PICALM, the phosphatidylinositol-binding clathrin assembly protein, also affects AD risk primarily by modulating production, transportation, and clearance of β-amyloid (Aβ) peptide, but other Aβ-independent pathways are discussed, including tauopathy (Dean and Shaw, 2010), synaptic dysfunction (Jahn and Scheller, 2006), disorganized lipid metabolism (Eisenstein, 2011), immune disorder (Carter, 2010), and disrupted iron homeostasis (Xu et al., 2014). Here, PICALM is linked to tauopathy.