Costantino Iadecola

SUMMARY: Tracking lysosomes and quantifying their pH in the living, intact brain has been challenging owing to the lack of suitable in vivo tools. Here we report the use of dextran polymers labeled with the pH sensor ApHID to visualize and quantify lysosomal pH in resident phagocytes of the meninges. ApHID-dextrans delivered systemically are rapidly endocytosed by mainly dural and subdural macrophages and accumulate in lysosomal compartments. Intravital pH imaging revealed a striking heterogeneity in lysosomal acidification, with only ∼5% of phagocytes reaching pH values below 5.0, in marked contrast with measurements in macrophage cell cultures. Photothrombotic ischemic lesions induced progressive lysosomal acidification in local phagocytes, while acute chloroquine treatment led to rapid alkalinization. Our methodology enables direct, quantitative pH measurements without genetic manipulations, and unveils a previously unappreciated heterogeneity in lysosomal acidification among phagocytic cells in the meninges.

Background: New antiamyloid therapies (AAT) for treating patients with early Alzheimer disease (AD) have become available in the past 3 years. Although AAT can be beneficial in slowing progression of AD, they also come with potentially serious side effects, particularly for patients requiring anticoagulation or thrombolysis for cardiovascular conditions. Given that most patients with AD are older and likely to have cardiovascular risk factors, there is urgent need for additional guidance for clinicians about potential risks and benefits associated with AAT for patients with cardiovascular comorbidities, best practices for management of these patients, and special considerations with respect to emergency evaluation and treatment of patients on AAT who develop acute neurological symptoms. Methods: The American Heart Association convened 75 multidisciplinary experts for the Amyloid‐Related Imaging Abnormalities Summit: Cardiovascular and Stroke Considerations for β‐Amyloid Immunotherapy in AD in July 2025. These experts were divided into 8 work groups to evaluate the current evidence related to AAT usage in patients with cardiovascular risk factors and conditions and develop consensus‐based guidance for clinicians. Results: This statement outlines the outcomes of the Summit, including considerations for prescribers, primary care professionals, emergency personnel, and health care system stakeholders. These considerations are intended to improve identification of patients as appropriate candidates for AAT, management of patients with co‐occurring AD and cardiovascular conditions, and their emergency evaluation and treatment. The statement also includes guidance for shared decision‐making, implementation of system changes for improving dementia care, and recommendations for future research and data collection to add to the body of evidence for treating patients with concomitant AD and cardiovascular conditions. Conclusions: Building on lessons learned from the establishment of stroke systems of care, the consensus‐based considerations outlined in this document can serve as a foundation for AD systems of care aimed at ensuring optimal use of these ground‐breaking therapies.

BACKGROUND: Acute myocardial infarction (MI) is associated with subsequent cognitive decline. Whether the detection of prior MI using routine ECG and self-reported history can identify different trajectories of cognitive decline is uncertain. We sought to determine the association between prior MI and longitudinal cognitive assessments within a national, biracial cohort study. METHODS: We included participants in the REGARDS (Reasons for Geographic and Racial Differences in Stroke) cohort, enrolled from 2003 to 2007, who had an interpretable ECG and no baseline cognitive impairment. Prior MI at baseline was determined by self-reported history and ECG evidence of MI. Individuals were subdivided into self-reported (no Q-wave with MI history), clinical (Q-wave with MI history), and silent MI (Q-wave without MI history). We examined the interaction between prior MI and longitudinal change in global cognitive function, assessed by annual telephone-based 6-item screener scores, using linear mixed-effects models adjusted for demographics, cardiovascular risk factors, and incident cardiovascular events with censoring for death. RESULTS: The primary analytic cohort consisted of 20 923 individuals followed over a median of 10.1 years with 2183 having evidence of prior MI at baseline (1098 self-reported, 281 clinical, and 804 silent MI). A total of 4884 participants died during follow-up and were censored at the time of death. Prior MI was associated with an excess adjusted annual decline of global cognition (−0.016 points [95% CI, −0.021 to −0.012]; P _interaction P _interaction P _interaction =0.001), and silent (−0.015 points [95% CI, −0.022 to −0.008]; P _interaction <0.001) MI. CONCLUSIONS: Evidence of prior MI, whether clinically recognized or silent, was associated with an accelerated decline in global cognition. Prior MI may identify individuals at risk for future cognitive impairment.

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.

Background: Cerebrovascular health is a major determinant of brain health. The cerebral microvasculature not only meets the brain’s energy demands by delivering O2 and glucose but also maintains microenvironmental homeostasis. This is achieved through the blood–brain barrier, clearance of toxic byproducts of neural activity such as amyloid‐beta (Abeta) and tau, and the regulation of immune cell trafficking in and out of the brain. Given these essential roles, it is not surprising that vascular factors exert a profound influence on brain health. In the aging population, the most common cause of dementia is mixed dementia combining features of both vascular and Alzheimer disease (AD) pathology, both of which are exacerbated by arterial hypertension and ApoE4 carriage Method: N/A Result: This presentation will explore the cellular and molecular mechanisms through which AD pathology, ApoE4, and hypertension impair key regulators of cerebral microcirculation—specifically, neurovascular coupling, endothelial function, and interstitial fluid clearance. Special emphasis will be placed on neuroimmune interactions, particularly the emerging role of border‐associated macrophages (BAMs)—a distinct population of brain‐resident innate immune cells. Evidence will be presented that Aβ, ApoE4, and hypertension activate BAMs positioned adjacent to blood vessels, triggering vascular oxidative stress and inflammation, which, in turn, contribute to neurovascular dysfunction, impaired clearance of metabolic waste, and cognitive decline. Conclusion: Finally, the implications of these neurovascular and neuroimmune effects for the Amyloid Related Imaging Abnormality (ARIA) syndrome, a treatment limiting and potentially fatal complication of Abeta immunotherapy, will be examined.

Tauopathies such as Alzheimer’s disease and frontotemporal dementia are leading causes of cognitive impairment, characterized by accumulation of hyperphosphorylated tau, a microtubule-associated protein, in brain. In addition to driving neural network hyperactivity and neuronal damage, tau disrupts neurovascular function, which may further contribute to disease pathogenesis. Using a mouse tauopathy model, we demonstrate that tau causes a profound breakdown of the normally well-coordinated segmental vasodilation induced by neural activity, resulting in dampened and delayed blood-flow increases, heterogeneous capillary perfusion, and frequent capillary stalling. These neurovascular alterations arise in the context of pronounced network hyperactivity and hypersynchrony, which combined with impaired neurovascular coupling, lead to reduced oxygen availability, episodic hypoxia, and disturbed metabolic homeostasis. Collectively, these findings identify reduced brain oxygenation driven by an imbalance between neuronal hyperactivity and diminished oxygen delivery as a previously-unappreciated early pathogenic consequence of tau accumulation and bolster the rationale for therapies to restore cerebral oxygenation.

Apolipoprotein E4 (ApoE4) genotype, hypertension, and biological sex are critical risk factors for Alzheimer’s disease and related dementias. Yet, their combined impact on early cerebrovascular dysfunction, brain inflammation, and memory impairment remains poorly understood. We developed a translational mouse model incorporating human ApoE4, hypertension via angiotensin II infusion, and induced accelerated ovarian failure (AOF) to mimic perimenopause in females to investigate these interactions. Hypertensive ApoE4 mice of both sexes exhibited impaired spatial working memory, decreased cerebral blood flow, increased neuroinflammation, and decreased blood brain barrier integrity, recapitulating key early clinical features observed in human populations with these risk factors. Brain blood flow reduction was associated with an increased incidence of capillary stalling, with notable sex differences in the extent and cellular composition of stalls: in males, stalling was strongly elevated and mostly due to red blood cell arrest, while stalling was modestly elevated in peri-AOF females with most stalls including leukocytes. Treatment with prasugrel, a P2Y12 receptor inhibitor, improved memory performance in both sexes but was correlated with different physiological effects – restored cerebral blood flow in males and reduced microglia motility and inflammation in peri-AOF females. Platelet depletion mimicked prasugrel’s blood flow and cognitive benefits in males, while microglia depletion selectively rescued memory in females. Our work emphasizes the necessity of including translationally relevant female mouse models in neurodegenerative disease studies, and our findings highlight the importance of risk profile-specific interventions and demonstrate that early vascular dysfunction may be a key, sex-dependent driver of cognitive decline.

Cerebral amyloid angiopathy (CAA) is a common cause of intracerebral hemorrhage (ICH) in older patients. Whether CAA is associated with isolated subdural hemorrhage (SDH), without an accompanying ICH, remains unclear. We, therefore, tested this relationship in a large, heterogeneous sample of patients across the United States. We performed a retrospective cohort study using administrative claims data from all admissions to nonfederal acute care hospitals in 11 states in the United States between 2016 and 2021. Among hospitalized patients, we included only those aged 50 years or older, a threshold necessary to meet Boston criteria v2.0 for CAA. We divided this population into 3 groups: those with a diagnosis of CAA, those with other cerebrovascular diseases (CVDs) but without CAA, and those with neither CAA nor other CVDs. The main outcome was a first-documented, isolated, nontraumatic SDH; we did not count SDH cases with a concurrent traumatic brain injury. The exposures and outcome were identified using previously validated ICD-10-CM diagnosis codes. Using Cox regression analyses, we compared the risk of incident SDH among the 3 groups after adjustment for demographics and comorbidities. In prespecified sensitivity analyses, patients with a baseline diagnosis of dementia were excluded. Among 8.5 million hospitalized patients aged 50 years or older, 2,335 had CAA and 600,646 had other CVDs. During a median follow-up of 2.0 years (interquartile range 1.0-3.9), incident SDH occurred in 34 patients with CAA (1.5%), 3,552 patients with other CVDs (0.6%), and 35,425 patients without CAA or other CVDs (0.4%). In adjusted Cox regression analysis, there was an increased risk of incident SDH seen with CAA (hazard ratio [HR] 3.1; 95% CI 2.2-4.4) and with prevalent CVD (HR 1.4; 95% CI 1.3-1.5). Findings were similar in sensitivity analyses excluding patients with dementia. In a large, heterogeneous cohort, we found that CAA was associated with a 3-fold heightened risk of SDH, higher than the increased risk seen in patients with other CVDs. These findings support the emerging hypothesis that CAA is a risk factor of isolated nontraumatic SDH.