Elsevier Inc. tau phosphatases tau kinases Abeta interacting partners Abeta electron transport chain pathway mitochondria dynamics pathway toxic Abeta ---| mitochondria dynamics pathway neurofibrillary tangles Abeta interacting partners ---- toxic Abeta senile amyloid plaques gamma-convertase ---> toxic Abeta App Apoe ---> lipoprotein metabolism gamma-convertase tau kinases ---> hyperphosphorylated Tau Bace1 gamma-convertase ---> App Bace1 ---> App Apoe ---> cholesterol transport Bace1 ---> Abeta gamma-convertase ---> Abeta Abeta degrading enzymes ---> toxic Abeta Abeta degrading enzymes ---> Abeta Abeta degrading enzymes Mapt tau phosphatases ---> Mapt tau kinases ---> Mapt Apoe astrocyte toxic Abeta ---| respiratory complex IV microtubule stabilization Mapt ---> microtubule stabilization oxidative stress --+> tau kinases oxidative stress ---| tau phosphatases proteostatic stress oxidative stress potential AD miRNA ---> Alzheimer Disease (AD) cholesterol transport lipoprotein metabolism ApoE4 ---> impaired cholesterol/lipid, impaired vesicle endocytosis AD susceptibility genes ---> synaptic dysfunction, synapse loss, cognitive decline AD susceptibility genes ---> impaired cholesterol/lipid, impaired vesicle endocytosis cerebral hypoperfusion ---> synaptic dysfunction, synapse loss, cognitive decline glucose hypometabolism ---> synaptic dysfunction, synapse loss, cognitive decline hyperphosphorylated Tau ---| mitochondria dynamics pathway hyperphosphorylated Tau ---| respiratory complex I impaired cholesterol/lipid, impaired vesicle endocytosis ApoE4 microglia respiratory complex IV respiratory complex I Psen1 Psen2 potential AD miRNA downregulated miRNA upregulated miRNA upregulated target translation downregulated target translation Alzheimer Disease (AD) early-onset, familial AD AD type 1 AD type 4 AD susceptibility genes neurovascular coupling neuroinflammation AD susceptibility genes ---> neuroinflammation cerebral hypoperfusion mitochondria dynamics pathway ---> synaptic dysfunction, synapse loss, cognitive decline late-onset, sporadic AD AD type 2 LTP toxic Abeta ---| LTP toxic Abeta ---| neurovascular coupling toxic Abeta --+> neuroinflammation toxic Abeta toxic Abeta --+> LTD LTD LTD ---> synaptic dysfunction, synapse loss, cognitive decline synaptic dysfunction, synapse loss, cognitive decline hyperphosphorylated Tau hyperphosphorylated Tau ---> synaptic dysfunction, synapse loss, cognitive decline glycolysis pathway glucose hypometabolism oxidative stress ---| glycolysis pathway astrogliosis