Alzheimer’s disease and other dementias are defined by hallmark protein abnormalities found in brain tissue post mortem. Despite increasingly accurate diagnosis of primary pathology in life, treatments targeting the underlying protein abnormalities in Alzheimer’s disease have so far not worked. Why is dementia proving so hard to treat? One argument is that treatments are given too late in the course of illness – by the time of diagnosis, disease has progressed for a decade or more, has initiated self-perpetuating secondary processes and is no longer modifiable. A related, but distinct argument is presented in this issue by Robinson and co-workers, who demonstrate concurrence of multiple different abnormal proteins in dementias such as Alzheimer’s disease, hinting at the likelihood that treatment might require a multi-pronged approach (REF – Robinson et al).