Pharmacotherapeutic combinations for the treatment of Alzheimer's disease

Alzheimer's disease (AD) is the most common form of dementia, and four medications are currently available as symptomatic therapies: three cholinesterase inhibitors (ChEI) and memantine. In June 2021, aducanumab was approved in the United States under an accelerated approval pathway as the first novel putative disease-modifying therapy (p-DMT) targeting the β-amyloid (Aβ) cascade in the brain. The combination of several monotherapies to address the multifactorial pathogenesis of neurodegenerative diseases is an anticipated next step.

The cholinergic hypothesis and the amyloid cascade hypothesis have been proposed as explanations for the pathogenesis of AD. Given the limited effectiveness of monotherapies based on these hypotheses, approaches using combination therapy are attempting to address the complexity of AD pathogenesis, including putative causative proteins-related neurodegeneration, neurotransmitters, and neuroinflammation, in a comprehensive manner.

The efficacy of an initial or add-on combination approach to counteracting neurodegenerative processes and functional deterioration has been investigated. The combination of symptomatic therapies with approved anti-dementia medicines (one ChEI and memantine) has been found to be functionally effective for a moderately severe disease stage. Furthermore, combination strategies involving p-DMTs, symptomatic therapies, and neuro-regeneration may be useful in the future.