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Objective: Ankle-brachial index (ABI) and interartery systolic blood pressure differences, as markers of vascular disease, are plausible risk factors for deficits in cognitive function among overweight and obese adults with type 2 diabetes.Methods: The ABI and maximum interartery differences (MIAD) in systolic blood pressures were assessed annually for five years among 479 participants assigned to the control condition in a randomized clinical trial of a behavioral weight loss intervention. A battery of standardized cognitive function tests was administered 4 to 5 years later. Analyses of covariance were used to assess relationships that ABI, MIAD, and progression of ABI and MIAD had with cognitive function.Results: There was a curvilinear relationship between ABI and a composite index of cognitive function (p = 0.03), with lower ABI being associated with poorer function. In graded fashions, both greater MIAD and increases in MIAD over time also had modest relationships with poorer verbal memory (both p ≤ 0.05), processing speed (both p ≤ 0.05), and composite cognitive function (both p < 0.04). These relationships were independent of each other and remained evident after extensive covariate adjustment.Conclusions: In overweight and obese adults with type 2 diabetes, lower ABI and larger interartery systolic blood pressure differences have modest, independent, graded relationships with poorer cognitive function 4-5 years later. [ABSTRACT FROM AUTHOR]

Background: Subjective cognitive decline (SCD) is associated with objective cognitive decline, incident cognitive impairment, and AD pathology in mostly white populations. Little data are available to describe SCD and objective cognitive impairment in diverse populations. Method: The Multi‐Ethnic Study of Atherosclerosis (MESA) began cognitive testing, including the Cognitive Abilities Screening Instrument (CASI), in 2010‐12 among four racial/ethnic groups: 38% white, 28% African‐American, 22% Hispanic, and 12% Chinese Americans across six field centers. MESA‐MIND and ancillary studies added repeated CASI by in‐person exam (2016‐2018) and the 12‐item Cognitive Change Index (CCI‐12) during the 2018 annual follow‐up call. Statistical analyses using the CCI‐12 item sum and two published thresholds (CCI‐12≥16 and CCI‐12≥23) established the point prevalence for SCD across racial/ethnic groups. Socio‐demographic factors were examined using multivariable logistic regression. Spearman correlations and general linear models related 5‐year subjective change (CCI‐12) and objective change in cognitive performance (change in CASI) over the same time period. Result: CCI‐12 data were available on 3,676 MESA participants (aged 60‐95) across all racial/ethnic groups and sites. Table 1 presents demographics, CCI‐12 scores, and CASI scores. The prevalence of SCD (CCI‐12≥16) across racial/ethnic groups ranged between 52% to 72%. There was a lower prevalence in African‐American and white and a higher prevalence in Chinese and Hispanic participants. In adjusted models, various socio‐demographic factors were significantly associated with a higher odds of reporting SCD (CCI‐12≥16), including: older age, female gender, Chinese language preference, diabetes, smoking, birth in the Western US or Mexico, and lacking health insurance coverage. African‐American ethnicity, higher education, and income greater than $75,000 were each associated with a lower reporting of SCD. CCI‐12 was weakly and inversely correlated with antecedent cognitive performance (2010‐12, n=3,200, Rho=‐0.16, p<0.01) and cognitive decline (n=1,800, Rho=‐0.06, p=0.01) over 6 years of follow‐up. In stratified analyses, associations between CCI‐12 and objective cognitive decline were observed in white participants only. Conclusion: In a large regionally and ethnically diverse cohort of older adults, SCD defined by subjective memory concerns on the CCI‐12 significantly differed by race/ethnicity and indicators of socioeconomic status, suggesting that cultural and institutional biases may influence reporting SCD in diverse populations. [ABSTRACT FROM AUTHOR]

Background: The highly encouraging findings from the Finnish Geriatric Intervention Study (known as FINGER) led to the global initiative for dementia risk reduction known as world‐wide FINGERS (WW FINGERS). As part of the collaboration, our Australian AU‐ARROW trial will follow the general protocol of the FINGER trial, and will also be aligned with the U.S. arm of the study, US‐POINTER, though will have minor cultural and dietary modifications to determine the validity of the intervention in an Australian setting. Method: AU‐ARROW is a randomised, single‐blind 2‐year clinical trial that will recruit 600 participants aged 60‐79 satisfying specific inclusion/exclusion criteria, including normal cognition and one or more cardiovascular risk factors that place them at greater risk of cognitive decline. Participants will be distributed across two sites (a) Macquarie University Health Clinics, Sydney, NSW and (b) Sarich Neuroscience Research Institute, Edith Cowan University, Perth, WA, and will be randomised equally into either the innovative multi‐modal intervention group or the study control group, who will receive general lifestyle advice and annual health check‐ups, without treatment. Multi‐modal intervention consists of aerobic exercise, resistance training and stretching; dietary advice with monitoring to encourage adherence to the MIND diet; cognitive training sessions via the Brain HQ computerised online training system; and medical monitoring and regular health education sessions. Heart rate trackers, diet and exercise log books, and the monitoring of Brain HQ sessions will all help with adherence. Primary outcome measure is improvement in global cognitive score, measured using neurocognitive tests identical to those in the US‐POINTER protocol. Additional neurocognitive tests, physical function improvements, detailed diet monitoring and sleep monitoring will provide added data. The unique extra value of AU‐ARROW trial consists of the testing for Alzheimer's disease (AD) blood biomarkers in all participants; as well as the AD Aβ amyloid‐specific ligand‐PET imaging, brain MRI and retinal biomarker tests that half of the participants will undergo. These tests will provide comprehensive data which have the ultimate purpose of increasing knowledge of the preclinical stages of AD, and help not only to develop preclinical AD diagnostic tests but also efficacy of AU‐ARROW's intervention. [ABSTRACT FROM AUTHOR]

Background: U.S. POINTER aims to test whether a multidomain lifestyle intervention focused on physical and cognitive activity, nutrition, and risk factor management reduces risk of cognitive decline in a heterogeneous population of older adults in the U.S. The study adapts the FINGER (Finnish Intervention Geriatric Study to Prevent Cognitive Impairment and Disability) interventions to fit American culture and works with community partners at 5 sites across the country to develop sustainable community‐based intervention programs. Methods: U.S. POINTER is a 2‐year RCT that is enrolling 2000 cognitively normal older adults (60‐79 years) who are at risk for decline due sedentary lifestyle, poor diet and other factors such as family history of memory impairment and suboptimum cardiovascular health. Recruitment utilizes electronic health records, as well as grassroots approaches to engage traditionally underrepresented groups. Participants are randomized to one of two lifestyle intervention groups – Self‐Guided or Structured Lifestyle Intervention – that differ in format, intensity and accountability. U.S. POINTER includes partnerships with local chapters of the Alzheimer's Association and lifestyle specialists to assist with intervention delivery. The primary outcome is 2‐year change in cognitive function measured with a composite score that permits harmonization with FINGER. Results: Recruitment began in 2019 at the vanguard site in North Carolina. Study progress at all 5 participating sites will be presented. Progress toward harmonization with FINGER and other international study teams in the WW‐FINGERS network will also be discussed. Conclusion: As a member of the WW‐FINGERS network of trials, U.S. POINTER provides an unprecedented opportunity to leverage lessons learned in FINGER and expand this work to test the generalizability of the findings to a heterogeneous American cohort with different cultural needs and practices. The results, in combination with those from other WW‐FINGERS studies, have the potential to identify a strategy to slow cognitive decline on a global scale. [ABSTRACT FROM AUTHOR]

Background: Increasingly, vascular diseases are implicated in risk for Alzheimer's disease and related dementias. Heart failure (HF) with preserved ejection fraction (HFpEF) is the most common form of HF in the U.S and most commonly affects older women with overweight/obesity. Given known systemic microvascular effects of HFpEF, dementia risk may be a potential unrecognized downstream effect of the disease. Method: Harmonized cognitive testing and brain MRI protocols were employed in Wake Forest's Alzheimer's Disease Research Center's Clinical Core and the SECRET‐2 clinical trial of HFpEF. Cognitive tests included components of NACC's Uniform Data Set version 3. Brain imaging protocols included structural MRI and cerebral blood flow images. Statistical comparisons of cognitive and imaging data by cognitive/group status were done using multivariable general linear models adjusting for basic covariates including age, race, and sex in basic models and additional adjustments for intracranial volume (for MRI) and education (for cognitive test scores) in fully adjusted models using SAS 9.4. Result: The analysis includes a comparison of 89 participants recruited into the Wake Forest ADRC (adjudicated as cognitively normal, n=43; MCI, n=22; and dementia, n=5) and SECTRET‐2 intervention trail in HFpEF (n=19) patients. Compared to cognitively normal participants, patients with HFpEF were significantly more likely to be Black (47% vs 2%, p<0.01), have a higher body mass index (38.2 vs. 28.0, p<0.01), and a diagnosis of hypertension (84% vs 26%). Patients with HFpEF had poorer global cognitive performance [MoCA score, beta(SE)=‐1.76(0.77), p=0.02)], but no differences in Craft Story delayed recall in models adjusted for age, gender, race and education. HFpEF was also significantly associated with smaller gray matter volume [beta(SE)=‐20.7(11.6), p=<0.01)] at levels worse than MCI and dementia in models adjusted for age, gender, race and ICV. No initial differences were observed in resting cerebral blood flow or evoked cerebrovascular response due to hypercapnia. Conclusion: HFpEF participants showed deficits in global cognitive function that were comparable to those with MCI, as well as global decreases in brain volume. Additional follow‐up of these participants with HFpEF will more deeply phenotype cognitive impairments by domain and adjudication criteria used for MCI and dementia. [ABSTRACT FROM AUTHOR]

Background: EXERT is a large multi‐site randomized controlled trial testing the effects of aerobic exercise vs. stretching (control) on cognition and biomarkers of brain health in sedentary adults with MCI. Here, we describe challenges and successes of strategies used to recruit the EXERT cohort. Method: EXERT recruited sedentary adults 65‐89 years old who were willing to exercise 4 days/week at the YMCA with trainer supervision for 12 months, and unsupervised for an additional 6 months. The trial is conducted at 14 clinical sites that include 30 corresponding YMCAs. The ADCS serves as the Coordinating Center, and intervention oversight is provided by Wake Forest School of Medicine in partnership with the YMCA. Result: EXERT recruitment occurred over 43 months and several strategies were deployed to address recruitment challenges. The most notable challenge was that EXERT aimed to recruit adults with a cognitive impairment that is mentally/physically taxing given the expectations of an intensive exercise intervention study. For these individuals, transportation to the YMCA was also often a barrier to participation. Early recruitment methods relied on memory clinic patient rosters and electronic health records, which yielded only a few enrollments. Use of other common strategies (e.g., newspaper advertising) was only minimally successful in identifying candidates. Recruitment gained momentum only after geotargeted mailings of pictorial postcards and brochures were initiated. After the first mailing at 3 sites, the rate of in‐person screenings increased by more than 100% (Figure 1). In total, 500,000 geotargeted mailings across all sites were sent from which more than 50% of all randomized participants were recruited. Recruitment also benefited from high‐profile media coverage (Maria Shriver video, NPR) in 2018 and 2019. Early in 2019, the ADCS established centralized telephone prescreening to reduce burden on site staff. A total of 692 mailing responders were prescreened by the ADCS, of whom 228 were referred to sites. As of January 2020, 984 study candidates completed in‐person screening and 278 participants were enrolled into EXERT. Conclusion: Age and geotargeted mass mailings combined with centralized telephone prescreening and national media campaigns proved to be effective strategies for enrolling people with MCI in a long‐term exercise trial. [ABSTRACT FROM AUTHOR]

Background: Non‐pharmacological approaches that target modifiable risks through lifestyle interventions provide the most promising evidence to delay disease. In older adults, chronic sleep disturbances marked by sleep‐disordered breathing (SDB) and sleep fragmentation are associated with impaired hippocampal functioning, increased beta‐amyloid burden, and greater Alzheimer's risk. These and other sleep abnormalities are associated with reduced vascular health. Although some evidence suggests that diet, exercise, and cardiovascular risk reduction can improve sleep and improved sleep benefits cognition in older adults, these effects have not been confirmed in a rigorous clinical trial. Methods: The U.S. study to PrOtect brain health through lifestyle INTErvention to Reduce risk (U.S. POINTER), funded by the Alzheimer's Association, was launched in the Fall of 2018. It is investigating whether lifestyle interventions ‐ Self‐Guided (SG) versus a Structured (STR) lifestyle intervention ‐ influence cognitive trajectories over 2 years in 2000 older cognitively normal adults (aged 60‐79 yrs) who are at increased risk for cognitive decline, Alzheimer's disease and other dementias. The NIH‐funded POINTER‐zzz ancillary study adds in‐home objective sleep assessments for 700 participants to examine the effects of lifestyle modification and cardiovascular risk management on sleep disturbances that are linked to cognitive decline and Alzheimer's disease and that may improve with U.S. POINTER interventions. Results: POINTER‐zzz methods and study design will be presented, which will permit over 2000 objective sleep assessments to be completed over 2 years. These assessments will provide extensive oximetry and actigraphy data for analysis by lifestyle intervention group assignment. Sleep data will be examined relative to intervention effects on cognition and other parent trial and ancillary study outcomes, including MRI and amyloid/tau PET brain imaging. POINTER‐zzz leverages resources provided by the parent trial and other funded ancillary studies, and by well‐established collaborations with sleep experts. Conclusions: POINTER‐zzz provides an unparalleled opportunity to test the effects of a multi‐domain lifestyle intervention on sleep abnormalities that are linked to cognitive decline and Alzheimer's in a well‐characterized, diverse cohort of at‐risk older adults. The study may identify an effective strategy for improving sleep that could have important consequences for reduced risk of Alzheimer's disease and related dementias. [ABSTRACT FROM AUTHOR]

Background: Identification of factors that help preserve cognitive function in late life could facilitate interventions that can improve the lives of millions of people as they age. However, the large number of potential factors associated with cognitive resiliency pose an analytical challenge. Machine learning can be used to discover complex functional relationships in high dimensional data. We used data from the Women's Health Initiative Memory Study (WHIMS) and Random Forests (RF) methods to investigate predictors of cognitive resiliency in 80+ year old women from a set of demographic, biological, behavioral, social, and psychological variables. Method: We included WHIMS women who were at least 80 years old as of 01/01/18, and had at least one cognitive assessment following their 80th birthday. We created two groups of participants: a cognitively resilient group and an impaired group of participants. The cognitively resilient group (N=205) included participants: (a) not previously adjudicated to have mild cognitive impairment (MCI) or probable dementia; (b) had a score >39 on the most recent administration of the TICSm and (c) the average of scores in previous visits>=39. The cognitively impaired group (N=176) included participants: (a) adjudicated with probable dementia within the first 14 years of follow‐up or; (b) who had at least two classifications of MCI within the first 14 years of follow‐up and (c) whose last TICS score was<31. RF classification was used to identify discriminative predictors of these two groups based on 67 baseline variables available in WHIMS. Analyses used the randomForestSRC R library. The minimal depth index (MDI) was used to determine predictors' relevance. Result: Discrimination between the resilient and impaired groups based on area under the curve was 0.80(95% CI‐0.76‐0.85). Figure 1 shows that according to the MDI values the most relevant predictors were age, self‐reported forgetfulness, physical function, optimism, hemoglobin, glucose, sleep disturbances, education, systolic pressure and depression. Conclusion: We investigated discrimination of cognitively resilient older women from women who develop cognitive impairment using machine learning applied to a large set of predictors. The potential contributors to cognitive resilience include demographic, psychological, physical, metabolic and vascular factors suggesting multiple influences contributing to cognitive resiliency. [ABSTRACT FROM AUTHOR]

Background: Recent studies suggest that lifestyle changes (physical exercise, Mediterranean diet adherence, cognitive stimulation, vascular risk management) may protect against cognitive decline and reduce AD pathophysiology. The U.S. Study to Protect Brain Health Through Lifestyle Intervention to Reduce Risk (U.S. POINTER) is a 2‐year randomized controlled trial to evaluate whether lifestyle interventions can protect cognitive function in older adults (60‐79 years) who are at increased risk for cognitive impairment and dementia. The POINTER Imaging ancillary study will assess effects of the POINTER lifestyle interventions on neuroimaging biomarkers of AD and cerebrovascular pathophysiology, and whether baseline neuroimaging measures predict cognitive responses to the interventions. Method: The POINTER Imaging ancillary study aims to enroll 1250 participants from the five U.S. POINTER sites. Ancillary study participants will undergo PET imaging (Baseline, Month 24) to measure Aβ ([18F]Florbetaben) and tau ([18F]MK‐6240) burden, and MRI (Baseline, Months 12 & 24) to measure brain morphometry, white matter (WM) hyperintensities and microstructure, and cerebral blood flow. U.S. POINTER provides standardized cognitive, clinical, genetic (e.g. APOE), and lifestyle activity assessments, and demographics for integration with neuroimaging data. Result: The study design and methods for the POINTER Imaging ancillary study will be presented. The study will examine whether: (1) neuroimaging biomarkers at baseline (Aβ, tau, hippocampal volume, WM hyperintensities) predict intervention‐related cognitive changes and (2) biomarker outcomes are differentially modified by participation in lifestyle interventions. It will also examine changes in exploratory biomarkers (tensor‐based morphometry, microstructural integrity, microbleeds, cerebral blood flow). Conclusion: The POINTER Imaging study aims to address gaps in our understanding of how a variety of lifestyle practices (diet, exercise, cognitive stimulation and vascular risk management) influence brain health. In particular, the study will determine whether imaging measurements of AD and cerebrovascular pathophysiology are amenable to improvement with the POINTER lifestyle interventions. It also aims to determine pathological profiles of individuals who benefit most from such interventions. [ABSTRACT FROM AUTHOR]

The recognition of Alzheimer's disease (AD) as a heterogeneous disorder that results from incremental pathological changes in dynamic organismic systems is essential to move beyond the unidimensional approaches to prevention and therapy that have proven largely ineffective to date. Biological systems related to insulin metabolism are arguably the most critical regulators of longevity and corporeal aging. Our work has focused on identifying the relationship of the insulin network to brain aging, and determining the mechanisms through which insulin dysregulation promotes AD pathological processes. Candidate mechanisms include the effects of insulin on amyloid-β, cerebral glucose metabolism, vascular function, lipid metabolism, and inflammation/oxidative stress. It is likely that different nodes of the insulin network are perturbed for subgroups of AD patients, or that for some subgroups, pathways independent of insulin are critical pathogenetic factors. New methods from systems network analyses may help to identify these subgroups, which will be critical for devising tailored prevention and treatment strategies. In the following review, we will provide a brief description of the role of insulin in normal brain function, and then focus more closely on recent evidence regarding the mechanisms through which disruption of that role may promote AD pathological processes. Finally, we will discuss the implications of this area for AD therapeutics and prevention. [ABSTRACT FROM AUTHOR]

The present study examined the relationships among statin use, APOE genotype, and insulin resistance as measured by the homeostasis model assessment of insulin resistance (HOMA-IR) in healthy older adults. APOE ℇ4- (i.e., not having an ℇ4 allele) statin users had higher HOMA-IR values compared with ℇ4+/statin users (p=0.0169), and with non-users who were ℇ4- (p=0.0003) or ℇ4+ (p=0.0006). These results suggest that statin use may modulate insulin levels for individuals without an APOE ℇ4 allele. [ABSTRACT FROM AUTHOR]

Background: Sleep disturbances are common in individuals with Mild Cognitive Impairment (MCI); and sleep disturbances increase the risk of Alzheimer's disease (AD). Lower ratings of quality of life (QoL) are also found in MCI. We examined the association between sleep disturbances and QoL ratings among participants with MCI. Methods: Baseline in‐home sleep assessments using the WatchPAT (Itamar Medical) and the QoL in AD questionnaire were collected from amnestic MCI (aMCI) participants from the diet intervention trial, Brain Energy for Amyloid Transformation in Alzheimer's Disease (BEAT‐AD) at the Wake Forest ADRC. The WatchPAT assessed sleep time, efficiency, and sleep‐related hypoxemia measures including the apnea‐hypopnea index (AHI), oxygen desaturation index (ODI) and respiratory disturbance index (RDI), where higher values indicate greater disturbances in sleep. The QoL in AD scale ranged from 13–52 with lower scores indicating poorer QoL ratings. We assessed the association between total sleep time and sleep efficiency with QoL. Pearson correlations and regression models measured the association of sleep metrics with QoL scores. Results: Forty‐two aMCI participants (mean age =69.0 ± 7.4 years; N=23 female; mean BMI =27.6) were studied. Disturbed sleep indicated by the average number of apneas and hypopneas (AHI, mean = 18.6 ± 14.6) and respiratory events or related arousals (RDI, mean = 20.7 ± 14.2) was negatively associated with lower subjective measures of QoL. Higher AHI and RDI scores, indicating greater intermittent hypoxia and respiratory burden, were associated with lower QoL (AHI: r= ‐0.359, p=0.027; RDI: r= ‐0.340, p=0.037). There was a trend toward a negative association of ODI and QoL scores (r= ‐0.309, p=0.059). Regression models including age, sex, and BMI did not significantly predict QoL scores with AHI (F(4,35)=1.95, p>.1) or RDI (F(4,34)=1.76, p>.15), however, AHI and RDI individually added significantly to the prediction of QoL scores (AHI: B=‐.136, t=‐2.4,P<.05; RDI: B=‐.162, t=‐2.4, p<.05). Conclusions: Greater sleep disturbances related to hypoxic and respiratory events were associated with lower self‐ratings of QoL in MCI participants. Further research will increase the sample, investigate the impact of hypoxic and respiratory events on brain function, and whether longitudinal changes in diet influence the relationship of sleep‐related hypoxemia and QoL. [ABSTRACT FROM AUTHOR]

Intranasal insulin administration raises central nervous system (CNS) insulin levels in humans and acutely facilitates verbal memory in patients with Alzheimer's disease (AD), an effect that may differ by APOE genotype. The purpose of this study was to examine the cognitive dose response curves for intranasal insulin administration, and determine whether the effects of insulin differ between participants with (epsilon4+) and without (epsilon4-) the APOE- epsilon4 allele. On separate mornings, 33 memory-impaired adults with AD or amnestic mild cognitive impairment and 59 normal adults each underwent five intranasal treatment conditions consisting of insulin (10, 20, 40, or 60 IU) or placebo. Cognition was tested 15-minutes post-treatment, and blood was acquired at baseline and 45-minutes post-treatment. Plasma insulin and glucose levels were unaffected by treatment. Insulin administration facilitated recall on two measures of verbal memory in memory-impaired epsilon4- adults, with performance generally peaking at 20 IU. In contrast, memory-impaired epsilon4+ subjects demonstrated a relative decline in verbal memory. Insulin also differentially modulated plasma amyloid-beta for memory-impaired subjects and normal controls, effects that again differed by APOE genotype. These findings suggest that groups with different genetic risks for AD may show differential dose-response curves following intranasal insulin administration. [ABSTRACT FROM AUTHOR]