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Background Adults from underrepresented populations (URPs), including non‐Latinx NLB (NLB) and Latinx adults, have higher Alzheimer’s disease and related dementia (ADRD) rates than non‐Latinx Whites (NLWs). Young onset dementia is diagnosed when symptom onset occurs before age 65, and little is known about mild cognitive impairment (MCI) and dementia rates in younger URPs. We examined neurocognitive diagnoses, amyloid positivity, and psychiatric symptoms in adults from URPs under 65. Methods A total of 1,562 participants under 65 (Mage = 57.8, SD = 4.18; Meducation = 13.08, SD = 4.09; Ethnocultural Status: 28.9% NLB, 46.2% Latinx, 24.9% NLW; Gender: 65.5% Female) from the Health and Aging Brain Study‐Health Disparities (HABS‐HD) completed a neuropsychological (NP) battery and received Clinical Dementia Rating Scale (CDR) scores. Study partners completed the Physician’s Estimate of Duration for AD‐related psychiatric symptoms (e.g., mood changes, anxiety/nervousness). Diagnoses (i.e., cognitively unimpaired (CU), MCI, dementia) were conferred using HABS‐HD consensus diagnosis criteria. A subset of 756 participants (M = 57.4, SD = 4.21; 57.7% NLB, 27.6% Latinx) underwent PET imaging with Florbetaben (FBB); amyloid positivity was defined by an SUVR of 1.08. Chi‐square tests were computed to examine associations across ethnocultural groups (i.e., NLB, Latinx, and NLW) and neurocognitive diagnoses, amyloid positivity, and psychiatric symptoms. Results The NLB group had significantly higher rates of MCI and lower rates of CU based on consensus diagnoses (n = 451; MCI = 30.6%, CU = 63.2%), compared to NLW (n = 389; MCI = 14.1%; CU = 80.7%, X2 = 41.20, p<.001) and Latinx groups (n = 722; MCI = 18.6%; CU = 76.2%, X2 = 40.09, p<.001). The NLB group also had higher rates of psychiatric symptoms, including mood changes (X2 = 17.70, p<.001), anxiety/nervousness (X2 = 13.05, p = .001), and aggression/irritability (X2 = 15.29, p<.001) compared to NLW and Latinx groups. In contrast, amyloid positivity and dementia rates did not significantly differ across groups (all ps>.05). Conclusion Young NLB participants in HABS‐HD had increased rates of MCI and psychiatric symptoms compared to NLW and Latinx participants. Also notable, there were no significant ethnocultural differences in amyloid positivity or dementia diagnosis. These patterns differ from those previously documented in primarily NLW samples, suggesting that psychosocial and possibly sociocultural factors may differentially affect cognitive health outcomes among middle‐aged NLB adults. Future research, with deeper sociocultural phenotyping, may help elucidate the potential mechanisms driving these differences.

Background Early onset dementia (EOD) affects people at the peak of personal and professional responsibilities and economic productivity. Alzheimer's disease (AD) and Frontotemporal Dementia (FTD) are the most common EOD etiologies, but have not been studied in a sample representative of the general US population. Multiple barriers impede research participation for many groups, but community‐engaged research (CER) strategies to enhance recruitment may make research participation more accessible and convenient for all. Method BEYONDD is an NIH‐funded, community‐based study focused on understanding the etiology of EOD, uses CER strategies such as remote assessments and return of research results as tools for enhancing sample representativeness. Participants are recruited using social media and local in‐person CER strategies and screened via an online platform for eligibility (age 40‐64, with concerns about cognitive or behavioral function). Remote completion of online questionnaires, cognitive testing, and an in‐home blood draw for standard labs, Aβ42/40 and p‐tau217 ratios, and plasma NfL comprise the initial visit. Participants are invited for more comprehensive onsite evaluation at one of 7 BEYOND in‐clinic sites, followed by tailored referral to other NIH‐funded research programs. Participants can learn their results remotely or in person. Result Using a novel, CER‐based approach for social media ad deployment, BEYONDD has recruited over 1700 potential participants across the US and Puerto Rico; over half (n = 881) completed the online screening survey. Of the 206 participants enrolled in the online procedures, 80% (n = 165) were women and most were Latino (n = 83; 40%) or Black (n = 68; 33%) and over a quarter (n = 74; 36%) reported less than 16 years of education. We have completed over 95 blood draws across 17 states and invited participants for onsite visits. Results have been shared with 22 participants (10 on‐site, 12 remotely). Preliminary analyses reveal a high Aβ42/40 positivity rate (∼30%) and the most prevalent routine lab abnormalities include: LDL‐Cholesterol (63%), homocysteine (36%), hs‐CRP (35%) and HgbA1C (33%). Abnormal p‐tau217 ratios (n = 4; 5%) and APS2 scores (n = 3; 4%) have also been identified in this community‐based sample. Conclusion Preliminary results suggest feasibility and acceptability of this innovative CER approach in a more representative sample of the US population.

Background It is imperative to identify underrepresented populations (URPs) at risk for progression to Mild Cognitive Impairment (MCI) and dementia due to Alzheimer’s disease (AD), yet substantial heterogeneity exists in the presentation and risk of AD among URPs. Previous research with predominantly non‐Latinx White participants indicates early functional decline is associated with increased risk and can be effectively evaluated by participants and study partners (SPs). This study aims to understand the association between subjective functional/cognitive decline and objectively‐measured cognitive decline in URPs. Specifically, we hypothesize that SP‐reported decline predicts diagnostic progression over time better than participant‐reported decline in URPs. Method A sample of 283 Alzheimer’s Disease Neuroimaging Initiative (ADNI) participant‐study partner dyads (Mage69.6 at baseline (±8.1), 62.1% female, 48.4% Black/African American, 29.0% Latinx, 15.5% Asian American, 0.4% Native Hawaiian/Pacific Islander, 1.4% American Indian/Alaska Native, and 8.8% of more than one race), completed the Everyday Cognition Questionnaire (ECog), which assesses real‐world functioning related to specific neuropsychological domains, and received consensus neurocognitive diagnoses. An autoregressive, cross‐lagged panel analysis examined whether ECog and diagnostic conversion from cognitively normal to MCI or MCI to AD were concurrently associated, whether participant‐reported ECog predicted future diagnostic conversion, and whether SP‐reported ECog predicted future diagnostic conversion across 3 time points (baseline, 12‐months, and 24‐months). Result All autoregressive paths of ECog and diagnostic progression were positive and significant (ps < .05). Cross‐lagged paths of SP‐reported ECog more strongly predicted diagnostic progression than participant‐reported ECog, and significantly predicted diagnostic progression from Time 2 (n = 130) to Time 3 (n = 92) (b = 2.03, SE = 0.64, p = .002). Cross‐lagged paths of participant‐reported ECog were not a significant predictor of diagnostic progression across three time points (ps > .05). Both models including SP‐reported ECog were significantly stronger at predicting diagnostic progression. Conclusion Early functional decline reported by SPs may be an independent predictor for cognitive decline in URPs. SPs also more accurately predicted cognitive decline cross‐sectionally and longitudinally than their participant counterparts. Further characterization of the relationships between URP participants and their SPs and their involvement in AD research should be prioritized.

Early onset dementia (EOD) affects people at the peak of personal and professional responsibilities and economic productivity. Alzheimer's disease (AD) and Frontotemporal Dementia (FTD) are the most common EOD etiologies, but have not been studied in a sample representative of the general US population. Multiple barriers impede research participation for many groups, but community-engaged research (CER) strategies to enhance recruitment may make research participation more accessible and convenient for all. BEYONDD is an NIH-funded, community-based study focused on understanding the etiology of EOD, uses CER strategies such as remote assessments and return of research results as tools for enhancing sample representativeness. Participants are recruited using social media and local in-person CER strategies and screened via an online platform for eligibility (age 40-64, with concerns about cognitive or behavioral function). Remote completion of online questionnaires, cognitive testing, and an in-home blood draw for standard labs, Aβ42/40 and p-tau217 ratios, and plasma NfL comprise the initial visit. Participants are invited for more comprehensive onsite evaluation at one of 7 BEYOND in-clinic sites, followed by tailored referral to other NIH-funded research programs. Participants can learn their results remotely or in person. Using a novel, CER-based approach for social media ad deployment, BEYONDD has recruited over 1700 potential participants across the US and Puerto Rico; over half (n = 881) completed the online screening survey. Of the 206 participants enrolled in the online procedures, 80% (n = 165) were women and most were Latino (n = 83; 40%) or Black (n = 68; 33%) and over a quarter (n = 74; 36%) reported less than 16 years of education. We have completed over 95 blood draws across 17 states and invited participants for onsite visits. Results have been shared with 22 participants (10 on-site, 12 remotely). Preliminary analyses reveal a high Aβ42/40 positivity rate (∼30%) and the most prevalent routine lab abnormalities include: LDL-Cholesterol (63%), homocysteine (36%), hs-CRP (35%) and HgbA1C (33%). Abnormal p-tau217 ratios (n = 4; 5%) and APS2 scores (n = 3; 4%) have also been identified in this community-based sample. Preliminary results suggest feasibility and acceptability of this innovative CER approach in a more representative sample of the US population.

Background Molecular biomarkers of chronic traumatic encephalopathy (CTE) are lacking. We evaluated 18 F-MK-6240 tau PET as a biomarker for CTE. Two studies were done: (1) 3 H-MK-6240 autoradiography and an in-vitro brain homogenate binding studies on postmortem CTE tissue, (2) an in-vivo 18 F-MK-6240 tau PET study in former American football players. Methods Autoradiography and in-vitro binding studies were done using 3 H-MK-6240 on frozen temporal and frontal cortex tissue from six autopsy cases with stage III CTE compared to Alzheimer’s disease. Thirty male former National Football League (NFL) players with cognitive concerns (mean age = 58.9, SD = 7.8) completed tau ( 18 F-MK-6240) and Aβ ( 18 F-Florbetapir) PET. Controls included 39 Aβ-PET negative, cognitively normal males (mean age = 65.7, SD = 6.3). 18 F-MK-6240 SUVr images were created using 70–90 min post-injection data with inferior cerebellar gray matter as the reference. We compared SUVr between players and controls using voxelwise and region-of-interest approaches. Correlations between 18 F-MK-6240 SUVr and cognitive scores were tested. Results All six CTE stage III cases had Braak NFT stage III but no neuritic plaques. Two had Thal Phase 1 for Aβ; one showed a laminar pattern of 3 H-MK-6240 autoradiography binding in the superior temporal cortex and less so in the dorsolateral frontal cortex, corresponding to tau-immunoreactive lesions detected using the AT8 antibody (pSer202/pThr205 tau) in adjacent tissue sections. The other CTE cases had low frequencies of cortical tau-immunoreactive deposits and no well-defined autoradiography binding. In-vitro 3 H-MK-6240 binding studies to CTE brain homogenates in the case with autoradiography signal indicated high binding affinity (K D  = 2.0 ± 0.9 nM, B max  = 97 ± 24 nM, n  = 3). All NFL players had negative Aβ-PET. There was variable, low-to-intermediate intensity 18 F-MK-6240 uptake across participants: 16 had no cortical signal, 7 had medial temporal lobe (MTL) uptake, 2 had frontal uptake, and 4 had MTL and frontal uptake. NFL players had higher SUVr in the entorhinal cortex (d = 0.86, p  = 0.001), and the parahippocampal gyrus (d = 0.39, p  = 0.08). Voxelwise regressions showed increased uptake in NFL players in two bilateral anterior MTL clusters ( p  < 0.05 FWE). Higher parahippocampal and frontal–temporal SUVrs correlated with worse memory ( r  = -0.38, r  = -0.40) and semantic fluency ( r  = -0.38, r  = -0.48), respectively. Conclusion We present evidence of 3 H-MK-6240 in-vitro binding to post-mortem CTE tissue homogenates and in vivo 18 F-MK-6240 PET binding in the MTL among a subset of participants. Additional studies in larger samples and PET-to-autopsy correlations are required to further elucidate the potential of 18 F-MK-6240 to detect tau pathology in CTE.

Molecular biomarkers of chronic traumatic encephalopathy (CTE) are lacking. We evaluated F-MK-6240 tau PET as a biomarker for CTE. Two studies were done: (1) H-MK-6240 autoradiography and an in-vitro brain homogenate binding studies on postmortem CTE tissue, (2) an in-vivo F-MK-6240 tau PET study in former American football players. Autoradiography and in-vitro binding studies were done using H-MK-6240 on frozen temporal and frontal cortex tissue from six autopsy cases with stage III CTE compared to Alzheimer's disease. Thirty male former National Football League (NFL) players with cognitive concerns (mean age = 58.9, SD = 7.8) completed tau ( F-MK-6240) and Aβ ( F-Florbetapir) PET. Controls included 39 Aβ-PET negative, cognitively normal males (mean age = 65.7, SD = 6.3). F-MK-6240 SUVr images were created using 70-90 min post-injection data with inferior cerebellar gray matter as the reference. We compared SUVr between players and controls using voxelwise and region-of-interest approaches. Correlations between F-MK-6240 SUVr and cognitive scores were tested. All six CTE stage III cases had Braak NFT stage III but no neuritic plaques. Two had Thal Phase 1 for Aβ; one showed a laminar pattern of H-MK-6240 autoradiography binding in the superior temporal cortex and less so in the dorsolateral frontal cortex, corresponding to tau-immunoreactive lesions detected using the AT8 antibody (pSer202/pThr205 tau) in adjacent tissue sections. The other CTE cases had low frequencies of cortical tau-immunoreactive deposits and no well-defined autoradiography binding. In-vitro H-MK-6240 binding studies to CTE brain homogenates in the case with autoradiography signal indicated high binding affinity (K  = 2.0 ± 0.9 nM, B  = 97 ± 24 nM, n = 3). All NFL players had negative Aβ-PET. There was variable, low-to-intermediate intensity F-MK-6240 uptake across participants: 16 had no cortical signal, 7 had medial temporal lobe (MTL) uptake, 2 had frontal uptake, and 4 had MTL and frontal uptake. NFL players had higher SUVr in the entorhinal cortex (d = 0.86, p = 0.001), and the parahippocampal gyrus (d = 0.39, p = 0.08). Voxelwise regressions showed increased uptake in NFL players in two bilateral anterior MTL clusters (p < 0.05 FWE). Higher parahippocampal and frontal-temporal SUVrs correlated with worse memory (r = -0.38, r = -0.40) and semantic fluency (r = -0.38, r = -0.48), respectively. We present evidence of H-MK-6240 in-vitro binding to post-mortem CTE tissue homogenates and in vivo F-MK-6240 PET binding in the MTL among a subset of participants. Additional studies in larger samples and PET-to-autopsy correlations are required to further elucidate the potential of F-MK-6240 to detect tau pathology in CTE.