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AbstractBackgroundBoth 11C‐Pittsburgh compound‐B (PiB) and 18F‐Flutemetamol (FMT) have off‐target white matter (WM) signal that increases with age, but WM uptake is stronger with FMT than PiB. Although their WM patterns are comparably associated with age, the difference between them may impact visual and quantitative assessments of cortical amyloid‐β uptake. Our objective was to determine whether PiB PET and FMT PET visual assessments agree with quantitative cortical amyloid‐β evaluations.MethodA cohort of cognitively unimpaired (CU) younger adults with median (range) of 39 (30, 48) years (N = 30), CU older adults with age of 67 (61, 83) years (N = 30) and older adults with AD dementia with age of 67 (54‐84) years (N = 23) underwent MRI, PiB PET and FMT PET. PiB‐PET and FMT PET scans were evaluated visually by two nuclear medicine specialists blinded to participant information. Disagreements were reconciled with a second, joint round of visual reads. Readers applied standard visual assessment criteria using the absence of regional gray matter (GM) and WM contrast as an indication of a positive scan. The global cortical PiB standard uptake value ratio (SUVr) was obtained referencing to cerebellar crus uptake and converted to centiloid values. Participants were classified as PiB positive/negative using a centiloid cut‐off of 22.ResultPiB and FMT visual positivity agreed with quantitative positivity on PiB‐based centiloid values in 69/83 for PiB and 78/83 for FMT. There were 10 disagreements with PiB, 1 disagreement with FMT and 4 disagreements with both. Few disagreements occurred near the centiloid threshold. Interestingly, all disagreements between visual reads (amyloid‐β positive) and centiloid (amyloid‐β negative) in the CU younger were with PiB. FMT disagreements were always in the CU older and AD groups.ConclusionDisagreements between amyloid‐β positivity on visual reads and quantitative measurements (centiloid) may depend on age and tracer. PiB WM uptake is lower than FMT WM uptake, which may lead to reduced contrast between GM and WM (part of the standard criteria for visual reads), especially in younger ages. In contrast, WM uptake increases at older ages, and increased WM signal may bleed more into cortical regions, hiding subtle, near‐threshold cortical uptake, especially with FMT.

AbstractMayo Clinic Alzheimer’s Disease Research Center (ADRC) has been operational since 1990 supported by the US National Institutes of Health. In addition, in the aging and Alzheimer’s disease (AD) spectrum research, Mayo Clinic has been active in since 1986 with the Mayo Alzheimer’s Disease Patient Registry that evolved to the Mayo Clinic Study of Aging (MCSA) to become a population‐based study of aging and cognitive impairment in 2004.The overall goal of Mayo Clinic ADRC is to provide a structured environment that supports innovative research and enable translation aimed at accelerating the development of effective treatment and prevention for AD and related dementias at all stages of the disease. Our comprehensive ADRC is located in Rochester, Minnesota (MCR), and Jacksonville, Florida (MCF), and shares its operations in all of the Cores between the two geographic sites. ADRC core activities include the Administrative Core, Clinical Core, Data Management and Statistics Core, Neuropathology Core, Neuroimaging Core, Biomarker Core, the Outreach and Education Core (ORE Core), and the Research Education Component. ADRC Cores also interact directly with the MCSA.The theme of the center during the current cycle is “Similarities and Differences Among Neurodegenerative Disorders”. Therefore, in addition to focusing on the recruitment of participants along the AD spectrum, we continue to focus on the recruitment of persons on the frontotemporal lobar degeneration (FTLD) and the Lewy body disorders (LBD) spectra, including the prodromal stages of the neurodegenerative dementias.This focus expands on previous accomplishments of the ADRC across the neurodegenerative disease spectra. The acquisition and development of new biomarkers for the neurodegenerative diseases is a major focus of the Center, and the recruitment of research participants in all three disorders enhance randomized controlled trial studies.The Mayo ADRC interacts with other ADRCs on various collaborative efforts and supports Developmental Projects that utilize ADRC resources with the goal of attracting early‐stage and established investigators into the AD research field.

AbstractBackgroundHearing loss is associated with cognitive decline and dementia. The ongoing ACHIEVE Study was the first randomized trial to test the effects of hearing treatment on three‐year cognitive change. The ACHIEVE – Brain Health Follow‐Up Study will extend follow‐up to six years post‐randomization to determine the long‐term and potentially nonlinear effects of hearing treatment vs. health education control with delayed treatment on dementia and cognitive decline.MethodsParticipants will be recruited from the 977 participants enrolled in the ACHIEVE Study. After Year 3, hearing intervention participants will continue to receive hearing care and the control group will be offered the hearing intervention. Co‐primary study outcomes will be cognitive decline and a composite of incident mild cognitive impairment (MCI)/probable dementia. Secondary outcomes include domain‐specific cognitive decline, brain structural changes on magnetic resonance imaging (MRI), and other functional outcomes (e.g., physical activity, social isolation). Power analyses for the co‐primary outcomes assumed an annual attrition rate of 10% and an immediate, lagged, or cumulative treatment effect.ResultsWhen comparing multi‐year cognitive decline (Table 1), in the scenario of a constant treatment effect that assumes a strong and immediate treatment effect, the benefit of extended follow‐up is not greater power, but additional information on the long‐term effects of hearing intervention. In a scenario of a lagged treatment effect, a two‐year lag in the treatment effect causes the Year 3 assessment to be severely underpowered (28%) but provides sufficient power (80%) at Year 6 despite attrition. In a scenario of a cumulative treatment effect that increases with time, analyses are similarly underpowered at Year 3 (65%) but not at Year 6 (82%). The same pattern is evident when estimating the power at Year 3 (57%) and Year 6 (80%) to detect incident MCI/probable dementia in a Cox regression model that assumes a protective hazard ratio of 0.70 (Figure 1).ConclusionAcross all non‐constant scenarios of potential treatment effect, six years of follow‐up increases precision and provides valuable information to better delineate long‐term cognitive trajectories. The ACHIEVE ‐ Brain Health Follow‐Up Study will be completed in 2025.

AbstractBackgroundPhysical activity can improve the physical health of people living with mild cognitive impairment (MCI) and dementia and may have cognitive benefits. Identifying modifiable social factors inhibiting physical activity among this group is important. We examined the relationship between reported physical activity levels and social determinants of health (SDOH) in a population of older adults living with MCI or dementia.MethodWe included people with a diagnosis of MCI or dementia, age 55 years and older, who were empaneled to Community Internal Medicine at Mayo Clinic (Rochester, Minnesota), had a clinic visit between June 1, 2019 and June 30, 2021 and had completed a SDOH questionnaire. We focused on 8 SDOH domains: education, depression, alcohol use, stress, financial resource strain, social connections, food insecurity and transportation needs. Self‐reported activity levels were categorized as inactive (0 minutes of exercise per week), insufficiently active (10‐140 minutes per week) or sufficiently active (≥150 minutes per week). SDOH domains were compared according to physical activity level using χ2 tests and multinomial logistic regression.ResultA total of 3224 persons with MCI (n = 1371) or dementia (n = 1853) who had completed questions on physical activity were included. Of these, 1936 (60%) were characterized as physically inactive and 837 (26%) insufficiently active. Characteristics associated with an increased likelihood of physical inactivity were older age, female sex, obesity, lower education, dementia diagnosis, depression risk and increased social isolation (all p<0.001).ConclusionPhysical inactivity is common among people living with MCI and dementia. Physical activity levels may be influenced by many modifiable factors, highlighting potential areas for intervention in this population.

AbstractBackgroundThe rural‐urban commuting area (RUCA) codes classify communities using measures of population density, urbanization, and daily commuting from U.S. Census Bureau information. The ARTFL LEFFTDS Longitudinal Frontotemporal Lobar Degeneration (ALLFTD) study generated RUCA codes for enrolled participants to better understand our cohort demographics. The rural‐urban distribution of participants may provide important insights for clinical trial planning.MethodsThe current RUCA codes are generated from the 2010 decennial census and the 2006‐10 American Community Survey data. The codes are numbers (1‐10) that describe metropolitan, micropolitan, small town, and rural commuting areas based on the size and direction of the primary (largest) commuting flows.ResultsRUCA codes were generated on 784 ALLFTD participants. At their most recent visit, participant median age was 60, 51.1% female, and a median education of 16 years. Participants were classified as clinically normal (39.1%), behavioral variant FTD (25%), nonfluent PPA (6.7%), semantic variant PPA (6.6%), PSP (4.7%), MBCI (4.8%), corticobasal syndrome (5.9%), and the remaining 7% of participants had other dementia‐related diagnoses. For participants with sporadic disease, 87.4% live in a metropolitan area, 6.7% a micropolitan area, 3.2% a small‐town area, and 3.2% live in a rural area. In familial FTLD, a larger percentage of participants live in micropolitan or small town/rural community (18.8% combined; p = 0.029), driven largely by MAPT family participants (n = 101). 10% of those with a familial MAPT mutation live in a rural area; with an additional 18% in micropolitan (12.9%) or small‐town areas (5%). Among those with a familial C9orf72 expansion, 83.3% live in a metropolitan area, 8.9% micropolitan area, 5.6% in a small‐town area, and 2.2% in a rural area. Participants with a familial GRN mutation show a similar distribution: 84.7% live in a metropolitan area, 5.6% micropolitan, 6.9% small‐town, 2.8% rural.ConclusionsAdditional analyses to better understand if FTD families are disproportionately living in rural communities are underway. These analyses will better characterize sporadic and familial FTD demographics to assist with clinical trial design.

AbstractBackgroundPlasma biomarkers such as Aβ 42/40 have emerged as important tools to detect dementia risk, although whether plasma Aβ 42/40 levels and the associations with dementia risk differ by race is unclear. As part of the Health, Aging, and Body Composition study, we compared the plasma levels of Aβ 42/40 ratio and the associations with 15‐year dementia risk by race among community‐dwelling Black and White older adults.MethodsWe studied 997 dementia‐free participants (55% women, 54% Blacks) aged 70‐79 years (mean age 74.5±2.9) enrolled at baseline (1997‐98). We defined incidence dementia over 15 years based on hospital records, prescription for dementia medication, or a decline ≥1.5 standard deviations in the Modified Mini‐Mental State Examination score. Stored plasma obtained one year after baseline was used to measure Aβ with Innogenetics INNO‐BIA assays at Mayo Clinic, Jacksonville, FL. Plasma Aβ42/40 ratio was categorized into low, medium, and high tertiles. We used linear regression to estimate the difference in log‐transformed Aβ42/40 in Black and White participants and back‐transformed the effect estimates. We assess the association between Aβ42/40 (by tertiles) and dementia risk using Cox proportional hazards model stratified by race. All models were adjusted for age, sex, hypertension, diabetes, high cholesterol, and obesity, and we tested for interactions by race.ResultsBlack participants had significantly lower Aβ42/40 than White participants (‐4.4%, 95% CI ‐8.1% to ‐0.6%). In stratified analysis, lower Aβ42/40 was significantly associated with an increased risk of incident dementia among Black participants: 27.8% in medium (hazard ratio [HR] 1.69, 95% CI 1.07 to 2.68) and 33.5% in low (HR 2.07, 95% CI 1.32 to 3.24) compared with 17.3% in high Aβ42/40 tertile. The associations were somewhat weaker but showed the same trend among White participants: 20.3% in medium (HR 1.49, 95% CI 0.85 to 2.61) and 22.9% in low (HR 1.59, 95% CI 0.92 to 2.76) compared with 15% in high Aβ42/40 tertile. The interaction between Aβ42/40 and race was not statistically significant.ConclusionAmong community‐dwelling, non‐demented older adults, plasma Aβ42/40 differs by race, although the association with dementia risk does not differ by race.

AbstractBackgroundCardiovascular health plays an important role in brain aging; yet its role in development of autosomal dominant forms of dementia and frontotemporal dementia (FTD) has not been fully elucidated. Life’s Simple 7 (LS7) is a metric of cardiovascular health associated with reduced dementia risk and may represent a transdiagnostic heuristic to promote brain health. We examined the extent to which baseline LS7 associated with cognitive and brain aging trajectories in individuals with genetic FTD.Method243 adults carrying autosomal dominant genetic mutations for FTD and 189 non‐carriers completed neuroimaging, neuropsychological testing, and medical interviews. LS7 at baseline was computed following established procedures based on physical activity, diet, body mass index, smoking, hypertension, diabetes, and hypercholesterolemia; higher scores indicate more optimal cardiovascular health. We examined interactions between baseline LS7 and mutation carrier status on cognitive and brain structural outcomes at baseline (via linear regression) and longitudinally (via linear mixed‐effects models). All models adjusted for baseline age, sex, and education, and CDR®+NACC FTLD.ResultMutation carriers and non‐carriers did not significantly differ on baseline LS7 (t = ‐1.42, p = 0.156). At baseline, there were significant interactions between LS7 and carrier status on frontotemporal (FTL) volume and executive functioning (all p‐values<0.046), such that positive associations between LS7 and neurobehavioral outcomes were stronger among mutation carriers versus noncarriers. Longitudinally, there was also a significant interaction between carrier status and baseline LS7 on memory over time (b = 0.04,p = 0.035) and the interaction approached significance for language trajectories (b = 0.03,p = 0.079); again, the association between higher LS7 and slower cognitive decline was stronger among mutation carriers versus noncarriers, even when excluding symptomatic carriers (b = 0.04,p = 0.047). Among mutation carriers only, higher baseline LS7 related to slower memory (b = 0.04,p = 0.006) and language declines over time (b = 0.044,p = 0.004), but did not significantly relate to FTL volume (b = ‐0.01,p = 0.307) or executive functioning trajectories (b = 0.004,p = 0.913)ConclusionBetter cardiovascular health relates to larger baseline frontotemporal volume and slower cognitive decline in individuals with autosomal dominant FTD. Interaction models suggested the degree to which cardiovascular health associates with better neurobehavioral outcomes is stronger in mutation carriers. Optimizing cardiovascular health may be a particularly important, modifiable approach to mitigate the symptoms associated with pathogenic variants of FTD.

AbstractBackgroundSeveral studies suggest that premenopausal bilateral oophorectomy (PBO) is associated with an increased risk of cognitive impairment and dementia; however, the underlying brain changes are not well understood. Animal studies suggest that long‐term ovarian hormone deprivation in rats is associated with reduced white matter integrity, but few studies have been conducted among women. We assessed the impact of age at PBO before age 50 years on white matter integrity in a community‐based cohort of older women.MethodParticipants included 1,011 women enrolled in the Mayo Clinic Study on Aging (MCSA; 22 with PBO<40 years; 43 with PBO 40‐45 years; 39 with PBO 46‐49 years and 907 referent women). MCSA is a population‐based study of aging in Olmsted County, MN. PBO was abstracted from the medical records. Regional DTI metrics of fractional anisotropy (FA) and mean diffusivity (MD) were investigated using the Johns Hopkins University Atlas. Linear regression was used to examine the association between PBO age group and z‐scores of either FA or MD after adjusting for age at imaging and APOE.ResultThere were no differences in age at study visit (median = 72 years), education, APOE E4 frequency, or vascular comorbidities between the 3 groups of women with a history of PBO or referent women. Women with PBO<40 years, compared to referent women, had lower FA and higher MD in the anterior corona radiata, genu of the corpus collosum, inferior fronto‐occipital fasciculus, superior occipital, and superior temporal white matter. Women with PBO<40 years also had lower inferior frontal white matter FA and higher posterior thalamic radiation MD. Women who underwent PBO between 40‐44 years or 45‐49 generally did not have significant changes in white matter integrity compared to referent women.ConclusionWomen who underwent premenopausal bilateral oophorectomy prior to the age of 40 years had reduced white matter integrity across multiple regions in later‐life. These results are important for the education of women at a low risk for ovarian cancer who are considering PBO for benign conditions.

AbstractBackgroundEthnoculturally diverse individuals from underrepresented populations (URPs), including but not limited to Black/African American and Hispanic/Latinx adults, are disproportionally affected by Alzheimer’s disease (AD) compared to non‐Hispanic/Latinx white (NLW) adults. However, URPs have historically been under‐included in AD studies. The objective of this study is to describe efforts, and the results of those efforts, to increase enrollment and engagement of ethnoculturally diverse individuals from URPs in the Alzheimer’s Disease Neuroimaging Initiative 3 (ADNI3).MethodsEfforts undertaken by ADNI to increase enrollment and engagement of URPs included (1) launching of a Diversity Taskforce (DVTF) lead by two health disparities experts in July 2020, charged with overseeing ADNI’s mission in this space. Specific DVTF activities included: (2) the establishment, funding, and instrumental support (e.g., training, consultation, resources) of diversity at 13 ADNI3 sites; (3) changing ADNI protocol to facilitate research participation of URPs (e.g., optional lumbar puncture and sharing of amyloid PET results); (4) hiring a marketing agency to launch culturally‐informed digital/social media campaigns for the 13 DVTF Sites, with local websites; (5) development of a database to capture performance metrics of inclusion efforts at the 13 DVTF Sites; and (6) formation of a six‐member External Advisory Board, comprised of leaders in health disparities research, to guide DVTF efforts.ResultURP enrollment at these 13 DVTF sites improved from 1.1 URPs per month previously to >4 URPs per month, a 264% increase. Across all 59 ADNI sites, overall enrollment of ethnoculturally diverse individuals from URPs went from 89 (16.8%) to 126 (21.1%), representing a 25% increase in enrollment between May 2020 and September 2021. Moreover, since February 1st, 2021, ADNI enrolled 43 new participants of which 33 (77%) were from URPs.ConclusionIt is possible to improve the enrollment and retention of URPs in AD research using a multi‐pronged community engaged approach that also provides human capital, infrastructure, and financial resources. The success of the DVTF has led to the formation of a new Engagement Core in ADNI4, tasked with implementing a scaled‐up culturally‐informed, community‐engaged research approach to URP inclusion and retention across all 59 ADNI sites.

AbstractBackgroundAfrican Americans experience a high dementia burden yet are critically underrepresented in observational studies and clinical trials in memory and aging. Lack of adequate representation increases the likelihood that research findings may not generalize to African Americans. A deeper understanding of the barriers and facilitators that influence participation by younger and older African American adults is needed to support recruitment and retention in studies focused on early‐ and late‐onset neurodegenerative diseases.MethodAfrican American community leaders collaborated in design of an electronic survey that was distributed via social media focused on local zip codes. Survey respondents rated barriers and facilitators to research participation on a 0–3‐point Likert scale. Responses ≥2 corresponded with barriers/facilitators likely to influence participation decisions. Differences across age groups were evaluated using nonparametric Kruskal‐Wallis tests. Strategies to mitigate barriers and reinforce facilitators were further explored via community‐based focus groups.ResultSurvey data included responses from 240 African Americans (18‐44‐years, n = 76; 45‐64‐years, n = 83; ≥65‐years, n = 81). Requirement to undergo a diagnostic lumbar puncture was a substantial barrier to research participation across all age groups. Attending weekday visits (median = 2.0), including visits ≥2 hours (median 2.0), was a substantial barrier for individuals 18‐44‐years, but not older respondents (p = 0.001). Compensation for meals/transportation was beneficial across all age groups (median = 2.0; p<0.05). The option to attend visits in the local community or on weekends and access to door‐to‐door transportation were substantial facilitators for respondents <65‐years (median = 2.0) vs ≥65‐years (median = 0; p = 0.001). The option to complete some tests at home was a substantial facilitator for younger (18‐44‐years, median = 2.0) but not older respondents (≥65‐years, median = 0; p = 0.001). Focus group results supported survey findings and showed slight variations in priorities across age groups. Older participants (≥65‐years‐old) more frequently cited the longstanding effects of racism as a barrier to research participation compared to younger participants (45‐64‐years‐old; p = 0.008), who more frequently cited concerns regarding testing requirements (p = 0.034).ConclusionPerceived barriers and facilitators to research participation vary with age. Age‐specific strategies are needed to increase engagement, address disparities in recruitment, and promote retention of African American participants in studies of memory and aging across the lifespan.