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The objective of this study was to examine clinicians' patient selection and result interpretation of a clinically validated mass spectrometry test measuring amyloid beta and ApoE blood biomarkers combined with patient age (PrecivityAD® blood test) in symptomatic patients evaluated for Alzheimer's disease (AD) or other causes of cognitive decline. The Quality Improvement and Clinical Utility PrecivityAD Clinician Survey (QUIP I, ClinicalTrials.gov Identifier: NCT05477056) was a prospective, single-arm cohort study among 366 patients evaluated by neurologists and other cognitive specialists. Participants underwent blood biomarker testing and received an amyloid probability score (APS), indicating the likelihood of a positive result on an amyloid positron emission tomography (PET) scan. The primary study outcomes were appropriateness of patient selection as well as result interpretation associated with PrecivityAD blood testing. A 95% (347/366) concordance rate was noted between clinicians' patient selection and the test's intended use criteria. In the final analysis including these 347 patients (median age 75 years, 56% women), prespecified test result categories incorporated 133 (38%) low APS, 162 (47%) high APS, and 52 (15%) intermediate APS patients. Clinicians' pretest and posttest AD diagnosis probability changed from 58% to 23% in low APS patients and 71% to 89% in high APS patients (p < 0.0001). Anti-AD drug therapy decreased by 46% in low APS patients (p < 0.0001) and increased by 57% in high APS patients (p < 0.0001). These findings demonstrate the clinical utility of the PrecivityAD blood test in clinical care and may have added relevance as new AD therapies are introduced.

Promising therapeutic interventions that target the underlying pathophysiology are changing the landscape of Alzheimer's disease (AD) research. The AD care pathway must be transformed to meet the challenge of bringing these new therapies to the increasing number of people living with AD within the existing healthcare framework. Challenges include identifying patients who may benefit from treatment interventions early in the course of the disease, ensuring that diagnostic tools are accessible and accurate, and developing capabilities to monitor the effectiveness of interventions over time. These challenges must be addressed at all levels, from primary care settings to tertiary treatment centers; this will require collaborative efforts between health systems, drug manufacturers, and research institutions to navigate this evolving landscape and ensure system readiness for patients and their families with AD. The Spring 2024 Alzheimer's Association Research Roundtable (AARR) meeting gathered industry representatives and clinicians to discuss insights, challenges, and solutions that will help researchers and health systems identify patients in the early stages of AD and deliver emerging therapies efficiently and safely. In this paper, we provide highlights from the Spring 2024 AARR meeting.

The two major intracellular protein degradation systems, the ubiquitin-proteasome system (UPS) and autophagy, work collaboratively in many biological processes including development, apoptosis, aging, and countering oxidative injuries. We report here that, in human retinal pigment epithelial cells (RPE), ARPE-19 cells, proteasome inhibitors, clasto-lactacystinβ-lactone (LA) or epoxomicin (Epo), at non-lethal doses, increased the protein levels of autophagy-specific genes Atg5 and Atg7 and enhanced the conversion of microtubule-associated protein light chain (LC3) from LC3-I to its lipidative form, LC3-II, which was enhanced by co-addition of the saturated concentration of Bafilomycin A1 (Baf). Detection of co-localization for LC3 staining and labeled-lysosome further confirmed autophagic flux induced by LA or Epo. LA or Epo reduced the phosphorylation of the protein kinase B (Akt), a downstream target of phosphatidylinositol-3-kinases (PI3K), and mammalian target of rapamycin (mTOR) in ARPE-19 cells; by contrast, the induced changes of autophagy substrate, p62, showed biphasic pattern. The autophagy inhibitor, Baf, attenuated the reduction in oxidative injury conferred by treatment with low doses of LA and Epo in ARPE-19 cells exposed to menadione (VK3) or 4-hydroxynonenal (4-HNE). Knockdown of Atg7 with siRNA in ARPE-19 cells reduced the protective effects of LA or Epo against VK3. Overall, our results suggest that treatment with low levels of proteasome inhibitors confers resistance to oxidative injury by a pathway involving inhibition of the PI3K-Akt-mTOR pathway and activation of autophagy.

The Knight-Alzheimer Disease Research Center (Knight-ADRC) at Washington University in St. Louis has pioneered and led worldwide seminal studies that have expanded our clinical, social, pathological, and molecular understanding of Alzheimer Disease. Over more than 40 years, research volunteers have been recruited to participate in cognitive, neuropsychologic, imaging, fluid biomarkers, genomic and multi-omic studies. Tissue and longitudinal data collected to foster, facilitate, and support research on dementia and aging. The Genetics and high throughput - omics core (GHTO) have collected of more than 26,000 biological samples from 6,625 Knight-ADRC participants. Samples available include longitudinal DNA, RNA, non-fasted plasma, cerebrospinal fluid pellets, and peripheral blood mononuclear cells. The GHTO has performed deep molecular profiling (genomic, transcriptomic, epigenomic, proteomic, and metabolomic) from large number of brain (n = 2,117), CSF (n = 2,012) and blood/plasma (n = 8,265) samples with the goal of identifying novel risk and protective variants, identify novel molecular biomarkers and causal and druggable targets. Overall, the resources available at GHTO support the increase of our understanding of Alzheimer Disease.

Lecanemab is an anti-beta-amyloid immunotherapy approved by the FDA in 2023 for Alzheimer's Disease (AD). One known side effect is the development of amyloid-related imaging abnormalities (ARIA), manifesting as cerebral edema (ARIA-E), or microhemorrhage with siderosis (ARIA-H). Appropriate use recommendations for lecanemab recommend brain MRI (clinical scan) at baseline, and approximately 4.5 months, 5.5 months, and 9 months into therapy. The requirement for these scans and the limitations of access to MRI-capable facilities levies significant burdens on patients, their caregivers, and facilities. Patients who may otherwise benefit have been without this therapy due to lack of MRI access. We aim to demonstrate the viability of an ultra-low field, portable MRI as an appropriate vehicle for baseline and safety monitoring. 31 patients with AD on lecanemab therapy or off due to known ARIA were recruited for the study. Participants underwent MRI on the low-field 0.064T Hyperfine Swoop® Portable MR Imaging® system within 1 week of their corresponding clinical screening MRI. Historical data collected from the medical record included age, the reads of baseline and any prior monitoring scans, and ARIA history. The average age of participants was 74.6, and 54.8% were female. 44 scans were obtained on the low-field MRI that were paired temporally with their clinical counterparts (Figure 1). In total, 14 clinical scans read by a neuroradiologist had at least 1 type and 1 degree of ARIA. Of these, 7 had Mild ARIA-E, 4 Moderate ARIA-E, and 8 ARIA-H (mild to severe). 2 separate, independent neuroradiologists identified all cases of ARIA-E (mild and moderate, Figure 2) on the low-field MRI scans. None of the 8 cases of ARIA-H could be identified on low-field MRI scans. 1 incidental finding of subdural hematoma (SDH) that was read on a clinical scan was identifiable on its low-field MRI counterpart (Figure 3). We found the low-field MRI to have a 100% sensitivity for both mild and moderate ARIA-E, but was not sensitive to microhemorrhages. Should this portable MRI modality be further as an adequate surrogate for 1.5/3T clinical scans, it could ease burdens on patients, their caregivers, and hospitals.

White matter hyperintensities (WMH) are known predictors of amyloid-related imaging abnormalities (ARIA) in patients undergoing anti-amyloid immunotherapy (AAT) for Alzheimer disease. WMHs and brain volumetric changes can potentially be captured by low-field magnetic resonance imaging (MRI) that imposes minimal safety risks to those with contraindicators to high-field MRI. We investigate the recently released FreeSurfer WMH-SynthSeg for volumetric and WMH lesion processing of low-field MRI and its comparability to 3T MRI. Low-field head MRI scans for 19 healthy controls and 23 patients undergoing AAT were acquired on a 0.064T Hyperfine SwoopÒ Portable MRI scanner. Treated patients also underwent a 3T MRI for ARIA screening by a clinical neuro-radiologist per treatment protocol. Volumetric measures of cortical grey matter, white matter, ventricles, and hippocampus were extracted from WMH-SynthSeg for low-field and FreeSurfer-7.4 for 3T MRI. WMH lesion probability maps were generated for all participants from WMH-SynthSeg. Linear regressions examined agreement between volumetrics for low-field and 3T MRI in treated patients without ARIA. Spatial localization of WMH lesions with ARIA pathology were visually assessed and compared with the clinical 3T scan. Finally, WMH volume measures were assessed amongst healthy controls and patients with and without ARIA using a pairwise Wilcoxon with Benjamini-Hochberg correction for multiple comparisons. Four patients were clinically identified as having ARIA with cerebral edema (ARIA-E) from 3T MRI. WMH-SynthSeg estimates of lateral ventricular, white matter, and cortical grey matter volumes agreed with 3T MRI but tended to be significantly underestimated for the hippocampus (Figure 1). WMH lesion probability maps aligned with known ARIA but failed to capture the entire area affected (Figure 2). While WMH volumes for healthy controls were significantly lower than those on AAT therapy, WMH volumes were not significantly different between AAT patients with and without ARIA-E (Figure 3). WMH-SynthSeg provides comparable volumetric measures to 3T for large brain regions and can spatially capture known ARIA. However, in our small sample, these measures were not sensitive enough to fully identify areas of ARIA. Further development is needed to improve small region quantification and WMH lesion detection, particularly at low-fields.

Lecanemab is an anti-beta-amyloid immunotherapy approved by the FDA in 2023 for Alzheimer's Disease (AD). One known side effect is the development of amyloid-related imaging abnormalities (ARIA), manifesting as cerebral edema (ARIA-E), or microhemorrhage with siderosis (ARIA-H). Appropriate use recommendations for lecanemab recommend brain MRI (clinical scan) at baseline, and approximately 4.5 months, 5.5 months, and 9 months into therapy. The requirement for these scans and the limitations of access to MRI-capable facilities levies significant burdens on patients, their caregivers, and facilities. Patients who may otherwise benefit have been without this therapy due to lack of MRI access. We aim to demonstrate the viability of an ultra-low field, portable MRI as an appropriate vehicle for baseline and safety monitoring. 31 patients with AD on lecanemab therapy or off due to known ARIA were recruited for the study. Participants underwent MRI on the low-field 0.064T Hyperfine Swoop® Portable MR Imaging® system within 1 week of their corresponding clinical screening MRI. Historical data collected from the medical record included age, the reads of baseline and any prior monitoring scans, and ARIA history. The average age of participants was 74.6, and 54.8% were female. 44 scans were obtained on the low-field MRI that were paired temporally with their clinical counterparts (Figure 1). In total, 14 clinical scans read by a neuroradiologist had at least 1 type and 1 degree of ARIA. Of these, 7 had Mild ARIA-E, 4 Moderate ARIA-E, and 8 ARIA-H (mild to severe). 2 separate, independent neuroradiologists identified all cases of ARIA-E (mild and moderate, Figure 2) on the low-field MRI scans. None of the 8 cases of ARIA-H could be identified on low-field MRI scans. 1 incidental finding of subdural hematoma (SDH) that was read on a clinical scan was identifiable on its low-field MRI counterpart (Figure 3). We found the low-field MRI to have a 100% sensitivity for both mild and moderate ARIA-E, but was not sensitive to microhemorrhages. Should this portable MRI modality be further as an adequate surrogate for 1.5/3T clinical scans, it could ease burdens on patients, their caregivers, and hospitals.

INTRODUCTION Usage of biomarker tests for Alzheimer's disease pathology and rates of positivity were assessed at the Washington University Memory Diagnostic Center. METHODS Patients who underwent at least one biomarker test for clinical purposes between June 2021 and March 2025 were included (n = 1136). Data were retrospectively extracted from electronic health records. RESULTS The median age was 73.2 years (52% female; 93% White). In total, 455 amyloid positron emission tomography (PET) scans, 505 cerebrospinal fluid tests, and 242 blood tests were performed. The number of biomarker tests increased seven‐fold over the past 4 years. The rate of positivity was ≈70% across modalities. Higher rates of biomarker positivity were associated with older age, female sex, and White race; lower rates were associated with hypertension and diabetes. DISCUSSION Biomarker testing greatly increased following the approval of amyloid‐targeting treatments. The overall rate of biomarker positivity was high and varied by demographic factors and medical comorbidities. Highlights Alzheimer's disease biomarker testing increased seven‐fold over four years AD biomarker positivity was associated with older age, female sex, and White race AD biomarker negativity was associated with hypertension and diabetes

INTRODUCTION Accurate clinical diagnosis of neurodegenerative diseases remains challenging, particularly when individuals have mixed pathologies. We implemented the generalizable protein‐based neurodegenerative disease artificial intelligence (GPND‐AI) classifier using the NUcleic acid‐Linked Immuno‐Sandwich Assay (NULISA) central nervous system (CNS) panel to classify Alzheimer's disease, Parkinson's disease, frontotemporal dementia, dementia with Lewy bodies, and healthy controls, while disentangling mixed pathologies. METHODS Proteomic and clinical information from the Charles F. and Joanne Knight Alzheimer's Disease Research Center (Knight‐ADRC) and Movement Disorder Clinic were used to train and test the GPND‐AI classifier. External validation was performed in a Banner Sun Health Research Institute cohort and additional Knight‐ADRC samples with neuropathologically confirmed diagnoses. RESULTS GPND‐AI identified 15 proteins that achieve an area under the curve (AUC) of 0.955 and 92.3% accuracy across five diagnostic categories. In validation cohort, predicted co‐pathologies significantly correlated with clinical characteristics. DISCUSSION GPND‐AI identified a 15‐protein panel that accurately classifies individuals across the four major neurodegenerative diseases. Validation against neuropathology‐confirmed diagnoses supports the utility of proteomics‐based approaches for mapping disease‐specific and co‐existing neurodegenerative processes. Highlights A streamlined 15‐protein NUcleic acid‐Linked Immuno‐Sandwich Assay (NULISA) plasma panel accurately distinguished four major neurodegenerative diseases and healthy brain aging. In an independent external cohort, the NULISA classifier distinguished the neurodegenerative diseases as defined by neuropathology. Individual‐level probability outputs capture early, ambiguous, and mixed pathological signatures, aligning with underlying amyloid/tau burden and cognitive decline.

Amyloid related imaging abnormality edema (ARIA-E) occurs in about 19% of individuals with autosomal dominant Alzheimer disease (ADAD) treated with an anti-amyloid-b monoclonal antibody (Salloway et al., 2021). In a previously reported case, ARIA-E appeared to colocalize with decreases in PiB-PET uptake (Joseph-Mathurin, Llibre-Guerra, et al, 2022), suggesting an association between amyloid-b (Aβ) removal and ARIA-E. Here, we compare longitudinal neuroimaging and corresponding neuropathology in an ADAD individual treated with gantenerumab, who experienced multiple ARIA-E episodes as sulcal effusions that resolved by the end of the four-year trial. PiB-PET and MRI were collected pre- and post-randomization (2 and 4 years). The participant consented to brain donation, which was received a year after trial completion. Four tissue samples were taken from the location of the ARIA-E in the parieto-occipital left hemibrain as identified by MRI (one block contained the sulcus affected by ARIA-E; the rest of the coronal section was captured in the remaining three blocks). Area fractions (AFs) of Aβ (10D5 immunohistochemistry (IHC)), tauopathy (PHF1), microglia (Iba1), and astrocytes (GFAP) in one sulcal region of interest (ROI) from each block and PiB-PET SUVRs of corresponding ROIs were extracted (n = 4, Figure 1). Additionally, we included PiB-PET SUVRs corresponding to ARIA-E findings observed in the right hemisphere at baseline, two-year, and four-year visits (n = 6). Overall PiB-PET uptake increased during the first two years (before ARIA-E) and decreased during the last two years (including ARIA-E episodes) (0.03±0.05 vs. -0.04±0.04 SUVR/year, p-value=0.01, Figure 2). The decrease seemed more pronounced in ARIA-E ROIs versus normal-appearing sulcus ROIs (-0.05±0.04 vs. -0.02±0.03 SUVR/year). Lower PiB uptake at last visit appeared associated with lower Aβ AF (estimates=0.03±0.01, p-value=0.07). The ARIA-E ROI had an Aβ AF of 0.009 while normal-appearing sulcus ROIs had a mean of 0.02+0.003 (Figure 3). AFs for tauopathy, microglia, and astrocytes were within the range of those of normal-appearing sulcus ROIs, suggesting an Aβ-specific effect, although unexamined markers may play a role. Our preliminary findings indicated that ARIA-E is associated with longitudinal PiB-PET decrease and Aβ AF, supporting the link between ARIA-E, changes in PiB-PET, and local Aβ removal observed at autopsy. K01AG080123; U01AG042791; R01AG046179; R01AG053267.