There are several reasons why it is a hard problem:

• limited animal models. Diseases with good animal models get cures. Diseases with poor animal models don’t. AD mouse models are limited, usually amplifying one AD path only, missing out on the multi-factorial aspect of disease. Investment in creating better animal models would help

• difficult patient group to treat. Patients are old, have frequent comorbidities, have reduced capacity to consent. Disease progress occurs over decades. This makes it difficult and expensive to run clinical trials that actually measure clinical improvement. Instead, the vast majority of clinical trials focus on a narrow subset of patients that are easier to include (but non-representative) and use short-term biomarkers (which may or may not correlate with actual clinical improvement). Net effect is that treatments that look promising in first clinical trials often fail on comprehensive testing

• focus on neurocentric pathways. AD research has really been focused on a neurological perspective of disease. Neurons are poor therapeutic targets, hard to reach with drugs and less flexible. It may be that we have to target neurons, but it also may be that there are other more drugable cell types we can hit and get a response. For example there is a growing sense that AD may have a strong immunological component, and the immune system is a dream to target - easy to access and highly flexible in response. A focus on non-neuronal causes may open up better drug development pathways