The study examined whether trust in researchers affects interest in AD (Alzheimer’s disease) biomarker research participation, specifically AD blood biomarkers and MRI and PET neuroimaging, and whether this was independent of other factors commonly associated with hesitancy to participate in research, including race and knowledge of AD. 258 community-dwelling Black and 141 non-Hispanic White adults (age ≥ 55) who had never participated in AD research completed a survey about their perceptions of AD biomarker research. The survey asked participants to select one of three responses, “Yes,” “Unsure,” and “No” to 6 trust statements, with yes being the highest level of trust. Questions specifically assessed whether survey participants trusted researchers to keep information confidential, be honest, component, not cause harm, treat them equally, and share results with them and their community. Those who answered yes to all 6 questions were categorized as having very high trust, and those who answered no or unsure to any of the 6 questions were categorized as having lower trust. Ordinal logistic regression models were used for the analysis of outcome variables with three possible responses ( i.e . interest in participation in an AD biomarker study and individual procedures, motivators for research participation). We adjusted for age, education, sex, race, and knowledge about AD. Participants with very high trust in researchers were less hesitant about doing AD biomarker research (OR 0.32 (95% CI (0.20-0.52), P < 0.001). Participants with concerns about confidentiality, study risks, and being treated equally had greater hesitancy about doing AD biomarker research ( P ’s < 0.05). Concerns about researchers’ competency were associated specifically with lower interest in doing neuroimaging procedures ( P ’s < 0.05). Very high trust in researchers was associated with greater interest in return of results, particularly brain scans (OR 1.92 (95% CI 1.06-3.48), P = 0.032). Even after other factors known to affect AD research participation, trust remains a highly significant factor affecting the interest in AD research participation in blood biomarker neuroimaging procedures. Recruitment strategies for AD biomarker research may need to address participants’ trust concerns, specifically confidentiality, study risks, and equity.

Abstract Introduction The study examined Black and White prospective participants’ views of barriers to and facilitators of participation in Alzheimer's disease (AD) biomarker research. Methods In a mixed‐methods study, 399 community‐dwelling Black and White older adults (age ≥55) who had never participated in AD research completed a survey about their perceptions of AD biomarker research. Individuals from lower socioeconomic and education backgrounds and Black men were over‐sampled to address perspectives of traditionally under‐represented groups. A subset of participants (n = 29) completed qualitative interviews. Results Most participants expressed interest in biomarker research (overall 69%). However, Black participants were comparatively more hesitant than White participants (28.9% vs 15.1%), were more concerned about study risks (28.9% vs 15.1%), and perceived multiple barriers to participating in brain scans. These results persisted even after adjusting for trust and perceived knowledge of AD. Information was a primary barrier (when absent) and incentive (when provided) for AD biomarker research participation. Black older adults desired more information about AD (eg, risk, prevention), general research processes, and specific biomarker procedures. They also desired return of results to make informed decisions about their health, research‐sponsored community awareness events, and for researchers to mitigate the burden placed on participants in research (eg, transportation, basic needs). Conclusion Our findings increase representativeness in the literature by focusing on individuals with no history of AD research experience and those from traditionally underrepresented groups in research. Results suggest that the research community needs to improve information sharing and raising awareness, increase their presence in the communities of underrepresented groups, reduce incidental costs, and provide valuable personal health information to participants to increase interest. Specific recommendations for improving recruitment are addressed. Future studies will assess the implementation of evidence‐based, socioculturally sensitive recruitment strategies to increase enrollment of Black older adults into AD biomarker studies. HIGHLIGHTS Individuals from under‐represented groups are interested in Alzheimer's disease (AD) biomarker research. After adjusting for trust and AD knowledge, Black participants were still more hesitant. Information is a barrier (when absent) to and incentive (when given) for biomarker studies. Reducing burden (e.g., transportation) is essential for recruiting Black older adults.

Introduction The study aimed to identify strategies to increase older Black adults’ participation in Alzheimer’s disease (AD) biomarker research studies.Methods 399 community-dwelling Black and White older adults (age ≥ 55) who had never participated in AD research completed a survey about their perceptions of AD research involving blood draw, MRI, and PET.Results Although most participants expressed interest in AD biomarker research (Black participants: 63.0%, White participants: 80.6%), Black participants were significantly more hesitant than White participants (28.9% vs 15.1%), were more concerned about study risks, (30.8% vs. 11.1%) and perceived multiple barriers to participating in brain scans. Lack of information was perceived as a barrier to participation across groups (45.8%) and return of study results was perceived as a participation incentive (78.9-85.7%) ( P s < .05).Discussion Strategies to increase Black older adult participation in AD research may include disseminating additional study information and return of results.Declaration of Interest None of the investigators have a conflict of interest. JE receives support from VA IK HX002283, NIA P30AG072976, and NIA P30AG010133. AJP receives support from NIA (NIA U01 AG057195) and Alzheimer’s Association (LDRFP-21-818464). SW receives support from multiple NIA grants (K23AG062555, P30AG072976, P30AG010133, and R21AG074179) and the VA for clinical services. She receives book royalties from APPI and DSMB consultant fees (total less than $2000/year). AJS receives support from multiple NIH grants (P30 AG010133, P30 AG072976, R01 AG019771, R01 AG057739, U01 AG024904, R01 LM013463, R01 AG068193, T32 AG071444, and U01 AG068057 and U01 AG072177). He has also received support from Avid Radiopharmaceuticals, a subsidiary of Eli Lilly (in kind contribution of PET tracer precursor); Bayer Oncology (Scientific Advisory Board); Eisai (Scientific Advisory Board); Siemens Medical Solutions USA, Inc. (Dementia Advisory Board); Springer-Nature Publishing (Editorial Office Support as Editor-in-Chief, Brain Imaging and Behavior).### Competing Interest StatementNone of the investigators have a conflict of interest. JE receives support from VA IK HX002283, NIA P30AG072976, and NIA P30AG010133. AJP receives support from NIA (NIA U01 AG057195) and Alzheimer's Association (LDRFP-21-818464). SW receives support from multiple NIA grants (K23AG062555, P30AG072976, P30AG010133, and R21AG074179) and the VA for clinical services. She receives book royalties from APPI and DSMB consultant fees (total less than $2000/year). AJS receives support from multiple NIH grants (P30 AG010133, P30 AG072976, R01 AG019771, R01 AG057739, U01 AG024904, R01 LM013463, R01 AG068193, T32 AG071444, and U01 AG068057 and U01 AG072177). He has also received support from Avid Radiopharmaceuticals, a subsidiary of Eli Lilly (in kind contribution of PET tracer precursor); Bayer Oncology (Scientific Advisory Board); Eisai (Scientific Advisory Board); Siemens Medical Solutions USA, Inc. (Dementia Advisory Board); Springer-Nature Publishing (Editorial Office Support as Editor-in-Chief, Brain Imaging and Behavior).### Funding StatementThis research was supported by the National Institutes of Health's National Institute on Aging, P30AG10133-30 (A.J.S., S.W.), P30 AG072976-01 (A.J.S.; S.W.; J.E.), and R01 AG019771 (A.J.S.) and by the Alzheimer's Association, LDRFP-21-818464 (S.W.; A.J.P.). This content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health's National Institute on Aging or the Alzheimer;s Association. This material was supported with resources and the use of facilities at the Roudebush VAMC. This research also does not represent the official view of the VA Medical Center. The contents do not represent the views of VA or the United States Government. ### Author DeclarationsI confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained.YesThe details of the IRB/oversight body that provided approval or exemption for the research described are given below:IRB of Indiana University gave ethical approval of this workI confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals.YesI understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance).YesI have followed all appropriate research reporting guidelines and uploaded the relevant EQUATOR Network research reporting checklist(s) and other pertinent material as supplementary files, if applicable.YesAll data produced in the present study are available upon reasonable request to the authors

In sporadic and dominantly inherited Alzheimer disease (AD), aggregation of both tau and α-synuclein may occur in neurons. Aggregates of either protein occur separately or coexist in the same neuron. It is not known whether the coaggregation of tau and α-synuclein in dominantly inherited AD occurs in association with specific mutations of the APP, PSEN1, or PSEN2 genes. The aim of this study was to provide the first characterization of the neuropathologic phenotype associated with the PSEN1 p.A396T mutation in a man who was clinically diagnosed as having AD, but for whom the PSEN1 mutation was found postmortem. The proband, who was 56 years old when cognitive impairment first manifested, died at 67 years of age. Neuropathologically, 3 proteinopathies were present in the brain. Widespread α-synuclein-immunopositive neuronal inclusions suggested a diagnosis of diffuse Lewy body disease (DLBD), while severe and widespread tau and amyloid-β pathologies confirmed the clinical diagnosis of AD. Immunohistochemistry revealed the coexistence of tau and α-synuclein aggregates in the same neuron. Neuropathologic and molecular studies in brains of carriers of the PSEN1 p.A396T mutation or other PSEN1 or PSEN2 mutations associated with the coexistence of DLBD and AD are needed to clarify whether tau and α-synuclein proteinopathies occur independently or whether a relationship exists between α-synuclein and tau that might explain the mechanisms of coaggregation.

This study aimed to determine the pattern of [18F]flortaucipir uptake in individuals affected by Gerstmann-Sträussler-Scheinker disease (GSS) associated with the PRNP F198S mutation. The aims were to: 1) determine the pattern of [18F]flortaucipir uptake in two GSS patients; 2) compare tau distribution by [18F]flortaucipir PET imaging among three groups: two GSS patients, two early onset Alzheimer’s disease patients (EOAD), two cognitively normal older adults (CN); 3) validate the PET imaging by comparing the pattern of [18F]flortaucipir uptake, in vivo, with that of tau neuropathology, post-mortem. Scans were processed to generate standardized uptake value ratio (SUVR) images. Regional [18F]flortaucipir SUVR was extracted and compared between GSS patients, EOADs, and CNs. Neuropathology and tau immunohistochemistry were carried out post-mortem on a GSS patient who died 9 months after the [18F]flortaucipir scan. The GSS patients were at different stages of disease progression. Patient A was mildly to moderately affected, suffering from cognitive, psychiatric, and ataxia symptoms. Patient B was moderately to severely affected, suffering from ataxia and parkinsonism accompanied by psychiatric and cognitive symptoms. The [18F]flortaucipir scans showed uptake in frontal, cingulate, and insular cortices, as well as in the striatum and thalamus. Uptake was greater in Patient B than in Patient A. Both GSS patients showed greater uptake in the striatum and thalamus than the EOADs and greater uptake in all evaluated regions than the CNs. Thioflavin S fluorescence and immunohistochemistry revealed that the anatomical distribution of tau pathology is consistent with that of [18F]flortaucipir uptake. In GSS patients, the neuroanatomical localization of pathologic tau, as detected by [18F]flortaucipir, suggests correlation with the psychiatric, motor, and cognitive symptoms. The topography of uptake in PRNP F198S GSS is strikingly different from that seen in AD. Further studies of the sensitivity, specificity, and anatomical patterns of tau PET in diseases with tau pathology are warranted.

In the course of a published, large molecular study of Alzheimer disease in Turkey, the Presenilin 1 (PSEN1) variant GCC to ACC was identified at c.1186 in the coding region of Exon 11. The same DNA change was found by analyzing archival brain tissue obtained by the National Cell Repository for Alzheimer's Disease. A re-examination of the brain was carried out and available clinical records reviewed. DNA was isolated from frozen brain tissue and the APP and PSEN1 genes were sequenced. For histology, the following methods were used: Hematoxylin Eosin, Woelcke-Heidenhain, and Bielschowsky; for immunohistochemistry, antibodies against tau (ALZ-50), amyloid β (10D5), and α-synuclein were used. A 58 year old male complained of problems of concentration. At age 60, he noted word finding problems. An MRI, at age 61, showed atrophy and white matter changes more pronounced in the right occipital lobe; a SPECT scan at age 62 showed decreased perfusion in the right parietal lobe. The subject died at age 66. The subject's father developed a dementing illness after age 65. The fresh brain weighed 1200 grams. The left hemibrain was examined neuropathologically, while the right hemibrain was frozen for molecular studies. Histologic and immuno-histochemical studies revealed numerous Lewy bodies and neurites in cingulate, frontal, insular, temporal, parietal and occipital cortices, in hippocampus, caudate nucleus, putamen, substantia innominata, amygdala, thalamus, substantia nigra, ocular motor nerve nucleus, locus coeruleus, and nucleus ambiguus. Numerous neurofibrillary tangles and neuritic plaques, tau immuno-positive neurons and neuropril threads, as well as Aβ immuno-positive plaques were also present in the above mentioned anatomical regions. Aβ angiopathy was noted. DNA analysis revealed a GCC>ACC point mutation predicting an amino acid substitution of Alanine (A) to Threonine (T) at residue 396 in Presenilin 1. This is the first study of the neuropathologic features associated with the PSEN1 A396T mutation. The neuropathologic diagnoses established prior to molecular analysis were: 1) Lewy body disease and 2) Alzheimer disease. The reexamination forces us to reconsider the neuropathologic diagnosis and potential pathogenetic mechanisms operating in the presence of PSEN1 mutations. Acknowledgements: P30 AG 010133; U24 AG 21886.

Gerstmann-Sträussler-Scheinker Disease (GSS) is a familial neurodegenerative disorder characterized clinically by ataxia, parkinsonism, and dementia, and neuropathologically by deposition of diffuse and amyloid plaques composed of prion protein (PrP). The purpose of this study was to evaluate if [(11)C]Pittsburgh Compound B (PiB) positron emission tomography (PET) is capable of detecting PrP-amyloid in PRNP gene carriers. Six individuals at risk for GSS and eight controls underwent [(11)C]PiB PET scans using standard methods. Approximately one year after the initial scan, each of the three asymptomatic carriers (two with PRNP P102L mutation, one with PRNP F198S mutation) underwent a second [(11)C]PiB PET scan. Three P102L carriers, one F198S carrier, and one non-carrier of the F198S mutation were cognitively normal, while one F198S carrier was cognitively impaired during the course of this study. No [(11)C]PiB uptake was observed in any subject at baseline or at follow-up. Neuropathologic study of the symptomatic individual revealed PrP-immunopositive plaques and tau-immunopositive neurofibrillary tangles in cerebral cortex, subcortical nuclei, and brainstem. PrP deposits were also numerous in the cerebellar cortex. This is the first study to investigate the ability of [(11)C]PiB PET to bind to PrP-amyloid in GSS F198S subjects. This finding suggests that [(11)C]PiB PET is not suitable for in vivo assessment of PrP-amyloid plaques in patients with GSS.