Redefining the battle against Alzheimer’s with tau-focused treatments

In a recent article published in the journal Nature Reviews Neurology, researchers discuss the efficacy of tau-targeting Alzheimer’s disease (AD) therapies and strategies that can be implemented to improve these treatments, especially immunotherapies.

Study: Tau-targeting therapies for Alzheimer disease: Current status and future directions. Image Credit: Gorodenkoff / Shutterstock.com

Background

Since 2018, the prevalence of AD has increased from 5.4 to 6.5 million in the United States. The alarming rise in AD cases amid a growing proportion of aged people worldwide underscores the need for effective AD therapies. 

There are two cardinal hallmarks of AD pathology, including the accumulation of amyloid-β (Aβ), which is the primary component of extracellular plaques, and tau protein, the main constituent of neurofibrillary tangles (NFTs). Previous attempts to develop AD-modifying therapeutics focused on Aβ pathology; however, most immunotherapies and secretase modifiers targeting Aβ, except for lecanemab and donanemab, either lacked efficacy or led to adverse effects.

The challenges associated with Aβ-targeted therapies led researchers to divert their attention to targeting the tau protein which, in addition to AD, is also present in other diseases, including progressive supranuclear palsy (PSP), corticobasal degeneration (CBD), Pick disease, frontotemporal dementia (FTD), and primary-age related tauopathy.

Therapies targeting post-translational modifications

Several post-translational modifications of pathological tau have been targeted through novel therapies, which include hyperphosphorylation, acetylation, truncation, and glycosylation.

Tau phosphorylation

In addition to the reduced activity of protein phosphatase 2A (PP2A), tau kinases are believed to contribute to tau hyperphosphorylation observed in AD. These enzymes can be indirectly or directly activated by Aβ, which can subsequently contribute to increased phosphorylation of tau and its misfolding.

Several therapies have been developed to specifically target tau phosphorylation in AD. Memantine, for example, enhances PP2A activity, whereas sodium selenate reduces tau phosphorylation. Although sodium selenate was effective in preclinical animal models, only modest benefits were observed in AD patients.

Lithium chloride, widely used for treating bipolar disorder, has also been shown to inhibit glycogen synthase kinase 3β (GSK3β), which phosphorylates tau. To date, GSK3β activity has not been significantly affected by lithium chloride treatment; however, clinical trials are still ongoing.

Tau acetylation

Tau acetylation has also been observed in AD and can lead to reduced solubility and degradation of tau protein. Salsalate, which is a small-molecule non-steroidal anti-inflammatory drug (NSAID), has been shown to inhibit tau acetylation in preclinical mouse studies; however, this agent was not found to be successful in a phase I clinical trial.

Tau truncation

The truncation of tau proteins has also been observed in AD and other tauopathies; however, these tau fragments have also been observed in healthy individuals. Minocycline, a caspase inhibitor, has been evaluated in phase II clinical trials; however, this treatment failed to slow cognitive decline in patients with mild AD, with higher doses associated with adverse effects.

Glycosylation

O-GlcNAcylation, a specialized and protective form of O-glycosylation that reduces phosphorylation and tau aggregation, is reduced during AD. To date, several O-GlycNAcase (OGA) inhibitors have demonstrated clinical safety in adults and are currently being investigated in phase II trials.

Active tau immunotherapies 

Both active and passive immunotherapies have been developed to target tau proteins. Active immunotherapy delivers a tau immunogen and is associated with several advantages, including low costs, a polyclonal antibody response, and long-term efficacy. However, the endogenous roles of tau protein outside of its contribution to AD can lead to adverse autoimmune responses, which have been observed in preclinical mouse studies.

AADvac1 is an active vaccine that has been developed to specifically target N-terminally truncated tau fragments. Phase I and II trials of AADvac1 have confirmed the safety and immunogenicity in AD patients, in addition to cognitive benefits, thus necessitating the need for more extensive studies to confirm its clinical efficacy.

ACI-35 is another AD vaccine that is liposome-based and specifically targets p-tau396404. ACI-35 has been found to be both safe and well-tolerated in AD patients; however, it failed to elicit a sufficient immune response, even after booster doses. Since then, ACI-35.030 has been developed to improve the vaccine’s immunogenicity and binding efficiency to p-tau.

Passive tau immunotherapies

Passive immunotherapy involves targeting specific tau epitopes that are involved in AD. An additional advantage of this approach is that any adverse effects can be mitigated through subsequent antibody clearance. Nevertheless, passive immunotherapy is often more expensive and must be administered more frequently, thus increasing the risk of secondary infection and other adverse effects.  

APNmAb005 is an anti-tau immunoglobulin G (IgG) antibody that preferentially targets tau protein in brain lysates from individuals with AD and mouse models of tauopathy. The safety of APNmAb005 is currently being evaluated in a phase I trial conducted in healthy individuals.

Bepranemab is an IgG4 antibody that binds to amino acids 235-250, which is adjacent to the microtubule-binding region within the tau protein. Phase I trials have largely confirmed the safety of bepranemab, and phase II trials are currently being conducted to evaluate the efficacy of this immunotherapy in patients with mild cognitive impairment (MCI) and mild AD.

E2814 is an IgG1 antibody that recognizes the microtubule-binding domain of tau and binds to extracellular tau. In preclinical mouse studies, E2814 has successfully reduced insoluble tau levels, which led to its subsequent investigation in clinical trials that have confirmed its safety in healthy adults. Currently, phase II/III trials are being conducted to determine the efficacy of E2814 in combination with anti-Aβ treatments.

JNJ-63733657 is another IgG1 antibody that specifically targets p-tau217. Phase I clinical trials have confirmed the safety of this antibody in healthy patients, as well as those with prodromal or mild AD. Currently, a phase II study is being conducted in early-stage AD patients to evaluate the efficacy of JNJ-63733657.