Table 1 Examples of different types of therapeutic agents in clinical trials for Alzheimer's disease, each with their own advantages and disadvantages. For a complete list, see Cummings et al. (2021) [19]
From: The promise of microRNA-based therapies in Alzheimer’s disease: challenges and perspectives
Agent type | Name | Target type | Mechanism of action | Clinical stage | Advantages | Disadvantages |
|---|---|---|---|---|---|---|
Small molecule | Donepezil Galantamine Rivastigmine | Cholinergic system | Cholinesterase inhibitor, increases level of neurotransmitter acetylcholine | FDA-approved | Often easy dosing, such as oral administration Can target extracellular and intracellular targets Some can cross the BBB Combination therapy possible/ongoing Faster clearance than mAbs, good to avoid some side-effects Stable | 'One-drug, one target' Specificity can be dependent on binding-site, affinity, etc. Slow and laborious optimization |
Memantine | Glutamatergic system | N-methyl-D-aspartate (NMDA) receptor antagonist, affects glutamatergic transmission | ||||
LMTX (TRx0237) | TAU-targeting agent | TAU aggregation inhibitor | Phase III ongoing | |||
ALZT-OP1 | Inflammation-modifying agent | Combination therapy: ibuprofen is a nonsteroidal anti-inflammatory; cromolyn is a mast cell stabilizer with anti-Aβ effects | Phase III ongoing | |||
Mastinib | Tyrosine kinase inhibitor, modulates neuroinflammation | Phase III completed | ||||
Immunotherapy/antibody/protein | Aducanumab | Aβ-targeting agent | Monoclonal antibody, binds aggregated Aβ fibrils and soluble oligomers | FDA-approved | Targeted, specific therapeutics Available knowledge, plenty of antibody-based drugs approved Not a lot of toxicity due to humanization of antibody-based drugs | Only one monoclonal antibody has shown sufficient efficacy in humans so far (due to low effective dose in brain) Delivery issues, do not cross BBB Mostly extracellular targets, unstable, difficult manufacturing/slow and laborious optimization Need relative invasive intravenous or subcutaneous injections |
BAN2401 | Monoclonal antibody, binds soluble Aβ protofibrils | Phase III ongoing | ||||
Gantenerumab | Monoclonal antibody, binds aggregated Aβ | Phase III ongoing | ||||
Gosuranemab | TAU-targeting agent | Monoclonal anti-TAU antibody, binds extracellular, N-terminal fragments of tau | Phase II ongoing | |||
RNA-based | AAVrh.10-APOE2 | APOE | Viral delivery of APOE2 | Phase I ongoing | Single administration, targeted delivery | Delivery issues, do not cross BBB Need invasive intathecal injections Cytotoxicity |
IONIS-MAPTRx | TAU-targeting agent | ASO, binds TAU mRNA and inhibits translation | Phase I/II ongoing | Easy to manufacture, targeted/specific therapeutic, can target at any site | ||
miRNAs | Multi-targeting agent | miRNA mimic oligonucleotides (miRNA supplementation), miRNA antisense oligonucleotides (miRNA knockdown) | Preclinical | Simultaneous targeting of multiple AD-related pathways |