Why acetylcholinesterase inhibitors should be considered disease-modifying drugs for Alzheimer’s disease?

Disease-modifying drugs (DMDs) are defined as treatments capable of altering the underlying course of a disease by slowing or modifying its biological progression rather than merely alleviating symptoms. In Alzheimer’s disease (AD), therapeutic options with proven disease-modifying effects remain limited, despite the recent approval of anti-amyloid monoclonal antibodies. Acetylcholinesterase inhibitors (AChEI), currently classified as symptomatic treatments, have accumulated a number of clinical and experimental evidence suggesting a broader role. Long-term clinical and observational studies indicate that AChEI are associated with slower cognitive and functional decline, reduced hippocampal atrophy, lower mortality rates, and improved behavioral and psychological symptoms of dementia. In parallel, preclinical and clinical data show that AChEI may influence multiple key pathogenic mechanisms of AD, including amyloid-β production/aggregation/toxicity, neuroinflammation, glutamatergic excitotoxicity, synaptic dysfunction, and cerebral hypoperfusion. Taken together, these findings support the view that AChEI fulfill the criteria of DMDs, and should be reconsidered as such in the complex therapeutic framework of Alzheimer’s disease.