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AbstractBackgroundApproximately 10% of patients with acute SARS‐CoV‐2 infection present with persistent symptoms recognized as the long‐COVID. Neurological and cognitive symptoms are prevalent in long‐COVID, requiring a deeper understanding of the biological basis of this condition for potential therapeutic interventions. Cerebrovascular complications are observed during acute infection, underscoring the importance of understanding cerebrovascular outcomes. Our objective was to investigate white matter hyperintensities (WMH) as a potential indicator of microvascular disease associated with long‐COVID in the brainMethodParticipants with long‐COVID (n=71; hospitalized, n=9, non‐hospitalized, n=62 during the acute infection) and controls (n=50) who did not have a reported infection were recruited from the community at five US sites that participated in the COVID‐Brain‐Advanced‐Imaging‐Network (COVID‐BRAIN) project. To be included, participants with long‐COVID had to experience neurological or cognitive sequelae within 6 months after a confirmed infection and continued to show at least one neurological symptom. Clinical evaluation and MRI were performed an average of 20±10 months after the acute infection. WMH volumes were measured from the 3D T2‐weighted FLAIR MRIs using a semi‐automated approach for the WMH segmentation. A linear regression model predicting log transformed WMH volume was used to investigate the association of age, groups (hospitalized long‐COVID, non‐hospitalized long‐COVID, controls), and the interaction of these two predictors along with an adjustment for total intracranial volume. Additionally, predicted regression lines have been plotted on the untransformed WMH scale.ResultWe observed a greater age‐dependent increase in WMH volumes in the hospitalized patients with long‐COVID compared to the control group (group*age interaction, p=0.005). We did not observe this difference in slopes in the non‐hospitalized patients with long‐COVID compared to the controls. Figure shows the slopes of WMH volume as a percentage of the total intracranial volume by age in the three groups.ConclusionOur preliminary observation in this ongoing long‐Covid study suggests that hospitalization during acute COVID is associated with the age‐dependent increase in microvascular injury in the white matter. Older adults with acute infection that require hospitalization are more susceptible to cerebrovascular adverse outcomes than controls or those who do not require hospitalization. Impact of such microvascular changes on cognitive outcomes and persistence of post‐COVID symptoms is yet to be studied.

AbstractBackgroundCerebral small vessel disease (SVD) related vascular contributions represent a major factor contributing to cognitive decline and dementia (VCID) in older adults. However, there has not been a validated biomarker for the diagnosis and treatment monitoring of this condition. Recently, the US National Institute on Neurological Disorders and Stroke (NINDS) funded the MarkVCID Consortium to identify and validate clinical‐trial‐ready biomarkers for VCID. Cerebrovascular reactivity (CVR) MRI is one of the selected biomarkers that underwent multi‐site testing in the Consortium. The present study aimed to report the relationship between CVR and cognitive function at independent sites, based on a pre‐specified hypothesis.MethodCVR, the ability of cerebral small vessels to dilate upon stimulus, is thought to directly reflect physiological function of the brain microvasculature. Based on previous single‐site findings, the pre‐defined hypothesis was that CVR will be associated with the global cognitive function measured by Montreal Cognitive Assessment (MoCA) after adjusting for age, sex, and education, and this association will be observed in data collected and analyzed at each individual site.A total of 264 older participants from three sites were included (Table 1). Each site performed an identical CVR MRI procedure using 5% CO2 inhalation, and a standardized clinical and cognitive evaluation. Multi‐linear regression analysis was conducted on a site‐by‐site basis to examine the pre‐defined hypothesis.ResultGray‐matter CVR showed a positive association with MoCA score after adjustment for age, sex, and education, in which participants with higher CVR had higher MoCA scores. This relationship was reproduced at each site (Figure 1, p<0.05 for each), confirming our pre‐specified hypothesis.In the secondary analysis of all data together, higher gray‐matter CVR was found to be significantly associated with better executive function measure of item response theory (IRT) score (β=2.87, p=0.003).ConclusionThe present study evaluated the relationship between CVR and cognition in a multi‐center setting. CVR was found to be positively associated with global cognitive function measured by the MoCA, which was shown to be reproducible across different sites with diverse cohorts. These findings support the utility of CVR as a biomarker in future clinical trials of SVD and VCID.

AbstractBackgroundScalable, efficient methods are needed to enroll diverse populations of older adults into AD observational studies and clinical trials. We evaluated preliminary feasibility of a novel, digital, culturally informed approach to recruit and screen participants for the Alzheimer’s Disease Neuroimaging Initiative (ADNI4).MethodsDigital advertising tailored towards Black/African American and Latinx older adults residing near six clinical ADNI sites directed potential participants to a recruitment website (Figure 1). They completed digital surveys of demographics, ADNI exclusion criteria, memory concerns and changes, self‐report cognitive impairment, and the Everyday Cognition Scale (ECog)‐12 item. Participants also completed Novoic Storyteller, a self‐administered speech‐based cognitive test. Digital assessment results were used to prioritize those from minoritized ethnocultural groups, with low educational attainment, and possible Mild Cognitive Impairment (MCI) for remote blood draw at local Quest phlebotomy centers to obtain AD plasma biomarkers. Completion rates and digital assessment performance were compared between minoritized and non‐minoritized groups.ResultsOf 989 participants recruited from digital advertising efforts who provided contact information, 230 (23%) signed consent, and 183 (19%) completed at least one remote assessment (Table 1). 45% were from minoritized ethnocultural groups, 4% had ≤12 years of education, and 53% had evidence of possible MCI from digital assessments. 34 (19%) were referred to the plasma biomarker study, of which 21% completed blood draw. Compared to non‐minoritized participants, minoritized participants were less likely to report a diagnosed cognitive impairment or a family history of AD, less likely to have ECog scores indicative of MCI, and less likely to have a study partner. Minoritized participants had lower ECog and Novoic Storyteller completion rates.ConclusionRecruitment and assessment of a diverse cohort of older adults, including those with possible cognitive impairment, is feasible using culturally informed digital advertising. Improving study engagement and achieving educational diversity are key challenges. This approach is now being scaled up to facilitate recruitment into in‐clinic ADNI4, with the goal of enrolling 500 new participants: >50% from minoritized groups, 40% with MCI, and 80% amyloid positive across diagnostic groups. This approach can be adapted to facilitate recruitment and longitudinal assessment in other AD studies and trials.

AbstractBackgroundApproximately 10% of patients with acute SARS‐CoV‐2 infection present with persistent symptoms recognized as the long‐COVID. Neurological and cognitive symptoms are prevalent in long‐COVID, requiring a deeper understanding of the biological basis of this condition for potential therapeutic interventions. Cerebrovascular complications are observed during acute infection, underscoring the importance of understanding cerebrovascular outcomes. Our objective was to investigate white matter hyperintensities (WMH) as a potential indicator of microvascular disease associated with long‐COVID in the brainMethodParticipants with long‐COVID (n = 71; hospitalized,n = 9,non‐hospitalized,n = 62 during the acute infection) and controls(n = 50) who did not have a reported infection were recruited from the community at five US sites that participated in the COVID‐Brain‐Advanced‐Imaging‐Network (COVID‐BRAIN) project. To be included, participants with long‐COVID had to experience neurological or cognitive sequelae within 6 months after a confirmed infection and continued to show at least one neurological symptom. Clinical evaluation and MRI were performed an average of 20±10 months after the acute infection. WMH volumes were measured from the 3D T2‐weighted FLAIR MRIs using a semi‐automated approach for the WMH segmentation. A linear regression model predicting log transformed WMH volume was used to investigate the association of age, groups (hospitalized long‐COVID, non‐hospitalized long‐COVID, controls), and the interaction of these two predictors along with an adjustment for total intracranial volume. Additionally, predicted regression lines have been plotted on the untransformed WMH scale.ResultWe observed a greater age‐dependent increase in WMH volumes in the hospitalized patients with long‐COVID compared to the control group (group*age interaction, p = 0.005). We did not observe this difference in slopes in the non‐hospitalized patients with long‐COVID compared to the controls. Figure shows the slopes of WMH volume as a percentage of the total intracranial volume by age in the three groups.ConclusionOur preliminary observation in this ongoing long‐Covid study suggests that hospitalization during acute COVID is associated with the age‐dependent increase in microvascular injury in the white matter. Older adults with acute infection that require hospitalization are more susceptible to cerebrovascular adverse outcomes than controls or those who do not require hospitalization. Impact of such microvascular changes on cognitive outcomes and persistence of post‐COVID symptoms is yet to be studied.

AbstractBackgroundThe immune system is substantially involved in the development and progression of age‐related cognitive decline and Alzheimer’s disease (AD).MethodAs genetic and environmental factors interactively impact these conditions, we investigated how risk factors such as APOE genotype, age, and sex influence immune activation markers and AD biomarkers in cerebrospinal fluid (CSF) in elderly individuals enrolled in the Mayo Clinic Study of Aging cohort. Among cognitively unimpaired individuals aged over 65 at the baseline visit (N=298), we measured 365 CSF immune activation markers using the proximity extension assay.ResultWe found that age, sex, and diabetes status are associated with altered CSF levels of immune activation markers independently of other factors. For CSF AD biomarkers, we observed significant positive correlations between age and total tau, phosphorylated tau‐181 (p‐tau181), neurofilament light (NfL), and YKL40. APOE4 was also associated with lower Aß42 and higher SNAP25 in CSF. We further examined whether baseline visit variables can predict cognitive decline, represented by the conversion from CDR=0 to CDR>0. We found that age, Aß42, NfL, and REG4 were independently correlated with CDR conversion risk. When the cohort was dichotomized by their median values, older participants with lower Aß42, higher NfL, and higher REG4 at baseline developed cognitive impairment during the follow up with a c‐index of 0.762 while age alone had a c‐index of 0.699.ConclusionTogether, our results suggest that assessing CSF immune activation markers and AD biomarkers can improve the prediction of cognitive impairment risk in the elderly.

AbstractBackgroundSubjective cognitive concerns are common in functionally intact adults, potentially indicating future cognitive decline. Remote smartphone cognitive testing holds promise for objectively tracking cognition in individuals reporting complaints. In our initial exploration of the link between subjective cognitive complaints and digital clinical outcomes, we examined participants' self‐reported cognitive complaints' association with smartphone tests on memory and executive functioning.MethodsParticipants, without self‐reported MCI or dementia, were recruited from the UCSF Brain Healthy Registry (BHR) to complete cognitive tasks on their personal smartphone with the ALLFTD Mobile App. Participants also completed the 12‐item Everyday Cognition Screening Tool (ECog‐12), assessing subjective cognitive impairment, online as part of BHR. Average ECog‐12 scores, including Memory and Executive Functioning subdomains, were calculated. Correlations between scores from online ECog‐12 scores and app‐based smartphone tasks were examined. Regression analyses, adjusting for age, education, and sex, were performed to evaluate the relationship between ECog‐12 and smartphone tasks (Stroop & Flanker) measuring executive function and memory.ResultsOut of 2,283 invited BHR participants, 456 (mean age: 64.6 years (SD = 11.8) and education: 16.3 years (SD = 2.4)) completed smartphone tasks (81.1% completion rate). Age was negatively associated with executive functioning and memory tasks (ß’s = ‐0.51 to ‐0.54, p’s<0.05), while higher education correlated with better performance (ß’s = 0.10‐0.14, p’s<0.05). Sex was not significantly associated with performance on any task (ß’s = ‐0.04 to 0.09, p’s>0.05). Subjective cognitive concerns were linked to tasks of executive functioning (Stroop: ß = ‐0.18, p = 0.002) and memory (ß = ‐0.14, p = 0.02). Endorsement of executive functioning items on ECog‐12 associated with Stroop performance (ß = ‐0.16, p = 0.005), and memory‐specific complaints were related to memory performance (ß = ‐0.1, p = 0.09). The relationship with flanker scores was not significant (ß = ‐0.08, p = 0.17). Similar patterns emerged with the online ECog‐12; online and app‐based scores are strongly correlated (ß = 0.75, p<0.05).ConclusionsIn this cognitively intact sample, subjective cognitive concerns were linked to poorer performance on ALLFTD Mobile App tasks assessing executive functioning and memory. These findings suggest that unsupervised remote smartphone testing merits further consideration to monitor cognition in individuals with subjective cognitive concerns. Subsequent studies in deeply phenotyped cohorts with follow‐up assessments are essential for understanding the clinical relevance of these results.

AbstractBackgroundGenome‐wide association studies (GWAS) in Alzheimer’s disease (AD) leveraging endophenotypes beyond case/control diagnosis, such as brain amyloid β pathology, have shown promise in identifying novel variants and understanding their potential functional impact. In this study, we leverage two brain amyloid β pathology measurement modalities, PET imaging and neuropathology, to address sample size limitations and to discover novel genetic drivers of disease.MethodWe conducted a meta‐analysis on an amyloid PET imaging GWAS (N = 7,036, 35% amyloid positive, 53.67% female, age = 71) and an autopsy GWAS of brain amyloidosis (N = 6,519, 63.08% amyloid positive, 51.34% female, age at death = 83), both adjusted for covariates including age, sex and principal components of genetic ancestry. All participants in both GWAS were unrelated individuals of European descent. We defined amyloid positivity as moderate or frequent neuritic plaques using the Consortium to Establish a Registry for Alzheimer’s Disease (CERAD) staging scores within each autopsy cohort. A Gaussian mixture model (GMM) was applied to each amyloid PET imaging cohort to identify the cohort and tracer‐specific cut‐offs that differentiate amyloid positive and negative populations.ResultThe genome‐wide significant results from the meta‐analysis identified three known AD loci (APOE, CR1, and BIN1) and a novel chromosome 17 locus (rs35635959, intergenic, MAF = 0.27, OR = 1.18, p = 1.47 × 10‐8). The MAGMA gene‐level analysis excluding the APOE region suggests significant associations between rs35635959 and COASY, PLEKHH3, and TUBG2 on chromosome 17, implying the potential roles of these genes on amyloidosis. Functional annotations of rs35635959 leveraging brain eQTL databases indicate its association with differential gene expression of COASY and TUBG2 in AD brains. ROSMAP bulk and single‐nucleus RNAseq analyses link TUBG2 downregulation to the higher amyloid burden and AD diagnosis while suggesting such observations are enriched in excitatory and inhibitory neurons, reaching FDR significance.ConclusionThis study is the most extensive European GWAS of brain amyloidosis, and our findings replicate known AD loci and identify a possible novel locus (index SNP rs35635959) on chromosome 17. Functional annotations of the novel variant indicate TUBG2, implicating in microtubule organization, warrants further assessment. Ongoing efforts aim to validate these novel effects using independent datasets.

Abstract Purpose: Around 10% to 15% of prostate cancers harbor recurrent aberrations in the Forkhead Box A1 gene, FOXA1, whereby the alteration type and the effect on the forkhead (FKH) domain affect protein function. We developed a FOXA1 classification system to inform clinical management. Experimental Design: A total of 5,014 prostate cancer samples were examined using whole-exome and -transcriptome sequencing from the Caris Life Sciences database. We denoted class 1 FOXA1 alterations as missense and in-frame insertions/deletions with subclasses oriented with respect to the FKH domain. These were in the first part of the FKH domain [class 1A: amino acids (AA) 168–246], within the Wing2 region of FKH (class 1B: AA 247–269), or outside FKH (class 1C: AA 1–167, 270+). Two hotspot missense mutations at R219 were denoted class 2. Class 3 included predicted truncating mutations with subclasses partitioned based on the FKH domain (class 3A: AA 1–269 and class 3B: AA 270+). Class 4 represented FOXA1 amplifications. Real-world overall survival and therapy outcomes were determined from insurance claims. Results: FOXA1 alterations did not influence survival when considered in aggregate but had distinct prognostic effects when stratified by class. In primary prostate samples, class 1A alterations were associated with overall improved survival (HR, 0.57; P = 0.03); a similar trend was seen in metastatic biopsies with class 1B (HR, 0.84; P = 0.09). Conversely, in primary specimens, class 1C exhibited worse survival upon second-generation androgen receptor signaling inhibitor treatment (HR, 1.93; P &lt; 0.001). Class 2 mutations (R219C/S) were enriched in neuroendocrine prostate cancers and were associated with overall poor survival (HR, 2.05; P &lt; 0.001) and worse outcomes to first-line androgen-deprivation therapies (HR, 2.5; P &lt; 0.001). Class 3A alterations indicated improved survival (HR, 0.70; P = 0.01), whereas class 3B alterations portended poor outcomes (HR, 1.50; P &lt; 0.001). Amplifications (class 4) indicated poor outcomes in metastatic samples (HR, 1.48; P = 0.02). Molecularly, different FOXA1 alteration classes harbored distinct mutational and immunologic features as well as unique transcriptional programs. Finally, relative to European Americans, African Americans had increased class 1C alterations, whereas Asian/Pacific Islander patients had increased class 1B alterations. Conclusions: FOXA1 alterations should not be interpreted in aggregate, as different classes are associated with divergent molecular features and clinical outcomes. Our revised classification schema facilitates clinical decision-making for patients with prostate cancer and uncovers important racial differences.

Abstract The overall goal of the Alzheimer's Disease Neuroimaging Initiative (ADNI) is to optimize and validate biomarkers for clinical trials while sharing all data and biofluid samples with the global scientific community. ADNI has been instrumental in standardizing and validating amyloid beta (Aβ) and tau positron emission tomography (PET) imaging. ADNI data were used for the US Food and Drug Administration (FDA) approval of the Fujirebio and Roche Elecsys cerebrospinal fluid diagnostic tests. Additionally, ADNI provided data for the trials of the FDA‐approved treatments aducanumab, lecanemab, and donanemab. More than 6000 scientific papers have been published using ADNI data, reflecting ADNI's promotion of open science and data sharing. Despite its enormous success, ADNI has some limitations, particularly in generalizing its data and findings to the entire US/Canadian population. This introduction provides a historical overview of ADNI and highlights its significant accomplishments and future vision to pioneer “the clinical trial of the future” focusing on demographic inclusivity. Highlights The Alzheimer's Disease Neuroimaging Initiative (ADNI) introduced a novel model for public‐private partnerships and data sharing. It successfully validated amyloid and Tau PET imaging, as well as CSF and plasma biomarkers, for diagnosing Alzheimer's disease. ADNI generated and disseminated vital data for designing AD clinical trials.

Abstract The antiapoptotic protein, myeloid cell leukemia-1 (Mcl-1), contributes to the pathophysiology of acute myeloid leukemia (AML) and certain B-cell malignancies. Tumor dependence on Mcl-1 is associated with resistance to venetoclax. Voruciclib, an oral cyclin-dependent kinase (CDK) inhibitor targeting CDK9, indirectly decreases Mcl-1 protein expression and synergizes with venetoclax in preclinical models. This dose escalation study evaluated voruciclib in patients with previously treated hematologic malignancies. Initially, voruciclib was administered daily, continuously, on a 28-day cycle (group 1). After 2 patients with prior allogeneic stem cell transplantation had a dose-limiting toxicity (DLT) of interstitial pneumonitis at 100 mg, voruciclib administration was changed to days 1 to 14 of a 28-day cycle (group 2). Forty patients, 21 with AML and 19 with B-cell malignancies, were enrolled. Patients had a median of 3 prior lines of therapy (range, 1-8). Dose escalation in group 2 was stopped at 200 mg, a dose that achieved plasma concentrations sufficient for target inhibition, without DLTs observed. The most common adverse events were diarrhea (30%), nausea (25%), anemia (22%), fatigue (22%), constipation (17%), dizziness (15%), and dyspnea (15%). In AML, 1 patient achieved a morphologic leukemia-free state, and 2 had stable disease. Voruciclib treatment led to a decrease in MCL1 messenger RNA expression, downregulation of myelocytomatosis (MYC) and NF-κB transcriptional gene sets, and reduced phosphorylation of RNA polymerase 2. Voruciclib on intermittent dosing was well tolerated, with no DLTs, paving the way for evaluation of the combination of voruciclib with venetoclax for patients with previously treated AML. This trial was registered at www.clinicaltrials.gov as #NCT03547115.