Tau-targeting therapies for Alzheimer disease: current status and future directions

Abstract

Alzheimer disease (AD) is the most common cause of dementia in older individuals. AD is characterized pathologically by amyloid-β (Aβ) plaques and tau neurofibrillary tangles in the brain, with associated loss of synapses and neurons, which eventually results in dementia. Many of the early attempts to develop treatments for AD focused on Aβ, but a lack of efficacy of these treatments in terms of slowing disease progression led to a change of strategy towards targeting of tau pathology. Given that tau shows a stronger correlation with symptom severity than does Aβ, targeting of tau is more likely to be efficacious once cognitive decline begins. Anti-tau therapies initially focused on post-translational modifications, inhibition of tau aggregation and stabilization of microtubules. However, trials of many potential drugs were discontinued because of toxicity and/or lack of efficacy. Currently, the majority of tau-targeting agents in clinical trials are immunotherapies. In this Review, we provide an update on the results from the initial immunotherapy trials and an overview of new therapeutic candidates that are in clinical development, as well as considering future directions for tau-targeting therapies.

Figure 1 |. Tau-related therapeutic targets.

The figure shows the various tau-targeting approaches that are in preclinical or clinical development for the treatment of Alzheimer disease and primary tauopathies. Antisense oligonucleotides can be used to reduce tau expression. Inhibitors of tau aggregation include curcumin and the methylene blue derivative LMTX. Microtubule stabilizers such as TPI-287 and NAP can be used to compensate for loss of the normal microtubule-stabilizing function of tau. Clearance of pathological tau can be enhanced using modulators of autophagy or proteasomal degradation. Active and passive immunotherapies use antibodies to target pathological tau intracellularly or extracellularly and promote its degradation and clearance. Pathological tau is characterized by extensive post-translational modifications, including hyperphosphorylation, acetylation, truncation. Glycosylation can be protective or detrimental. The inset shows various inhibitors that target the enzymes involved in these modifications. Ac, acetyl group, Gly, glycosyl group; OGA, O-GlcNAcase; P, phosphate. Adapted from ref.

Figure 2 |. Current status of clinical trials of tau-targeting drugs.

At the time of writing, the most active field is tau immunotherapy, with two active vaccines (AADvac1 and ACI-35) and nine antibodies (APNmAb005, E2814, JNJ-63733657, Lu AF87908, MK-2214, PNT001, PRX005, semorinemab and bepranemab) in ongoing clinical trials. Several of the other compounds in trials have complex or incompletely defined mechanisms of action; in this diagram, these compounds are categorized according to their presumed tau-related mode of action. X indicates trials that, to our knowledge, have been halted or terminated, as detailed in the main text, although their current status is sometimes difficult to determine, ? reflects uncertainty about the current status of trials. Adapted from ref..

Figure 3 |. Proposed modes of action of anti-tau antibodies.

a | Tau antibodies can consist of whole IgGs (~150 kDa) antibody fragments such as antigen-binding fragments (50 kDa), single-chain variable fragments (~25 kDa), and single-domain antibodies (~13 kDa). b | Antibodies might target tau intracellularly or extracellularly, and should ideally act in both compartments to maximize efficacy. Extracellularly, antibodies could sequester tau aggregates, prevent tau aggregation, promote microglial phagocytosis of tau–antibody complexes and/or facilitate removal of tau to the periphery. These mechanisms would all reduce the spread of tau between neurons and subsequent pathological seeding. Antibodies, with or without tau, can also be internalized by neurons through either receptor-mediated or bulk endocytosis. Inside the neuron, these antibodies can bind to tau aggregates within the endosomal–lysosomal system. There, they can promote disassembly of tau aggregates, allowing greater access for lysosomal enzymes. Formation of tau–antibody complexes within the endosomal–lysosomal system might also prevent tau from disrupting endosomal membranes and escaping back into the cytosol, thereby aiding complete tau degradation. Some antibodies might also enter the cytosol, where they can sequester misfolded tau or promote proteasomal clearance through tripartite motif containing 21 (TRIM21) binding, thereby enhancing clearance and preventing tau secretion. Antibodies bound to larger tau aggregates could be cleared via the autophagosome. Antibody fragments, either administered or encoded by adeno-associated virus (AAV) vectors, also have therapeutic potential. Astrocytic tau pathology can presumably be targeted using the same mechanisms of action, although experimental confirmation is required.

Figure 4 |. Modified immunotherapy strategies.

a | Targeted protein degradation via the ubiquitin–proteasome system. Proteolysis-targeting chimaeras (PROTACs) are hetero-bivalent complexes comprising a target binder (single-domain antibody (sdAb) or single-chain variable fragment (scFv)), a short linker and an E3 ligase-recruiting molecule. These complexes bring the target protein (in this case, tau) and E3 ligase into close proximity and trigger proteasome-based degradation. b | Targeted protein degradation via the endosomal–lysosomal degradation pathway. Lysosome-targeting chimaeras (LYTACs) are hetero-bivalent complexes are comprising a target binder (sdAb or scFv), a short linker and a ligand for the lysosome-targeting receptor (LTR). They shuttle extracellular tau into the neuron for degradation. c | Targeted protein degradation via the autophagy–lysosomal degradation pathway. Autophagy-targeting chimaeras are hetero-bivalent complexes comprising a target binder (sdAb, or scFv), a short linker and a degradation tag, which can enhance tau degradation through the autophagy–lysosomal degradation pathway. CI-M6PR, cation-independent mannose-6-phosphate receptor; RING, really interesting new gene; Ub, ubiquitin.