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:

• Tau
• monoclonal antibodies
• passive immunotherapy
• Alzheimer’s disease
• clinical trials

Article highlights

• Biomarker changes precede clinically discernable changes in cognition.

• Therapy must be initiated as early as possible due to clear indication that the pathophysiological processes of Alzheimer’s dementia begin before the onset of cognitive decline.

• Misfolded tau aggregates released from presynaptic neurons are taken up by postsynaptic neurons where tauons acts as ‘seeds’ to form additional tau aggregates via a process similar to prionosis.

• The rationale behind active immunotherapy is to elicit an immune response that targets specific pathological conformers of tau-specific to the biology of a given patient.

• Generalized inflammation is one of the potentially serious consequences of vaccine therapy.

This box summarizes key points contained in the article.

Declaration of interest

No potential conflict of interest was reported by the authors.

Additional information

Funding

Supported by National Institute on Aging (5P20GM109025, 7K01AG047279, and Keep Memory Alive Foundation).