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

In an article recently published in the journal Dr Nature Reviews Neurology, The researchers discuss the efficacy of tau-targeting Alzheimer’s disease (AD) therapies and strategies that could be applied to improve these treatments, particularly immunotherapies.

Study: Tau-targeting therapy for Alzheimer’s disease: current status and future directions. Image credit: Gorodenkoff / Shutterstock.com

Background

As of 2018, the prevalence of AD in the United States has increased from 5.4 to 6.5 million. The alarming increase in AD cases among the growing proportion of elderly people worldwide emphasizes the need for effective AD therapy.

AD pathology has two main features, including the accumulation of amyloid-β (Aβ), the primary component of extracellular plaques, and tau protein, the main component of neurofibrillary tangles (NFTs). Previous efforts to develop AD-modifying therapeutics focused on Aβ pathology; However, most immunotherapies and secretase modifiers targeting Aβ, with the exception of lecanemab and donanemab, either lack efficacy or lead to adverse effects.

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

Therapies targeting post-translational modifications

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

Tau phosphorylation

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

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

Lithium chloride, widely used to treat bipolar disorder, also inhibits glycogen synthase kinase 3β (GSK3β), which phosphorylates it. To date, GSK3β activity has not been significantly affected by lithium chloride treatment; However, clinical trials are still ongoing.

Its acetylation

Tau acetylation has also been observed in AD and may lead to protein solubilization and degradation. Salsalate, a small-molecule steroidal anti-inflammatory drug (NSAID), has been shown to inhibit tau acetylation in preclinical mouse studies; However, this agent has not been found to be successful in phase I clinical trials.

His incision

Truncation of tau protein 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 mild AD patients, with high doses associated with adverse effects.

Glycosylation

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

Active tau immunotherapy

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

AADvac1 is an active vaccine designed to specifically target N-terminally truncated tau fragments. Phase I and II trials of AADvac1 confirmed safety and immunogenicity in AD patients in addition to cognitive benefits, thus requiring 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 was found to be safe and well tolerated in AD patients; However, it failed to produce an adequate immune response even after booster doses. Since then, ACI-35.030 has been developed to improve the immunogenicity and binding efficiency of the vaccine to p-tau.

Passive tau immunotherapy

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

APNmAb005 is an anti-tau immunoglobulin G (IgG) antibody that selectively binds to tau protein in brain lysates from individuals with AD and mouse models of tauopathy. The safety of APNmAb005 is currently being evaluated in Phase I trials conducted in healthy subjects.

Bepranemab is an IgG4 antibody that binds to amino acids 235-250, 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 successfully reduced insoluble tau levels, leading to subsequent investigation into clinical trials that 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 treatment.

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 in patients 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.