The search for novel targets in Alzheimer's disease-The 90s redux

Alzheimer's disease (AD) is a complex disease of the brain. Despite over 100 years of basic and clinical research, significantly intensified in the last three decades, the exact cause of this neurodegeneration is still an enigma. Based on neuroanatomical, experimental, and clinical findings, a series of hypotheses on AD pathogenesis have evolved. Among them, the "amyloid cascade hypothesis" has been most prominent. Clinical efforts targeting the biochemistry of amyloid β-protein (Aβ) as causal therapy have all failed so far, which may mean that the pathogenic mechanism of AD is less straightforward than initially thought. While there was good scientific reason to support this hypothesis before, the exclusive concentration on it may have impeded a more objective look and prevented the pursuit of alternative approaches to decipher the cause of AD. Here, a few key hypotheses of AD are summarized, and it is proposed that our view of the cause (or causes) of this detrimental disease be widened. This includes looking back, reactivating, and revisiting findings that were ignored over the last decades. Alternative and amyloid-independent ways to explain AD pathogenesis should receive more attention and are appearing.