Costantino Iadecola, MD
Anne Parrish Titzell Professor of Neurology
Director and Chair, Feil Family Brain and Mind Research Institute
Weill Cornell Medicine

Vascular cognitive impairment and Alzheimer’s disease (AD) have traditionally been considered distinct disease entities. However, a growing body of evidence indicates that there is considerable overlap between these conditions. While vascular lesions (intracranial atherosclerosis, white matter lesions, macro- and micro-infarcts, etc.) often coexist with AD pathology (plaques and tangles) enhancing the expression of the cognitive deficits, cerebral perfusion is reduced early in AD. Furthermore, midlife vascular risk factors have emerged as important contributors to AD risk, suggesting commonality of mechanisms. Cerebrovascular health is a major determinant of brain health. The cerebral microvasculature not only sustains the brain’s energy demands by delivering O2 and glucose, but also safeguards the homeostasis of the brain microenvironment thought the blood brain barrier and by clearing toxic byproducts of brain activity including Abeta and tau. It is therefore not surprising that vascular factors are involved in AD. Work in animal models has provided some insight into how AD pathology may alter neurovascular regulation and contribute to cognitive dysfunction. This presentation will provide evidence of the deleterious effects that AD pathology has on critical mechanisms regulating the cerebral microcirculation, and how AD risk factors, such as ApoE4 and arterial hypertension, may alter microvascular function and promote AD pathology. Emphasis will be placed on neuroimmune mechanisms focusing on the emerging role of border associated macrophages, brain resident innate immune cells distinct from microglia, in the neurovascular dysfunction induced by AD pathology and ApoE4. Finally, the implications of these neurovascular and neuroimmune effects for the ARIA syndrome, a treatment limiting and potentially fatal complication of Abeta immunotherapy, will be examined.

Lawrence S. Honig, MD, PhD
Professor of Neurology (in the Gertrude H. Sergievsky Center and the Taub Institute)

A revolution in adult neurodegenerative disease therapy is now underway. Alzheimer’s disease (AD), previously impervious to any disease modifying interventions, is now treatable with two licensed efficacious therapies, that slow the course of progression. These therapies were developed through the use of a transgenic mouse model. The drugs lecanemab and donanemab are humanized monoclonal antibodies that administered to patients with AD, cause removal of cerebral beta-amyloid protein, decrease neurofibrillary degeneration, and ameliorate clinical disease progression. Because of their specificity, use of these therapies requires “amyloid confirmation” – namely evidence that the disease symptoms in question likely owe to the cerebral deposition of beta-amyloid. This requirement has accelerated our development of biomarkers for different aspects of AD including indicators of amyloid deposition, neurofibrillary tangles, glial reaction, and neuronal degeneration and loss. At the Taub, we have collaborated through use of a variety of cohorts, including samples of autopsy-proven brain diseases, clinic convenience populations, and epidemiological populations including WHICAP, EFIGA, Peruvian, and long-lived family cohorts to further assess the ongoing biological processes, determine risk/prognosis, aid in diagnosis, and begin to develop understanding of factors affecting the development of AD in these different populations.

Scott A. Small, MD
Boris and Rose Katz Professor of Neurology (in the Taub Institute, the Gertrude H. Sergievsky Center, Radiology and Psychiatry)

Drug discovery and development typically begins with academic research that identifies and validates therapeutic targets, at which point the baton is typically passed to industry whose expertise is required for drug develop. In this talk I will instantiate this pathway, sharing my lab’s experience developing novel therapies for Alzheimer’s disease (AD) and aging. I will review how we have identified novel targets by relying on ‘anatomical biology’-- that is, uncovering biological reasons that can explain why one brain area is vulnerable to a disorder and neighboring region is resistant. Once identified we then integrated anatomical biology with cell and molecular biology thereby validating the therapeutic targets, at which point we began working with the pharmaceutical industry to develop novel therapeutics. Lessons learned will be shared, on the challenges and pitfalls of drug discovery. I will end with ideas for collaborations with the community of Taub investigators who are interested in drug discovery.

Yian Gu, MD, MS, PhD
Associate Professor of Neurological Sciences (in Neurology, Epidemiology, the Gertrude H. Sergievsky Center and the Taub Institute)

For decades, the use of cerebrospinal fluid protein biomarkers has been a mainstay for biological determination of Alzheimer’s disease (AD) pathology. In recent years, the development of measurement systems for biomarkers in plasma has now allowed more widespread probing of biological brain disease. At the Taub Institute, collaborations between laboratory and clinical epidemiological work has allowed use of a variety of biomarkers, including phosphorylated tau (P-tau) isoforms such as P-tau217, P-tau181, and P-tau231, along with amyloid beta forms (Aβ) 40, Aβ42, and degeneration markers such as Glial Fibrillary Acidic Protein (GFAP), and Neurofilament Light Chain (NfL) to be used as critical tools for identifying or excluding AD pathology in longitudinally followed populations. Our collaborative work in the multiethnic population Washington Heights/Inwood Columbia Aging Project (WHICAP) and in the Caribbean Hispanic participants of Estudio Familiar de Influencia Genetica en Alzheimer (EFIGA), two large cohort studies consisting of underrepresented populations, has allowed investigation of these plasma biomarkers in relation to clinical findings of mild cognitive impairment (MCI) and AD. Our findings show that these biomarkers have utility in identifying AD in diverse populations including Hispanics, non-Hispanic blacks, and non-Hispanic whites. Plasma biomarkers may become integrated into clinical practice, since they potentially provide an accessible, cost-effective means of identifying individuals with the earliest signs of AD. They may also assist in patient identification and therapeutic monitoring of new medication therapies.

Adam M. Brickman, PhD
Professor of Neuropsychology (in Neurology, the Taub Institute, and the Gertrude H. Sergievsky Center)

The prevailing hypothesis about the pathogenesis of Alzheimer’s disease (AD) suggests a cascade of biological events initiated by abnormal beta-amyloid processing that leads to tau-related neuronal dysfunction, neurodegeneration, and dementia. This conceptualization has directly informed current diagnostic schemes, which evolved from diagnosing AD based on the characterization of a clinical syndrome to diagnosing AD based on the presence of biological markers of amyloid and tau alone. However, the vast majority of individuals with symptomatic AD have mixed pathological profiles, comprising plaque and tangle pathology together with cerebrovascular disease. In fact, “pure” AD pathological profiles are extremely rare and typically occur only in people who are asymptomatic.

One of the challenges of studying mixed pathology in AD has been the lack of available biomarkers to characterize in vivo cerebrovascular disease and dysfunction. Our laboratory develops and implements magnetic resonance imaging (MRI)-based measurements that reflect various aspects of vascular brain injury and dysfunction, including markers of ischemic injury, hemorrhagic lesions, enlarged perivascular spaces, blood brain barrier (BBB) dysfunction, microstructural damage, and cerebral blood flow. We have also begun to incorporate recently-developed blood-based biomarkers related to angiogenesis and BBB breakdown, such as vascular endothelial growth factor (VEGF) signalling proteins and placental growth factor (PlGF).

In this presentation, I will review neuroimaging and fluidic biomarkers currently in use in the laboratory and review recent findings that establish cerebrovascular disease as a “core feature” of AD, evident in genetically deterministic forms of the disease, clinical samples, and community-based populations. In addition to contributing independently to clinical risk and progression, cerebrovascular disease appears to be linked to tau pathology and subsequent neurodegeneration via astrocytosis and BBB dysfunction.

Philip L. De Jager, MD, PhD
Weil-Granat Professor of Neurology (in the Taub Institute)

Starting from single cell and nucleus RNA sequence profiles in which we identified associations between certain cell subtypes and pathologic as well as cognitive traits related to Alzheimer’s disease (AD), we attempted to translate these insights to cerebrospinal fluid (CSF), which is accessible in living individuals. In our initial effort, we worked with colleagues in the Taub to assess which genes that mark microglial cell subtypes of interest are expressed in the CSF at the protein level. Here, we will discuss the evaluation of VSIG4 as a proxy for a microglia subtype enriched for an antigen presenting cell phenotype. Interestingly, it is elevated in AD but not in multiple sclerosis patients which have an acute inflammatory lesion. This case illustrates our broader approach to develop CSF (and ultimately) blood biomarkers that can serve as a proxy for certain glial cell types that have a role in AD.

Badri N. Vardarajan, PhD, MS
Assistant Professor of Neurological Sciences (in Neurology, the Gertrude H. Sergievsky Center, and the Taub Institute)

We investigated the relationship between the cerebrospinal fluid (CSF) proteome and circulating plasma metabolites with Alzheimer’s Disease (AD) and biomarker levels of AD. We used an untargeted approach in a cohort of non-Hispanic white, African Americans, and Caribbean Hispanic individuals from Dominican Republic and New York City to measure CSF proteins and circulating metabolites in plasma. Biomarkers of AD were measured in CSF and plasma including P-tau181, Aβ40, Aβ42, total-tau, neurofilament light chain (NfL) and glial fibrillary acidic protein (GFAP). Association of individual and co-abundant modules of proteins and metabolites were tested with clinical and biomarker- assisted diagnosis of AD and biomarker levels. Results from replicated in Accelerated Medicine Partnership-Alzheimer’s Disease cohort and significantly associated proteins were functionally validated in postmortem human brains and zebrafish models. Autotaxin (ENPP2) and lysophosphatidylcholines (lysoPC) were reduced in the CSF and plasma of AD patients and were inversely correlated with levels of P-tau181. Integrative analyses point to role of convergent cellular signaling pathways mediated by lysoglycerophospholipids in AD.

Sabrina Simoes, PhD
Assistant Professor of Neurological Sciences (in Neurology and the Taub Institute)

Over the past two decades, compelling evidence has accumulated supporting dysfunction of the endolysosomal system during the early stages of various neurological disorders, including Alzheimer's disease (AD). However, biomarkers linked to endolysosomal disruption have yet to emerge. Such biomarker(s) would be invaluable for detecting cellular changes occurring during the presymptomatic phase of the disease, and potentially accelerate the design and development of therapeutic interventions targeting endolysosomal trafficking. Published and unpublished research conducted by my team led to the discovery of APLP1 as a potential endosomal biomarker of AD. Using an in-house CSF APLP1 immunoassay, we showed alterations in APLP1 concentration levels in the CSF of prodromal AD individuals compared to cognitively healthy controls. Given that the biomarker field has shifted its focus towards the development of blood-based immunoassays for broader accessibility, the need for a blood-based APLP1 immunoassay is imperative. Towards this goal, we recently developed a plasma APLP1 immunoassay on the Mesoscale Discovery (MSD) platform. With this new highly sensitive and quantitative immunoassay, we are uniquely positioned to determine the concentration of APLP1 in blood and evaluate its utility as an early biomarker of endosomal dysfunction. We are currently assessing APLP1 concentration levels in different biofluids from individuals recruited to our Alzheimer’s Disease Research Center. At the same time, we are expanding our findings to other neurological diseases, including genetic forms of Parkinson’s disease. In this presentation, I will share strategies used by our laboratory to identify, validate, and develop novel disease biomarkers. Challenges in the wide implementation of such biomarker(s) in the clinical setting will be also discussed.

Carol M. Troy, MD, PhD
Professor of Pathology and Cell Biology and Neurology (in the Taub Institute)

Neuronal degeneration and death are the hallmarks of many neurological diseases, including Alzheimer’s Disease and stroke, and there is considerable evidence that the caspase family of cell death proteases play a critical role in the progression of these diseases. There is also evidence that neurovascular disease, including stroke, is a risk factor for AD. A central question of our work is the function of the individual members of the multi-membered caspase family in the nervous system. Our studies have found that different death pathways are initiated by different death stimuli, key to both a mechanistic and a therapeutic standpoint as it provides for the possibility of specific interventions that abrogate aberrant death signaling but do not interfere with the normal death pathways that are necessary for normal organismal function. To study degeneration pathways, over more than two decades we have developed molecular tools that allow the study of individual members of protein families. We have pioneered techniques for molecular manipulation of caspase expression and activity measures in primary neuronal cultures and in vivo. The tools that we have developed have allowed us to study the function of individual caspases in neurons and the neurovascular unit in retina and brain both in vitro and in vivo. We identified caspase-9 as the proximal caspase activated in rat and mouse models of cerebral ischemia and developed a cell permeant highly selective peptide caspase-9 inhibitor which, when delivered via intranasal instillation, provided neuroprotection and substantially blocked edema. That work led to our building a program to study the neurovascular unit in the retina to determine if the same mechanisms we identified in the brain were also activated in a model of retinal ischemia. With these approaches we have found that non-apoptotic activation of endothelial caspase-9 regulates edema, inflammation and neuronal dysfunction in a model of retinal edema; eye drop application of a highly selective caspase-9 inhibitor provides therapeutic protection. Our data show that caspase-9 is a critical mediator of neurovascular disease.