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Accurate measurement of Alzheimer's disease (AD) pathology in older adults without significant clinical impairment is critical to assessing intervention strategies aimed at slowing AD-related cognitive decline. The U.S. Study to Protect Brain Health Through Lifestyle Intervention to Reduce Risk (POINTER) is a 2-year randomized controlled trial to evaluate the effect of multicomponent risk reduction strategies in older adults (60-79 years) who are cognitively unimpaired but at increased risk for cognitive decline/dementia due to factors such as cardiovascular disease and family history. The POINTER Imaging ancillary study is collecting tau-PET ([18F]MK6240), beta-amyloid (Aβ)-PET ([18F]florbetaben [FBB]) and MRI data to evaluate neuroimaging biomarkers of AD and cerebrovascular pathophysiology in this at-risk sample. Here 481 participants (70.0±5.0; 66% F) with baseline MK6240, FBB and structural MRI scans were included. PET scans were coregistered to the structural MRI which was used to create FreeSurfer-defined reference regions and target regions of interest (ROIs). We also created off-target signal (OTS) ROIs to examine the magnitude and distribution of MK6240 OTS across the brain as well as relationships between OTS and age, sex, and race. OTS was unimodally distributed, highly correlated across OTS ROIs and related to younger age and sex but not race. Aiming to identify an optimal processing approach for MK6240 that would reduce the influence of OTS, we compared our previously validated MRI-guided standard PET processing and 6 alternative approaches. The alternate approaches included combinations of reference region erosion and meningeal OTS masking before spatial smoothing as well as partial volume correction. To compare processing approaches we examined relationships between target ROIs (entorhinal cortex (ERC), hippocampus or a temporal meta-ROI (MetaROI)) SUVR and age, sex, race, Aβ and a general cognitive status measure, the Modified Telephone Interview for Cognitive Status (TICSm). Overall, the processing approaches performed similarly, and none showed a meaningful improvement over standard processing. Across processing approaches we observed previously reported relationships with MK6240 target ROIs including positive associations with age, an Aβ+> Aβ- effect and negative associations with cognition. In sum, we demonstrated that different methods for minimizing effects of OTS, which is highly correlated across the brain within subject, produced no substantive change in our performance metrics. This is likely because OTS contaminates both reference and target regions and this contamination largely cancels out in SUVR data. Caution should be used when efforts to reduce OTS focus on target or reference regions in isolation as this may exacerbate OTS contamination in SUVR data.

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]

Background: The U.S. Study to Protect Brain Health Through Lifestyle Intervention to Reduce Risk (U.S. POINTER) is a two‐year randomized controlled trial designed to evaluate the effects of lifestyle interventions on older adults aged 60‐79 years. The POINTER Imaging ancillary study employs arterial spin labeling (ASL) magnetic resonance imaging (MRI) with two inversion times, enabling the mapping of arterial transit time (ATT) and the investigation of its relationship with dementia risk factors. This study examines the effect of the Framingham Risk Score (FRS) on ATT, which provides hemodynamic information on the cerebral vasculature. Method: A subset of POINTER Imaging participants (n = 134; F/M = 81/53; age = 68.1±5.1; FRS = 11.3±10.4) from two imaging sites underwent two ASL MRI scans during the baseline session. Two 3D Pulsed ASL scans were obtained with TI1 of 790ms and TI2 values of 2000ms or 2750ms, providing delay times (between labeling and imaging) of 1210ms or 1960ms. ATT, the time required for blood to travel from the neck to the tissue, was estimated in the range of 1210ms and 1960ms using a kinetic model (Figure 1). ATT maps were normalized to a standard space, and a voxel‐wise linear regression (ATT∼age+sex+log(FRS)) was performed on ATT maps in gray matter to assess the effect of FRS on ATT. To control false positives, clusters smaller than 1.4ml were removed based on a simulation with α = 0.05. Result: Figure 2 depicts three clusters found in the occipital, precuneus and frontal gray matter regions, all of which demonstrate a positive relationship between ATT and log(FRS). Participants with higher FRS exhibit prolonged mean ATT values in the clusters as shown in Figure 3. After stratifying into sex groups, both groups show the same direction. Conclusion: Although the detectable range of ATT with two ASL scans was limited, the analysis suggests that an increased risk of cardiovascular disease, as quantified by the Framingham Risk Score, can serve as an indicator of potential cerebrovascular disease leading to prolonged ATT, which is associated with arterial stiffness, and vascular resistance. The clusters demonstrating the association between FRS and ATT are the brain regions that may have heightened vulnerability to vascular risk factors, according to previous studies. [ABSTRACT FROM AUTHOR]

Background: Multicentric initiatives to study brain cognition in the elderly offers us a unique collection of brain imaging data accompanied by detailed neuroclinical and neuropsychological evaluations. U.S. POINTER and LatAm‐FINGERS, part of the World Wide FINGERS, are both large‐scale investigations of lifestyle interventions and its impact on cognitive function. These large‐scale detailed data may offer an unprecedented opportunity to compare diverse populations. Method: Baseline MRI of subjects from multiple US centers (POINTER‐US), distributed in 5 geographical regions, and from 9 latin‐american countries (LatAm‐FINGERS). The protocols vary from basic (3D T1, 3D FLAIR,T2* GRE, Cor T2 hippocampus, DWI) to advanced which also included ASL, rs‐FMRI and DTI. Demographic information and clinical, cognitive and neuropsychological assessment were also included. Result: MRI data was collected from 662 participants in the United States (about 65% of the total anticipated U.S. POINTER neuroimaging sample) and from 542 subjects from 9 countries in latin‐america (about 80% of the total anticipated LatAm‐FINGERS neuroimaging sample), with around 1200 participants scanned (table1). All participants have 3D T1, 3D FLAIR, T2* GRE images and either DWI or DTI images. Comparative demographics from the 2 datasets shows similar mean age, a predominance of females, and slight differences in education (table 2). This will allow us to compare multiethnic and multicultural volumetric and functional brain MRI information, as well as disease markers, associated with thorough neurological and clinical assessment. Reasons for not acquiring MRI were mainly due to claustrophobia or scanner unavailability. Conclusion: This is an exceptional opportunity to have comparative large‐scale databases, with anatomical and functional brain imaging from different populations, allowing us to study real world diverse brain data and better understand its relationships with demographics, health and risk characteristics, and cognition. [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: 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: 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: 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: 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]

Introduction: The U.S. Study to Protect Brain Health Through Lifestyle Intervention to Reduce Risk (U.S. POINTER) is evaluating lifestyle interventions in older adults at risk for cognitive decline and dementia. Here we characterize the baseline data set of the POINTER Imaging ancillary study., Methods: Participants underwent health and cognitive assessments and neuroimaging with multimodal positron emission tomography (PET) (beta-amyloid [Aβ] and tau) and magnetic resonance imaging (MRI). Framingham risk score (FRS) was used to quantify cardiovascular disease (CVD) risk., Results: A total of 1052 participants (31% from underrepresented ethnoracial groups) were enrolled. Compared to Aβ-, Aβ+ (29%) participants were older, had higher apolipoprotein E (APOE) ε4 carriage rate and white matter hyperintensity volume, and greater temporal tau. FRS was related to MRI measures, but not AD biomarkers. FRS and tau had independent effects on cognition., Discussion: In this heterogenous, at-risk cohort, CVD risk was related to more abnormal brain structure and poorer cognition, representing a putative non-AD (Alzheimer's disease) pathway to brain injury and cognitive decline., Highlights: ·The U.S. Study to Protect Brain Health Through Lifestyle Intervention to Reduce Risk (U.S. POINTER) cohort is enriched for cardiovascular disease (CVD) and poor lifestyle ·POINTER Imaging collected multimodal neuroimaging data in this unique, at-risk cohort ·Amyloid burden was related to age, apolipoprotein E (APOE) ε4 carriage, and measures of disease progression ·Associations between amyloid and tau, and tau and cognition, were relatively weak ·CVD risk and tau pathology were independently related to memory., (© 2024 The Author(s). Alzheimer's & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer's Association.)

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., (© 2023 The Authors. Alzheimer's & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer's Association.)