Tau immunotherapies for Alzheimer's disease

Abstract

Introduction: Alzheimer's dementia (AD) is the most common form of dementia in the World. Pathologically, it is characterized by extracellular β-amyloid plaques and intraneuronal neurofibrillary tangles (NFTs). The latter is composed of irregular, pathological forms of the tau protein. Currently, FDA-approved symptomatic treatments are limited to the targeting of cholinergic deficits and glutamatergic dysfunctions. However, as understanding of β-amyloid plaques and NFTs expands, these dysfunctional proteins represent potential therapeutic interventions. The present review article evaluates active and passive immunotherapies in clinical development for AD to date and their potential to significantly improve the treatment of AD going forward.

Areas covered: All clinical trials that have targeted β-amyloid to date have produced somewhat disappointing results, leading to a shift in intervention focus to targeting tau protein. A key component in understanding the value of targeting tau in therapeutic paradigms has come from the conceptualization of prion-like pathological spread of tau isoforms from neuron to neuron, and referred to as 'tauons'. Immunotherapies currently under investigation include approaches aiming at preventing pathological tau aggregation, stabilizing microtubules, and blocking of tauons.

Expert opinion: A multi-targeted approach that would use biologics targeting tau offers great promise to the development of effective AD therapeutic interventions.

Keywords: Alzheimer’s disease; Tau; clinical trials; monoclonal antibodies; passive immunotherapy.

Figure 1.

Modified from Jack et al. [91] that describes biomarker curves in reference to time/disease progression. This figure illustrates the patient dependent variability cognitive reserve in determining cognitive impairment. For example, a comparison between high risk and low-risk patient (open circle) may indicate similar biomarker levels (closed circle), however with a clear difference cognitive outcomes. Also stressed here is the progression of markers that can provide the basis of early screening, detection, and diagnosis. (Image recreated with Dr. Jack’s permission). Low and high-risk cognitive impairment is based on family history and environmental factors, such as traumatic brain injuries.