The past decade has brought tremendous progress in unraveling the 
pathophysiology of Alzheimer's disease (AD). While increasingly sophisticated 
immunotherapy targeting soluble and aggregated brain amyloid-beta (Aβ) continues 
to dominate clinical research in AD, a deeper understanding of Aβ physiology has 
led to the recognition of distinct neuronal signaling pathways linking Aβ to 
synaptotoxicity and neurodegeneration and to new targets for therapeutic 
intervention. Identifying specific signaling pathways involving Aβ has allowed 
for the development of more precise therapeutic interventions targeting the most 
relevant molecular mechanisms leading to AD. In this review, I highlight the 
discovery of cellular prion protein as a high-affinity receptor for Aβ 
oligomers, and the downstream signaling pathway elucidated to date, converging 
on nonreceptor tyrosine kinase Fyn. I discuss preclinical studies targeting Fyn 
as a therapeutic intervention in AD and our recent experience with the safety, 
tolerability, and cerebrospinal fluid penetration of the Src family kinase 
inhibitor saracatinib in patients with AD. Fyn is an attractive target for AD 
therapeutics, not only based on its activation by Aβ via cellular prion protein 
but also due to its known interaction with tau, uniquely linking the two key 
pathologies in AD. Fyn is also a challenging target, with broad expression 
throughout the body and significant homology with other members of the Src 
family kinases, which may lead to unintended off-target effects. A phase 2a 
proof-of-concept clinical trial in patients with AD is currently under way, 
providing critical first data on the potential effectiveness of targeting Fyn in 
AD.