Plasma oxysterols are associated with serum lipids and dementia risk in older women.

INTRODUCTION: Apolipoprotein E4 (APOE4) carriers' tendency toward hypercholesterolemia may contribute to Alzheimer's disease (AD) risk through oxysterols, which traverse the blood-brain barrier. METHODS: Relationships between baseline plasma oxysterols, APOE status, serum lipids, and cognitive impairment risk were examined in 328 postmenopausal women from the Women's Health Initiative Memory Study. Women were followed for 25 years or until incident dementia or cognitive impairment. RESULTS: Levels of 24(S)-hydroxycholesterol (24-OHC), 27-hydroxycholesterol (27-OHC), and 24-OHC/27-OHC ratio did not differ by APOE status (p's > 0.05). Higher 24-OHC and 27-OHC were associated with higher total, low density lipoprotein (LDL), non-high density lipoprotein (HDL), remnant, LDL/HDL, and total/HDL cholesterol and triglycerides (p's < 0.05). Higher 24-OHC/27-OHC was associated with greater dementia risk (hazard ratio = 1.51, 95% confidence interval:1.02-2.22), which interaction analyses revealed as significant for APOE3 and APOE4+, but not APOE2+ carriers. DISCUSSION: Less favorable lipid profiles were associated with higher oxysterol levels. A higher ratio of 24-OHC/27-OHC may contribute to dementia risk in APOE3 and APOE4+ carriers.

Alzheimer's Related Neurodegeneration Mediates Air Pollution Effects on Medial Temporal Lobe Atrophy.

Exposure to ambient air pollution, especially particulate matter with aerodynamic diameter <2.5 µm (PM2.5) and nitrogen dioxide (NO2), are environmental risk factors for Alzheimer's disease and related dementia. The medial temporal lobe (MTL) is an important brain region subserving episodic memory that atrophies with age, during the Alzheimer's disease continuum, and is vulnerable to the effects of cerebrovascular disease. Despite the importance of air pollution it is unclear whether exposure leads to atrophy of the MTL and by what pathways. Here we conducted a longitudinal study examining associations between ambient air pollution exposure and MTL atrophy and whether putative air pollution exposure effects resembled Alzheimer's disease-related neurodegeneration or cerebrovascular disease-related neurodegeneration. Participants included older women (n = 627; aged 71-87) who underwent two structural brain MRI scans (MRI-1: 2005-6; MRI-2: 2009-10) as part of the Women's Health Initiative Memory Study of Magnetic Resonance Imaging. Regionalized universal kriging was used to estimate annual concentrations of PM2.5 and NO2 at residential locations aggregated to 3-year averages prior to MRI-1. The outcome was 5-year standardized change in MTL volumes. Mediators included voxel-based MRI measures of the spatial pattern of neurodegeneration of Alzheimer's disease (Alzheimer's disease pattern similarity scores [AD-PS]) and whole-brain white matter small-vessel ischemic disease (WM-SVID) volume as a proxy of global cerebrovascular damage. Structural equation models were constructed to examine whether the associations between exposures with MTL atrophy were mediated by the initial level or concurrent change in AD-PS score or WM-SVID while adjusting for sociodemographic, lifestyle, clinical characteristics, and intracranial volume. Living in locations with higher PM2.5 (per interquartile range [IQR]=3.17µg/m3) or NO2 (per IQR=6.63ppb) was associated with greater MTL atrophy (ßPM2.5 = -0.29, 95% confidence interval [CI]=[-0.41,-0.18]; ßNO2 =-0.12, 95%CI=[-0.23,-0.02]). Greater PM2.5 was associated with larger increases in AD-PS (ßPM2.5 = 0.23, 95%CI=[0.12,0.33]) over time, which partially mediated associations with MTL atrophy (indirect effect= -0.10; 95%CI=[-0.15, -0.05]), explaining approximately 32% of the total effect. NO2 was positively associated with AD-PS at MRI-1 (ßNO2=0.13, 95%CI=[0.03,0.24]), which partially mediated the association with MTL atrophy (indirect effect= -0.01, 95% CI=[-0.03,-0.001]). Global WM-SVID at MRI-1 or concurrent change were not significant mediators between exposures and MTL atrophy. Findings support the mediating role of Alzheimer's disease-related neurodegeneration contributing to MTL atrophy associated with late-life exposures to air pollutants. Alzheimer's disease-related neurodegeneration only partially explained associations between exposure and MTL atrophy suggesting the role of multiple neuropathological processes underlying air pollution neurotoxicity on brain aging.

Association between late-life air pollution exposure and medial temporal lobe atrophy in older women.

Background: Ambient air pollution exposures increase risk for Alzheimer's disease (AD) and related dementias, possibly due to structural changes in the medial temporal lobe (MTL). However, existing MRI studies examining exposure effects on the MTL were cross-sectional and focused on the hippocampus, yielding mixed results. Method: To determine whether air pollution exposures were associated with MTL atrophy over time, we conducted a longitudinal study including 653 cognitively unimpaired community-dwelling older women from the Women's Health Initiative Memory Study with two MRI brain scans (MRI-1: 2005-6; MRI-2: 2009-10; Mage at MRI-1=77.3±3.5years). Using regionalized universal kriging models, exposures at residential locations were estimated as 3-year annual averages of fine particulate matter (PM2.5) and nitrogen dioxide (NO2) prior to MRI-1. Bilateral gray matter volumes of the hippocampus, amygdala, parahippocampal gyrus (PHG), and entorhinal cortex (ERC) were summed to operationalize the MTL. We used linear regressions to estimate exposure effects on 5-year volume changes in the MTL and its subregions, adjusting for intracranial volume, sociodemographic, lifestyle, and clinical characteristics. Results: On average, MTL volume decreased by 0.53±1.00cm3 over 5 years. For each interquartile increase of PM2.5 (3.26µg/m3) and NO2 (6.77ppb), adjusted MTL volume had greater shrinkage by 0.32cm3 (95%CI=[-0.43, -0.21]) and 0.12cm3 (95%CI=[-0.22, -0.01]), respectively. The exposure effects did not differ by APOE ε4 genotype, sociodemographic, and cardiovascular risk factors, and remained among women with low-level PM2.5 exposure. Greater PHG atrophy was associated with higher PM2.5 (b=-0.24, 95%CI=[-0.29, -0.19]) and NO2 exposures (b=-0.09, 95%CI=[-0.14, -0.04]). Higher exposure to PM2.5 but not NO2 was also associated with greater ERC atrophy. Exposures were not associated with amygdala or hippocampal atrophy. Conclusion: In summary, higher late-life PM2.5 and NO2 exposures were associated with greater MTL atrophy over time in cognitively unimpaired older women. The PHG and ERC - the MTL cortical subregions where AD neuropathologies likely begin, may be preferentially vulnerable to air pollution neurotoxicity.

Cardiorespiratory Fitness Attenuates the Deleterious Effects of Sleep Apnea on Cerebral Structure and Perfusion in the Wisconsin Sleep Cohort Study.

BACKGROUND: Emerging evidence suggests that age-related changes in cerebral health may be sensitive to vascular risk modifiers, such as physical activity and sleep. OBJECTIVE: We examine whether cardiorespiratory fitness modifies the association of obstructive sleep apnea (OSA) severity with MRI-assessed measures of cerebral structure and perfusion. METHODS: Using data from a cross-sectional sample of participants (n = 129, 51% female, age range 49.6-85.3 years) in the Wisconsin Sleep Cohort study, we estimated linear models of MRI-assessed total and regional gray matter (GM) and white matter (WM) volumes, WM hyperintensity (WMH:ICV ratio), total lesion volume, and arterial spin labeling (ASL) cerebral blood flow (CBF), using an estimated measure of cardiorespiratory fitness (CRF) and OSA severity as predictors. Participants' sleep was assessed using overnight in-laboratory polysomnography, and OSA severity was measured using the apnea-hypopnea index (AHI), or the mean number of recorded apnea and hypopnea events per hour of sleep. The mean±SD time difference between PSG data collection and MRI data collection was 1.7±1.5 years (range: [0, 4.9 years]). RESULTS: OSA severity was associated with reduced total GM volume (ß=-0.064; SE = 0.023; p = 0.007), greater total WM lesion volume (interaction p = 0.023), and greater WMHs (interaction p = 0.017) in less-fit subjects. Perfusion models revealed significant differences in the association of AHI and regional CBF between fitness groups (interaction ps < 0.05). CONCLUSION: This work provides new evidence for the protective role of cardiorespiratory fitness against the deleterious effects of OSA on brain aging in late-middle age to older adults.

Associations of dietary cholesterol and fat, blood lipids, and risk for dementia in older women vary by APOE genotype.

INTRODUCTION: Whether apolipoprotein E's (APOE's) involvement in lipid metabolism contributes to Alzheimer's disease (AD) risk remains unknown. METHODS: Incident probable dementia and cognitive impairment (probable dementia+mild cognitive impairment) were analyzed in relation to baseline serum lipids (total, low-density lipoprotein [LDL], high-density lipoprotein [HDL], non-HDL cholesterol, total-to-HDL, LDL-to-HDL, remnant cholesterol, and triglycerides) using Mendelian randomization in 5358 postmenopausal women from the Women's Health Initiative Memory Study. We also examined associations of baseline dietary cholesterol and fat with lipids based on APOE status. RESULTS: After an average of 11.13 years, less favorable lipid levels related to greater dementia and cognitive impairment risk. Dementia (odds ratio [OR] = 3.13; 95% confidence interval [CI]: 2.31 to 4.24) and cognitive impairment (OR = 2.38; 95% CI: 1.85 to 3.06) risk were greatest in relation to higher remnant cholesterol levels. Greater cholesterol consumption related to poorer lipids in APOE4+ compared to APOE3 carriers. DISCUSSION: APOE4+ carriers consuming more cholesterol had less favorable lipids, which were associated with greater dementia and cognitive impairment risk. HIGHLIGHTS: Less favorable serum lipids were associated with higher dementia incidence. Mendelian randomization findings suggest causality between lipids and dementia. Lipid levels in older women may be clinical indicators of dementia risk. APOE4 carriers had poorest lipid profiles in relation to cholesterol consumption. APOE risk for dementia may be modifiable through lipid management.

Racialized experience, biomarkers of lead exposure, and later-life cognition: a mediation analysis.

We evaluated the role of the neurotoxicant lead (Pb) in mediating racial disparities in later-life cognition in 1,085 non-Hispanic Black and 2,839 non-Hispanic white participants in NHANES (1999-2002, 2011-2014) 60+ years of age. We operationalized Black race as a marker for the experience of racialization and exposure to systemic racism. We estimated patella bone Pb via predictive models using blood Pb and demographics. Concurrent cognition (processing speed, sustained attention, working memory) was measured by the Digit Symbol Substitution Test (DSST) and a global measure combining four cognitive tests. To obtain the portion mediated, we used regression coefficients (race on Pb * Pb on cognitive score)/(race on cognitive score), adjusting for age, NHANES cycle, and sample weights. Other confounder adjustment (education, poverty income ratio, smoking) was limited to the mediator-outcome (i.e., Pb-cognition) pathway because these factors do not lie upstream of race and so cannot confound associations with race. Pb was estimated to mediate 0.6% of the association between race and global cognition, and 4% of the DSST. Our results suggest that later-life cognitive health disparities may be impacted by avoidable lead exposure driven by environmental injustice, noting that a large proportion of the pathway of systemic racism harming cognition remains.

Enhanced simulations of whole-brain dynamics using hybrid resting-state structural connectomes.

The human brain, composed of billions of neurons and synaptic connections, is an intricate network coordinating a sophisticated balance of excitatory and inhibitory activity between brain regions. The dynamical balance between excitation and inhibition is vital for adjusting neural input/output relationships in cortical networks and regulating the dynamic range of their responses to stimuli. To infer this balance using connectomics, we recently introduced a computational framework based on the Ising model, first developed to explain phase transitions in ferromagnets, and proposed a novel hybrid resting-state structural connectome (rsSC). Here, we show that a generative model based on the Kuramoto phase oscillator can be used to simulate static and dynamic functional connectomes (FC) with rsSC as the coupling weight coefficients, such that the simulated FC well aligns with the observed FC when compared to that simulated with traditional structural connectome. Simulations were performed using the open source framework The Virtual Brain on High Performance Computing infrastructure.

Enhanced simulations of whole-brain dynamics using hybrid resting-state structural connectomes.

The human brain, composed of billions of neurons and synaptic connections, is an intricate network coordinating a sophisticated balance of excitatory and inhibitory activities between brain regions. The dynamical balance between excitation and inhibition is vital for adjusting neural input/output relationships in cortical networks and regulating the dynamic range of their responses to stimuli. To infer this balance using connectomics, we recently introduced a computational framework based on the Ising model, which was first developed to explain phase transitions in ferromagnets, and proposed a novel hybrid resting-state structural connectome (rsSC). Here, we show that a generative model based on the Kuramoto phase oscillator can be used to simulate static and dynamic functional connectomes (FC) with rsSC as the coupling weight coefficients, such that the simulated FC aligns well with the observed FC when compared with that simulated traditional structural connectome.

AD-associated CSF biomolecular changes are attenuated in KL-VS heterozygotes.

Introduction: Dementia as an inevitable aging consequence has been challenged and underscores the need for investigations of the factors that confer resilience. We examine whether the functionally advantageous KL-VS variant of the putative aging suppressor KLOTHO gene attenuates age-related cognitive decline and deleterious biomolecular changes. Methods: Trajectories of change in memory and executive function (N = 360; 2-12 visits) and cerebrospinal fluid (CSF) Alzheimer's disease (AD) biomarkers-amyloid beta (Aß)42, total tau (t-tau), phosphorylated tau (p-tau) (N = 112; 2-4 samplings)-were compared between KL-VS non-carriers and heterozygotes in middle-aged and older adults from the Wisconsin Registry for Alzheimer's Prevention and the Wisconsin Alzheimer's Disease Research Center studies. Results: Memory and executive function declined (p's ≤ 0.001) and CSF t-tau, p-tau, t-tau/Aß42, and p-tau/Aß42 levels increased (all p's ≤ 0.004) with age. The rate of p-tau accumulation was attenuated for KL-VS heterozygotes (p = 0.03). Discussion: KL-VS heterozygosity may confer resilience to AD-associated biomolecular changes.

The relationship between depressive symptoms and subtypes of mild cognitive impairment in post-menopausal women: Results from the Women's Health Initiative Memory Study.

BACKGROUND: Depressive symptoms are associated with age-related cognitive impairment, but the relative risk of specific subtypes of mild cognitive impairment (MCI) conferred by depressive symptoms is unclear. The purpose of this exploratory study was to determine the longitudinal association between baseline depressive symptoms and incident cases of MCI subtypes (amnestic vs. non-amnestic) and probable dementia (PD) (Alzheimer's disease, vascular, mixed) among postmenopausal women. METHODS: Depressive symptoms were assessed at study baseline using an 8-item Burnam algorithm in 7043 postmenopausal women who participated in the Women's Health Initiative Memory Study (WHIMS) and the WHIMS-Epidemiology of Cognitive Health Outcomes (WHIMS-ECHO) extension study. During the median 9.4-year follow-up interval, the presence of MCI and PD was classified by a central adjudication committee. Classification of participants by MCI subtype (amnestic single and multi-domain, non-amnestic single and multi-domain) was done algorithmically based on established criteria using data from annual cognitive testing. RESULTS: At baseline, 557 women (7.9%) had clinically significant depressive symptoms based on Burnam algorithm cut-point of 0.06. Depressive symptoms at baseline were associated with an increased risk of incident amnestic MCI (hazard ratio [HR] = 1.91, 95% confidence interval [CI] 1.32-2.78, p < 0.0001), but not non-amnestic MCI (HR = 1.39, 95% CI 0.91-2.14, p = 0.13) after controlling for demographic factors. This relationship between depressive symptoms and amnestic MCI remained consistent after controlling for lifestyle variables, cardiovascular risk factors, antidepressant use, and history of hormone therapy. There were no significant associations between depressive symptoms and incidence of PD. CONCLUSION: Depressive symptoms at baseline among postmenopausal older women are associated with higher incidence of amnestic MCI, suggesting that they may be an independent risk factor or part of the early prodrome of dementia.

Inferring excitation-inhibition dynamics using a maximum entropy model unifying brain structure and function.

Neural activity coordinated across different scales from neuronal circuits to large-scale brain networks gives rise to complex cognitive functions. Bridging the gap between micro- and macroscale processes, we present a novel framework based on the maximum entropy model to infer a hybrid resting-state structural connectome, representing functional interactions constrained by structural connectivity. We demonstrate that the structurally informed network outperforms the unconstrained model in simulating brain dynamics, wherein by constraining the inference model with the network structure we may improve the estimation of pairwise BOLD signal interactions. Further, we simulate brain network dynamics using Monte Carlo simulations with the new hybrid connectome to probe connectome-level differences in excitation-inhibition balance between apolipoprotein E (APOE)-ε4 carriers and noncarriers. Our results reveal sex differences among APOE-ε4 carriers in functional dynamics at criticality; specifically, female carriers appear to exhibit a lower tolerance to network disruptions resulting from increased excitatory interactions. In sum, the new multimodal network explored here enables analysis of brain dynamics through the integration of structure and function, providing insight into the complex interactions underlying neural activity such as the balance of excitation and inhibition.

BDNF and KIBRA Polymorphisms Are Related to Altered Resting State Network Connectivity in Middle Age.

BACKGROUND: Disease-modifying treatments for Alzheimer's disease (AD) may be more successful if interventions occur early, prior to significant neurodegeneration and subsequent to the onset of clinical symptoms, potentially during middle age. Polymorphisms within BDNF, COMT, and KIBRA have been implicated in AD and relate to episodic memory and executive functioning, two domains that decline early in AD. OBJECTIVE: The purpose of the current study was to use an endophenotype approach to examine in healthy, non-demented middle-aged adults the association between polymorphisms in BDNF, COMT, and KIBRA and functional connectivity within networks related to episodic memory and executive function (i.e., default mode network (DMN), executive control network (ECN), and frontoparietal network (FPN)). METHODS: Resting state networks were identified using independent component analysis and spatial maps with associated time courses were extracted using a dual regression approach. RESULTS: Functional connectivity within the DMN was associated with polymorphisms in BDNF (rs11030096, rs1491850) and KIBRA (rs1030182, rs6555791, rs6555802) (ps < 0.05), ECN connectivity was associated with polymorphisms in KIBRA (rs10475878, rs6555791) (ps < 0.05), and FPN connectivity was associated with KIBRA rs6555791 (p < 0.05). There were no COMT-related differences in functional connectivity of any of the three networks investigated (ps > 0.05). CONCLUSION: Our study demonstrates that in middle age, polymorphisms in BDNF and KIBRA are associated with altered functional connectivity in networks that are affected early in AD. Future preclinical work should consider these polymorphisms to further elucidate their role in pathological aging and to aid in the identification of biomarkers.

Total Cholesterol and APOE-Related Risk for Alzheimer's Disease in the Alzheimer's Disease Neuroimaging Initiative.

BACKGROUND: APOEɛ4 allele confers greatest genetic risk for Alzheimer's disease (AD), yet mechanisms underlying this risk remain elusive. APOE is involved in lipid metabolism, and literature suggest relationships between high total cholesterol, APOE, and AD. Further investigation is needed to elucidate the potential role of total cholesterol in AD risk. OBJECTIVE: To investigate the relationship between total cholesterol and APOE-related AD risk in the Alzheimer's Disease Neuroimaging Initiative. METHODS: Participants (N = 1,534) were classified as controls (cognitively normal; N = 404), early mild cognitive impairment (MCI; N = 294), late MCI (N = 539), or AD (N = 297). Total cholesterol levels were compared across APOE genotype and diagnosis. Mendelian randomization was performed to examine causality between total cholesterol and AD risk using APOE as a genetic instrument. RESULTS: Total cholesterol was higher in APOE4+ compared to APOE3 and APOE2+ (ps < 0.04) carriers. Those with AD and late MCI (ps < 0.001) had higher total cholesterol than the control group. Comparing APOE4+ to APOE3 carriers, the predicted odds ratios per mg/dL greater total cholesterol were 1.11 for MCI (95% confidence interval, 1.04-7.32), 1.05 for early MCI (1.01-3.22), 1.13 for late MCI (1.05-11.70), 1.21 for AD (1.09-54.05), and 1.13 for composite dementia (MCI or AD; 1.06-11.59) (ps < 0.05, F-statistics > 10). CONCLUSION: Higher total cholesterol may be a significant contributor to AD risk, particularly in APOE4 carriers who, based on existing literature, tend to have impaired cholesterol metabolism. Our findings highlight a possible mechanism by which APOE confers AD risk and indicate potential for AD risk modification through maintenance of healthy total cholesterol levels.

Brain-behavior investigation of potential cognitive markers of Alzheimer's disease in middle age: a multi-modal imaging study.

Early detection of Alzheimer's disease remains a challenge, and the development and validation of novel cognitive markers of Alzheimer's disease is critical to earlier disease detection. The goal of the present study is to examine brain-behavior relationships of translational cognitive paradigms dependent on the medial temporal lobes and prefrontal cortices, regions that are first to undergo Alzheimer's-associated changes. We employed multi-modal structural and functional MRI to examine brain-behavior relationships in a healthy, middle-aged sample (N = 133; 40-60 years). Participants completed two medial temporal lobe-dependent tasks (virtual Morris Water Task and Transverse Patterning Discriminations Task), and a prefrontal cortex-dependent task (Reversal Learning Task). No associations were found between various MRI measures of brain integrity and the Transverse Patterning or Reversal Learning tasks (p's > .05). We report associations between virtual Morris Water Task performance and medial temporal lobe volume, hippocampal microstructural organization, fornix integrity, and functional connectivity within the executive control and frontoparietal control resting state networks (all p's < 0.05; did not survive correction for multiple comparisons). This study suggests that virtual Morris Water Task performance is associated with medial temporal lobe integrity in middle age, a critical window for detection and prevention of Alzheimer's disease, and may be useful as an early cognitive marker of Alzheimer's disease risk.

Age-Related Tau Burden and Cognitive Deficits Are Attenuated in KLOTHO KL-VS Heterozygotes.

BACKGROUND: Identification of new genetic variants that modify Alzheimer's disease (AD) risk will elucidate novel targets for curbing the disease progression or delaying symptom onset. OBJECTIVE: To examine whether the functionally advantageous KLOTHO gene KL-VS variant attenuates age-related alteration in cerebrospinal fluid (CSF) biomarkers or cognitive function in middle-aged and older adults enriched for AD risk. METHODS: Sample included non-demented adults (N = 225, mean age = 63±8, 68% women) from the Wisconsin Registry for Alzheimer's Prevention and the Wisconsin Alzheimer's Disease Research Center who were genotyped for KL-VS, underwent CSF sampling and had neuropsychological testing data available proximal to CSF draw. Covariate-adjusted multivariate regression examined relationships between age group (Younger versus Older; mean split at 63 years), AD biomarkers, and neuropsychological performance tapping memory and executive function, and whether these relationships differed between KL-VS non-carriers (KL-VSNC) and heterozygote (KL-VSHET). RESULTS: In the pooled analyses, older age was associated with higher levels of total tau (tTau), phosphorylated tau (pTau), and their respective ratios to amyloid-ß (Aß)42 (ps ≤ 0.002), and with poorer performance on neuropsychological tests (ps ≤ 0.001). In the stratified analyses, KL-VSNC exhibited this age-related pattern of associations with CSF biomarkers (all ps ≤ 0.001), and memory and executive function (ps ≤ 0.003), which were attenuated in KL-VSHET (ps ≥ 0.14). CONCLUSION: Worse memory and executive function, and higher tau burden with age were attenuated in carriers of a functionally advantageous KLOTHO variant. KL-VS heterozygosity seems to be protective against age-related cognitive and biomolecular alterations that confer risk for AD.

Reversal learning in young and middle-age neurotypicals: Individual difference reaction time considerations.

Reversal learning is frequently used to assess components of executive function that contribute to understanding age-related cognitive differences. Reaction time (RT) is less characterized in the reversal learning literature, perhaps due to the daunting task of analyzing the entire RT distribution, but has been deemed a generally sensitive measure of cognitive aging. The current study extends our prior work to further characterize distributional properties of the reversal RT distribution and to distinguish groups of individuals with fractionated profiles of performance, which may be of clinical importance within the context of cognitive aging. Participant sample included young (n = 43) and community-dwelling, healthy, middle-aged (n = 139) adults. To explore individual differences, recursive partitioning analysis achieved a high classification rate by specifying decision tree rules that split participants into young and middle-aged groups. Mu (µ, efficient RT) was the most successful parameter in distinguishing age groups while sigma ( σ) and tau ( τ , ex-Gaussian indices of intra-individual variability) revealed more subtle individual differences. Accuracy measures did not contribute to separating the groups, suggesting that fractionated components of RT, as opposed to accuracy, can distinguish differences between young and middle-aged participants.

Single Nucleotide Polymorphisms in Alzheimer's Disease Risk Genes Are Associated with Intrinsic Connectivity in Middle Age.

BACKGROUND: It is critical to identify individuals at risk for Alzheimer's disease (AD) earlier in the disease time course, such as middle age and preferably well prior to the onset of clinical symptoms, when intervention efforts may be more successful. Genome-wide association and candidate gene studies have identified single nucleotide polymorphisms (SNPs) in APOE, CLU, CR1, PICALM, and SORL1 that confer increased risk of AD. OBJECTIVE: In the current study, we investigated the associations between SNPs in these genes and resting-state functional connectivity within the default mode network (DMN), frontoparietal network (FPN), and executive control network (ECN) in healthy, non-demented middle-aged adults (age 40 -60; N = 123; 74 females). METHODS: Resting state networks of interest were identified through independent components analysis using a template-matching procedure and individual spatial maps and time courses were extracted using dual regression. RESULTS: Within the posterior DMN, functional connectivity was associated with CR1 rs1408077 and CLU rs9331888 polymorphisms (p's < 0.05). FPN connectivity was associated with CR1 rs1408077, CLU rs1136000, SORL1 rs641120, and SORL1 rs689021 (p's < 0.05). Functional connectivity within the ECN was associated with the CLU rs11136000 (p < 0.05). There were no APOE- or PICALM-related differences in any of the networks investigated (p's > 0.05). CONCLUSION: This is the first demonstration of the relationship between intrinsic network connectivity and AD risk alleles in CLU, CR1, and SORL1 in healthy, middle-aged adults. These SNPs should be considered in future investigations aimed at identifying potential preclinical biomarkers for AD.

Connectome Signatures of Hyperexcitation in Cognitively Intact Middle-Aged Female APOE-ε4 Carriers.

Synaptic dysfunction is hypothesized to be one of the earliest brain changes in Alzheimer's disease, leading to "hyperexcitability" in neuronal circuits. In this study, we evaluated a novel hyperexcitation indicator (HI) for each brain region using a hybrid resting-state structural connectome to probe connectome-level excitation-inhibition balance in cognitively intact middle-aged apolipoprotein E (APOE) ε4 carriers with noncarriers (16 male/22 female in each group). Regression with three-way interactions (sex, age, and APOE-ε4 carrier status) to assess the effect of APOE-ε4 on excitation-inhibition balance within each sex and across an age range of 40-60 years yielded a significant shift toward higher HI in female carriers compared with noncarriers (beginning at 50 years). Hyperexcitation was insignificant in the male group. Further, in female carriers the degree of hyperexcitation exhibited significant positive correlation with working memory performance (evaluated via a virtual Morris Water task) in three regions: the left pars triangularis, left hippocampus, and left isthmus of cingulate gyrus. Increased excitation of memory-related circuits may be evidence of compensatory recruitment of neuronal resources for memory-focused activities. In sum, our results are consistent with known Alzheimer's disease sex differences; in that female APOE-ε4 carriers have globally disrupted excitation-inhibition balance that may confer greater vulnerability to disease neuropathology.

A distributional and theoretical analysis of reaction time in the reversal task across adulthood.

Reversal learning assesses components of executive function important for understanding cognitive changes with age. Extant reversal learning literature has largely assessed measures of accuracy, but reaction time (RT) has not yet been well characterized, perhaps due to the daunting task of analyzing non-normal RT distributions. The current study contributes to the literature by examining distributional and theoretical aspects of the entire RT distribution in addition to accuracy. Participant sample included young (N = 43) and community-dwelling, healthy, middle-aged (N = 139) adults. Results showed a Normal-3 Mixture distribution best fits the sample as a whole, with the ex-Gaussian distribution passing visual inspection. Age related significantly to various measures of RT (p's < 0.5); older age was associated with higher both efficient and overall RT, perhaps due to a more conservative criterion of decision-making. In a generalized adaptive elastic net regression, RT explained age-related differences in performance while accuracy did not contribute. Specifically, middle-aged adults were slower in efficient RT and had increased intra-individual variability which has been previously linked to poorer frontal lobe processes and age-related cognitive decline. Overall, these findings highlight the importance of examining the entire RT distribution and measuring RT as a fractionated construct to further explain age-related differences in reversal learning, even in middle-aged individuals.