Understanding Health Beliefs and Health Behaviors in Older Adults at Risk for Alzheimer's Disease.

Background: There are significant public health benefits to delaying the onset of Alzheimer's disease (AD) in individuals at risk. However, adherence to brain healthy behaviors is low. The Health Belief Model proposes that specific beliefs are mediators of behavior change. Objective: To characterize health belief measures from the Science of Behavior Change Research Network (SBCRN) in an older adult population and associations between health beliefs, AD risk, and current health behaviors. Methods: A total of 172 individuals from the Rhode Island AD Prevention Registry participated. SBCRN health belief measures included assessments of future time perspective, self-efficacy, deferment of gratification, and consideration of future consequences. Outcome measures included individual AD risk index score, dementia risk awareness, and lifestyle behaviors including physical, cognitive, and social activity. Results: Participants who were older had higher scores for AD risk, lower future time perspective, and lower generalized self-efficacy (all at p < 0.001). Higher generalized self-efficacy was related to increased physical activity (p < 0.010). Higher future time perspective (p < 0.001) and generalized self-efficacy (p = 0.48) were associated with lower AD risk score. Subjective cognitive decline (SCD) was associated with lower self-efficacy, ability to delay gratification, and a less expansive future time perspective. Conclusions: Greater self-efficacy and perceived future time remaining were associated with lower AD risk and greater engagement in physical activity. SCD was associated with health beliefs that may negatively affect engagement in positive brain health behaviors. Assessment of and psychoeducation about these intrapersonal health belief constructs may be important targets for behavioral interventions to reduce AD risk.

Association between neuropsychological assessment and amyloid status in a clinical setting.

OBJECTIVE: Large research cohorts show robust associations between neuropsychological tests and Alzheimer's disease (AD) biomarkers, but studies in clinical settings are limited. The increasing availability of AD biomarkers to the practicing clinician makes it important to understand the relationship between comprehensive clinical neuropsychological assessment and biomarker status. This study examined concordance between practicing clinical neuropsychologists' diagnostic impressions and AD biomarker status in patients seen at an outpatient medical center, with a secondary aim of defining the characteristics of discordant cases. METHOD: Participants (N = 79) seen for clinical neuropsychological assessment who subsequently underwent lumbar puncture or amyloid positron emission tomography imaging were identified via retrospective chart review. Concordance between clinical neuropsychological diagnosis (non-AD, indeterminate, possible/probable AD) and AD biomarker status (negative, indeterminate, positive) was determined. Individual test score data were used to examine between-group differences based on amyloid status. RESULTS: AD biomarker positive and negative patients did not differ on individual neuropsychological tests after correcting for multiple comparisons, though the small number of AD biomarker indeterminate individuals performed better than biomarker positive patients. However, there was 76.7% concordance between neuropsychologists' diagnostic impressions and AD biomarker status (88% sensitivity and 55% specificity of neuropsychological assessment in detecting AD biomarker status). AD biomarker negative patients diagnosed as possible/probable AD (discordant) versus non-AD (concordant) had significantly lower Neuropsychological Assessment Battery Story Delayed Recall, higher Wechsler Adult Intelligence Scale-Fourth Edition Coding, and higher Trail-Making A (i.e., an amnestic memory profile). CONCLUSIONS: Comprehensive neuropsychological assessment showed modest concordance with AD biomarker status in patients seen in an outpatient medical center for routine clinical care. Low specificity for the clinical diagnosis of AD could be explained by the multiplicity of etiologies that cause memory impairment (i.e., TAR DNA-binding protein 43, suspected non-AD pathology). (PsycInfo Database Record (c) 2024 APA, all rights reserved).

Elevated Amyloid-ß PET Scan and Cognitive and Functional Decline in Mild Cognitive Impairment and Dementia of Uncertain Etiology.

BACKGROUND: Elevated amyloid-ß (Aß) on positron emission tomography (PET) scan is used to aid diagnosis of Alzheimer's disease (AD), but many prior studies have focused on patients with a typical AD phenotype such as amnestic mild cognitive impairment (MCI). Little is known about whether elevated Aß on PET scan predicts rate of cognitive and functional decline among those with MCI or dementia that is clinically less typical of early AD, thus leading to etiologic uncertainty. OBJECTIVE: We aimed to investigate whether elevated Aß on PET scan predicts cognitive and functional decline over an 18-month period in those with MCI or dementia of uncertain etiology. METHODS: In 1,028 individuals with MCI or dementia of uncertain etiology, we evaluated the association between elevated Aß on PET scan and change on a telephone cognitive status measure administered to the participant and change in everyday function as reported by their care partner. RESULTS: Individuals with either MCI or dementia and elevated Aß (66.6% of the sample) showed greater cognitive decline compared to those without elevated Aß on PET scan, whose cognition was relatively stable over 18 months. Those with either MCI or dementia and elevated Aß were also reported to have greater functional decline compared to those without elevated Aß, even though the latter group showed significant care partner-reported functional decline over time. CONCLUSIONS: Elevated Aß on PET scan can be helpful in predicting rates of both cognitive and functional decline, even among cognitively impaired individuals with atypical presentations of AD.

Effects of aging on externally cued and internally driven uncertainty representations.

OBJECTIVE: The Hick-Hyman law states that response time (RT) increases linearly with increasing information uncertainty. The effects of aging on uncertainty representations in choice RT paradigms remain unclear, including whether aging differentially affects processes mediating externally cued versus internally driven uncertainty. This study sought to characterize age-related differences in uncertainty representations using a card-sorting task. METHOD: The task separately manipulated internally driven uncertainty (i.e., probability of each stimulus type with fixed number of response piles) and externally cued uncertainty (i.e., number of response piles with fixed probability of each stimulus type). RESULTS: Older adults (OA) showed greater RT slowing than younger adults in response to uncertainty load, an effect that was stronger in the externally cued than internally driven condition. While both age groups showed lower accuracy and greater RTs in response to unexpected (surprising) stimuli in the internally driven condition at low uncertainty loads, OA were unable to distinguish between expected and nonexpected stimuli at higher uncertainty loads when the probability of each stimulus type was close to equal. Among OA, better performance on the internally driven, but not externally cued, condition was associated with better global cognitive performance and verbal fluency. CONCLUSIONS: Collectively, these findings provide behavioral evidence of age-related disruptions to bottom-up (externally cued) and top-down (supporting internally driven mental representations) resources to process uncertainty and coordinate task-relevant action. (PsycInfo Database Record (c) 2024 APA, all rights reserved).

The Drosophila drop-dead gene is required for eggshell integrity.

The eggshell of the fruit fly Drosophila melanogaster is a useful model for understanding the synthesis of a complex extracellular matrix. The eggshell is synthesized during mid-to-late oogenesis by the somatic follicle cells that surround the developing oocyte. We previously reported that female flies mutant for the gene drop-dead (drd) are sterile, but the underlying cause of the sterility remained unknown. In this study, we examined the role of drd in eggshell synthesis. We show that eggs laid by drd mutant females are fertilized but arrest early in embryogenesis, and that the innermost layer of the eggshell, the vitelline membrane, is abnormally permeable to dye in these eggs. In addition, the major vitelline membrane proteins fail to become crosslinked by nonreducible bonds, a process that normally occurs during egg activation following ovulation, as evidenced by their solubility and detection by Western blot in laid eggs. In contrast, the Cp36 protein, which is found in the outer chorion layers of the eggshell, becomes crosslinked normally. To link the drd expression pattern with these phenotypes, we show that drd is expressed in the ovarian follicle cells beginning in mid-oogenesis, and, importantly, that all drd mutant eggshell phenotypes could be recapitulated by selective knockdown of drd expression in the follicle cells. To determine whether drd expression was required for the crosslinking itself, we performed in vitro activation and crosslinking experiments. The vitelline membranes of control egg chambers could become crosslinked either by incubation in hyperosmotic medium, which activates the egg chambers, or by exogenous peroxidase and hydrogen peroxide. In contrast, neither treatment resulted in the crosslinking of the vitelline membrane in drd mutant egg chambers. These results indicate that drd expression in the follicle cells is necessary for vitelline membrane proteins to serve as substrates for peroxidase-mediated cross-linking at the end of oogenesis.

The Drosophila drop-dead gene is required for eggshell integrity.

The eggshell of the fruit fly Drosophila melanogaster is a useful model for understanding the synthesis of a complex extracellular matrix. The eggshell is synthesized during mid-to-late oogenesis by the somatic follicle cells that surround the developing oocyte. We previously reported that female flies mutant for the gene drop-dead ( drd ) are sterile, but the underlying cause of the sterility remained unknown. In this study, we examined the role of drd in eggshell synthesis. We show that eggs laid by drd mutant females are fertilized but arrest early in embryogenesis, and that the innermost layer of the eggshell, the vitelline membrane, is abnormally permeable to dye in these eggs. In addition, the major vitelline membrane proteins fail to become crosslinked by nonreducible bonds, a process that normally occurs during egg activation following ovulation, as evidenced by their solubility and detection by Western blot in laid eggs. In contrast, the Cp36 protein, which is found in the outer chorion layers of the eggshell, becomes crosslinked normally. To link the drd expression pattern with these phenotypes, we show that drd is expressed in the ovarian follicle cells beginning in mid-oogenesis, and, importantly, that all drd mutant eggshell phenotypes could be recapitulated by selective knockdown of drd expression in the follicle cells. To determine whether drd expression was required for the crosslinking itself, we performed in vitro activation and crosslinking experiments. The vitelline membranes of control egg chambers could become crosslinked either by incubation in hyperosmotic medium, which activates the egg chambers, or by exogenous peroxidase and hydrogen peroxide. In contrast, neither treatment resulted in the crosslinking of the vitelline membrane in drd mutant egg chambers. These results indicate that drd expression in the follicle cells is necessary for vitelline membrane proteins to serve as substrates for peroxidase-mediated cross-linking at the end of oogenesis.

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.

No association between APOE genotype and lipid lowering with cognitive function in a randomized controlled trial of evolocumab.

APOE encodes a cholesterol transporter, and the ε4 allele is associated with higher circulating cholesterol levels, ß-amyloid burden, and risk of Alzheimer's disease. Prior studies demonstrated no significant differences in objective or subjective cognitive function for patients receiving the PCSK9 inhibitor evolocumab vs. placebo added to statin therapy. There is some evidence that cholesterol-lowering medications may confer greater cognitive benefits in APOE ε4 carriers. Thus, the purpose of this study was to determine whether APOE genotype moderates the relationships between evolocumab use and cognitive function. APOE-genotyped patients (N = 13,481; 28% ε4 carriers) from FOURIER, a randomized, placebo-controlled trial of evolocumab added to statin therapy in patients with stable atherosclerotic cardiovascular disease followed for a median of 2.2 years, completed the Everyday Cognition Scale (ECog) to self-report cognitive changes from the end of the trial compared to its beginning; a subset (N = 835) underwent objective cognitive testing using the Cambridge Neuropsychological Test Automated Battery as part of the EBBINGHAUS trial. There was a dose-dependent relationship between APOE ε4 genotype and patient-reported memory decline on the ECog in the placebo arm (p = .003 for trend across genotypes; ε4/ε4 carriers vs. non-carriers: OR = 1.46, 95% CI [1.03, 2.08]) but not in the evolocumab arm (p = .50, OR = 1.18, 95% CI [.83,1.66]). However, the genotype by treatment interaction was not significant (p = .30). In the subset of participants who underwent objective cognitive testing with the CANTAB, APOE genotype did not significantly modify the relationship between treatment arm and CANTAB performance after adjustment for demographic and medical covariates, (p's>.05). Although analyses were limited by the low population frequency of the ε4/ε4 genotype, this supports the cognitive safety of evolocumab among ε4 carriers, guiding future research on possible benefits of cholesterol-lowering medications in people at genetic risk for Alzheimer's disease.

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.

Pilot study of an Alzheimer's disease risk assessment program in a primary care setting.

INTRODUCTION: The goal of this study was to pilot a referral-based cognitive screening and genetic testing program for Alzheimer's disease (AD) risk assessment in a primary care setting. METHODS: Primary care providers (PCPs; N = 6) referred patients (N = 94; M = 63 years) to the Rhode Island Alzheimer's Disease Prevention Registry for apolipoprotein E (APOE) genotyping and cognitive screening. PCPs disclosed test results to patients and counseled them about risk factor modification. RESULTS: Compared to the Registry as a whole, participants were younger, more likely to be non-White, and had lower cognitive screening scores. Mild cognitive impairment participants correctly reported a higher perceived risk of developing AD. Patients who recalled being counseled about modifiable risk factors were more likely to report positive health behavior changes. DISCUSSION: A referral-based program for cognitive and genetic AD risk assessment in a primary care setting is feasible, acceptable to patients, and yielded a more demographically diverse sample than an AD prevention registry.

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.

Impaired integration of object feature knowledge in amnestic mild cognitive impairment.

OBJECTIVE: Accessing semantic representations of real-world objects requires integration of multimodal perceptual features that are represented across relevant neocortical areas. Early Alzheimer's disease (AD) neuropathology, including neurofibrillary tangles in the perirhinal cortex as well as disrupted cortico-cortical connectivity, would be expected to disrupt the integration of object features. This integration deficit may underlie AD patients' semantic memory deficits and would be predicted to be more prominent for living objects, which tend to be more defined by sensory features compared with nonliving objects. METHOD: Two experiments were conducted to assess feature integration in cognitively healthy older adults and patients with amnestic mild cognitive impairment (MCI). In both experiments, pictures of real-world objects were presented in congruent or incongruent colors. Participants were instructed to make a speeded color congruency judgment (Experiment 1) or name the presented surface color (Experiment 2). RESULTS: Across experiments, MCI patients showed a selective integration deficit for living, but not nonliving, objects across both experimental paradigms that was consistent with a deterioration in semantic structural representations rather than a deficit in controlled semantic retrieval. Planned secondary analyses with a subset of patients (Experiment 1) for whom PET imaging was available indicated that the degree of impairment was associated with the magnitude of cortical amyloid burden. CONCLUSIONS: These findings suggest that early AD pathology leads to impaired integration of distributed semantic object representations. The development of integration tasks as sensitive markers of early AD pathology may lead to more effective diagnostic tools for early detection and intervention. (PsycInfo Database Record (c) 2020 APA, all rights reserved).

Alzheimer's disease and the processing of uncertainty during choice task performance: Executive dysfunction within the Hick-Hyman law.

The Hick-Hyman law states that choice response time (RT) increases linearly with increasing information uncertainty. Neuroimaging studies suggest that the representation of uncertainty in support of response generation is mediated by the cognitive control network (CCN), which is disrupted in Alzheimer's disease (AD). Thus, we predicted that patients with AD would be sensitive to increased uncertainty particularly under conditions that place demands on the internal representation of uncertainty, and that choice RT performance under these conditions would be associated with performance on tests of executive function. Cognitively normal older adults (CN) and patients with AD completed card-sorting tasks that separately manipulated either externally cued uncertainty (i.e., number of sorting piles with a fixed probability of each stimulus type) or more internally driven uncertainty (i.e., the probability of each stimulus type with a fixed number of sorting piles). Consistent with our predictions, AD patients were impaired relative to CN particularly on the internally driven uncertainty task, and RT in this task was associated with performance on neuropsychological measures of executive functioning but not episodic memory. We suggest that this pattern of findings is consistent with presumed disruptions to the CCN in AD and provides neuropsychological evidence in support of the role of the CCN in the representation of uncertainty.

Genetic Risk for Age-Related Cognitive Impairment Does Not Predict Cognitive Performance in Middle Age.

Alzheimer's disease (AD) is characterized by memory loss and executive dysfunction, which correspond to structural changes to the medial temporal lobes (MTL) and prefrontal cortex (PFC), respectively. Given the overlap in cognitive deficits between healthy aging and the earliest stages of AD, early detection of AD remains a challenge. The goal of the present study was to study MTL- and PFC-dependent cognitive functioning in middle-aged individuals at genetic risk for AD or cognitive impairment who do not currently manifest any clinical symptoms. Participants (N = 150; aged 40-60 years) underwent genotyping of 47 single nucleotide polymorphisms (SNPs) in six genes previously associated with memory or executive functioning: APOE, SORL1, BDNF, TOMM40, KIBRA, and COMT. They completed two MTL-dependent tasks, the virtual Morris Water Task (vMWT) and transverse patterning discriminations task (TPDT), and the PFC-dependent reversal learning task. Although age was associated with poorer performance on the vMWT and TPDT within this middle-aged sample, there were no genotype-associated differences in cognitive performance. Although the vMWT and TPDT may be sensitive to age-related changes in cognition, carriers of APOE, SORL1, BDNF, TOMM40, KIBRA, and COMT risk alleles do not exhibit alteration in MTL- and PFC-dependent functioning in middle age compared to non-carriers.

Negative Affect Is Associated With Higher Risk of Incident Cognitive Impairment in Nondepressed Postmenopausal Women.

Background: Positive affect (PA) and negative affect (NA) reflect subjective emotional experiences. Although related to depression and anxiety, these dimensions are distinct constructs representing affective states and patterns. Prior studies suggest that elevated depressive symptoms are associated with risk of mild cognitive impairment (MCI) and probable dementia, but whether affective states are associated with cognitive impairment is still unknown. The present study examined relationships between baseline affective states and cognitive impairment (MCI, probable dementia) in nondepressed women. Method: Baseline PA and NA were assessed in postmenopausal women (N = 2,137; mean age = 73.8 years) from the Women's Health Initiative Study of Cognitive Aging (WHISCA) using the Positive and Negative Affect Schedule (PANAS). Women were followed annually for an average of 11.3 years; those with elevated depressive symptoms at baseline were excluded. Results: Higher NA was associated with a higher risk of MCI and probable dementia, even after adjusting for important covariates including age, education, sociodemographic, lifestyle, and cardiovascular risk factors, global cognition, and hormone therapy assignment at baseline. PA was not significantly associated with either outcome. Conclusions: We present the first evidence to date that greater NA, even in the absence of elevated depressive symptoms, is associated with higher risk of MCI and dementia. This suggests that NA may be an important, measureable and potentially modifiable risk factor for age-related cognitive decline.

Correlates of virtual navigation performance in older adults.

Despite considerable evidence for deleterious effects of aging on place learning and memory, less is known about the trajectory and the putative neural mechanisms of these decrements. The virtual Morris water task (vMWT) is a human analog of a nonhuman spatial navigation task. The present study investigated longitudinal changes in place learning in 51 healthy, nondemented adults (age 30-83 years) who completed the vMWT and a neuropsychological battery at 2 time-points (interval = ∼8 years). We also assessed cross-sectional associations between vMWT and brain structure, biochemical integrity, and standardized neuropsychological measures in a subset of 22 individuals who underwent magnetic resonance imaging at follow-up. Despite no longitudinal decrement in vMWT performance, there were cross-sectional age differences on the vMWT favoring younger adults. Negative associations were observed between vMWT latency and gray matter volumes in the right hippocampus, bilateral thalamus, and right medial orbitofrontal cortex and between vMWT latency and white matter fractional anisotropy in the bilateral uncinate fasciculus. Collectively, these results suggest a pattern of differences in the structural integrity of regions supporting successful navigation even in the absence of longitudinal performance decrements.