The minimal amyloid accumulation (MAA) in cognitively unimpaired individuals that predicts the onset of cognitive impairment remains unknown. In a multi-center amyloid positron emission tomography (PET) study of 1834 cognitively unimpaired participants with longitudinal clinical/cognitive assessments for up to 20.3 years, we found that 48.7% of the amyloid-negative participants with MAA starting from an amyloid PET centiloid of 1.03 had a higher risk of cognitive impairment than those with the lowest centiloid values (<1.03; hazards ratio (HR)=1.40, p=0.0046), although their risk was clearly lower than amyloid-positive participants (centiloid>20; HR=0.47, p<0.0001). Amyloid positivity was also associated with the fastest longitudinal amyloid accumulation and cognitive decline, followed by the MAA, and finally by the lowest amyloid. These findings suggest that current thresholds of amyloid positivity used for Alzheimer disease diagnosis may be overly restrictive, potentially excluding a large portion of amyloid-negative participants at elevated risk of developing cognitive impairment from prevention trials.

Abstract INTRODUCTION Positron emission tomography (PET) without usable or accompanying magnetic resonance imaging (MRI) is typically excluded in quantitative analyses of Alzheimer's disease, potentially limiting study generalizability. We investigated participant features predicting data exclusion in magnetic resonance (MR)‐dependent analyses and evaluated an existing MR‐free PET pipeline to quantify these missing data. METHODS Imaging, clinical, cognitive, and sociodemographic data were analyzed for 2119 individuals in a multi‐site cohort. Agreement between MR‐dependent and MR‐free Centiloids (CL) assessed using intra‐class correlations and features predicting data exclusion were examined using logistic regressions. RESULTS MR‐free and MR‐dependent CLs generally agreed, but MR‐free CLs underestimated MR‐dependent cross‐sectionally and longitudinally. Approximately 19.5% (n = 405) of our cohort would have been excluded in MR‐dependent analyses. Age and cerebrovascular comorbidities were consistent exclusion features across multiple sites. DISCUSSION Data exclusion in imaging studies is not entirely random. Flexible quantification methods like MR‐free PET could supplement traditional methods to improve generalizability in large, multi‐site studies.

Cerebral hypoperfusion and blood-brain barrier (BBB) leakiness are related to cognitive decline and the onset and spread of Aβ and tau pathology in Alzheimer's disease (AD). Disrupted angiopoietin/TIE (ANGPT/TIE) signalling causes neurovascular instability and BBB leakiness accelerating cognitive decline and disease pathology in mouse models of AD. To explore ANGPT/TIE signalling in human AD, we measured CSF TIE-1 and TIE-2 levels by ELISA in two independent clinical dementia cohorts, and serum and CSF Tie-1/-2 in paired CSF and serum samples from neurologically normal individuals. ANGPT1, ANGPT2, TIE-1 and TIE-2 levels were measured by ELISA in crude homogenate (CH) and microvessel-enriched fractions (MVFs) of post-mortem human parietal cortex in relation to biochemical markers of cerebral perfusion (MAG:PLP1) and BBB leakiness (parenchymal fibrinogen) in a control, AD, and vascular dementia (VaD) cohort. CSF soluble TIE-2 was elevated in AD biomarker+ve individuals and correlated positively with CSF t-tau and p-tau, and markers of BBB leakiness, neuronal injury, and neuroinflammation. Tissue TIE-2 levels were significantly reduced in Braak tangle stage (BS) III-IV, that is, brains with early-intermediate AD pathology, and were lower in MVFs in end-stage AD pathology (BSV-VI) than in controls or VaD. Lower levels of MVF TIE-2 correlated with markers of cerebral hypoperfusion and BBB leakiness. Our study reveals a reciprocal relationship between elevated CSF and reduced tissue TIE-2 expression that is related to markers of tau pathology, BBB leakiness, and cerebral hypoperfusion, providing novel insights into ANGPT/TIE signalling in AD.

Prior research has highlighted the impact of neighborhood quality on health outcomes. Given veterans' unique experiences and challenges, exploring the association between neighborhood quality on cognitive measures and vascular risk scores is crucial for guiding targeted interventions, improving overall cognitive well-being, promoting health equity, and contributing to our understanding of Alzheimer’s Disease (AD) risk factors. The Brain Amyloid and Vascular Effects of Eicosapentaenoic Acid study (BRAVE) was an 18-month randomized, placebo-controlled, double-blind, clinical trial conducted at William S. Middleton Memorial Veteran’s Hospital in Madison, Wisconsin. This analysis used cross-sectional data on VA-eligible Veterans between the ages of 50 and 75 with no clinical diagnosis of a memory disorder. Study analyses included N = 201 Veterans who completed pre-study screening and N = 129 who completed a baseline visit. Cognitive outcomes were collected at the baseline visit and ASCVD scores were collected during screening. Of the Veterans who completed a pre-study screening, live in Wisconsin (N = 164), Illinois (N = 34), Iowa (N = 2) and Minnesota (N = 1). The main outcomes are ASCVD risk score and Preclinical Alzheimer’s Cognitive Composite (PACC). The Area Deprivation Index (ADI) state decile measures neighborhood quality on 18 metrics. For this study, participants in the most disadvantaged (ADI 7-10) were compared to participants in the least disadvantaged neighborhoods (ADI 1-6). In the prescreening cohort, 87.7% of participants were male and 89.4% non-Hispanic, white. In the baseline cohort, 84.5% of participants were male and 94.7% were non-Hispanic, white. PACC scores were significantly lower (PACC; p = 0.007; Cohen’s D = 0.562) for participants living in the most disadvantaged neighborhoods (-0.42, SD = 0.98, N = 31) compared to the least disadvantaged (0.13, SD = 0.97, N = 98). The group mean differences in ASCVD scores were not statistically significant. Our findings reveal that Veterans in the most disadvantaged neighborhoods exhibit lower cognitive performance. We found no significant association between neighborhood disadvantage and cardiovascular risk scores. These findings emphasize the importance of implementing targeted interventions to address cognitive health disparities in disadvantaged areas. Further exploration with a larger and more representative sample is essential to gain a comprehensive understanding of the relationship between neighborhood disadvantage, cognitive health disparities, and cardiovascular risk factors among Veterans.

AbstractINTRODUCTIONUnderstanding how a research sample compares to the population from which it is drawn can help inform future recruitment planning. We compared the Wisconsin Alzheimer's Disease Research Center (WADRC) participant sample to the Wisconsin state population (WI‐pop) on key demographic, social exposome, and vascular risk measures.METHODSThe WADRC sample included 930 participants. Population statistics were estimated using several national and state data sources. We compared WADRC to WI‐pop for two age groups, 45–64 years and ≥65 years, separately.RESULTSCompared to WI‐pop, WADRC participants were older and included more women, more Black and American Indian individuals, and fewer Hispanic and Asian individuals. WADRC participants had higher levels of educational attainment, consisted of smaller proportions living in rural areas and disadvantaged neighborhoods, and showed lower vascular risks. Greater differences between WADRC and WI‐pop were found for most metrics in the ≥65 group compared to the 45–64 group.DISCUSSIONThe findings revealed opportunities to increase enrollment from the Hispanic/Latino and Asian American populations, to include participants from a broader range of educational backgrounds, and to enroll more residents from rural areas and disadvantaged neighborhoods, which may lead to a broader distribution of cardiovascular risk factors. Expanding sociodemographic and health profiles represented in the participant candidate pool for study selection and including those who are underrepresented in research may potentially reduce selection bias but not eliminate it. Statistical approaches can be applied to address bias and generalize findings from a study sample to its target population by adjusting for their differences in the joint distribution of covariates. Although research centers have different regional populations and specific recruitment focuses for scientific reasons, evaluating their participant characteristics may help plan engagement efforts to improve the inclusion of underrepresented groups and collaboratively support generalizable research nationwide.Highlights We compared the characteristics of Wisconsin Alzheimer's Disease Research Center (WADRC) participants with the Wisconsin population. Metrics of comparison included demographics, social exposomes, and vascular risks. WADRC participants are different from the Wisconsin population. We explored the implications and causes of the differences. We discussed strategies for engaging and recruiting underrepresented groups.

Individuals’ attitudes toward research predict recruitment, engagement, and retention. The Research Attitudes Questionnaire (RAQ), developed to predict individuals’ willingness to participate, is often used in AD research. It can be used to identify strategies to mitigate individuals’ reluctance to engage in research. To date, there are mixed findings regarding diverse groups’ willingness to engage in AD research. Between-group comparisons are only meaningful and valid when the measures being used reflect true group differences in the construct i.e., measurement invariance (MI). One of the prerequisites for meaningful comparisons across diverse groups is to have measurement invariance. The study goal was to examine the suitability of the RAQ across age and ethno-racialized identities. We explored the MI of the 7-item RAQ using Confirmatory Factor Analysis (CFA) via Mplus in a community-derived sample of 457 younger and 594 older African American, 307 younger and 339 older American Indian/Alaska Native, and 173 younger and 679 older Non-Hispanic White male and female individuals. CFA evaluated the one-factor model across the groups. Subsequently, loadings, means, and residuals were consecutively constrained to equality. We examined whether the increased restrictions produced significant changes in the data-model fit to determine whether conditions were met to demonstrate varying levels of measurement invariance. Table 1 summarizes sample demographics and provides mean total RAQ scores. The RAQ showed good internal consistency across age and ethno-racialized groups (Cronbach’s a ranging from 0.78 to .85). A one-factor model showed acceptable fit across the groups (Table 2). The results of the cross-sample invariance tests are provided in Table 3. We found evidence of configural invariance; comparisons of successive models supported metric invariance, and scalar invariance. Strict invariance was not supported. These data suggest that across the 6 groups, who differed in terms of age and ethno-racial identity, the strengths of associations between the specific scale items and the latent construct being assessed by the RAQ are the same. However, the groups may differ in the extent to which they are characterized by the latent variable. This finding supports the suitability of the RAQ for cross-cultural comparisons of willingness to engage in research.

OBJECTIVES:To assess the long-term effects of 4 years of menopausal hormone therapy (mHT) on the brain's white matter architecture in women who initiated mHT within 3 years of menopause onset. METHODS:The Kronos Early Estrogen Prevention Study (KEEPS) was a multicenter, double-blind, randomized, placebo-controlled 4-year mHT trial with treatment arms of oral conjugated equine estrogens (oCEE), transdermal 17β-estradiol (tE2), and placebo in recently postmenopausal women. KEEPS Continuation was an observational follow-up of KEEPS participants. White matter integrity was evaluated in KEEPS Continuation participants 10 years after KEEPS completion using white matter hyperintensity volume, diffusion magnetic resonance imaging (dMRI) techniques, and cerebral infarcts. Linear regression models were fitted for each brain region to evaluate if there were differences in white matter between KEEPS treatment arms. RESULTS:There was no evidence to suggest the long-term effects of 4 years of mHT on brain white matter in KEEPS Continuation participants [n=266, mean age 67 (58-73)]. No differences in dMRI metrics were found in each of the treatment arms (oCEE n=70; tE2 n=79) when compared to placebo (n=94), following a false discovery rate adjustment for multiple comparisons. There were no statistically significant differences in white matter hyperintensity volume or infarct occurrence when comparing each of the treatment arms to placebo. CONCLUSIONS:We found no evidence of the long-term effect of 4-year mHT on white matter integrity when compared to placebo, consistent with emerging evidence of the safety of short-term use of mHT in recently postmenopausal women.

Background:The Research Attitudes Questionnaire (RAQ), developed to predict individuals' willingness to participate, is often used in Alzheimer's Disease and related dementia research. Objective:The present investigation aimed to examine the suitability of the RAQ across age groups and three different racialized identities, i.e., to see whether the RAQ showed measurement invariance. Methods:We administered the RAQ to six groups of participants: 457 younger and 594 older African Americans, 207 younger and 339 older American Indian/Alaska Native, and 173 younger and 679 older non-Hispanic White adults. Results:Confirmatory factor analysis indicated that the best-fitting model was one-factor. All six groups fit the model well, with Comparative Fit Indices > 0.95. A series of cross-sample invariance tests using increasing constraints on factor loadings, means, and residuals revealed evidence of configural invariance, metric invariance, and partial scalar invariance. Conclusions:These findings support the suitability of the RAQ for cross-cultural and/or age comparisons of willingness to engage in research in the groups and context studied.

OBJECTIVE:To assess the association of systolic and diastolic blood pressure (SBP and DBP) in recently menopausal women with white matter hyperintensity (WMH) volume later in life and determine whether short-term menopausal hormone therapy (mHT) modifies these associations. METHODS:Kronos Early Estrogen Prevention Study (KEEPS) was a multicenter, randomized, double-blinded, placebo-controlled 4-year mHT trial (oral conjugated equine estrogens or transdermal 17β-estradiol). KEEPS continuation was an observational follow-up of the participants 10 years after the end of mHT. The associations between KEEPS baseline blood pressure (BP) with KEEPS continuation WMH volume were examined adjusting for covariates in model 1 (age, total intracranial volume, study site, mHT type) and model 2 (additionally conventional CVD risk factors). Interaction terms (BP × mHT type) were added into the linear regression models. RESULTS:The mean ± SD ages of participants were 53 (±2) years at KEEPS baseline and 67 (±2) years at KEEPS continuation. Elevated BP at KEEPS baseline was associated with greater WMH volume measured 14 years later (model 1: SBP: β = 0.01 [95% CI, 0.001-0.01] and DBP: β = 0.01 [95% CI, 0.003-0.03]) and after additionally adjusting for CVD risk factors (model 2). We did not find any evidence that mHT versus placebo modified these associations. Topographically, higher BP was associated with greater periventricular WMH in the frontal and parietal lobes. CONCLUSION:Our findings suggest the importance of maintaining normal BP in recently postmenopausal women with low CVD risk, irrespective of short-term mHT usage, to potentially reduce the risk of WMH later in life.

Despite decades of evidence of the problem, participant samples in aging research often fail to adequately represent the population of older adults. For example, clinical research studies of Alzheimer’s Disease, which disproportionately affects African American and Latine adults, frequently include over-representations of non-Hispanic White participants, limiting our full understanding of disease presentation and our ability to provide appropriate care for patients and caregivers. Authentically participant-centered research engagement offers promise to address this problem. However, few studies have specifically addressed how to create studies that participants, particularly those who are underrepresented currently, find acceptable and accessible. This presentation will include findings from a study of the real-world decision-making processes for African American adults (aged 53-77 years old) who had recently decided on their willingness to participate in the African Americans Fighting Alzheimer’s in Midlife (AA-FAIM) study. Semi-structured interviews were conducted with those who eventually agreed to participate in AA-FAIM (n = 25) and those who declined participation (n = 18). Interviews were recorded and transcribed to facilitate a thematic analysis following Braun and Clarke. Findings reveal both positive and negative factors weighed in decision-making, including study team interactions, past experiences in research, personal experiences with Alzheimer’s Disease, study requirements, and accessibility. Participants also offered that relationships with other study participants, a factor not reported in similar studies, figured into decision-making for many of those we interviewed.

Plasma pTau217 (tau phosphorylated at threonine 217) assays will expand access to screening for Alzheimer’s disease (AD). However, clinical interpretation is not well-established, particularly during the preclinical window when interventions may be most effective. Using plasma samples from primarily late-midlife, cognitively unimpaired Wisconsin Registry for Alzheimer’s Prevention (WRAP) and Wisconsin Alzheimer’s Disease Center (WADRC) participants, we investigated pTau217 agreement with amyloid and tau PET then compared trajectories between participants grouped by baseline pTau217. EDTA plasma samples from 428 participants were analyzed using the ALZpath pTau217 Simoa assay on a Quanterix HD-X (Table 1). Amyloid and tau positivity were defined as global [ 11 C]-PiB DVR>1.19 (21.6 centiloids) and [ 18 F]-MK6240 temporal meta-ROI SUVR>1.3, respectively. In separate receiver operating characteristic (ROC) analyses using pTau217 to classify amyloid and tau PET, the area under the curve (95% CI) and optimal (Youden) cutoffs were, respectively: 0.91 (0.87-0.94), 0.37 pg/mL; and 0.89 (0.83-0.94), 0.53 pg/mL. To characterize pTau217 rates of change based on baseline measurements, participants were clustered into low (≤0.37 pg/mL), intermediate (0.37 < pTau217 < 0.53 pg/mL), and high (≥0.53 pg/mL) groups according to the ROC thresholds. Linear mixed models were then run with group and age as fixed effects and including random person-level intercept and age slopes. Mean pTau217 concentration was 2.5 times higher for amyloid positive participants compared to amyloid negative (Figure 1A; p < 0.001). Significant differences were also observed between CU, MCI, and dementia groups (Figure 1B; CU-MCI: p < 0.001, CU-MCI: p<0.001, Dementia-MCI: p<0.001). Mixed effects models indicated that pTau217 increased at a higher rate in the high group compared to other groups (Figure 2; simple slopes low-high: t(361)=-7.010, p<0.001, intermediate-high: t(318)=-5.712, p < 0.001). No differences were observed between simple slopes for low and intermediate groups (t(235)=-0.314, p=0.9470). These results suggest that plasma ALZpath pTau217 is a very good proxy for molecular PET for detecting AD pathology prior to symptoms. Strategies such as assigning an indeterminate zone for secondary confirmation (Brum, W., et al, 2023) would improve accuracy and lessen the burden on existing resources while expanding access to the broader community.

This paper presents findings from the Indigenous Cultural Understandings of Alzheimer’s Disease and Dementia (ICARE) Project. We share our analysis of qualitative data generated in partnership with four Indigenous communities in Canada and the US. We interviewed dementia program and health care administrators (n = 20) and held sequential focus groups with local health care staff/formal caregivers who work with Indigenous older adults (18 sessions, n = 17) between 2018-2021. Topics focused on the community experience of dementia across the disease trajectory. Four qualitative analysts coded and analyzed data in partnership with PIs, community-based researchers, and senior researchers. The analysis resulted in identifying three key cultural responses communities employ to care for people living with dementia across the disease continuum. First, a relationality perspective that underscores the importance of ongoing care needs rooted in relationship-building through cultural practices such as visiting. Second, community care activates community support systems, prioritizing training opportunities and decentralizing responsibilities and rights to care away from Western institutions. Finally, care models that support and center the family; coordinating with family members across institutions and specialists were a key concern. These findings have been translated into an Indigenous dementia care framework that highlights these three domains and prioritizes strength-based strategies that communities use to mitigate the colonial erasure of Indigenous practices and worldviews. Working with community partners, we have received further feedback on the framework, identifying differences in community uses for the framework and issues that apply more broadly across the four sites for future work.

In this paper, we present our framework for community-engaged research in our American Indigenous Cognitive Assessment (AMICA) project (R01AG074231). AMICA aims to develop and validate a culturally appropriate dementia screening toolkit, which includes a cognitive assessment, caregiver report, depression scale, and inventory of Activities of Daily Living. Our multi-site project involves community partners in Red Lake Nation, Minnesota; an urban Indigenous population in Albuquerque, New Mexico; and the Oneida Nation in Wisconsin. Each site includes local community-based researchers and Indigenous Knowledge Advisory Groups (IKAGs) that review and adapt dementia screening tools to be more culturally safe and relevant. In order to develop a single dementia evaluation toolkit for Indigenous populations throughout the United States, two IKAG members from each partner site were nominated to form a National IKAG to come to consensus on the adapted tools. Our methodology also includes the integration and use of Two-Eyed Seeing as an iterative framework, which incorporates both biomedical and Indigenous ways of knowing. In addition to the National IKAG, the AMICA project also includes an Assessment Expert Panel (AEP) consisting of experts in medical anthropology, geriatric medicine, neuropsychology, and other disciplines. We implement our community-engaged research framework to create a single intercultural dementia screening toolkit for Indigenous populations throughout the United States.

INTRODUCTION:Elevated tau (T+) is temporally proximal to dementia onset but less is known about factors influencing T+ onset age and time to dementia after T+ in Alzheimer's disease (AD). We used sampled iterative local approximation (SILA) estimated T+ onset age (ETOA) to investigate factors associated with T+ age and time from T+ to dementia onset in the Alzheimer's Disease Neuroimaging Initiative. METHODS:Using SILA-estimated amyloid positivity and T+ onset ages derived from 18F-Flortaucipir, 18F-Florbetapir, and 18F-Florbetaben positron emission tomography and Cox proportional hazards and accelerated failure time models, we analyzed apolipoprotein E (APOE), sex, amyloid burden, age, educational attainment, and literacy associations with ETOA and time from T+ to dementia. RESULTS:Higher amyloid, APOE-ε4, lower education, and lower literacy associated with younger ETOA. Older ETOA and higher amyloid associated with shorter time from T+ to dementia. DISCUSSION:This work highlights the prognostic value of ETOA and the need to better characterize factors contributing to ETOA and dementia onset in AD. HIGHLIGHTS:We applied sampled iterative local approximation (SILA) to Alzheimer's Disease Neuroimaging Initiative 18F-Flortaucipir data, to estimate individuals' age of tau pathology onset (T+) and time from T+ onset to dementia. Higher amyloid, apolipoprotein E ε4, lower education, and lower literacy associated with younger estimated T+ onset age. Older T+ onset age and higher amyloid associated with shorter time from T+ to dementia. Only one individual was observed to remain dementia free 14 years after T+ onset. This work highlights the prognostic value of T+ onset age and the need to better characterize factors contributing to T+ onset age and dementia onset in Alzheimer's disease.

Objectives To determine whether MBI associates with worse cognitive performance over time and with incident cognitive decline in an older, racially/ethnically diverse cohort at early stages of cognitive change. Design This observational cohort study followed participants from the Wisconsin Alzheimer’s Disease Research Center Clinical Core (WADRC) for up to 13 visits. Setting An urban university research center. Participants Participants from the WADRC Clinical Core were included in this convenience sample if they were without dementia, had undergone at least 1 cognitive assessment, and completed measures of cognitive, clinical and affective function. Measurements MBI was assessed using the Neuropsychiatric Inventory. Linear mixed effects models (LME) were fit to cognitive outcomes Trailmaking Tests A and B (TMT-A, B) and Wechsler Logical Memory (LM). Cox proportional hazard models assessed whether MBI was related to risk for incident global Clinical Dementia Rating Scale (CDR >0). Results N = 584 participants with mean age 64.6 years, range 46-92.6 years, 59.4% female and 17% African American. LME results indicated participants with MBI exhibited worse age-associated decline on TMT-B, compared to those without MBI (beta=0.008, p = 0.01, CI: 0.002, 0.01, t(337) = 2.4, p = 0.01). MBI at baseline was associated with a significant hazard ratio (HR) indicating an increased risk of decline on the CDR (HR: 2.84; HR 95% CI: 1.68 — 4.81; p = 0.0001). Conclusions MBI associated with worse cognitive performance and incident cognitive decline in a racially diverse, older adult sample at early stages of cognitive change. Increased awareness of the late life emergence of neuropsychiatric symptoms is warranted to assist in identification and improve prognostication and treatment of neurodegenerative disease.

To increase participation of underrepresented groups (URG) into clinical research studies such as the AHEAD study, a study assessing lecanemab in participants with preclinical Alzheimer’s disease (AD), it is necessary to understand and address barriers in an effort to mitigate them. Toward this goal, methods assessing community needs and plans to meet those needs are imperative. Our ultimate goal is to aid URG in understanding the clinical research process and to empower them to participate in AD research so that approved therapies are applicable to them. This work was made possible by an AHEAD Diversity Recruitment Supplement grant funded to University of Wisconsin-Madison (UW-Madison) by the Alzheimer’s Clinical Trial Consortium (ACTC) to increase URG participation in the AHEAD study. Our approaches include using surveys to identify barriers in order to develop a strategic plan to overcome them. Surveys assessed whether potential participants had knowledge of 1) lecanemab, 2) the AHEAD study, and 3) if they would be comfortable in a study involving a medication, among others. Interested individuals were rewarded with a swag bag for completing the surveys The findings showed that URG were not likely to be aware of lecanemab or the AHEAD study. Additionally, while they wanted to know if they met the criteria for the study, they were less comfortable about a clinical study involving a medicine (Figures 1). Moreover, we identified other barriers to research participation, such as factors that were more likely to prevent URG from meeting study criteria. These included not knowing family history or their AD biomarker status, which was necessary inclusion criteria for individuals age 55-64 (Figure 2). Surveys at community events are useful in identifying barriers to the engagement of URG in AD clinical trials. To decrease barriers and push the pendulum towards increased participation of URG in biomedical research, increased educational efforts are needed on AD, the clinical trial process, and drug development. Moreover, researchers must make sure that URG are not ruled out from the study onset, meaning inclusion criteria must consider some unknown challenges such as not knowing medical or family history.

Ethnic and racial diversity in clinical research is critical for developing generalizable treatments and caregiving strategies. Barriers to participation among persons from underrepresented groups (URG) are systemic in clinical research. To increase URG research participation, we designed a community-based data collection site where study participants complete full research visits. For an Alzheimer’s disease study, we established the first community-based data collection site in Madison, WI, forging connections with Black community leaders and campus outreach staff. The site is proximal to diverse neighborhoods, public transportation, and is a hub for multi-ethnic businesses. We rent space in the South Madison Partnership Office, an established community outreach center. This has allowed us to cultivate a consistent presence in the Black community, which evolved into a full data-collection site. Staff include research specialists, community liaisons, nurse practitioners, and clinicians who are culturally-aware and members of the Black community. The site is decorated with art from local Black and Indigenous artists, and food served is from a local Black-owned business. We established proof of concept by successfully launching a fully-equipped research site in the community, used for memory testing, biometric readings, blood draws, and one-on-one conversations with clinicians. Initial comments suggest participants prefer this comfortable, familiar setting over that of a hospital setting. Researchers can use culturally-aware and convenient data collection sites. Our site prioritizes the needs of participants toward the goal of achieving representation of racialized groups in research. This model has potential for broad implementation across aging and biomedical research.

Recent advances in Alzheimer’s disease (AD) temporal biomarker modeling have revealed considerable heterogeneity in age at amyloid onset, and recently we and others identified sex and APOE differences in tau onset age and subsequent dementia development. Here we assessed whether amyloid burden, APOE-ε4 dose, and sex interact to predict estimated T+ onset age (ETOA). Alzheimer’s Disease Neuroimaging Initiative participants (N=911, Table 1) underwent serial PET imaging to quantify global cortical amyloid ([18F]Florbetapir SUVR 50-70 , [18F]Florbetaben SUVR 90-110 ) and meta-temporal tau ([18F]Flortaucipir SUVR 80-100 ) burden. Cortical amyloid SUVRs were harmonized using linear transformation to Centiloids (CL). Sampled iterative local approximation (SILA) was used to model ETOA and, separately, to estimate amyloid CL burden at ETOA. Kaplan-Meier survival curves and Cox regression were used to test CL*APOE-ε4*sex interaction effects on ETOA. Event time was ETOA for T+ individuals and age at last tau PET scan (right censored) for T- individuals who could become T+. We observed a significant CL*APOE-ε4*sex interaction on ETOA (p=0.013, Table 2). APOE-ε4 was associated with earlier ETOA in a dose-dependent manner and effects were greater in females compared to males. ETOA differences between sexes and across APOE-ε4 were attenuated at higher amyloid burden, largely due to the increased presence of T+ across all APOE-ε4 statuses and both sexes (Figure 1). Main effects also revealed that higher cortical amyloid burden at ETOA was associated with earlier ETOA and greater T+ risk, as was greater APOE-ε4 dose (Table 2). These results suggest that amyloid burden, APOE-ε4, and sex may influence when temporal tau deposition becomes abnormal. Smaller sample size among APOE-ε4 carriers, and especially ε4 homozygotes, limits the estimates in this cohort. Future extensions of this work will expand to a multicohort sample, to attempt replication of these findings and to investigate how these factors and their interaction predict time from amyloid and tau onset to dementia.

Each year, millions of Americans experience mild traumatic brain injury (mTBI). Current research on the long-term effects of mTBI vary considerably. Several mechanisms linking mTBI to dementia have been proposed including amyloid plaque formation and cerebrovascular injury following mTBI. Veterans have higher rates of mTBI than non-Veterans. As efforts to increase Veteran enrollment in clinical trials and studies related to Alzheimer disease expand, it is critical to understand the potential impact of mTBI on cognitive ability and factors related to risk for AD. This study leveraged two cohorts to examine the association between history of mTBI and white matter hyperintensity lesion volume (WMLV), CSF pTau181, total tau, and Aβ42, and cognitive ability. The sample comprises, N = 131 VA eligible Veterans without memory impairment enrolled in the Brain Amyloid and Vascular Effects of Eicosapentaenoic Acid (BRAVE) clinical trial (NCT02719327) and N = 320 participants in the Wisconsin ADRC clinical core, including n = 36 identified as Veterans. BRAVE participants reported if they had experienced symptoms of mTBI (e.g. loss of consciousness, dizziness, headache). ADRC participants indicated if they had a recent or remote mTBI; participants with a recent mTBI were excluded (n = 6). CSF samples were assayed using elecsys® beta-Amyloid(1_42) CSF II, phopho-Tau (181P), and Total tau assays (Roche Diagnostics International, Switzerland) and log-transfomed prior to analyses. WMHLV adjusted for TIV was binarized to WMH presence or absence. Separate Preclinical Alzheimer’s Cognitive Composite scores were created for BRAVE and were analyzed separately. Regression models included gender, age at study visit, clinical status and education level (PACC only) as covariates. Demographics and study outcomes stratified by cohort and Veteran status are shown in Table 1 and 2. Veterans had higher rates of mTBI than non-Veterans. History of mild TBI status was unrelated to study outcomes (see Figure 1; WMH presence: p = .06; CSF biomarkers: p s = .50 to .88; BRAVE-PACC: p = .15, ADRC-PACC, p = .48). History of mild TBI had no long-term impact on cerebrovascular dysfunction, AD biomarkers or baseline cognitive performance. Further analyses will explore severity of TBI (with or without loss of consciousness) on study outcomes as well asexamine the impact of mTBIon change in cognitive performance and biomarkers of neuroinflammation.