Donna M. Wilcock

The MarkVCID consortium investigating biomarkers for vascular contributions to cognitive impairment and dementia (VCID) found placental growth factor (PlGF) correlated with white matter hyperintensities and cognitive impairment. PlGF, thought to be redundant in function compared to VEGF-A, is associated with increased blood–brain barrier permeability, although the exact mechanism remains unknown. We examined the effects of a functional knockout of PlGF in mice (PlGF-DE-Ki) on vascular injury resulting from dietary induction of hyperhomocysteinemia (HHcy), a model of spontaneous cerebral small vessel disease. Immunohistochemistry showed reductions in vascular density and reductions in astrocytic endfoot coverage and pericytes in PlGF-DE-Ki mice compared to wild-type mice, regardless of diet. Vascular leakage assessed by multiphoton microscopy showed minimal changes, although PlGF-DE-Ki showed increased microhemorrhages compared to wild-type mice with Prussian blue staining. PlGF-DE-Ki mice also showed increased neuroinflammation by greater numbers of GFAP-positive cells and transcriptional upregulation of the complement pathway. Introduction of HHcy further increased the number of cerebral microhemorrhages and the number of microglia in the hippocampus. These results indicate that lifetime knockdown of PlGF functionality increases susceptibility to vascular injury.

INTRODUCTION: The Indiana University Brain Health Program was developed to support safe implementation of amyloid‐targeting therapies (ATTs) for early Alzheimer's disease (AD). METHODS: We established Neurology Brain Health Navigators (neuroBHNs) to extend our Brain Health Navigator model into specialty care. NeuroBHNs pre‐screen patients for ATT eligibility, coordinate biomarker and imaging evaluation, provide structured education, and guide treatment initiation and monitoring. The program includes a dedicated social worker and insurance pre‐authorization specialist to streamline infusion access. Blood pressure is monitored at each visit, and infusions are deferred if readings exceed 140/90 mmHg. RESULTS: Through December 16, 2025, 243 patients initiated lecanemab therapy. Apolipoprotein E (APOE) ε4 homozygotes were not excluded; 74% of treated patients carried at least one Apoε4 allele. The ARIA rate was 13.2%, and 40% of patients experienced infusion‐related reactions. CONCLUSIONS: A navigator‐centered model can efficiently deliver ATT while supporting structured education, screening, and safety monitoring, potentially contributing to favorable safety outcomes.

The FDA approval of amyloid beta (Aβ) targeting immunotherapies offered the first opportunity to clinically modify Alzheimer's disease progression and give patients back precious months in the course of disease progression. The administration of these therapeutics has uncovered a common side effect called Amyloid Related Imaging Abnormalities (ARIA). While often asymptomatic, these adverse events have potential to escalate, and their commonality has encouraged further studies to mitigate their incidence. Increases in immune activation are important in immunotherapy action, though heightened release of cytokines have also been shown in ARIA development. TNF has been shown in early studies to increase with immunotherapy administration and subsequent ARIA development and TNF itself has been implicated in blood brain barrier dysfunction which could contribute to hemorrhagic ARIA (ARIA-H) development. This study assessed hemorrhage outcomes in an aged mouse model using MRI and Prussian blue histology, explored transcriptomic and protein changes with NanoString nCounter and Meso Scale Discovery, and we performed immunohistochemical stains for microglia/macrophages, astrocytes, and pericyte changes. In this study, we established ARIA-H pathology in a humanized mouse model (hAβ^SAA) via chronic Aβ immunotherapy administration. We saw significant hemorrhagic lesions in our model, despite low levels of cortical cerebral amyloid angiopathy (CAA) suggesting a role for CAA as a risk factor for ARIA but potentially not its driver. We also explored the role of TNF in ARIA progression by inhibiting soluble TNF alongside immunotherapy administration as a potential combination therapeutic to address ARIA. With TNF inhibition, we saw a reduction of hemorrhages in the hippocampus, but not in the cortex, suggesting a regional effect. Further, we saw additional regional differences between the cortex and hippocampus with TNF inhibition including macrophage activation markers and amyloid levels, suggesting a differential role for TNF signaling in these areas and a potential heterogeneity of cellular responses in each region. We induced ARIA without significant cortical CAA pathology and identified regional differences with TNF inhibition including a potential benefit of treatment in the hippocampus and possible detriment to pathology in the cortex.

The first Vascular Contributions to Cognitive Impairment and Dementia (VCID) Workshop, held on May12-16, 2025 at The Jackson Laboratory, provided scientific content and career development training in the latest developments in VCID and Alzheimer’s Disease (AD) and related dementia (ADRD). The Workshop aimed to foster interdisciplinary collaborations and empower the next generation of diverse scientists to advance ADRD research from mechanism to intervention. The meeting placed a strong emphasis on neurovascular pathology, its central role in ADRD pathogenesis, its modulation by both central and peripheral factors, and the critical need to dissect the mechanistic basis of VCID through experimental models. The workshop included talks from both faculty and trainees and was bookended by two keynote addresses by Drs. Donna Wilcock and Costantino Iadecola, leaders and pioneers in the VCID field. The second VCID workshop is planned for April 28-May 1, 2026, to be held at Washington University in St. Louis.

Alzheimer's disease (AD) is a complex neurodegenerative disease that leads to cognitive decline and dementia. Over the past two decades, many scientists have contributed to the discovery of therapeutics that target amyloid-beta (Aβ) to slow the progression of AD. These discoveries have led to the development of the first disease-modifying therapeutics in AD, though these come with the risk of side effects known as amyloid-related imaging abnormalities (ARIA). There are currently many exciting studies and trials working to mitigate ARIA risk that range from modifying antibodies to potential combination therapeutics. This review addresses some of the ongoing research areas for improving safety in Aβ targeting as well as clinical considerations for current patient treatment.

INTRODUCTION: While the anti‐amyloid‐lowering immunotherapies provide the first disease‐targeting therapies for the treatment of Alzheimer's disease, there remain harmful adverse events causing hesitation among patients, families, physicians, and regulatory bodies. Though these drugs have been repeatedly proven to lower brain amyloid plaque burden, the specific cellular mechanisms and pathways by which the immunotherapy impacts the brain remain unclear. METHODS: This study aimed to transcriptionally profile the brain's immediate immune response to anti‐amyloid beta (anti‐Aβ) antibodies. To evaluate acute cellular priorities, we intracranially injected anti‐Aβ antibody (3D6) or an isotype‐matched control immunoglobulin G (IgG) antibody and performed single‐cell sequencing analysis after 3 days. RESULTS: We found reduced numbers of a motile microglia cluster and homeostatic microglia in the 3D6 antibody‐injected cortex compared to the IgG‐injected cortex. It was also found that chemokine/cytokine signaling was enriched across homeostatic‐proinflammatory microglia, interferon‐responding microglia, and disease‐associated microglia 2 (DAM2) following 3D6 antibody injection. We explored “CCL” signaling, which suggested a change in outgoing signaling coordinated by all microglia types targeting homeostatic microglia, surprisingly not targeting DAM1 or DAM2. We then analyzed enriched signaling pathways clustered by k‐means river plots and identified pathways enriched and dampened with acute 3D6 treatment. DISCUSSION: Together these data supply evidence for significant involvement of microglia in the anti‐Aβ response in the brain after just 3 days. Most interestingly, there are changes in cytokine/chemokine signaling across microglia subtypes, specifically with communication in CCL pathways targeting homeostatic microglia and T cells. These acute signaling changes provide novel insights and generate unique hypotheses on the brain's immediate immune reaction to anti‐Aβ antibody. Highlights: Intracranially injected anti‐amyloid beta (anti‐Aβ) antibody promotes an immediate microglial response. 3D6 exposure resulted in fewer homeostatic and motile microglia subtypes. Acute 3D6 enriches for chemokine/cytokine signaling pathways.

Background: Amyloid related imaging abnormalities (ARIA) remain a major obstacle to the widespread use of anti‐amyloid immunotherapy. Data has indicated an association of neuroinflammation and subsequent MMP activation as being associated with anti‐amyloid immunotherapy. We therefore performed a co‐administration study of anti‐amyloid immunotherapy (3D6) with marimastat, an MMP inhibitor that targets MMP1, 2, 3, 7 and 9, with the highest affinity for MMP9. Method: We initiated treatment with both agents in 19 mo hAbetaSAA knockin mice. Monthly MRI imaging was performed and, upon euthanasia, we performed scRNAseq on the frontal cortex using a glial enrichment preparation, and histological analysis for microhemorrhages. Result: We found that anti‐amyloid immunotherapy‐mediated Prussian blue microhemorrhages were not significantly reduced by marimastat co‐administration. However, MRI detected microhemorrhages were reduced by marimastat treatment. In our scRNAseq dataset we found significant shifts in microglial state with anti‐amyloid immunotherapy not detected with the control IgG. Conclusion: MMP inhibition does not appear to impact small microhemorrhages detected histologically. However, the reduced microhemorrhages detected using MRI suggests that marimastat prevented the development of larger sized microhemorrhage events. Data analysis continues to gain further insights from this study.

Objective: To establish a framework for validating candidate biomarkers of cerebral small vessel diseases (SVD) associated with cognitive impairment and characterize individuals enrolled by the MarkVCID2 consortium under this framework. Methods: Participants age 60 to 90 years were enrolled across 17 MarkVCID2 sites. Recruitment was targeted to enrich in cognitive symptoms (mild dementia, mild cognitive impairment, subjective cognitive decline), defined risk factors (diabetes mellitus, advanced hypertension), and Black/African American, White, and Hispanic/Latino subgroups. Enrolled participants underwent baseline visits that included cognitive testing, multimodal magnetic resonance imaging (MRI), and biofluid collection. Provisional risk for SVD‐related cognitive decline was estimated primarily by baseline cognitive symptoms plus SVD risk factors. Adjudicated risk status was estimated by cognitive symptoms plus presence of moderate‐to‐severe white matter hyperintensities, microbleeds, or lacunes on baseline MRI. Results: MarkVCID2 enrolled 1883 individuals age 73.4 ± 7.5 years, 65.0% female, 24.2% Hispanic, and 27.1% non‐Hispanic Black. Among enrollees, 44.8% were provisionally designated high‐risk. After baseline MRI, 48.5% were categorized as adjudicated high‐risk status, with substantial recategorization both from low‐ to high‐risk (primarily because of MRI lesions without SVD risk factors) and high‐ to low‐risk (primarily suspected cognitive impairment at screening not confirmed by baseline testing). Interpretation: MarkVCID2 baseline data indicate successful enrollment of diverse individuals enriched in factors associated with SVD‐related cognitive decline. Changes over 3 years of longitudinal follow‐up will be analyzed to validate the candidate biomarkers for 2 projected contexts of use: subject selection (identifying likelihood of future SVD progression) and study outcome (efficiently measuring SVD progression). ANN NEUROL 2026;99:449–458