Table 1.

Novel pathophysiological mechanisms in AD.

Feature	Pathophysiological mechanisms	References
Impaired hypothalamic function	– Aβ deposits in hypothalamic nuclei leading to disturbances in circadian rhythm; – Reduced dendrite arborization and neurodegeneration; – Inflammation driving endoplasmic reticulum stress and insulin resistance.	Ogomori et al., 1989; Standaert et al., 1991; Duncan et al., 2012; Lim et al., 2014; Baloyannis et al., 2015; Clarke et al., 2015; Musiek et al., 2015; Musiek and Holtzman, 2016; Kincheski et al., 2017; Stevanovic et al., 2017
Metabolic derangement	– Reduced cerebral glucose metabolism; – Altered peripheral metabolism with hyperglycemia and hyperinsulinemia; – Defective glucose metabolism and insulin signaling induced by Aβ;	Chase et al., 1984; Janson et al., 2004; Rivera et al., 2005; Steen et al., 2005; Lester-Coll et al., 2006; De Felice et al., 2009; de la Monte, 2009; Matsuzaki et al., 2010; Moloney et al., 2010; Bomfim et al., 2012; Talbot et al., 2012; Crane et al., 2013; De Felice, 2013; Lourenco et al., 2013; De Felice and Ferreira, 2014; Clarke et al., 2015
Disturbances in monoamine signaling and mood	– Aβ induces both depressive-like behavior and decreases brain serotonin levels; – Increased microglial activity of IDO might partially explain reduced serotonin levels; – Reduced tryptophan and increased quinolinic acid in plasma might drive depressive-like behavior in AD; – Alterations in the dopaminergic system, including reduced levels of dopamine and its receptors might contribute to hippocampus-dependent memory deficits and reward circuitry dysfunction.	Gibb et al., 1989; Storga et al., 1996; Burns et al., 2005; Bonda et al., 2010; Gulaj et al., 2010; Jürgensen et al., 2011; Ledo et al., 2013, 2016; Romano et al., 2014; Masters et al., 2015; Nobili et al., 2017
Inflammation	– Pro-inflammatory cytokines are elevated in AD brains and mediate neurotoxic signals; – Brain inflammation underlies defective neuronal insulin signaling and peripheral metabolic deregulation; – Inflammation may drive synaptic failure in the monoaminergic systems, thereby linking cognitive and non-cognitive symptoms found in AD patients.	Heneka and O'Banion, 2007; Bonda et al., 2010; Lee and Landreth, 2010; Swardfager et al., 2010; Bomfim et al., 2012; Czirr and Wyss-Coray, 2012; Ledo et al., 2013, 2016; Lourenco et al., 2013; Alcolea et al., 2014; De Felice and Ferreira, 2014; Morales et al., 2014; Clarke et al., 2015; Heneka et al., 2015a,b; Yirmiya et al., 2015; Hong et al., 2016a,a; Santos et al., 2016; Nobili et al., 2017; Salter and Stevens, 2017

Aβ, amyloid-β peptide; AD, Alzheimer's disease; CNS, central nervous system; IDO, indolamine-2,3-dioxygenase; T2D, type 2 diabetes.