Reaching Structurally Vulnerable Populations Using Low-Barrier COVID-19 Testing Clinics Co-Created with Community-Based Organizations.

BACKGROUND: The COVID-19 pandemic disproportionately affected people from structurally vulnerable communities. There was a need to improve COVID-19 testing in these communities to reduce viral spread and connect to treatment. OBJECTIVE: We created a partnership between an academic medical center and three community-based organizations (CBOs) to offer low-barrier COVID-19 walk-up testing clinics in Portland, Maine. Our objective was to examine whether the co-created testing clinics reached structurally vulnerable populations. DESIGN: The clinics offered COVID-19 rapid antigen tests three times a week outside CBO sites from January 2022 to May 2023. Clinic staff administered a brief survey on reason for testing and then instructed participants on how to self-swab. While staff processed the test, participants were invited to complete an additional survey about their demographics and testing perceptions. PARTICIPANTS: Adults seeking COVID-19 testing with specific outreach to people who are unhoused, immigrants, and low-income and/or uninsured. MAIN MEASURES: Number of tests conducted and result, reasons for testing, and testing perceptions. KEY RESULTS: Of 246 completed tests, 18 were positive for COVID-19 (7%). Participants sought testing for a variety of reasons, including symptoms (60%), close contact exposure (29%), and/or need for a negative test result to access services or an activity (33%). Overall, people primarily tested due to symptoms with only 7% testing due to close contact exposure alone. The clinics reached vulnerable populations. Among the 130 people completing the participant survey, 39% were unhoused, 22% spoke a language other than English at home, 23% were uninsured, and 46% earned less than $20,000 in 2019. Qualitative field notes captured key elements of clinics that influenced reach, and how this collaboration with CBOs helped build trust with our target populations. CONCLUSIONS: Providing low-barrier walk-up clinics partnering with trusted CBOs was observed to be helpful in reaching structurally vulnerable populations for COVID-19 testing.

APP and DYRK1A regulate axonal and synaptic vesicle protein networks and mediate Alzheimer's pathology in trisomy 21 neurons.

Trisomy 21 (T21) causes Down syndrome and an early-onset form of Alzheimer's disease (AD). Here, we used human induced pluripotent stem cells (hiPSCs) along with CRISPR-Cas9 gene editing to investigate the contribution of chromosome 21 candidate genes to AD-relevant neuronal phenotypes. We utilized a direct neuronal differentiation protocol to bypass neurodevelopmental cell fate phenotypes caused by T21 followed by unbiased proteomics and western blotting to define the proteins dysregulated in T21 postmitotic neurons. We show that normalization of copy number of APP and DYRK1A each rescue elevated tau phosphorylation in T21 neurons, while reductions of RCAN1 and SYNJ1 do not. To determine the T21 alterations relevant to early-onset AD, we identified common pathways altered in familial Alzheimer's disease neurons and determined which of these were rescued by normalization of APP and DYRK1A copy number in T21 neurons. These studies identified disruptions in T21 neurons in both the axonal cytoskeletal network and presynaptic proteins that play critical roles in axonal transport and synaptic vesicle cycling. These alterations in the proteomic profiles have functional consequences: fAD and T21 neurons exhibit dysregulated axonal trafficking and T21 neurons display enhanced synaptic vesicle release. Taken together, our findings provide insights into the initial molecular alterations within neurons that ultimately lead to synaptic loss and axonal degeneration in Down syndrome and early-onset AD.

Stem cell-derived neurons reflect features of protein networks, neuropathology, and cognitive outcome of their aged human donors.

We have generated a controlled and manipulable resource that captures genetic risk for Alzheimer's disease: iPSC lines from 53 individuals coupled with RNA and proteomic profiling of both iPSC-derived neurons and brain tissue of the same individuals. Data collected for each person include genome sequencing, longitudinal cognitive scores, and quantitative neuropathology. The utility of this resource is exemplified here by analyses of neurons derived from these lines, revealing significant associations between specific Aß and tau species and the levels of plaque and tangle deposition in the brain and, more importantly, with the trajectory of cognitive decline. Proteins and networks are identified that are associated with AD phenotypes in iPSC neurons, and relevant associations are validated in brain. The data presented establish this iPSC collection as a resource for investigating person-specific processes in the brain that can aid in identifying and validating molecular pathways underlying AD.