Other modules linked genes related to protein metabolism such as CAST (calpastatin), CAPN2 (calpain-2), HDLBP,79 and AHNAK. 80Calpain activity has been shown to be upregulated prior to tau phosphorylation and loss of synaptic cells in AD brain,115 and calpain-2 specifically can create tauopathy-associated tau fragments.116. This evidence concerns the gene MAPT and Alzheimer disease.