Cerebrospinal fluid biomarkers of neurovascular dysfunction in mild dementia and Alzheimer's disease

Abstract

Alzheimer's disease (AD) is the most common form of age-related dementias. In addition to genetics, environment, and lifestyle, growing evidence supports vascular contributions to dementias including dementia because of AD. Alzheimer's disease affects multiple cell types within the neurovascular unit (NVU), including brain vascular cells (endothelial cells, pericytes, and vascular smooth muscle cells), glial cells (astrocytes and microglia), and neurons. Thus, identifying and integrating biomarkers of the NVU cell-specific responses and injury with established AD biomarkers, amyloid-β (Aβ) and tau, has a potential to contribute to better understanding of the disease process in dementias including AD. Here, we discuss the existing literature on cerebrospinal fluid biomarkers of the NVU cell-specific responses during early stages of dementia and AD. We suggest that the clinical usefulness of established AD biomarkers, Aβ and tau, could be further improved by developing an algorithm that will incorporate biomarkers of the NVU cell-specific responses and injury. Such biomarker algorithm could aid in early detection and intervention as well as identify novel treatment targets to delay disease onset, slow progression, and/or prevent AD.

Figure 1

Diagram of the neurovascular unit. The neurovascular unit represents an interactive network of vascular cells (pericytes and endothelial cells), glia (astrocytes and microglia), and neurons.

Figure 2

The two-hit vascular model of Alzheimer's disease (AD): amyloid-β (Aβ)-independent and Aβ-dependent mechanisms. The development of AD is influenced by genetic, vascular, and environmental risk factors and lifestyle. The pathophysiology of AD can progress through both Aβ-independent and Aβ-dependent pathways. There is interplay between the two mechanisms. Specifically, vascular damage initiates the Aβ-independent mechanism, which can in turn induce Aβ and tau accumulation and neuronal injury. The Aβ-dependent mechanism arises from enhanced Aβ processing, altered Aβ metabolism, and faulty Aβ clearance. Ultimately both pathways can lead to neuronal dysfunction and degeneration resulting in dementia.

Figure 3

Hypothetical model suggesting the relationship between cerebrospinal fluid (CSF) biomarkers of cell- and system-specific injury during cognitive decline. Relative CSF levels of vascular injury (red), inflammatory response (green), and neuronal injury (blue) are differentially altered during aging and in the progression from mild dementia (i.e., mild cognitive impairment (MCI)) to Alzheimer's disease (AD).