Introduction There are dozens of drugs in development for AD with billions of dollars invested. Despite the massive investment in AD drugs and a burgeoning pipeline, there have been more setbacks and failures than treatment successes. Areas Covered The classes of drugs that have failed to date include the monoclonal antibodies, the gamma secretase inhibitors, dimebon, neurochemical enhances and one tau drug. Data for these compounds was sought through pubmed search and clinicaltrials.gov search. Expert opinion The obvious question to be posed is: Why are they failing? Is the treatment of symptomatic dementia too late? Are the therapeutic targets incorrect? Are the clinical methodologies imprecise, misleading or inaccurate? This review summarizes the drugs that have failed 2010–2015 and offers possible theories as to why they have failed.

Introduction Reduction in the deposition of amyloid beta (Aβ) has been the primary target for Alzheimer’s disease (AD) therapeutics recently, but in clinical trials this approach has generally been unsuccessful. A common feature of AD pathology is a complex inflammatory component that could be a target for treatment. One feature of this inflammation has been the involvement of the receptor for advanced glycation endproducts (RAGE), whose ligands include advanced glycation-endproduct (AGE)-modified proteins as well as lipids and Aβ, which are found at elevated levels in AD brains. Areas Covered Herein, the authors describe the key features of RAGE and how it could have a role in AD pathogenesis. They also summarize the experimental animal and clinical data which demonstrates the therapeutic effect of RAGE inhibition and consider what these findings mean for human disease. Expert opinion RAGE has multiple ligands, including Aβ, that are increased in AD brains. Inhibiting RAGE-ligand interactions without activating receptor signaling can reduce multiple pathological pathways relevant for AD. Several RAGE inhibitors and modulators are now being tested as therapeutics for AD. Recent phase II studies have established the good safety and tolerability of TTP448 with some evidence of positive benefit at lower dose. This suggests that further studies are required.

The development of novel pharmacological interventions would be more fruitful if multitarget therapies were introduced, and unexplored mechanisms of action were expanded upon. Additionally, there is a rationale for intervening earlier in the disease, perhaps preceding or at the advent of symptoms.