and was associated with more medial temporal involvement, although there is evidence that non-carriers may be catching up over time.

Blood pressure variability and medial temporal atrophy in apolipoprotein ϵ4 carriers.

Blood pressure variability is an emerging risk factor for dementia but relationships with markers of neurodegeneration and Alzheimer's disease risk are understudied. We investigated blood pressure variability over one year and follow-up medial temporal brain volume change in apolipoprotein ϵ4 carriers and non-carriers, and in those with and without Alzheimer's disease biomarker abnormality. 1051 Alzheimer's Disease Neuroimaging Initiative participants without history of dementia or stroke underwent 3-4 blood pressure measurements over 12 months and ≥ 1 MRI thereafter. A subset (n = 252) underwent lumbar puncture to determine Alzheimer's disease cerebral spinal fluid amyloid-beta and phosphorylated tau biomarker abnormality. Blood pressure variability over 12 months was calculated as variability independent of mean. Longitudinal hippocampal and entorhinal cortex volume data were extracted from serial brain MRI scans obtained after the final blood pressure measurement. Apolipoprotein ϵ4 carrier status was defined as at least one ϵ4 allele. Bayesian growth modelling revealed a significant interaction of blood pressure variability by ϵ4 by time on hippocampal (ß: -2.61 [95% credible interval -3.02, -2.12]) and entorhinal cortex (ß: -1.47 [95% credible interval -1.71, -1.17]) volume decline. A similar pattern emerged in subsets with Alzheimer's disease pathophysiology (i.e., abnormal levels of both amyloid-beta and phosphorylated tau). Findings suggest that elevated blood pressure variability is related to medial temporal volume loss specifically in ϵ4 carriers, and in those with Alzheimer's disease biomarker abnormality. Findings could implicate blood pressure variability in medial temporal neurodegeneration observed in older ϵ4 carriers and those with prodromal Alzheimer's disease.

Reduced Hippocampal GABA+ Is Associated With Poorer Episodic Memory in Healthy Older Women: A Pilot Study.

Background: The current pilot study was designed to examine the association between hippocampal γ-aminobutyric acid (GABA) concentration and episodic memory in older individuals, as well as the impact of two major risk factors for Alzheimer's disease (AD)-female sex and Apolipoprotein ε4 (ApoE ε4) genotype-on this relationship. Methods: Twenty healthy, community-dwelling individuals aged 50-71 (11 women) took part in the study. Episodic memory was evaluated using a Directed Forgetting task, and GABA+ was measured in the right hippocampus using a Mescher-Garwood point-resolved magnetic resonance spectroscopy (MRS) sequence. Multiple linear regression models were used to quantify the relationship between episodic memory, GABA+, ApoE ɛ4, and sex, controlling for age and education. Results: While GABA+ did not interact with ApoE ɛ4 carrier status to influence episodic memory (p = 0.757), the relationship between GABA+ and episodic memory was moderated by sex: lower GABA+ predicted worse memory in women such that, for each standard deviation decrease in GABA+ concentration, memory scores were reduced by 11% (p = 0.001). Conclusions: This pilot study suggests that sex, but not ApoE ɛ4 genotype, moderates the relationship between hippocampal GABA+ and episodic memory, such that women with lower GABA+ concentration show worse memory performance. These findings, which must be interpreted with caution given the small sample size, may serve as a starting point for larger studies using multimodal neuroimaging to understand the contributions of GABA metabolism to age-related memory decline.

Early-start vs delayed-start donepezil against cognitive decline in Parkinson disease: a randomized clinical trial.

BACKGROUND: Cholinergic neurotransmission regulates neuroinflammation in Parkinson disease (PD). RESEARCH DESIGN AND METHODS: The authors conducted a delayed-start study of donepezil for cognitive decline in non-demented PD patients. The study consisted of a 96-week randomized placebo-controlled double-blind phase 1, followed by a 24-week donepezil extension phase 2. The primary outcome measure was a change in the Mini-Mental State Examination (MMSE) at week 120. RESULTS: A total of 98 patients were randomly allocated to the early-start (donepezil-to-donepezil) and delayed-start (placebo-to-donepezil) groups. Mean (SD) of the baseline MMSE was 27.6 (2.0) and 28.0 (2.1), respectively. MMSE change at week 120 was better in the early-start group than in the delayed-start group, but the difference was not significant. The MMSE declined in apolipoprotein ε4 carriers, but not in non-carriers, and the factor interaction (intervention × Îµ4 genotype) was highly significant (P < 0.001). Analyzed with the interaction, the difference was significant (group difference 1.95 [0.33 to 3.57], P = 0.018). The MMSE decline slope in phase 1 was significantly better in the early-start group than in the delayed-start group (P = 0.048). CONCLUSIONS: Cognitive function deteriorated in ε4 carriers, but not in non-carriers, and early-start donepezil may postpone cognitive decline in the former.

Sex differences in risk of Alzheimer's disease in adults with Down syndrome.

INTRODUCTION: Adults with Down syndrome (DS) older than 40 have Alzheimer's disease (AD) neuropathology and high risk for dementia, but little is known about the relationship of sex to AD risk in this population. METHODS: Using nonparametric methods and Cox proportional hazards models we analyzed differences in incidence of dementia, by sex, presence of an apolipoprotein E (APOE) ε4 or ε2 allele, and dementia duration and decline in 246 adults over 40 with DS. RESULTS: There was no significant sex difference in risk of AD or rate of cognitive decline. APOE ε4 allele significantly increased risk of AD irrespective of sex. No significant interactions were found between sex and APOE status on AD risk. Among those who died, dementia duration was significantly longer in women. DISCUSSION: This study showed no effect of sex nor interaction between sex and APOE for risk of AD in adults with DS; however, women had longer dementia duration.

Older, non-demented apolipoprotein ε4 carrier males show hyperactivation and structural differences in odor memory regions: a blood-oxygen-level-dependent and structural magnetic resonance imaging study.

The current study sought to examine the interaction of sex and Apolipoprotein ε4 status on olfactory recognition memory within non-demented, older individuals. We separated 39 participants into groups based on ε4 status and sex. Each participant completed an olfactory memory recognition task during 2 functional magnetic resonance imaging scans and 1 structural scan. The ε4 carriers had greater functional recruitment of memory regions during false positives relative to ε4 non-carriers. During hits, the male ε4 carriers showed greater functional recruitment compared to female ε4 carriers. The ε4 carriers had larger bilateral putamen volumes relative to ε4 non-carriers. Neuroimaging data were significantly associated with Dementia Rating Scale scores solely in males. Results suggest differential olfactory memory processing in relation to sex and ε4 status. Male ε4 carriers in particular, demonstrated hyperactivation during recognition memory, which we suspect reflects neuronal compensation to maintain functional performance. Future studies should consider examining underlying mechanisms that contribute to these sex differences within ε4 carriers.

Plasma Lipidomic Analyses in Cohorts With mTBI and/or PTSD Reveal Lipids Differentially Associated With Diagnosis and APOE ε4 Carrier Status.

The differential diagnosis between mild Traumatic Brain Injury (mTBI) sequelae and Post-Traumatic Stress Disorder (PTSD) is challenging due to their symptomatic overlap and co-morbidity. As such, there is a need to develop biomarkers which can help with differential diagnosis of these two conditions. Studies from our group and others suggest that blood and brain lipids are chronically altered in both mTBI and PTSD. Therefore, examining blood lipids presents a minimally invasive and cost-effective approach to identify promising biomarkers of these conditions. Using liquid chromatography-mass spectrometry (LC-MS) we examined hundreds of lipid species in the blood of healthy active duty soldiers (n = 52) and soldiers with mTBI (n = 21), PTSD (n = 34) as well as co-morbid mTBI and PTSD (n = 13) to test whether lipid levels were differentially altered with each. We also examined if the apolipoprotein E (APOE) ε4 allele can affect the association between diagnosis and peripheral lipid levels in this cohort. We show that several lipid classes are altered with diagnosis and that there is an interaction between diagnosis and the ε4 carrier status on these lipids. Indeed, total lipid levels as well as both the degree of unsaturation and chain lengths are differentially altered with diagnosis and ε4 status, specifically long chain unsaturated triglycerides (TG) and both saturated and mono-unsaturated diglycerides (DG). Additionally, an examination of lipid species reveals distinct profiles in each diagnostic group stratified by ε4 status, mainly in TG, saturated DG species and polyunsaturated phosphatidylserines. In summary, we show that peripheral lipids are promising biomarker candidates to assist with the differential diagnosis of mTBI and PTSD. Further, ε4 carrier status alone and in interaction with diagnosis has a strong influence on peripheral lipid levels. Therefore, examining ε4 status along with peripheral lipid levels could help with differential diagnosis of mTBI and PTSD.

Metabolic Syndrome and Cognitive Impairment among High Socioeconomic, Nondemented Older US Adults.

OBJECTIVES: Nondemented cognitive impairment (CI) presents opportunities for early interventions among individuals at risk for dementia. Identification of modifiable determinants is paramount to the development of effective clinical interventions. Metabolic syndrome (MetS) was theorized as a risk factor, but current research yields inconsistent findings. Few studies have examined the association between MetS and CI among US populations, and global results may be ungeneralizable. We investigated the MetS-CI association among high socioeconomic, nondemented older US adults, examining the roles of sociodemographic, clinical, behavioral, and genetic factors. DESIGN: Cross-sectional. SETTING: Cooper Clinic of Dallas, Texas: Cooper Center Longitudinal Study (2009-2017). PARTICIPANTS: A total of 5200 dementia-free older adult Cooper Clinic patients. MEASUREMENTS: CI was detected with a Montreal Cognitive Assessment (MoCA) score lower than 26. MetS was established based on National Cholesterol Education Program Adult Treatment Panel guidelines. Unadjusted and multivariable log-binomial regression were used to assess the MetS-CI association, with modification assessment by age, sex, education, cardiorespiratory fitness (CRF), and apolipoprotein-ε4 carrier status (APOE-ε4). RESULTS: MetS was not associated with CI when adjusting for age, sex, minority status, education, and marital status (prevalence ratio [PR] = 1.09; 95% confidence interval = .97-1.23) or when additionally adjusting for body mass index, CRF, alcohol consumption, current smoking status, and APOE-ε4 (PR = 1.07; 95% confidence interval = .80-1.45). The association was not modified by age, sex, CRF, or APOE-ε4 (P for interaction >.05). CONCLUSION: In contrast with some global and US studies, MetS and CI were not associated among our study population of nondemented older US adults. MetS may not be a suitable intervention target for poor cognitive outcomes among high socioeconomic older US adults, although separate MetS components may have different recommendations. Future studies should explore more diverse older US populations. If replicated, these findings would inform clinical efforts to reduce the burden of poor cognitive outcomes in the United States.

Vascular burden and APOE ε4 are associated with white matter microstructural decline in cognitively normal older adults.

White matter microstructure can be measured with diffusion tensor imaging (DTI). While increasing age is a predictor of white matter (WM) microstructure changes, roles of other possible modifiers, such as cardiovascular risk factors, APOE ε4 allele status and biological sex have not been clarified. We investigated 665 cognitively normal participants from the Baltimore Longitudinal Study of Aging (age 50-95, 56.7% female) with a total of 1384 DTI scans. WM microstructure was assessed by fractional anisotropy (FA) and mean diffusivity (MD). A vascular burden score was defined as the sum of five risk factors (hypertension, obesity, elevated cholesterol, diabetes and smoking status). Linear mixed effects models assessed the association of baseline vascular burden on baseline and on rates of change of FA and MD over a mean follow-up of 3.6 years, while controlling for age, race, and scanner type. We also compared DTI trajectories in APOE ε4 carriers vs. non-carriers and men vs. women. At baseline, higher vascular burden was associated with lower FA and higher MD in many WM structures including association, commissural, and projection fibers. Higher baseline vascular burden was also associated with greater longitudinal decline in FA in the hippocampal part of the cingulum and the fornix (crus)/stria terminalis and splenium of the corpus callosum, and with greater increases in MD in the splenium of the corpus callosum. APOE ε4 carriers did not differ from non-carriers in baseline DTI metrics but had greater decline in FA in the genu and splenium of the corpus callosum. Men had higher FA and lower MD in multiple WM regions at baseline but showed greater increase in MD in the genu of the corpus callosum. Women showed greater decreases over time in FA in the gyrus part of the cingulum, compared to men. Our findings show that modifiable vascular risk factors (1) have a negative impact on white matter microstructure and (2) are associated with faster microstructural deterioration of temporal WM regions and the splenium of the corpus callosum in cognitively normal adults. Reducing vascular burden in aging could modify the rate of WM deterioration and could decrease age-related cognitive decline and impairment.

Clinical Application of APOE in Alzheimer's Prevention: A Precision Medicine Approach.

Population-attributable risk models estimate that up to one-third of Alzheimer's disease (AD) cases may be preventable through risk factor modification. The field of AD prevention has largely focused on addressing these factors through universal risk reduction strategies for the general population. However, targeting these strategies in a clinical precision medicine fashion, including the use of genetic risk factors, allows for potentially greater impact on AD risk reduction. Apolipoprotein E (APOE), and specifically the APOE ε4 variant, is one of the most well-established genetic influencers on late-onset AD risk. In this review, we evaluate the impact of APOE ε4 carrier status on AD prevention interventions, including lifestyle, nutrigenomic, pharmacogenomic, AD comorbidities, and other biological and behavioral considerations. Using a clinical precision medicine strategy that incorporates APOE ε4 carrier status may provide a highly targeted and distinct approach to AD prevention with greater potential for success.

Precision Medicine for Alzheimer's Disease Prevention.

Precision medicine is an approach to medical treatment and prevention that takes into account individual variability in genes, environment, and lifestyle and allows for personalization that is based on factors that may affect the response to treatment. Several genetic and epigenetic risk factors have been shown to increase susceptibility to late-onset Alzheimer's disease (AD). As such, it may be beneficial to integrate genetic risk factors into the AD prevention approach, which in the past has primarily been focused on universal risk-reduction strategies for the general population rather than individualized interventions in a targeted fashion. This review discusses examples of a "one-size-fits-all" versus clinical precision medicine AD prevention strategy, in which the precision medicine approach considers two genes that can be commercially sequenced for polymorphisms associated with AD, apolipoprotein E (APOE), and methylenetetrahydrofolate reductase (MTHFR). Comparing these two distinct approaches provides support for a clinical precision medicine prevention strategy, which may ultimately lead to more favorable patient outcomes as the interventions are targeted to address individualized risks.

Changes of Functional and Directed Resting-State Connectivity Are Associated with Neuronal Oscillations, ApoE Genotype and Amyloid Deposition in Mild Cognitive Impairment.

The assessment of effects associated with cognitive impairment using electroencephalography (EEG) power mapping allows the visualization of frequency-band specific local changes in oscillatory activity. In contrast, measures of coherence and dynamic source synchronization allow for the study of functional and effective connectivity, respectively. Yet, these measures have rarely been assessed in parallel in the context of mild cognitive impairment (MCI) and furthermore it has not been examined if they are related to risk factors of Alzheimer's disease (AD) such as amyloid deposition and apolipoprotein ε4 (ApoE) allele occurrence. Here, we investigated functional and directed connectivities with Renormalized Partial Directed Coherence (RPDC) in 17 healthy controls (HC) and 17 participants with MCI. Participants underwent ApoE-genotyping and Pittsburgh compound B positron emission tomography (PiB-PET) to assess amyloid deposition. We observed lower spectral source power in MCI in the alpha and beta bands. Coherence was stronger in HC than MCI across different neuronal sources in the delta, theta, alpha, beta and gamma bands. The directed coherence analysis indicated lower information flow between fronto-temporal (including the hippocampus) sources and unidirectional connectivity in MCI. In MCI, alpha and beta RPDC showed an inverse correlation to age and gender; global amyloid deposition was inversely correlated to alpha coherence, RPDC and beta and gamma coherence. Furthermore, the ApoE status was negatively correlated to alpha coherence and RPDC, beta RPDC and gamma coherence. A classification analysis of cognitive state revealed the highest accuracy using EEG power, coherence and RPDC as input. For this small but statistically robust (Bayesian power analyses) sample, our results suggest that resting EEG related functional and directed connectivities are sensitive to the cognitive state and are linked to ApoE and amyloid burden.

Cortical Functional Connections and Fluid Intelligence in Adolescent APOE ε4 Carriers.

AIMS: This study examined differences in corticocortical communication between adolescent ε4 carriers (ε4+) and noncarriers (ε4-) during a fluid intelligence task (Comprehensive Test of Nonverbal Intelligence [CTONI]). METHODS: Sixteen ε4+ and 20 ε4- individuals aged 13-15 years performed the CTONI while real-time EEG signals were acquired. Inter- and intrahemispheric coherences were analyzed. RESULTS: The ε4+ subjects exhibited lower inter- and intrahemispheric coherences than the ε4- individuals. CONCLUSION: ε4 carriers have lower corticocortical communication than noncarriers during an intelligence task, implying that carrying the ε4 allele may reduce brain networking in adolescence, several decades before the onset of Alzheimer disease.

Greater Cognitive Deficits with Sleep-disordered Breathing among Individuals with Genetic Susceptibility to Alzheimer Disease. The Multi-Ethnic Study of Atherosclerosis.

RATIONALE: There are conflicting findings regarding the link between sleep apnea and cognitive dysfunction. OBJECTIVES: Investigate associations between indicators of sleep-disordered breathing (SDB) and cognitive function in the Multi-Ethnic Study of Atherosclerosis and assess effect modification by the apolipoprotein ε-4 (APOE-ε4) allele. METHODS: A diverse population (N = 1,752) underwent type 2 in-home polysomnography, which included measurement of percentage sleep time less than 90% oxyhemoglobin saturation (%Sat < 90%) and apnea-hypopnea index (AHI). Epworth Sleepiness Scale score (ESS) and sleep apnea syndrome (SAS; AHI ≥ 5 and ESS > 10) were also analyzed. Cognitive outcomes included the Cognitive Abilities Screening Instrument; Digit Symbol Coding (DSC) test; and Digit Span Tests (DST) Forward and Backward. RESULTS: Participants were 45.4% men, aged 68.1 years (SD, 9.1 yr) with a median AHI of 9.0 and mean ESS of 6.0. Approximately 9.7% had SAS, and 26.8% had at least one copy of the APOE-ε4 allele. In adjusted analyses, a 1-SD increase in %Sat < 90% and ESS score were associated with a poorer attention and memory assessed by the DST Forward score (ß = -0.12 [SE, 0.06] and ß = -0.13 [SE, 0.06], respectively; P ≤ 0.05). SAS and higher ESS scores were also associated with poorer attention and processing speed as measured by the DSC (ß = -0.69 [SE, 0.35] and ß = -1.42 [SE, 0.35], respectively; P < 0.05). The presence of APOE-ε4 allele modified the associations of %Sat < 90% with DST forward and of ESS with DSC (Pinteraction ≤ 0.05). CONCLUSIONS: Overnight hypoxemia and sleepiness were associated with cognition. The average effect estimates were small, similar to effect estimates for several other individual dementia risk factors. Associations were strongest in APOE-ε4 risk allele carriers. Our results (1) suggest that SDB be considered among a group of modifiable dementia risk factors, and (2) highlight the potential vulnerability of APOE-ε4 risk allele carriers with SDB.

Motor timing intraindividual variability in amnestic mild cognitive impairment and cognitively intact elders at genetic risk for Alzheimer's disease.

INTRODUCTION: Intraindividual variability (IIV) in motor performance has been shown to predict future cognitive decline. The apolipoprotein E-epsilon 4 (APOE-ε4) allele is also a well-established risk factor for memory decline. Here, we present novel findings examining the influence of the APOE-ε4 allele on the performance of asymptomatic healthy elders in comparison to individuals with amnestic MCI (aMCI) on a fine motor synchronization, paced finger-tapping task (PFTT). METHOD: Two Alzheimer's disease (AD) risk groups, individuals with aMCI (n = 24) and cognitively intact APOE-ε4 carriers (n = 41), and a control group consisting of cognitively intact APOE-ε4 noncarriers (n = 65) completed the Rey Auditory Verbal Learning Test and the PFTT, which requires index finger tapping in synchrony with a visual stimulus (interstimulus interval = 333 ms). RESULTS: Motor timing IIV, as reflected by the standard deviation of the intertap interval (ITI), was greater in the aMCI group than in the two groups of cognitively intact elders; in contrast, all three groups had statistically equivalent mean ITI. No significant IIV differences were observed between the asymptomatic APOE-ε4 carriers and noncarriers. Poorer episodic memory performance was associated with greater IIV, particularly in the aMCI group. CONCLUSIONS: Results suggest that increased IIV on a fine motor synchronization task is apparent in aMCI. This IIV measure was not sensitive in discriminating older asymptomatic individuals at genetic risk for AD from those without such a genetic risk. In contrast, episodic memory performance, a well-established predictor of cognitive decline in preclinical AD, was able to distinguish between the two cognitively intact groups based on genetic risk.