It is unclear how the above findings relate to accumulation of beta-amyloid (Aβ) in AD pathogenesis, but some relationship seems likely. For example, PICALM (phosphatidylinositol-binding clathrin assembly protein) and other endocytic molecules can modify Aβ toxicity in yeast and other model systems. 40 Although these genetic findings provide support for novel causal relationships that could be targeted by treatments, the association data point to genomic regions, not genes. Moreover, the proximal steps from genotype to phenotype are unclear, and many of the implicated genes are plausibly involved in multiple relevant functions (e.g., CLU is involved in altered immune function and lipid processing).
