Alzheimer's Disease with Vascular Pathology (ADv) -- focused dementia population with high unmet need.
Alzheimer’s Disease with Vascular Pathology (ADv)
In standard classifications, Alzheimer’s Disease (AD) and Vascular Dementia (VD) are the two most common forms of dementia. However, it is well accepted that many dementia patients have more than one form of underlying pathology. Over 50% of individuals with AD also have signs of VD, and these patients often have more rapidly progressing disease and higher symptom severity. There are no approved therapies for VD, and only symptomatic treatments with limited benefit are approved for AD.
ADv reflects the complex interplay of multiple pathological mechanisms underlying dementia, including neurovascular dysfunction, impaired cellular bioenergetics, and inflammation. The ADv patient is defined by a combination of AD pathology, sub-cortical vascular disease, and cardiovascular (CV) risk factors. We selected this population of dementia patients because CY6463 has the potential to address the pathophysiological processes driving their disease.
ADv – An identifiable subset of dementia patients
- AD pathology AND
- Sub-cortical vascular disease AND
- CV Risk Factors
Preclinical data suggest CY6463 has potential to:
- Cerebral blood flow
- Endothelial health
- Cellular energetics
- Once-daily CY6463
- Confirmed AD pathology (PET, CSF)
- 3+ cardiovascular risk factors
- Mild-moderate subcortical small-vessel disease on MRI
- Mini Mental State Exam score (16-26)
- Establish safety and pharmacodynamic effects of CY6463 in a short-term study
- De-risk progression to larger, longer symptomatic and disease modification trials
- Vascular dysfunction
- Mitochondrial dysfunction
- Cognitive impairment
- ASL (CBF)
- Neurofilament light chain
- Vascular cell adhesion molecule
- N-acetyl aspartate (MRS)
- Cognitive and behavior tests
Improved CBF, particularly in the context of memory improvements, would indicate an impact on the underlying disease mechanism and enable a targeted design for the next development stage.
- Cortes-Canteli M, Iadecola C. Alzheimer’s Disease and Vascular Aging: JACC Focus Seminar. J Am Coll Cardiol. 2020;75(8):942-951
This paper reviews the collective evidence that supports the contribution of vascular pathology to Alzheimer’s disease and age-related dementias. Alzheimer’s disease is the fifth leading cause of death worldwide and affects 10% of the population over 65 years old. Vascular alterations in AD are many and include cerebrovascular atherosclerosis, microvascular rarefaction, cerebral amyloid angiopathy, blood-brain barrier disruption, and reduced cerebral blood flow. These alterations are linked to Aβ deposition that may lead to and/or exacerbate the associated vascular dysfunction, for example through oxidative stress. In turn, Aβ deposition may be exacerbated by the vascular dysfunction, for example, via reduced vascular clearance. The central illustration summarizes vascular changes associated with Alzheimer’s disease, and Table 1, which includes illustrations, provides an overview of the cellular pathology of the neurovascular unit in Alzheimer’s disease. Cardiovascular risk factors associated with dementia and Alzheimer’s disease include arterial stiffening, hypertension, cardiac diseases/abnormalities, and a procoagulant state. Vascular aging and Alzheimer’s Aβ pathologies act in concert to “reduce cerebral perfusion and impair the ability of the cerebral circulation to supply energy substrates and oxygen to active brain regions” thereby leading to dementia