The synaptic dysfunction cluster encompasses genes mediating mitophagy suppression (TNIP1, KANSL1; Tier 1), glutamate receptor dysregulation (NSF; Tier 1 and SEZ6L2; Tier 2), and calcium imbalance (DOC2A; Tier 2), linking iAD2 and iAging2 to AD through excitotoxicity. Here, TNIP1 is linked to Alzheimer disease.