Search

INTRODUCTION: The U.S. study to protect brain health through lifestyle intervention to reduce risk (U.S. POINTER) is conducted to confirm and expand the results of the Finnish Geriatric Intervention Study to Prevent Cognitive Impairment and Disability (FINGER) in Americans. METHODS: U.S. POINTER was planned as a 2‐year randomized controlled trial of two lifestyle interventions in 2000 older adults at risk for dementia due to well‐established factors. The primary outcome is a global cognition composite that permits harmonization with FINGER. RESULTS: U.S. POINTER is centrally coordinated and conducted at five clinical sites (ClinicalTrials.gov: NCT03688126). Outcomes assessments are completed at baseline and every 6 months. Both interventions focus on exercise, diet, cognitive/social stimulation, and cardiovascular health, but differ in intensity and accountability. The study partners with a worldwide network of similar trials for harmonization of methods and data sharing. DISCUSSION: U.S. POINTER is testing a potentially sustainable intervention to support brain health and Alzheimer's prevention for Americans. Impact is strengthened by the targeted participant diversity and expanded scientific scope through ancillary studies. [ABSTRACT FROM AUTHOR]

INTRODUCTION: We assessed the effects of multivitamin‐mineral and cocoa extract supplementation on incident mild cognitive impairment (MCI) and all‐cause probable dementia. METHODS: COSMOS‐Mind (N = 2262), a 2 × 2 factorial, randomized‐controlled clinical trial administered a telephone‐based cognitive battery at baseline and annually for 3 years. Incidence rates of MCI, and separately dementia, were compared among treatment arms with proportional hazards regression. RESULTS: Over 3 years, 110 incident MCI and 14 incident dementia cases were adjudicated. Incidence rates did not vary by assignment to multivitamin‐mineral or cocoa extract (all p's ≥ 0.05); however, statistical power was low. When participants assigned to multivitamin‐mineral versus placebo converted to MCI, their scores for global cognition (p = 0.03) and executive function (p < 0.001) were higher and had declined less relative to the previous year (p = 0.03 for global cognition; p = 0.004 for executive function). DISCUSSION: Multivitamin‐mineral therapy may provide cognitive resilience, countering conversion to MCI, but not significantly reduce its incidence over 3 years. Highlights: Multivitamin‐mineral supplementation did not reduce risks for cognitive impairment.Cocoa extract supplementation did not reduce risks for cognitive impairment.Multivitamin‐mineral supplementation slowed cognitive declines for incident mild cognitive impairment. [ABSTRACT FROM AUTHOR]

INTRODUCTION: Post‐mortem analysis provides definitive diagnoses of neurodegenerative diseases; however, only a few can be diagnosed during life. METHODS: This study employed statistical tools and machine learning to predict 17 neuropathologic lesions from a cohort of 6518 individuals using 381 clinical features (Table S1). The multisite data allowed validation of the model's robustness by splitting train/test sets by clinical sites. A similar study was performed for predicting Alzheimer's disease (AD) neuropathologic change without specific comorbidities. RESULTS: Prediction results show high performance for certain lesions that match or exceed that of research annotation. Neurodegenerative comorbidities in addition to AD neuropathologic change resulted in compounded, but disproportionate, effects across cognitive domains as the comorbidity number increased. DISCUSSION: Certain clinical features could be strongly associated with multiple neurodegenerative diseases, others were lesion‐specific, and some were divergent between lesions. Our approach could benefit clinical research, and genetic and biomarker research by enriching cohorts for desired lesions. [ABSTRACT FROM AUTHOR]

Background: Elevated blood pressure levels during mid‐life have been found to be associated with an increased susceptibility to developing dementia later in life, particularly vascular dementia. Quantitative imaging biomarkers, such as Oxygen Extraction Fraction (OEF) and Cerebral Metabolism Rate of Oxygen (CMRO2), can be indicators of impaired cerebral metabolism. Calibrated Blood Oxygen Level Dependent (BOLD) functional Magnetic Resonance Imaging (fMRI) is a multi‐parametric approach utilizing hyperoxic and hypercapnic gas challenges (Figure 1). The impact of hypertension on OEF and CMRO2 has been investigated. Method: A cohort of 84 participants was recruited from the Wake Forest Alzheimer's Disease Research Center (ADRC) Clinical Core (Table 1). Among all the covariates, participants with prediabetes and diabetes were considered diabetic, and those who exhibited high blood pressure or were using medication to manage hypertension were classified as hypertensive. The MRI was conducted using a 3T Siemens Skyra MRI scanner with a 32‐channel head coil. Dynamic Pseudocontinuous Arterial Spin Labeling (PCASL) was used to acquire cerebral blood flow (CBF) and BOLD images during respiratory challenges with an end‐tidal forcing system. The ROI values in the frontal lobe, temporal lobe, parietal lobe, and occipital lobe regions were chosen. The correlation between hypertensive status and OEF and CMRO2 in the ROI was analyzed with a linear mixed model, with covariates of age, sex, cognitive status, APOE genotype, diabetic status, and hypertensive status. Result: A negative correlation was found between CBF, OEF, and CMRO2 with hypertensive status in frontal lobe region (Figure 2). Statistical significance was observed for OEF and CMRO2 (p = 0.049 and p = 0.028, respectively), indicating the potential influence of hypertensive status on these biomarkers. Conclusion: The study concludes that there is a significant negative association between hypertensive status and both OEF and CMRO2, particularly in the frontal lobe region. The observed reduction in OEF and CMRO2 is not solely due to decreased CBF, but rather complex and multifactorial processes involving vascular remodeling and altered oxygen metabolism. Additional research is necessary to fully understand the underlying pathophysiological mechanisms that link hypertension to decreased OEF and CMRO2, particularly in the context of regional specificity. [ABSTRACT FROM AUTHOR]

Background: The U.S. Study to Protect Brain Health Through Lifestyle Intervention to Reduce Risk (U.S. POINTER) will determine whether interventions that simultaneously include multiple risk reduction strategies can protect cognitive health in older adults. The primary outcome, a global cognitive composite score derived from the POINTER‐Modified Neuropsychological Test Battery (PmNTB), was developed to allow for outcome harmonization with its forerunner, the Finnish Geriatric Intervention Study to Prevent Cognitive Impairment and Disability (FINGER) and other large trials (e.g., A4, EXERT). Here we describe the PmNTB and its initial validation in the baseline U.S. POINTER sample. Method: U.S. POINTER is a Phase 3, multicenter, randomized 2‐year clinical trial of two interventions varying in intensity and format, in older adults at increased risk for cognitive decline and dementia. The PmNTB includes performance from 7 cognitive tests and is computed as the mean of three domain‐specific composites: Episodic Memory, Processing Speed, and Executive Function. The Episodic Memory Composite includes Free and Cued Selective Reminding Test, Story Recall, and Visual Paired Associates. The Processing Speed Composite includes Trail Making Test (TMTA) and Digit Symbol Substitution Test. The Executive Function Composite includes Number Span, Word Fluency, and TMTB. PmNTB was assessed in relation to age, clinical status (Clinical Dementia Rating‐CDR), and other cognitive composites able to be computed in the current sample using overlapping measures (i.e., FINGER NTB, Preclinical Alzheimer's Cognitive Composite‐PACC‐5). Result: 2094 participants completed the baseline assessment (mean age = 68.2±5.2 years; 68.8% female, 69.1% non‐hispanic white, mean MMSE = 28.9± 1.3). Global CDR was 0 for 79.5% of participants, and 0.5 for 20.5% of participants. After adjusting for education, race, ethnicity, and sex, each additional year in age was associated with a drop in PmNTB z‐score by ‐0.064 (95%CI = ‐0.071,‐0.056, p<0.001). Likewise, global CDR = 0.5 (questionable dementia) was associated with a lower PmNTB score (z = ‐0.549) compared with global CDR = 0 (‐0.134 z‐scores). PmNTB correlated with the FINGER NTB (r = 0.858, p<0.001) and the PACC‐5 (r = 0.876, p<0.001). Conclusion: The PmNTB is a valid measure of cognitive functioning, capturing age‐related cognitive decrements and is associated with clinically relevant, functional outcomes. It also exhibits convergent validity with established cognitive outcomes. [ABSTRACT FROM AUTHOR]

Background: Brain vascular health is closely related to cognitive performance, and cerebrovascular reactivity (CVR), an indicator of cerebral blood flow (CBF) compensatory capacity in response to vasoactive stimuli, may help elucidate this relationship. Arterial spin labeling (ASL) and blood‐oxygen‐level‐dependent (BOLD) are two representative methods for measuring CVR, although BOLD is a complex combination of CBF, cerebral volume, and cerebral metabolic rate of oxygen. This study aimed to investigate the relationship between cognition and two different CVR methods. Method: Seventy‐nine subjects (age: 68.7±7.2 years) enrolled in the Wake Forest Alzheimer's Disease Research Center (ADRC) Clinical Core underwent MRI, including both dynamic pseudo‐continuous ASL (PCASL) under a hypercapnic respiratory challenge and multi‐TI PCASL for resting CBF and ATT mapping. The dynamic PCASL with a longer TE (20ms) provided simultaneous acquisition of ASL and BOLD. CVR was obtained by calculating CBF or BOLD signal changes during a hypercapnic period. Voxel‐wise multiple linear regression analyses were performed to examine the relationship between CVR and mild cognitive impairment (MCI), adjusting for age, sex, glycemic status, APOE e4 allele, hypertensive status, and years of education. False positive cluster thresholding was applied for each modality. Additional statistical analyses were conducted to investigate differences in baseline CBF and ATT between cognitively healthy and MCI groups within the voxel clusters that showed significantly different CVR values. Result: In the BOLD‐based CVR analysis, two voxel clusters in the white matter (WM) of superior temporal and parietal lobes showed lower CVR in the MCI group compared to the cognitively healthy group (Figure 1). Additionally, reduced CBF and prolonged ATT were observed within the clusters (Figure 2 and 3). Conclusion: Subjects with MCI exhibited lower BOLD‐based CVR in WM, while no association was found between ASL‐based CVR and MCI. BOLD‐based CVR may be a more sensitive measure than ASL‐based CVR in association with cognition, particularly in WM where optimization of ASL acquisition is challenging. The impaired CVR in the MCI group may be due to cerebrovascular impairments, such as reduced CBF and prolonged ATT. [ABSTRACT FROM AUTHOR]

Background: Cognitive assessments sensitive to the integrity of the medial temporal lobe, an area vulnerable to early tau deposition, may serve as a low‐cost, effective marker of underlying tau burden in older adults at risk of Alzheimer's dementia. The current post hoc analyses from the EXERT study examined the relationship between CSF phosphorylated tau181 (p‐tau181), total tau (t‐tau), hippocampal volume, and cognitive performance on three distinct memory assessments in older adults with amnestic mild cognitive impairment (aMCI). Method: The study used baseline data from 41 older adults with aMCI in the EXERT trial who consented to lumbar puncture and had CSF data available (mean age = 74.10±11.98 years, mean education = 16.24±2.39 years, 61% female). P‐tau181 and t‐tau levels were quantified using Lumipulse from CSF samples. Structural brain images were processed using NeuroQuant. Hippocampal volume measures were averaged across hemispheres and adjusted for intracranial volume. Memory measures included the computerized Cogstate Behavioral Pattern Separation of Objects task (BPSO; fine memory discrimination), the Auditory Verbal Learning Test (AVLT; long delay free recall), and the Logical Memory test (delayed recall). Linear regression models were adjusted for age, sex, and education. Result: Lower CSF p‐tau181 was significantly associated with better fine memory discrimination (β = ‐0.11, SE = 0.03, p<0.01). Lower CSF t‐tau was significantly associated with better fine memory discrimination (β = ‐0.09, SE = 0.03, p = 0.01). Larger hippocampal volume was significantly associated with better fine memory discrimination (β = 0.08, SE = 0.02, p<0.01), better AVLT delayed recall (β = 1.69, SE = 0.32, p<0.01), and better Logical Memory delayed recall (β = 1.69, SE = 0.40, p<0.01). Neither p‐tau181 or t‐tau were significantly associated with AVLT delayed recall or Logical Memory delayed recall. Conclusion: Fine memory discrimination measured via the computerized BPSO test was associated with CSF p‐tau181, CSF t‐tau, and hippocampal volume, while more traditional verbal memory tests of list learning and story recall were associated only with hippocampal volume. The BPSO test may be a sensitive indicator of early pathology in individuals with aMCI with underlying tau burden. EXERT was supported by the Alzheimer's Disease Cooperative Study (ADCS) and funded by the National Institutes of Health Grant U19 AG010483. [ABSTRACT FROM AUTHOR]

Background: Mid‐ and late‐life exercise has been associated with lower dementia risk. The EXERT trial tested whether aerobic training (AX), compared to stretching/balance/range‐of‐motion training (SBR), could slow cognitive decline in MCI. While no difference was detected between exercise arms, EXERT participants overall showed little cognitive change over 12 months. It is possible that the amount of exercise, rather than the type, may be protective against decline. In this exploratory, post‐hoc analysis of EXERT data, we assessed whether intervention adherence, operationalized as the number of supervised exercise sessions completed, was associated with slower brain atrophy over 12 months. Method: 194 EXERT participants with baseline and follow‐up MRI were included in this analysis. For each participant, the number of supervised exercise sessions of at least 40 minutes in duration completed during the first 12 months was determined. MRI data were processed using FreeSurfer. Repeated measures ANOVAs were conducted using regional volume or thickness as the dependent variable, and the interaction between number of sessions (continuous scale) and study visit as the independent variable. Baseline age and sex, as well as their interactions with time were included in the model. FDR‐adjusted p‐values <0.05 were considered significant. Result: Greater number of sessions completed was associated with less brain atrophy over 12 months in the hippocampus and parahippocampus, and less ventricular expansion in the lateral and inferior lateral ventricles (Table 1, Figure 1; FDR‐corrected p<0.05 for interaction term). Results remained unchanged when including exercise type (AX vs. SBR), baseline CDR‐SB, or baseline plasma Aβ42/40 in the model. Findings were similar when analyses were restricted to participants who completed the study prior to the onset of the COVID‐19 pandemic. Conclusion: Our results show that higher adherence to a supervised exercise intervention over 12 months was associated with reduced brain atrophy in adults with amnestic MCI. These findings were obtained in post‐hoc, exploratory analyses, so causality should be interpreted with caution. EXERT was supported by the Alzheimer's Disease Cooperative Study and funded by the National Institutes of Health grant U19‐AG010483. [ABSTRACT FROM AUTHOR]

Background: Hypertension is one of the key vascular risk factors of AD and related dementia. Cerebral blood flow (CBF) and white matter (WM) integrity may play an essential role in understanding the vascular contributions to dementia (VCID). We investigated if hypertension is related to WM microstructural and vascular imaging metrics in WM. Method: Four‐hundred‐seven subjects (age: 69.7±8.1 years) enrolled in the Wake Forest Alzheimer's Disease Research Center (ADRC) Clinical Core underwent MRI, including neurite orientation dispersion and density imaging (NODDI) and eight‐phase pseudo‐continuous ASL (PCASL). The subjects included 158 MCI, 111 APOE e4 allele carriers, 224 with hypertension, and 249 with impaired glycemic status which includes type 2 diabetes and prediabetics. Hypertension status was defined as SBP≥130mmHG and DBP≥80mmHG. The microstructural imaging metrics including intracellular volume fraction (ICVF), isotropic volume fraction (ISOVF), and orientation dispersion index (ODI) were obtained from NODDI. The vascular imaging metric included CBF. CBF was obtained from PCASL sequence. Voxel‐wise linear regression analyses were performed to examine if CBF, ICVF, ISOVF, or ODI were related to hypertension adjusting for cognitive status, glycemic status, APOE e4 allele, age, sex, and years of education. All images were normalized into standard space. Tract‐based spatial statistics (TBSS) were used to normalize NODDI images. The false positive cluster thresholding was applied. Result: Hypertensive subjects showed impairments in both microstructural and vascular imaging metrics. Based on Figures 1‐(A), 2‐(A) and 3‐(A), there are overlapping brain image voxels between the microstructural and vascular imaging metrics. Additionally, the hypertensive subjects showed significantly lower CBF, higher ISOVF, and higher ODI than normal subjects within the voxel clusters (Figures 1‐(B), 2‐(B), and 3‐(B)). Note that APOE e4 allele, glycemic status, and cognitive status also showed statistical significance in the NODDI parameters, but there was no association in CBF. Conclusion: Hypertension showed the potential association between the microstructural and vascular impairments in the WM. Each risk factor and cognitive status differently affected WM microstructural and vascular dynamic imaging parameters. These findings warrant further investigations of contributions of hypertension to the microstructural and vascular abnormalities in dementia. [ABSTRACT FROM AUTHOR]

Background: A key focus of the U.S. Study to Protect Brain Health Through Lifestyle Intervention to Reduce Risk (U.S. POINTER) is recruitment of unimpaired older individuals at risk for cognitive decline with heterogeneous characteristics (under‐represented racial and ethnicity groups (URG), family history of cognitive decline, hypertension, geographic diversity), and a subset of individuals undergo PET and MRI. Method: To examine effects of heterogeneity on relationships between risk factors, AD biomarkers (Aß and entorhinal tau PET, hippocampal volume (HV)) and cognition (global, executive function, and memory) were examined from U.S. POINTER neuroimaging participants (N = 602, about 65% of the anticipated total sample) and a subset of Alzheimer's Disease Neuroimaging Initiative participants (N = 503). Neuroimaging data were processed and analyzed using harmonized methods across studies. Some cohort‐specific measurements were standardized using a within‐cohort reference group (Aß‐negative individuals <70yrs and with global CDR = 0). Result: U.S. POINTER imaging participants are younger than those in ADNI (68.6+/‐5.0yrs vs 70.7+/‐4.4yrs), more likely to be female (65% vs 58%) and from URG (27% vs 15%), and had lower education (14.7+/‐3.3yrs vs 16.7+/‐2.3yrs) and higher Framingham Cardiovascular Risk scores (9.9+/‐8.3 vs 7.7+/‐5.3). The groups differed on several AD biomarkers and cognitive measures (Table). In regression models, AD biomarkers were stronger predictors of cognitive performance in ADNI compared to POINTER. Specifically, Aß+ individuals with elevated tau had disproportionately poorer cognitive performance in ADNI, and this relationship remained consistent across cognitive measures (Figure). Conversely, demographic/risk variables were stronger predictors in POINTER. Demographic/risk predictors (age, sex, education, race, and FRS) together explained twice as much variance in global cognition in POINTER compared to ADNI (Adjusted R2 = 29% vs 14%). The addition of AD biomarkers to the model further increased the amount of variance in global cognition explained from 14% to 34% in ADNI, but addition of AD biomarkers did not increase variance explained in the POINTER model. Conclusion: Heterogeneity among study participants appears to influence baseline biomarker‐cognition relationships such that AD biomarkers explain more variability in cognitive performance in ADNI than POINTER. These findings further suggest that cohort characteristics may affect the potential influence of amyloid‐ and tau‐modifying treatments on cognition. [ABSTRACT FROM AUTHOR]

Introduction: Dietary supplements are touted for cognitive protection, but supporting evidence is mixed. COSMOS‐Mind tested whether daily administration of cocoa extract (containing 500 mg/day flavanols) versus placebo and a commercial multivitamin‐mineral (MVM) versus placebo improved cognition in older women and men. Methods: COSMOS‐Mind, a large randomized two‐by‐two factorial 3‐year trial, assessed cognition by telephone at baseline and annually. The primary outcome was a global cognition composite formed from mean standardized (z) scores (relative to baseline) from individual tests, including the Telephone Interview of Cognitive Status, Word List and Story Recall, Oral Trail‐Making, Verbal Fluency, Number Span, and Digit Ordering. Using intention‐to‐treat, the primary endpoint was change in this composite with 3 years of cocoa extract use. The pre‐specified secondary endpoint was change in the composite with 3 years of MVM supplementation. Treatment effects were also examined for executive function and memory composite scores, and in pre‐specified subgroups at higher risk for cognitive decline. Results: A total of 2262 participants were enrolled (mean age = 73y; 60% women; 89% non‐Hispanic White), and 92% completed the baseline and at least one annual assessment. Cocoa extract had no effect on global cognition (mean z‐score = 0.03, 95% CI: ‐0.02 to 0.08; P =.28). Daily MVM supplementation, relative to placebo, resulted in a statistically significant benefit on global cognition (mean z = 0.07, 95% CI 0.02 to 0.12; P =.007), and this effect was most pronounced in participants with a history of cardiovascular disease (no history: 0.06, 95% CI 0.01 to 0.11; history: 0.14, 95% CI ‐0.02 to 0.31; interaction, nominal P =.01). Multivitamin‐mineral benefits were also observed for memory and executive function. The cocoa extract by MVM group interaction was not significant for any of the cognitive composites. Discussion: Cocoa extract did not benefit cognition. However, COSMOS‐Mind provides the first evidence from a large, long‐term, pragmatic trial to support the potential efficacy of a MVM to improve cognition in older adults. Additional work is needed to confirm these findings in a more diverse cohort and to identify mechanisms to account for MVM effects. Highlights: COSMOS‐Mind was a large simple pragmatic randomized clinical trial in older adults conducted by mail and telephone.The trial used a two‐by‐two factorial design to assess treatment effects of two different interventions within a single large study.We found no cognitive benefit of daily cocoa extract administration (containing 500 mg flavanols) for 3 years.Daily multivitamin‐mineral (MVM) supplementation for 3 years improved global cognition, episodic memory, and executive function in older adults.The MVM benefit appeared to be greater for adults with cardiovascular disease. [ABSTRACT FROM AUTHOR]

Background: White matter (WM) degeneration in older adults is often characterized unimodally by diffusion tensor imaging (DTI), T1w and T2‐FLAIR MRI. However, approaches integrating multimodal MRI information will be necessary for better understanding WM degeneration in early stages of AD. Method: This study characterizes the longitudinal changes of WM structure among 66 participants with marked baseline white matter hyperintensity volume (WMHv > 2000 mm3). 42 cognitively normal [CN, 72±7.2y, F = 25] and 24 mild cognitive impairment [MCI, 74±5.7y, F = 14]) adults underwent longitudinal MRI (scan interval: 2.8±0.85 years) within the Wake Forest AD Research Center. DTI metrics were estimated using FMRIB's Diffusion Toolbox, voxel‐wise volumetric changes of WM (Jacobian Determinant [JD]) were estimated from fractional anisotropy (FA) maps using SPM CAT12, and WMHv were quantified using SPM's Lesion Segmentation Toolbox. We segmented WM into WMH and normal‐appearing WM (NAWM) to characterize different degeneration patterns by integrating multimodal MRI information. We performed a linear regression analysis of %WMHv change with cognitive status, scan interval, and baseline WMH volume as covariates. Result: Decreased FA and increased mean diffusivity (MD) were observed in WMH regions compared with NAWM. Within WMH, interestingly, volume and FA increased, while MD decreased (p <0.001) during the longitudinal follow‐up (Figs. 1 and 2). Baseline WMHv was not significantly associated with cognitive status, but trended toward higher WMHv in MCI compared to CN (p = 0.07). Adjusted for baseline WMHv, cognitive status was associated with WMHv change (p = 0.036, MCI faster than CN, Fig. 3). While FA (p = 0.99) and MD (p = 0.16) did not change in the NAWM, volumetric change rate (JD) indicated volumetric contraction (p<0.001, Figs. 4 and 5). WMH progresses with time in older adults at risk of AD dementia by occupying neighboring NAWM regions, resulting in relative increases in FA and decreases in MD. Conclusion: In NAWM, WM degeneration can be better characterized by volumetric contraction than white matter microstructural integrity. This observation could implicate that secondary or peripheral WM fibers may reveal more vulnerable tracts in early stages of AD. Further investigation incorporating imaging makers of blood perfusion and metabolism could better explain structural mechanisms of WM degeneration. [ABSTRACT FROM AUTHOR]

Background: Arterial stiffness may play a role in the development of dementia, presumably through its effects on white matter integrity and hyperintensities (WMH). However, relationships among arterial stiffness, white matter microstructure, and WMH volumes remain poorly understood. Arterial stiffness increases monotonically with age and its increase is accelerated by cardiometabolic disorders (e.g., hypertension, metabolic syndrome, diabetes). Further exploration of these relationships is key to the development of targeted therapies, early management, and detection. Method: Arterial stiffness was measured using carotid‐femoral pulse wave velocity (cfPWV) in ADRC participants with baseline systolic blood pressure (SBP) measurements, detailed cognitive testing, cognitive adjudication, and brain MRI. We examined associations of cfPWV and SBP with cognitive function (Montreal Cognitive Assessment [MoCA], Preclinical Alzheimer's Cognitive Composite [PACC5], and domain measures of memory and executive function) and brain MRI measures of: macrostructure (volume of gray matter [GM] and WMH from T1‐weighted and FLAIR imaging), white matter microstructure (neurite orientation dispersion and density imaging [NODDI] free water [FW] and diffusion tensor imaging [DTI] fractional anisotropy [FA]), and cerebral blood flow (CBF) in white matter (WM) and GM. Age, race, gender, education, and APOE‐4 status were included as covariates and in interaction terms in linear regression analyses. Result: Among 458 participants with a mean age 70±8 years and cognitive adjudication (44 dementia, 157 MCI, 257 normal cognition; Table 1), higher cfPWV was associated with worse cognitive performance (MoCA, PACC5), as was SBP (MoCA, PACC5, executive domain, language domain; Table 2). Higher cfPWV was associated with differences in WM microstructure (higher FW, lower FA) and higher WMH volume. While no overall associations between cfPWV and CBF were detected, cfPWV had stronger associations with FW, FA, and WMH in men. Higher SBP was associated with higher FW, higher WMH volume, and lower WM and GM CBF (Table 3). SBP had stronger associations with WMH in younger participants (<70y) and GM CBF in Black/AA participants and participants with impaired fasting glucose. No other interactions were detected. Conclusions: Arterial stiffness is associated with microstructural and macrostructural differences and poorer global and executive cognitive function. [ABSTRACT FROM AUTHOR]

Introduction: Mid‐life dietary patterns are associated with Alzheimer's disease (AD) risk, although few controlled trials have been conducted. Methods: Eighty‐seven participants (age range: 45 to 65) with normal cognition (NC, n = 56) or mild cognitive impairment (MCI, n = 31) received isocaloric diets high or low in saturated fat, glycemic index, and sodium (Western‐like/West‐diet vs. Mediterranean‐like/Med‐diet) for 4 weeks. Diet effects on cerebrospinal fluid (CSF) biomarkers, cognition, and cerebral perfusion were assessed to determine whether responses differed by cognitive status. Results: CSF amyloid beta (Aβ)42/40 ratios increased following the Med‐diet, and decreased after West‐diet for NC adults, whereas the MCI group showed the reverse pattern. For the MCI group, the West‐diet reduced and the Med‐diet increased total tau (t‐tau), whereas CSF Aβ42/t‐tau ratios increased following the West‐diet and decreased following the Med‐diet. For NC participants, the Med‐diet increased and the West‐diet decreased cerebral perfusion. Discussion: Diet response during middle age may highlight early pathophysiological processes that increase AD risk. [ABSTRACT FROM AUTHOR]

Background: Vascular risk factors are associated with cerebral small vessel disease and dementia pathology and reduced WM integrity is correlated with the severity of cognitive impairment in dementia. We have investigated if vascular risk factors are related to white matter structural and vascular imaging metrics. Imaging metrics include intracellular volume fraction (ICVF), white matter hyperintensities (WMH), and cerebrovascular measures such as cerebral blood flow (CBF), cerebrovascular reactivity (CVR), and arterial transit time (ATT). Method: Sixty‐four subjects (Table 1) enrolled in the Wake Forest Alzheimer's Disease Research Center (ADRC) Clinical Core cohort underwent MRI, including T2 FLAIR, neurite orientation dispersion and density imaging (NODDI), pseudo‐continuous ASL (PCASL). CVR was measured as a percent of increased CBF during a hypercapnic respiratory paradigm. ATT and resting CBF were obtained from a multi‐TI PCASL sequence. ICVF was obtained from NODDI. Head size adjusted WM total lesion volume (TLV) was calculated using SPM12‐LST2 toolbox with T2‐FLAIR image. Linear regression models were performed to examine if CBF, CVR, ATT, ICVF, or TLV are related to the risk factors or cognitive status adjusted covariates: age, sex, and years of education. A covariates adjusted logistic regression estimated weighting factors for each interrelated vascular imaging parameter to create novel cerebrovascular functional composites for each vascular risk group and mild cognitive impairment (MCI) group. The factor score p‐values were also calculated from two‐sample t‐tests with the cerebrovascular composite. The entire analyses were performed within the whole brain WM. Result: In the whole brain WM, hypertension subjects (p=0.031) showed higher CVR (Figure 1). T2DM subjects (p=0.007) showed higher WM TLV (Figure 2). T2DM and MCI subjects showed lower ICVF than normal subjects did (Figure 3). Based on the weights of each cerebrovascular parameter in the composite (Table 2), the effects of CBF and CVR are stronger in hypertension group while all three cerebrovascular measures had substantial contribution to cognition status. Conclusion: Each risk factor and cognitive status differently affected WM structural and vascular dynamic imaging parameters. The findings warrant further investigations of contributions of vascular risk factors to the structural and vascular abnormalities in dementia. [ABSTRACT FROM AUTHOR]

Background: Cerebrovascular functional parameters such as cerebral blood flow (CBF), cerebrovascular reactivity (CVR), and arterial transit time (ATT) may play an essential role in understanding the vascular contributions to dementia (VCID). We investigated the relationships between cerebrovascular functional parameters and AD risk factors, including APOE genotype, hypertension, and diabetes. Method: Sixty‐five subjects (Table 1) enrolled in the Wake Forest Alzheimer's Disease Research Center (ADRC) Clinical Core cohort underwent MRI, including pseudo‐continuous ASL (PCASL). CVR maps were obtained under a hypercapnic challenge using a computer‐controlled gas blender. A multi‐TI PCASL sequence was also employed to obtain resting CBF and ATT. Separate linear regression models were tested with response variables of quantitative CBF, CVR and ATT in whole brain gray matter (GM) and AD‐prone GM regions including hippocampus, parahippocampal, entorhinal, inferior parietal lobule, precuneus, and cuneus, adjusted for covariates: age, sex, and years of education. To investigate the effects of a risk factor on the interrelated vascular dynamic parameters, a cerebrovascular composite was created with the implementation of the weighting factors, obtained from covariates adjusted logistic regression, for each AD risk group and mild cognitive impairment (MCI). The factor score p‐values were calculated from two‐sample t‐tests with the cerebrovascular composite. Result: In both whole brain GM and AD‐prone GM regions, subjects with the risk factors generally had lower resting CBF, but differential relationship with CVR. Subjects with hypertension had significantly higher CVR, while APOE e4 carriers showed significantly lower CVR (Figure 1 and 2). From the cerebrovascular composite analysis, CVR showed higher weights in hypertension and APOE e4 carrier groups in both whole brain GM and AD‐prone GM regions (Table 2) although there still were fractions of linear weights of CBF or ATT, which were not negligible. Conclusion: Hypertension and APOE e4 carrier showed group differences of CVR in both whole brain GM and AD‐prone GM regions and the directions were opposite, implying their pathophysiological mechanisms may differ. As resting CBF and ATT showed lower weights in the composite than CVR, CVR may be a more sensitive brain perfusion parameter relating VCID. [ABSTRACT FROM AUTHOR]

Background: Arterial stiffness may play a role in the development of dementia, presumably through its effects on white matter integrity and hyperintensities (WMH). However, relationships among arterial stiffness, white matter microstructure, and WMH volumes remain poorly understood. Arterial stiffness increases monotonically with age and its increase is accelerated by cardiometabolic disorders (e.g., hypertension , metabolic syndrome, diabetes). Further exploration of these relationships is key to the development of targeted therapies, early management, and detection. Method: Arterial stiffness was measured using carotid‐femoral pulse wave velocity (cfPWV) in ADRC participants with baseline systolic blood pressure (SBP) measurements, detailed cognitive testing, cognitive adjudication, and brain MRI. We examined associations of cfPWV and SBP with cognitive function (Montreal Cognitive Assessment [MoCA], Preclinical Alzheimer's Cognitive Composite [PACC5], and domain measures of memory and executive function) and brain MRI measures of: macrostructure (volume of gray matter [GM] and WMH from T1‐weighted and FLAIR imaging), white matter microstructure (neurite orientation dispersion and density imaging [NODDI] free water [FW] and diffusion tensor imaging [DTI] fractional anisotropy [FA]), and cerebral blood flow (CBF) in white matter (WM) and GM. Age, race, gender, education, and APOE‐4 status were included as covariates and in interaction terms in linear regression analyses. Result: Among 458 participants with a mean age 70±8 years and cognitive adjudication (44 dementia, 157 MCI, 257 normal cognition; Table 1), higher cfPWV was associated with worse cognitive performance (MoCA, PACC5), as was SBP (MoCA, PACC5, executive domain, language domain; Table 2). Higher cfPWV was associated with differences in WM microstructure (higher FW, lower FA) and higher WMH volume. While no overall associations between cfPWV and CBF were detected, cfPWV had stronger associations with FW, FA, and WMH in men. Higher SBP was associated with higher FW, higher WMH volume, and lower WM and GM CBF (Table 3). SBP had stronger associations with WMH in younger participants (<70y) and GM CBF in Black/AA participants and participants with impaired fasting glucose. No other interactions were detected. Conclusions: Arterial stiffness is associated with microstructural and macrostructural differences and poorer global and executive cognitive function. [ABSTRACT FROM AUTHOR]

Background: Cerebrovascular reactivity (CVR) is an indicator of the compensatory dilatory capacity of blood vessel in the brain in response to vasoactive stimuli. BOLD MRI‐measured CVR showed that CVR is correlated with cognition. However, BOLD signal is a complex combination of multiple parameters such as cerebral blood flow (CBF), cerebral blood volume, and oxygen metabolism. In this study, we directly measured CBF using dynamic arterial spin labeling (ASL) during a hypercapnia challenge and tested if regional CVR or CBF is related to cognitive performance among people with risk of cognitive decline. Method: Seventy‐eight subjects (age: 69±7.18 years, M/F: 22/56; BMI: 27.29±5.12; years of education: 15.6 ±2.45; 12 Type 2 diabetes with 6 under treatment; 38 hypertension; 23 under treatment or 14 both; MMSE score: 28.41±1.43) enrolled in the Wake Forest Alzheimer’s Disease Research Center (ADRC) Clinical Core cohort underwent Pseudo‐continuous ASL during a 2‐minute baseline and a 2‐minute hypercapnic period with a RespirAct computer‐controlled gas blender, targeting 10mmHg higher end‐tidal CO2 level than the baseline while end‐tidal O2 level is maintained. Partial volume corrected voxel‐wise CVR was calculated (Figure 1). Multivariable linear regression analyses were performed to investigate the relationship between CBF or CVR and Mini‐Mental State Examination (MMSE) score in each ROI with adjustment for covariates: age, sex, race, BMI, years of education, hypertension/diabetic status, hypertension/diabetic medication status, and regional volume. Result: Multivariable linear regression analysis of CVR in the whole brain gray and white matter were positively associated with MMSE score (gray matter: =0.662, p=0.003, white matter: =0.474, p=0.027) (Figure 2‐a and b). Lower MMSE scores were significantly associated with lower CVR (corrected p<0.05) in 26 regions out of 122 gray matter ROIs (Figure 2‐c and 3). There was no significant relationship between regional white matter CVR and MMSE and between baseline CBF and MMSE score. Conclusion: Lower CVR in the whole brain gray and white matter and in the regional gray matter was related to lower MMSE score, while resting CBF showed no significant relationship with cognitive performance. Therefore, impaired CVR in the reported gray matter regions may be imaging biomarkers that predict cognitive performance. [ABSTRACT FROM AUTHOR]

Background: Alzheimer’s disease (AD) has a long preclinical phase that is often preceded by reduced white matter (WM) integrity; further, impaired cerebrovascular function is associated with AD biomarkers. However, the intersection of WM structure and cerebrovascular function in the risk and progression of Alzheimer’s disease is unclear. We examined the relationship between WM structure and cerebrovascular function in younger and older adults at risk for AD. Method: Participants enrolled in the Wake Forest Alzheimer’s Disease Research Center Clinical Core underwent: 3T MRI scan including neurite orientation dispersion and density imaging (NODDI) and arterial spin labeling (ASL), clinical exams, cognitive testing, and adjudication. Intra‐cellular volume fraction (ICVF) and cerebral blood flow (CBF) were obtained from NODDI and ASL, respectively. Multivariable linear regression analyses were performed to investigate the relationship between ICVF and CBF in 48 WM regions (JHU ICBM‐DTI‐81 atlas). Analyses were performed separately on participants grouped by age (median split at ≥71 years) and adjusted for covariates: sex, race, and cognition status, and grouped by cognitive status and adjusted for covariates: sex, race, and age. The Benjamini & Hochberg false discovery rate method was used to test multiple hypothesis across ROIs. Result: 330 participants completed MRI sequences for WM structure and perfusion (mean age: 70.3±8 yrs.; M/F: 105/225; 283 White, 47 Black or African American; 198 cognitively normal, 132 mild cognitive impairment (MCI)). The older group had lower mean ICVF and mean WM CBF (0.70±0.05; 18.9±3) than the younger group (0.73±0.04; 19.7±3). In the older group, mean ICVF was positively related to mean WM CBF (p<0.01). In older participants (≥71) there were eight regions where ICVF and CBF were positively related (corrected p<0.05). In younger participants (<71) there was one region where ICVF and CBF were positively related (fornix column and body; corrected p<0.05). When grouped by cognitive status (normal/MCI), no association was found between mean ICVF and mean WM CBF. Conclusion: Generally, reduced integrity in WM structure is associated with reduced CBF. This association appears related to age, not cognitive status. Differences in the associated regions by age suggest potential effects of brain aging on WM structure and CBF. [ABSTRACT FROM AUTHOR]

Introduction: Effective strategies to recruit older adults with mild cognitive impairment (MCI) into nonpharmacological intervention trials are lacking. Methods: Recruitment for EXERT, a multisite randomized controlled 18‐month trial examining the effects of aerobic exercise on cognitive trajectory in adults with amnestic MCI, involved a diverse portfolio of strategies to enroll 296 participants. Results: Recruitment occurred September 2016 through March 2020 and was initially slow. After mass mailings of 490,323 age‐ and geo‐targeted infographic postcards and brochures, recruitment rates increased substantially, peaking at 16 randomizations/month in early 2020. Mass mailings accounted for 52% of randomized participants, whereas 25% were recruited from memory clinic rosters, electronic health records, and national and local registries. Other sources included news broadcasts, public service announcements (PSA), local advertising, and community presentations. Discussion: Age‐ and geo‐targeted mass mailing of infographic materials was the most effective approach in recruiting older adults with amnestic MCI into an 18‐month exercise trial. [ABSTRACT FROM AUTHOR]

Background: Sleep disturbances in dementia occur often, are reported as neuropsychiatric symptoms, and are associated with higher caregiver burden and institutionalization. In mild cognitive impairment (MCI), sleep changes co‐occur with increasing neuropsychiatric symptoms and cognitive decline. Diet quality, like sleep, is a modifiable risk factor for Alzheimer's disease. It is unknown how dietary interventions may impact sleep quality. This controlled clinical trial investigates for the first time a modified Mediterranean ketogenic diet (MMKD) compared to a low‐fat American Heart Association diet (AHAD) over 4 months on multiple sleep indices in adults with amnestic MCI. Here we report our baseline sleep findings. Method: The WatchPAT Central Plus, an FDA approved home sleep test, was used to assess sleep quality. The WatchPAT quantifies numerous measures including total sleep time, pulse and sleep efficiency. Sleep‐disordered breathing is measured via the apnea‐hypopnea index (AHI) and oxygen‐desaturation index (ODI). Time spent in sleep stages is also quantified along with full night oxygen saturation and pulse rate. Independent samples t‐tests compared baseline sleep differences among male and female MCI participants. Result: A total of 64 MCI participants completed the baseline sleep assessments (mean age 70.2±7.0, BMI 27.0±4.3; 64.1% women). Mean sleep duration was 6 hrs46 min and 83.9% sleep efficiency. Mean AHI was 17.3±12.2 and mean ODI was 8.2±7.5 measured as >3% 02 desaturations, indicating on average moderate severity sleep apnea (AHI>15). Overnight sleep percentage by sleep stage (estimated from heart rate and accelerometer) averaged 15.4% in deep sleep and 22.3% in REM sleep. Mean REM latency was 105 minutes. Oxygen saturation averaged 94% and pulse, 61 bpm. Women had higher resting pulse (64.3bpm, p<.001). Sleep measures did not significantly differ by sex. Conclusion: The MCI sample, on average, had moderate severity sleep apnea at baseline, with sleep duration and efficiency slightly below standard recommendations of 7‐8 hours and efficiency > 85%, respectively. Future work will compare longitudinal changes in sleep quality across diet intervention groups. Understanding potential therapeutic effects of the MMKD on sleep quality and cognitive change will be vital in adding to the portfolio of targeted non‐pharmacological interventions for Alzheimer's disease prevention. [ABSTRACT FROM AUTHOR]

Background: U.S. POINTER is a Phase 3, multicenter, randomized 2‐year clinical trial of two multidomain lifestyle interventions in 2111 older adults who are at increased risk of cognitive decline and dementia due sedentary lifestyle, poor diet, and other factors such as family history of memory impairment and suboptimum cardiovascular health. Method: Enrollment took place at five geographically diverse sites, beginning in 2019 and completing in early 2023. Participants are randomly assigned to one of two lifestyle intervention groups that differ in format, intensity, and accountability. Those randomized to the Self‐Guided Lifestyle Intervention receive annual medical monitoring and health education information, tools, and support to encourage increased physical and cognitive activity and a healthier diet through 2‐3 annual group meetings. Those randomized to the Structured Lifestyle Intervention receive frequent medical monitoring of cardiovascular health and a structured program of exercise (primarily aerobic), nutritional counseling, cognitive training and social engagement initially through weekly and then monthly group meetings. 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 global cognition composite score that permits harmonization with FINGER and other trials. Secondary and tertiary outcomes include measures of executive function and episodic memory, physical activity, diet, cognitive and physical activity, cardiometabolic disease risks, mood, quality of life, health care costs, and health care utilization. Result: U.S. POINTER is generating a richly phenotyped cohort that will provide a rigorous comparison of two lifestyle interventions designed to preserve cognitive function. It has nurtured 4 ancillary studies to assess intervention effects on outcomes related to sleep quality, brain structure and pathology, peripheral and neurovascular function, and the microbiome. It also partners with clinical trials within the World‐Wide FINGERS international network. The study is generating an archive of biospecimens and de‐identified public use data. Plans for a post‐intervention observational study of the U.S. POINTER cohort are underway. Conclusion: U.S. POINTER provides an important national resource to advance the field in understanding the role of nonpharmacological interventions in reducing risk for cognitive decline and Alzheimer's disease and related dementia. [ABSTRACT FROM AUTHOR]

Background: The brain is particularly sensitive to excessive pressure and flow pulsatility. Disproportionate stiffening of the aorta can reduce wave reflection at the aorta‐carotid interface and facilitate transmission of excessive pulsatile energy into the cerebral microcirculation, leading to impaired cognitive function. The U.S. POINTER Neurovascular (POINTER‐NV) ancillary study is an ongoing study designed to evaluate vascular structure and function in participants from the U.S. POINTER trial. Here we describe the baseline characteristics of the POINTER‐NV participants, focusing on aortic and carotid variables and their association with cognitive function. Method: Ultrasound and tonometry were used to assess aortic and carotid measures. Hemodynamic and structural variables were compared according to cognitive status using the baseline Clinical Dementia Rating Scale Sum of Boxes (CDR‐SB) score categorized as normal (CDR‐SB = 0) or possibly impaired (CDR‐SB>0). Linear regression was used to assess cross‐sectional associations between aortic and carotid variables and composite scores for global cognition, executive function, memory, and processing speed, with and without adjustment for age, sex, race, and ethnicity. Result: Aortic and carotid hemodynamics were available for 165 POINTER‐NV participants (mean age: 67.9±5.1 years, 70% female, 37% people of color). A large proportion of the participants had evidence of subclinical cardiovascular disease based on a carotid intima‐media thickness ≥1.0 mm (n = 109/165, 66.1%) or increased aortic stiffness based on a carotid‐femoral pulse wave velocity >10 m/s (n = 70/131, 53.4%). There were no significant differences in aortic or carotid structure and function between participants with normal cognition (n = 109) and those with possible cognitive impairment (n = 56). Higher carotid‐femoral pulse wave velocity was associated with lower global cognition, executive function, and processing speed, even after adjustment for age, sex, race, and ethnicity (all p<0.05). Although there was some suggestion that higher carotid pulsatility, higher carotid transmission, and lower aorta‐carotid reflection may be associated with worse cognition, these associations were not consistent across cognitive domains and did not hold up after covariate adjustment. Conclusion: Age‐related changes in vascular structure and function can promote cognitive decline and dementia. Our data are consistent with prior evidence suggesting that higher aortic stiffness may be particularly important in this regard. [ABSTRACT FROM AUTHOR]

Background: The arterial baroreflex maintains stable blood flow to the brain. Reduced baroreflex sensitivity for modulation of heart rate (BRS) has been observed in patients with Alzheimer's disease (AD) and mild cognitive impairment and may be impacted by race, ethnicity, sex, and socioeconomic factors such as the Area Deprivation Index (ADI), a validated, neighborhood‐level composite index that incorporates 17 social determinants of health. However, these relationships have not been well described. Method: This study utilized baseline data from 196 participants enrolled in the U.S. POINTER Neurovascular study, an ancillary to the parent U.S. POINTER multi‐site lifestyle intervention trial that adds assessments of autonomic function and vascular structure and function. BRS was calculated from continuous blood pressure and electrocardiogram recording using the slope of the regression line between changes in systolic blood pressure and RR interval values in the same direction, with higher BRS indicating better autonomic function. ADI scores ranging from 1 to 10 were calculated using 9‐digit zip codes, with 10 indicating the greatest disadvantage. Analysis of variance and linear regression were used to evaluate associations between measures of interest. Result: The average age of the study population was 67.9 ± 5.4 years, 64 (17%) were males, and 60 (30.6%) identified as people of color (POC). Overall, the mean BRS was 9.2 ± 4.6 ms/mmHg, and the average ADI score was 4.56 ± 2.69 (range: 1 to 10), corresponding to a national ADI percentile of 40.7 ± 26.1 (range: 3 to 100). Less than a quarter of participants (n = 42, 21.4%) had an ADI percentile >67, indicating a moderate to high level of neighborhood disadvantage. White participants had lower BRS compared to POC (8.60 ± 4.49 vs. 10.60 ± 4.61 ms/mmHg, p = 0.0048). In a multiple regression model adjusting for demographics and ADI, sex (p = 0.0283), race and ethnicity (p = 0.0049), and education (p = 0.0196) were significantly associated with BRS, indicating better autonomic function in men, POC, and those with higher education. ADI was not associated with BRS. Conclusion: Race, ethnicity, and education impact autonomic function. Further investigations are needed to assess the impact of other demographic and socioeconomic factors on neurovascular health. [ABSTRACT FROM AUTHOR]

Background: Multidomain lifestyle interventions hold great promise world‐wide as interventions to slow cognitive aging, and delay and prevent Alzheimer's Disease and Related Disorders (ADRD). To have the greatest reach, they must be tailored for and assessed within local cultures in clinical trials. For trials to have the greatest impact, it's important that they are designed with common features that promote comparisons and potential harmonization. Method: World‐Wide FINGERS was launched in 2017 as a global network of multidomain lifestyle intervention trials to adapt, test, and optimize multidomain lifestyle intervention trials in regions worldwide. Two participating trials, the Latin American Initiative for Lifestyle Intervention to Prevent Cognitive Decline (LatAm‐FINGERS) and the U.S. Study to Protect Brain Health through Lifestyle Intervention to Reduce Risk (U.S. POINTER) have collaborated to promote harmonization to support joint initiatives. This presentation is organized to describe, in parallel, their study protocols, and cohort characteristics, and demonstrate how cross‐trial collaboration may expand the impact of individual trials. Result: The trials have overlapping aims, eligibility criteria, interventions, and assessment protocols. LatAm‐FINGERS and U.S. POINTER will enroll 1,200 and 2,000 participants, respectively. Table 1 describes sample characteristics. The samples of the two studies share similar sociodemographic and clinical characteristics with a few exceptions. In U.S. POINTER, there is a larger proportion of participants with a family history of memory impairment and physical inactivity, and a higher frequency of White participants. Additionally, mild memory impairment (Clinical Dementia Rating = 0.5) is more common in LatAm‐FINGERS participants. Conclusion: Harmonization of LatAm‐FINGERS and U.S. POINTER protocols provides unique opportunities for collaborative science for identifying effective strategies to promote cognitive resilience and reduce risks for Alzheimer's disease, and significantly expand the potential for scientific investigation in diverse populations. [ABSTRACT FROM AUTHOR]

Background: U.S. POINTER is a randomized, controlled, multi‐domain 2‐year clinical trial in 2000 older Americans to slow cognitive decline via culturally‐appropriate healthy lifestyle interventions. Participant diversity is essential, with targeted enrollment of 50% women and 23% enrollees from communities of color (reflecting the U.S. population in the 2016 Census). Other recruitment priorities include individuals with lower traditional educational attainment, older age within our eligibility range (75‐79 years old), and rural residence. This diversification aims to (1) better represent our communities particularly affected by ADRD, and (2) help ensure that this intervention can be successful across broad cultural differences for long‐term implementation. Method: U.S. POINTER developed and deployed a community‐based recruitment strategy via a centrally‐coordinated grassroots outreach team at each site. The strategy includes evidence‐based and innovative community engagement tactics and is a multi‐faceted, agile approach that accounts for variations in: demographics across sites' respective communities; levels of home institution‐community connectedness/integration; and outreach experience across team members. Tactics include: employing a multi‐tiered outreach framework that leverages existing community networks in order to augment team outreach capacity and ensure continuous community engagement; innovating approval procedures with central IRB to reduce barriers to producing timely outreach materials as needed; and standardizing onboarding for new team members across experience levels. Result: The POINTER grassroots recruitment strategy has accounted for 22% of the trial's overall enrollment. As of Jan 18, 2023, POINTER has enrolled 1879 participants, 29% of whom are from communities of color, 30% are men, 30% do not hold college degrees, and 13% are over 75 years old. Lessons learned include navigating local institutional reputations, retaining consistent team personnel for long‐term relationship building, setting trajectories for mutually‐beneficial long‐term community investment, and employing a formidable equity lens at all levels of staffing, outreach, and intervention design to better identify and eliminate barriers to participation, amongst others. Conclusion: Key recommendations emerging from recruitment success in enrolling a diverse cohort include: approaching recruitment with long‐term vision and commitment toward community investment; leveraging existing community assets and working in partnership with respected community voices; and employing consistent, diverse, multimodal community outreach touchpoints for traction. [ABSTRACT FROM AUTHOR]

Background: Sleep disordered breathing (SDB) leads to nocturnal hypoxemia and sleep disruption, which are linked to adverse health conditions, particularly in older adults at risk for dementia. Few prospective studies of SDB examine cognitive decline among those at increased risk for cognitive impairment and dementia. POINTER‐zzz, a sleep ancillary study of U.S. study to PrOtect brain health through lifestyle INTErvention to Reduce risk (U.S. POINTER), allows us to examine the role of lifestyle intervention on sleep quality, and potential moderating effects of sleep on cognition to the intervention in medically and cognitively vulnerable older adults. Method: U.S. POINTER was designed to investigate the effects of two 2‐year lifestyle interventions on cognitive trajectories in 2,000 older, cognitively normal adults (aged 60‐79 yrs) at increased risk for cognitive decline and dementia due to physical inactivity, poor diet and cardiovascular disease. POINTER‐zzz enrolled a subset of parent trial participants and administered in‐home sleep assessments using WatchPAT (1 night) and ActiGraph (6 nights) devices. We summarize participants' baseline characteristics including apnea hypopnea index (AHI), sleep duration and sleep efficiency. Result: To date, 688 POINTER‐zzz participants enrolled and completed baseline WatchPAT and/or Actigraph assessments. Participant ages averaged 68.6 years old (standard deviation, 5.13); 21% of participants self‐identified as Black/African American, 4% Hispanic/Latino, and 66% White. More than half (68%) were female, and 69% had a Bachelor's degree or higher. Overall, 87% of participants had at least mild sleep apnea (AHI>5). Severe sleep apnea (AHI≥30) was observed in 14% of participants overall, and 21% of those aged ≥75 yrs. Severe sleep apnea was more prevalent among males (19%) than females (11%). Overall, nightly sleep duration for the cohort averaged 6.6 hours, with 83% sleep efficiency, and an average of 79.3 minutes awake after sleep onset. Conclusion: POINTER‐zzz participants have sleep characteristics that align with expectations for a cohort that is broadly representative of a diverse older adult population in the US. POINTER‐zzz provides an unparalleled opportunity to test the effects of a multi‐domain lifestyle intervention on sleep disturbances that are linked to cognitive decline and AD in a well‐characterized, diverse cohort of at‐risk older adults. [ABSTRACT FROM AUTHOR]

Background: The U.S. POINTER study is a phase 3, multicenter, 2‐year randomized controlled trial (RCT) of two lifestyle interventions varying in intensity and format, conducted in older adults living in the U.S. who do not have objective cognitive impairment at study entry, but have increased risk of cognitive decline and dementia. Inclusion criteria included specific risk factors (e.g., family history of dementia, vascular risk factors) but not subjective cognitive concerns (SCCs). However, SCCs are likely to be common in this group of at‐risk individuals. U.S. POINTER provides a unique opportunity to evaluate the prevalence of SCCs and their demographic and clinical correlates in an at‐risk group. Methods: Recruitment for the U.S. POINTER study is still ongoing, and the following is based on a partial sample. The sample includes 1811 U.S. POINTER participants with complete baseline data (collected by December 2022), mean age = 68.2y (SD = 5.2), 73.5% are female, 70.2% have18+ years education, and 29.3% are from underrepresented groups. SCCs were measured by the brief 12‐item Everyday Cognition (ECog) questionnaire which includes two items in each of 6 domains: everyday memory, language, visuospatial abilities, planning, organization and divided attention. Responses on the ECog range from 0 = no change/better compared to baseline, 1 = questionably/inconsistently worse, 2 = consistently a little worse, 3 = much worse. Neuropsychological performance was measured using a global composite and episodic memory, executive functioning, and processing speed composites. Other variables included demographics, depression (Geriatric Depression Scale total score; GDS) and sleep (Insomnia severity index (ISI)) and vascular disease burden index. Results: Thirty‐five percent of the cohort endorsed having a subjective complaint on the ECog (score ≥2 on any item). The most frequent complaint was "Remembering where I have placed objects" (23%). SCCs did not differ by age, sex or education. ECog‐12 Total were related to insomnia and depression (p<.0001). After adjusting for age, sex, education, vascular risk burden, GDS and ISI, greater SCC (ECog‐12 Total) was still associated with the global composite and all three domains (ps < 0.003). Conclusions: SCCs, particularly everyday memory complaints, were relatively common in this at‐risk cohort. While SCCs were related to depression and sleep, they were also independently associated with slightly worse cognitive function. [ABSTRACT FROM AUTHOR]

Background: There has been little investigation into the relationship between physical, cognitive, and social activity and subjective concern about cognition (SCD) in the absence of objective cognitive decline. This concern about subjective change is an important concept in the field of Alzheimer's disease as it independently confers risk for developing MCI/AD. However, the exact relationship between SCD and engagement in positive daily activities is poorly understood. This project examines the relationship between SCD and self‐reported engagement in these activities. Method: U.S. POINTER is a phase 3, multicenter, 2‐year randomized controlled trial of two lifestyle interventions varying in intensity and format, conducted in older adults living in the U.S. who do not have objective cognitive impairment at study entry, but have increased risk of cognitive decline and dementia. Participants completed myriad measures at baseline, including the Cognitive Function Inventory (CFI) assessing subjective cognitive decline, and the Community Healthy Activities Model Program for Seniors (CHAMPS) which assesses self‐reported engagement in social, cognitive, and physical activities over the past 4 weeks. Results: Baseline study characteristics of the current sample (N = 1823) are: Mean age = 68.2y (5.2), 73.5% female, 29.8% with less than 18+ years education, and 29.3% from underrepresented groups (URG). In separate multivariate linear models, CFI was associated with weekly caloric expenditure in exercise (p<.001) and cognitive activity (p <.001), such that CFI scores were higher for participants with lower exercise‐related caloric expenditure and lower cognitive activity levels. Higher CFI scores also tended to predict social activity levels (p =.06). The inverse relationship between CFI and all three variables is significant in women (p =.04;.0001;.05, respectively) but not in men, and the CFI‐cognitive activity relationship is significant for URG (p =.005) but not White participants. Conclusion: In sum, SCD and engagement in physical, cognitive, and social activities are inversely related to varying degrees, such that individuals who report lower levels of engagement in these activities report more subjective cognitive concerns. However, different patterns emerged for some subgroups. Additional modeling is needed to demonstrate the directionality of the relationships between these activities and CFI, and the relationship with demographic variables of interest. [ABSTRACT FROM AUTHOR]

Background: Cognitive dispersion refers to the within‐person variability across tasks. Relative to the normative approach, cognitive dispersion may be more sensitive to subtle changes in preclinical Alzheimer's disease. Greater dispersion has been associated with increased risk for conversion to mild cognitive impairment and faster rates of medial temporal lobe atrophy. This metric can be derived from a regular neuropsychological assessment and complement traditional outcome approaches, particularly in those underrepresented in normative data. This study evaluated cognitive dispersion as an independent predictor of clinical status across racial and ethnic groups. Method: Baseline data on 1811 cognitively unimpaired older adults with high vascular risk from the U.S. POINTER multisite lifestyle intervention study were examined. Sample characteristics included mean age of 68 (SD = 5.2), 70% female, 30% less‐than‐college education, and 29% underrepresented groups (301 Black, 231 Other). Correlations between cognitive dispersion and other brain health risks (vascular, subjective cognitive decline (SCD), physical activity) were tested. Cognitive dispersion was defined as the standard deviation of individuals' z‐transformed scores of 8 cognitive tests. Vascular risk burden was the sum of 5 conditions (hypertension, diabetes, hypercholesterolemia, heart disease, obesity). Self‐report SCD was measured by the Cognitive Function Instrument (CFI) and Measurement of Everyday Cognition (ECOG12). Logistic Regression Models were fitted to predict Clinical Dementia Global Ratings (CDR 0.5 vs. 0) to evaluate cognitive dispersion as an independent predictor in the whole sample, White participants and Black participants, controlled for demographics, vascular risk, and physical activity. Logistic Regression Models were also evaluated with CFI or ECOG12 as additional covariate. Result: Greater cognitive dispersion was correlated with older age, greater vascular burden and less physical activity, but not SCD. Cognitive dispersion was significantly higher in men, Black participants, and participants with less education. Cognitive dispersion predicted CDR in Black participants (OR = 4.7, p<0.01), and trended in the whole sample (OR = 1.6, p = 0.05), but was not significant in White participants (OR = 1.2, p = 0.63). Results hold when controlled for SCD (Table 1). Conclusion: Results supported cognitive dispersion as a sensitive objective metric, in addition to self‐report SCD, to identify individuals showing the earliest clinical signs of decline, particularly among those underrepresented in traditional norms. [ABSTRACT FROM AUTHOR]

Background: Depressive symptoms play an important role in cognitive health of older adults, yet the exact nature of their influence has not been well established. There is strong evidence that depressive symptoms are independently associated with cognitive decline and dementia in older adults. Depressive symptoms have also been associated with cognitive dysfunction in the absence of dementia. Methods: We examined the association of depressive symptoms and cognitive functioning in U.S. POINTER participants at baseline. U.S. POINTER is a large multi‐site, 2‐year study testing the impact of interventions on cognition in 2000 older adults at risk for cognitive decline. This analysis included 1,814 study participants (aged 60‐79). Exclusion criteria included major depressive disorder and bipolar disorder. We measured cognition with the Neuropsychological Test Battery modified for U.S. POINTER, or PmNTB. The battery provides a global composite score and three domain‐specific composite scores for episodic memory, executive function, and processing speed. Depression was measured with the 15‐item Geriatric Depression Scale (GDS). Simple linear regression models were run to evaluate the relationship between cognitive function and GDS after controlling for age, sex, education, race, ethnicity, and site. In secondary analyses, simple linear regression models were used to evaluate the relationship between cognitive functioning and GDS, using a median split (0‐1, 2+) and the conventional/clinical GDS cut‐off of 4 (0‐4 vs 5+). Results: We found greater endorsement of depressive symptoms was not associated with the global composite score, episodic memory, or executive function. However, higher GDS scores were associated with slower processing speed (estimate = ‐0.023; 95% CI: ‐0.05, 0.00, p‐value = 0.05). In secondary analyses using the GDS median split, the association between GDS and processing speed was mildly attenuated (p‐value = 0.06) and the association between GDS and executive function became marginally associated (p‐value = 0.06). When using conventional GDS clinical cut‐offs, no associations between cognitive function and GDS were found. Conclusion: At baseline, subclinical depressive symptoms may be associated with decreased processing speed and executive function in U.S. POINTER participants. [ABSTRACT FROM AUTHOR]

Background: COSMOS‐Mind, a large, randomized placebo‐controlled pragmatic trial in older adults, recently reported that daily supplementation with multivitamin‐mineral, but not cocoa extract, benefited global cognition. We assessed effects of these supplements on prespecified secondary outcomes of mild cognitive impairment (MCI) and all‐cause dementia (DM). We also assessed treatment‐related cognitive trajectories leading to conversion to MCI or dementia. Method: COSMOS‐Mind (N = 2262) administered a telephone‐based cognitive battery at baseline and annually for 3 years. Proxies of participants meeting criteria for suspected cognitive impairment based on a cognitive screener (TICSm) were interviewed. An expert panel adjudicated cognitive status. Incidence rates of MCI, and separately DM, were compared among arms with proportional hazards regression. Changes in cognitive trajectories leading to MCI and DM were assessed with linear models. Result: At baseline, adjudication for suspected cognitive impairment was triggered for 419 (20%) participants, yielding adjudications of 217 (10%) MCI and 4 (0.2%) DM cases. During follow‐up, triggers were less frequent in the MVM than placebo arms: hazard ratio = 0.73 (p = 0.04). Across 3 years, 110 incident MCI and 14 incident DM cases were adjudicated. Incidence rates of these outcomes did not vary by assignment to multivitamin‐mineral or cocoa extract (all p≥0.05), however statistical power was low. Incident MCI was associated with a marked decline in cognitive function from the previous year (p<0.001). When participants assigned to multivitamin‐mineral versus placebo converted to MCI, their scores for global cognition (p = 0.03) and executive function (p<0.001) were higher and had declined less relative to the previous year (p = 0.03 for global cognition; p = 0.004 for executive function). Daily cocoa extract use did not attenuate cognitive decline leading up to MCI. Conclusion: COSMOS‐Mind does not provide evidence that cocoa extract or multivitamin‐mineral therapy lowers risk of incident MCI or DM. Multivitamin‐mineral therapy, but not cocoa extract, may provide cognitive resilience countering conversion to MCI. [ABSTRACT FROM AUTHOR]

Background: Autonomic regulation plays a major role in maintaining stable blood supply to the brain. Impaired autonomic function, as evidenced by high blood pressure variability (BPV) and/or low heart rate variability (HRV), is common in older adults and is associated with reduced perfusion, which can ultimately lead to impaired cognitive function. The U.S. POINTER Neurovascular (POINTER‐NV) ancillary study is an ongoing study designed to evaluate autonomic function in participants from the U.S. POINTER trial. Here we describe the baseline characteristics of the POINTER‐NV participants, focusing on autonomic measures and their relationship to cognitive function. Method: Continuous blood pressure and ECG recordings were used to assess BPV, HRV, and sympathovagal balance. Autonomic variables were compared according to cognitive status using the baseline Clinical Dementia Rating Scale Sum of Boxes (CDR‐SB) score. Linear regression was used to assess cross‐sectional associations between sympathovagal balance and BPV variables and composite scores for global cognition, executive function, memory, and processing speed, with and without adjustment for age, sex, and race/ethnicity. Result: Autonomic measures were available for 212 POINTER‐NV participants (mean age: 67.9 ± 5.4 years, 67% female, 33% people of color). There were no significant differences in BPV or HRV measures between participants with normal cognition (CDR‐SB score = 0) and those with possible cognitive impairment (CDR‐SB score = 0.5–1.0). Higher sympathovagal balance was significantly associated with higher scores of global cognition, executive function, and processing speed; however, this association became statistically insignificant after adjustment for age, sex, and race/ethnicity. Higher BPV measured as standard deviation of mean arterial pressure (SDMAP) was associated with lower scores for episodic memory after adjustment for age, sex, and race/ethnicity (p = 0.03). There was some suggestion that lower HRV might be associated with worse cognition, however, these associations were inconsistent across cognitive domains and did not remain after covariate adjustment. Conclusion: Age‐related changes in autonomic function can promote cognitive decline and dementia. Our data are consistent with prior evidence suggesting a role for sympathovagal balance and blood pressure variability in modulating cognitive function [ABSTRACT FROM AUTHOR]

Background: 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 the effect of lifestyle interventions in cognitively unimpaired older adults (60‐79 years) at risk for decline/dementia. Here, using data from the POINTER Imaging ancillary substudy, we explore how Alzheimer's disease pathology and cardiovascular risk influence brain structure, cognition and their relationship. Method: POINTER Imaging participants underwent cross‐sectional MRI, [18F]Florbetaben (FBB) Aβ‐PET and [18F]MK6240 tau‐PET. FBB and MK6240 data were processed using previously validated methods. MRIs were processed with voxel‐based morphometry. To quantify cardiovascular risk, the Framingham risk score (FRS) was calculated for each participant. We used linear regression models in the whole sample as well as in Aβ status subgroups to evaluate voxel‐wise associations of brain structure, measured using voxel‐based morphometry, with age, FRS, AD pathology (cortical summary Aβ and entorhinal cortex (ERC) tau burden), and a global cognition composite score. Result: Across all 624 participants (Table 1), cognition (age‐adjusted) was positively related to brain structure across temporal, frontal and medial parietal cortices (Fig. 1A). ERC tau‐PET was negatively associated with brain structure in bilateral medial temporal lobes (MTL) and, notably, in bilateral basal forebrain (Fig. 1B). FRS showed significant negative associations in superior temporal gyrus and occipital cortex (Fig. 1C), but tau‐PET associations remained similar when adjusting for FRS. In Aβ+ participants, cognition‐ and FRS‐structure relationships were weaker but tau‐PET‐structure associations were stronger and extended outside the MTL. In Aβ‐ participants, cognition‐ and FRS‐structure relationships were similar to those observed in the whole cohort and tau‐PET associations were no longer significant. Conclusion: In this heterogeneous cohort of older adults, tau was associated with brain structure in strikingly specific patterns that were related to Aβ but not to cardiovascular risk as measured by the FRS. Tau‐structure associations were restricted to temporal lobes and basal forebrain and were independent of more widespread cognition‐structure associations, indicating that factors other than tau may play a critical role. Our next steps include comparing the current cohort to others with different at‐risk characteristics (e.g., ADNI, Berkeley Aging Cohort Study). [ABSTRACT FROM AUTHOR]

Background: Cardiometabolic disorders (hypertension and diabetes) often co‐occur and are considered key modifiable risk factors for Alzheimer's disease and related disorders; yet, the extent to which they each affect brain structure and function is unclear. We examined their associations with neuroimaging biomarkers of white matter microstructure, cerebral perfusion, and cognitive function in a diverse cohort of older adults. Method: Participants aged 50‐85 years enrolled in Wake Forest Alzheimer's Disease Research Center's Clinical Core between 2016‐2020 received clinical evaluation, oral glucose tolerance testing (OGTT), neuroimaging, cognitive testing, and adjudication for mild cognitive impairment (MCI) and dementia. 3T brain MRI included T1 (for gray/white matter segmentation, regional volumes/thicknesses); FLAIR for white matter hyperintensity volume (WMHv); arterial spin labeling for cerebral blood flow (CBF); diffusion tensor imaging (DTI) for fractional anisotropy (FA); and neurite orientation dispersion and density imaging (NODDI) for Free Water. Hypertension (HTN) was staged using seated blood pressure (BP) and medications. Hyperglycemia was staged using OGTT 120 minute glucose levels (OGTT120), hemoglobin A1c, and fasting glucose as available. Cardiometabolic status was categorized (HTN only, hyperglycemia only, hyperglycemia+HTN, neither). Multivariable linear regression modeled associations with neuroimaging measures adjusted for age, gender, and race. Result: MRI was available on 478 participants (35% MCI and 10% dementia) with mean age of 70±8 years, 74% with HTN, 61% with hyperglycemia (4% with non‐insulin treated diabetes), and 15% African‐Americans. The combination of hyperglycemia+HTN was associated with significantly higher NODDI Free Water and WMHv, lower FA, and lower gray matter perfusion, compared to neither factor (Table). Continuous levels of systolic BP and OGTT120 broadly correlated with WM microstructure, WMHv, and gray matter CBF (Figure). In adjusted models, systolic BP remained significantly associated with higher NODDI Free Water and WMHv, and CBF in gray and white matter. OGTT120 and WMHv remained significant in adjusted models. Cardiometabolic factors were not associated with gray matter macrostructure (e.g. volumes, temporal lobe cortical thickness) or cognitive status in this sample. Conclusion: In this deeply phenotyped and racially diverse sample, individual cardiometabolic factors and the co‐occurrence of disorders was associated with reduced cerebral gray matter perfusion and reduced white matter microstructure. [ABSTRACT FROM AUTHOR]

Reducing the risk of dementia can halt the worldwide increase of affected people. The multifactorial and heterogeneous nature of late‐onset dementia, including Alzheimer's disease (AD), indicates a potential impact of multidomain lifestyle interventions on risk reduction. The positive results of the landmark multidomain Finnish Geriatric Intervention Study to Prevent Cognitive Impairment and Disability (FINGER) support such an approach. The World‐Wide FINGERS (WW‐FINGERS), launched in 2017 and including over 25 countries, is the first global network of multidomain lifestyle intervention trials for dementia risk reduction and prevention. WW‐FINGERS aims to adapt, test, and optimize the FINGER model to reduce risk across the spectrum of cognitive decline—from at‐risk asymptomatic states to early symptomatic stages—in different geographical, cultural, and economic settings. WW‐FINGERS aims to harmonize and adapt multidomain interventions across various countries and settings, to facilitate data sharing and analysis across studies, and to promote international joint initiatives to identify globally implementable and effective preventive strategies. [ABSTRACT FROM AUTHOR]

Background: The Finnish Geriatric Intervention Study (FINGER) reported that a multidomain lifestyle intervention could provide an effective and accessible means of protecting against age‐related cognitive decline and dementia. This led to the global dementia risk reduction initiative: World‐Wide FINGERS (WW‐FINGERS). As part of WW‐FINGERS, the AU‐ARROW study mirrors aspects of FINGER, as well as the U.S. study (US‐POINTER, also part of WW‐FINGERS), while allowing for Australian cultural and dietary adaptations. Method: AU‐ARROW is a randomised, single‐blind, 2‐year clinical trial, recruiting 600 participants aged 60‐79, who satisfy study‐specific eligibility inclusion/exclusion criteria. Participants will be recruited at (a) Macquarie University, Sydney, NSW and (b) Sarich Neuroscience Research Institute, Edith Cowan University, Perth, WA, and randomised into either the multimodal lifestyle intervention (ML) group or the Health Education and Coaching (HC) group. The ML group will engage in a) aerobic exercise, resistance training and stretching facilitated by local gym memberships, b) monthly telehealth diet monitoring and advice, to encourage MIND diet adherence whilst aligning with Australian Dietary Guidelines, c) online BrainHQ cognitive training sessions, and d) medical monitoring and health education sessions. The HC group will receive occasional health education sessions. All participants receive heart rate trackers, 6‐monthly blood tests, regular health monitoring and clinician advice. Result: AU‐ARROW's primary outcome measure involves assessment of changes in a global composite cognitive score, measured using neurocognitive tests as in US‐POINTER. Further neurocognitive tests, lifestyle questionnaires, physical function tests, diet and sleep monitoring will determine specific contributions of the various lifestyle changes. Extra value will emanate from Alzheimer's disease (AD) biomarker analysis of blood and urine samples collected yearly, as well as AD Aβ amyloid‐specific ligand‐PET imaging, brain MRI and retinal biomarker tests at 0 and 24 months. The final AU‐ARROW protocol design and methods will be presented. Initial recruitment data may also be presented. Conclusion: The finalised AU‐ARROW protocol is expected to facilitate study completion and maximise data sources, and allow a) development of an evidence‐based innovative treatment plan to reduce cognitive decline and dementia risk, b) effective transfer of research outcomes into Australian health policy, and c) validation of emerging blood and retinal diagnostic biomarkers in preclinical screening. [ABSTRACT FROM AUTHOR]

Background: While the use of non‐pharmacological interventions—such as physical activity, nutritional supplementation and cognitive stimulation—to prevent or delay cognitive decline and the onset of Alzheimer's disease (AD) has received increasing attention, evidence supporting the benefits of these interventions have been mixed, and underlying mechanisms are not well‐understood. Method: In participants enrolled in the PACE‐2 trial, which examined the impacts of 6‐month physical activity intervention on brain and cognitive outcomes, we evaluated the effects of aerobic exercise (n = 15, 63±10 yrs) on longitudinal changes in brain morphometry and white matter microstructure compared to stretching exercise controls (n = 17, 67±7 yrs.) using MRI among pre‐diabetic mild cognitive impairment adults. High‐resolution structural T1‐weighted and diffusion‐weighted images (DTI) were acquired before and after exercise intervention. Group differences in MRI markers (cortical volume and thickness, white matter DTI and free water metrics) after intervention and their longitudinal changes were compared for 68 cortical (Desikan‐Killany Atlas) and 48 white matter (JHU WM Atlas) regions using FreeSurfer SPM, FSL and Nextflow. Result: No statistically significant group difference in cortical thickness, volumes and conventional DTI metrics was observed. On the other hand, free water (FW)‐corrected fractional anisotropy (FA) remained unchanged in aerobic exercise group (p = 0.32) while FA decreased in stretching controls in the right cerebral peduncle(p<0.001), resulting in group differences in FW‐corrected FA after 6‐month exercise intervention (p = 0.02 after Bonferroni correction). These changes in stretching exercise group were negatively correlated with FW fraction changes (marker related with neuroinflammation) (r = ‐0.71, p = 0.001). Conclusion: Aerobic exercise could have neuroprotective effects by preventing white matter degeneration, and FW fraction and FW‐corrected imaging markers could be useful for more sensitive detection of early AD sign. [ABSTRACT FROM AUTHOR]

Background: It has been shown that cerebrovascular reactivity (CVR) is correlated with cognitive performance and alterations of CVR may be an indicator of vascular disfunction leading to cognitive decline. However, the underlying mechanism of CVR alterations in BOLD signal is not straight‐forward since other physiological parameters, such as oxygen utilization and blood volume, also contribute to its measurements. In this study, we measured cerebral blood flow (CBF) using a dynamic arterial spin labeling (ASL) technique during a hypercapnia challenge and tested if CVR is related to risk factors of cognitive decline and cognitive performance. Method: Sixty‐three subjects (age: 70.17±7.09 yrs, M/F: 18/45; BMI: 27.63±5.07; years in education: 15.79±2.38 yrs; 7 diabetes; 17 hypertension; MMSE score: 28.49±1.40) enrolled in the Wake Forest Alzheimer's Disease Research Center (ADRC) Clinical Core cohort underwent MRI, including ASL during a hypercapnia challenge with a RespirAct computer‐controlled gas blender, targeting 10mmHg higher end‐tidal CO2 level than the baseline while end‐tidal O2 level is maintained. Pseudo‐continuous ASL (PCASL) was collected during a 3‐minute baseline and a 2‐minute hypercapnic period. The whole brain CVR was obtained by calculating a percent change of CBF per the end‐tidal CO2 elevation in mmHg between the baseline and the hypercapnic challenge (Figure 1). A partial volume correction on CVR and baseline CBF was applied and the whole brain gray matter CVRgm and CBFgm were calculated. Linear regression analyses were performed (CVRgm or CBFgm ∼age+sex+BMI+years of education+diabetes+hypertension+MMSE) to examine the relationship between CVRgm or CBFgm and global cognitive performance (MMSE score). Result: CVRgm is positively associated with the MMSE scores (β=0.208, p=0.016) independent of other covariates (Figure 2). CBFgm is negatively associated with age (β=‐0.552, p=0.013) and BMI (β=‐0.623, p=0.037) with the adjustment for all other covariates (Figure 3). Conclusion: This study demonstrated that CVRgm is related to lower MMSE scores, while resting CBFgm showed significant relationships with age and BMI. Therefore, CVRgm may be a sensitive imaging parameter relating vascular and cognitive function. [ABSTRACT FROM AUTHOR]

Background: Undetected AD pathology in cognitively normal older adults may increase risk for mobility decline by both increasing white matter pathology and directly interfering with functional networks through Aβ deposition. Methods: Thirty‐one cognitively normal older adults (75.01 ± 4.15 y, 35.5% female) enrolled in the Brain Networks and Mobility Function (B‐NET) study received PiB PET and MRI. A global cortical PiB average for each participant was calculated by coregistering PET to MRI using Freesurfer v5.6 to generate masks and thresholding at 1.21 to create PiB positivity groups (PiB‐ = 16, PiB+ = 15). White matter hyperintensity (WMH) volume was calculated with the Lesion Segmentation Toolbox (LST) implemented in SPM12. Mobility function was assessed using the expanded Short Physical Performance Battery (eSPPB), a 4‐meter walk, and a 400‐meter walk. Cognitive measures included the Montreal Cognitive Assessment (MOCA) and Digit Symbol Substitution Task (DSST). Associations were explored using linear regression, correcting for age, sex, and BMI in the fully adjusted mobility model while age, sex, and education were used in the fully adjusted cognition and WMH model. Results: PiB+ individuals had significantly faster 4‐meter gait speed (p<0.05) and a trend for higher DSST (p=0.052). These associations were independent of WMH volume. PiB+ individuals also had significantly higher total (p<0.05) and motor WMH (p<0.05). Conclusions: The observation that PiB+ individuals had better physical function than PiB‐ was unexpected given existing literature showing associations between regional Aβ volume and slower gait speed. It was also unexpected given that the PiB+ group had higher WMH volume, which is associated with slower gait speed. The current sample, which includes primarily individuals with good physical and cognitive function, may represent a resilient phenotype. Continued recruitment of more diverse participants with lower physical function will be an important addition to this sample. Future analyses will allow for the inclusion of APOE and an increased sample size. Whole‐brain functional connectivity will also be assessed in this cohort using graph‐theory based methods. [ABSTRACT FROM AUTHOR]

Background: The EXERT trial (NCT02814526) was a Phase 3, multicenter, randomized single‐blind study that examined the effects of regular exercise on cognition and other measures of brain function in a planned sample of 300 older adults with amnestic mild cognitive impairment (MCI). Method: The Alzheimer's Disease Cooperative Study (ADCS) coordinated the trial, in partnership with Wake Forest and the YMCA of the USA. Participants were randomized to moderate intensity aerobic training (AX), or to stretching, balance and range of motion (SBR) for 18 months. In the first 12 months, exercise was supervised 2x/week and completed independently 2x/week. All exercise was unsupervised in Months 13‐18. Outcomes assessments were completed at baseline and every 6 months. The primary endpoint was 12‐month change from baseline on the ADAS‐Cog‐Exec, a validated measure of global cognitive function. In addition, 12‐month changes in the ADAS‐Cog‐Exec and CDR‐SB were compared for EXERT intervention groups relative to other cohorts to estimate effects of intervention versus no intervention (i.e., "Usual Care"). Result: 296 participants were enrolled, and over 31,000 exercise sessions were completed during the first 12 months. Attendance remained high (AX: 81%; SBR: 87%), and >60% of participants reported continued exercise through the pandemic. Neither the AX group nor the SBR group showed 12‐month declines on the ADAS‐Cog‐Exec and CDR‐SB. There were no significant treatment differences between AX and SBR on these outcomes. In the Usual Care analysis comparing ADNI‐1 and EXERT participants matched on key variables (demographics, baseline cognitive function, APOE4), ADNI‐1 MCI participants showed the expected 12‐month decline on the ADAS‐Cog‐Exec, but the EXERT AX and SBR groups did not (ADNI‐1 vs. AX: p = 0.012; vs. SBR: p = 0.00049). Conclusion: Global cognitive function did not change over 12 months of follow‐up for MCI participants in EXERT, suggesting that both the AX and SBR interventions may have stalled cognitive decline. EXERT is the longest exercise trial conducted in MCI to date, and greater 'volume' of exercise may have provided more protection, regardless of exercise intensity. Both groups received equal amounts of weekly socialization, which may have contributed to this protection. Our results are noteworthy given that trial was conducted during the COVID‐19 pandemic. [ABSTRACT FROM AUTHOR]

Background: In response to the global pandemic, U.S. POINTER procedures were adapted to include virtual intervention delivery. Here we describe the impact of this adaptation on adherence in a large community‐based lifestyle intervention trial. Method: U.S. POINTER is conducted through a partnership between the Alzheimer's Association (AA) and five clinical sites. A total of 2000 older adults at risk for cognitive decline are assigned to one of two 24‐month multi‐domain lifestyle interventions. The Self‐Guided (SG) group works toward lifestyle goals that best meet their individual needs and schedules. The Structured (STR) group follows a coordinated program with specific goals for physical activity, diet, cognitive/social challenge, and health monitoring. Both groups meet in teams of 12‐15 participants throughout the study for support and guidance, which are led by trained staff. SG teams meet six times over 24 months, and STR teams meet weekly for the first 4 months, then 2x/month for 2 months, and then monthly. Although Team Meetings for both intervention groups were planned as in‐person events, the global pandemic necessitated a pivot to virtual delivery. Result: From January through December 2021, N = 2103 Team Meetings were conducted in‐person and N = 4663 Team Meetings were conducted virtually for 824 participants. For both intervention groups, in‐person and virtual Team Meeting attendance was the same, at 90%. When Team Meetings were held in‐person, STR participants completed a median of 93 very active Fitbit minutes/week (IQR = 38,185) and reported a median MIND Diet score of 11.0 (IQR = 9.5,12.0). When Team Meetings were virtual, adherence metrics were comparable with median values of 101 very active Fitbit minutes/week (IQR = 43,192) and a MIND Diet score of 11.0 (IQR = 9.8,12.0). Blood pressure monitoring and cognitive training metrics were also comparable without regard to Team Meeting delivery format. Conclusion: Our findings demonstrate that a shift to virtual participant contact during the pandemic did not compromise adherence to a complex multi‐domain lifestyle intervention in older adults. These findings have high relevance for other ongoing lifestyle intervention studies within and outside of WW‐FINGERS, and highlight the importance of adaptability in clinical trial design and implementation to foster sustainability under challenging life circumstances. [ABSTRACT FROM AUTHOR]