Mounting evidence showed that amyloid-β (Aβ) peptides play a central role in the pathogenesis of AD. The initial “amyloid cascade” hypothesis suggested that Aβ peptides drive the neuropathological cascade responses leading to dementia [10] . The revised amyloid cascade hypothesis suggested that soluble Aβ oligomers initiate the pathological cascade of AD leading to synaptic dysfunction, neuronal cell death, and dementia [11] . Moreover, transgenic mice with overexpression of the human amyloid precursor protein (APP-tg mice) have learning and memory deficits, as well as neuritic plaques similar to those seen in humans with AD [12] . In view of this, several immunization programs have successfully cleared the amyloid in APP-tg mice [13] [14] . However, the immunization programs attempted to clear AD patients brain amyloid through monoclonal antibodies, AN1792 [15] , Solanezumab (LY2062430) and Bapineuzumab [16] [17] , were terminated because of adverse effects 14 and lack of clinical treatment effect [16] [17] . The results of concurrent neuropsychological tests and magnetic resonance imaging (MRI) tests were surprising and disappointing, the brain

atrophy in immunized patients was worse than that of placebo-controlled patients [18] . These findings suggested that amyloid deposition is not the only one pathogenic cause of AD (Figure 1).

Other research indicated that oxidative stress may be involved in the pathogenesis of AD. Further study showed that oxidative stress markedly elevated in preclinical AD patients and amnestic mild cognitive impairment (aMCI) patients [19] [20] . The mechanism may be that the oxidative stress leads to membrane damage, cytoskeleton alterations [21] and destroy the synaptic homeostasis in the hippocampus early in the AD process and ultimately speeding up the progression of AD [19] . Growing evidence indicates that many oxidative markers are increased in the AD brain, including protein oxidation [22] , lipid peroxidation [23] , and nucleic acid oxidation [21] . Reactive oxygen species (ROS), which are cytotoxic byproducts of oxygen metabolism, are accumulated during aging, hyperglycemia, hypoxic insults and inflammation [24] . In the AD brain, these may induce synaptic loss and eventually promote neurofibrillary tangles and neuritic plaques formation [25] . Moreover, there is a positive feedback loop between oxidative stress and Aβ, which contributes to the pathologic progress of AD [26] [27] [28] . This is because ROS alter the expression of β-APP cleaving enzyme (BACE₁), the rate-limiting enzyme of AD [29] [30] , and Presenilins1 (PS1), the catalytic submit of the γ-secretase [26] , thereby promoting Aβ production in AD. Meanwhile, Aβ induces oxidative stress and the generation of HNE, which is a neurotoxic lipid peroxidation product and associated with Aβ pathology in AD [26] . Several studies suggested that antioxidants vitamin E and vitamin C play a role in delaying the onset of AD [31] [32] [33] [34] . These studies further confirmed that oxidative stress is involved in the occurrence and progression of AD (Figure 2).

Besides the amyloid plaques and oxidative stress, neuroinflammation in the central nervous system (CNS) also causes neuronal injury, and pro-inflammatory changes exist in early stages of the disease in AD patients, when microglial cells are activated and produce pro-inflammatory mediators [35] . Acute systemic inflammatory events with increased levels of pro-inflammatory cytokines such as tumor necrosis factor-α (TNF-α), were associated with an increasing rate of cognitive decline in mild to severe dementia [36] . Animal models of lipopolysaccharide (LPS) induced sepsis showed CNS inflammation, neuronal death and cognitive decline [37] [38] [39] . Correspondingly, non-steroidal anti-inflammatory drugs (NSAIDs) can ameliorate behavioral and pathology deficits in AD transgenic mouse models [40] [41] . Although clinical trials have failed to reproduce the beneficial effects of NSAIDs in AD patients, they may be beneficial when administered in the early stage of the disease [42] . The anti-inflammatory effects of NSAIDs may be that NSAIDs directly bind to peroxisome proliferator-activated receptor γ (PPAR γ) [42] , which expressed in human brain [43] and inhibited microglial activation and the expression of a wide range of proinflammatory genes [42] [44] [45] , and activate its transcriptional regulatory activities [42] . Other anti-inflammatory drugs such as trifusal showed a significant low rate of conversion to dementia in clinical trials with mild cognitive impairment patients [37] [46] . The diversity of effects may depend on the drug, because different anti- inflammatory drugs may have different molecular targets. And anti-TNFα treatment with the antibody against TNFα, infliximab, reduced Aβ and tau phosphorylation in transgenic mice [41] . In addition, the TNFα inhibitor thalidomide can decrease the activation of both astrocytes and microglia, Aβ load, plaque formation and tau phosphorylation [41] (Figure 3). Further studies assessing the potential for targeting these specific inflammatory processes are needed to elucidate more effective treatments and provide a clearer understanding of the complexities of inflammatory signaling in AD [41] .

Accumulating evidence also suggests that insulin resistance acts as a known risk factor for AD [2] [47] . Brain insulin signaling plays a critical role in the regulation of food intake, body weight, reproduction, and learning and memory [48] [49] . Defective insulin signaling is associated with decreased cognitive ability and the development of dementia and AD [2] [50] . Insulin resistance, induced by peripheral metabolic syndrome, impairs the insulin signaling in the brain, which mainly impacts the PIK3/Akt pathway, then reduces Aβ and tau phosphorylation by inhibiting the activation of glycogen synthase kinase 3-α and -β separately, which are the key signaling molecules downstream of Akt [51] . There is a feed-forward interaction between impaired insulin signaling and Aβ production, which contributes to the pathologic progress of the AD and cognitive decline [2] [52] . Insulin resistance also can promote Aβ generation through altering

insulin signal transduction, increasing BACE1 and γ-secretase activities, and accumulation of autophagosomes [52] [53] . Moreover, insulin resistance causes both cerebral glucose hypometabolism and a systemic hyperinsulinemic state [49] . Brain glucose hypometabolism was found even at the preclinical stage of AD [49] . Peripheral insulin resistance not only reduced cerebral glucose metabolism, but also decreased Aβ clearance in the CNS [47] [48] . Rosiglitazone, a ligand for peroxisome proliferator-activated receptors (PPARs), improve cognitive function by facilitating Aβ clearance, reducing amyloid plaques and tau phosphorylation in AD mouse models [2] [54] [55] . Rosiglitazone can also protect cognitive decline in MCI patients [56] [57] [58] , while pioglitazone can improve cognitive deficiency and stabilize the disease in the individuals with mild AD [59] [60] . Treatments to enhance cerebral glucose metabolism showed improvement in cognition and AD symptomatology [61] . Collectively, insulin resistance is closely related with the pathologic process of AD (Figure 4).

In summary, Aβ peptides play a central role in the pathogenesis of AD, while oxidative stress, neuroinflammation and insulin resistance participate in the pathogenic process of AD.

Growing evidence demonstrates that FGF21 activated peroxisome proliferator- activated receptor γ coactivator-1α (PGC-1α) [70] [77] [78] [79] [80] , which is abundantly expressed in the brain [81] [82] . The expression of PGC-1α is reduced in the brain of AD patients. Exogenous human PGC-1α (hPGC-1α) expressed in primary neurons from the Tg2576 mouse of AD decreased Aβ generation by reducing BACE1 transcription which was dependent on PPAR γ [83] [84] . In accordance with this result, gene delivery of hPGC-1α in the brain of transgenic APP23 mice reduced amyloid deposition, which correlated with a decrease in BACE1 expression [85] . These findings suggest that FGF21 may reduce Aβ generation by decreasing BACE1 expression, as illustrated in Figure 1.

As widely known, ROS, the cytotoxic byproducts of oxygen metabolism, could induce synaptic loss, promote neurofibrillary tangles, form neuritic plaques and finally cause neuron death [24] . This plays an essential role in the pathologic progress of AD. Recent work has shown that FGF21 participates in regulating oxidative stress [86] [87] [88] . It upregulated the expression of genes encoding proteins involved in antioxidative pathways, including mitochondrial uncoupling proteins (Ucp2 and Ucp3), superoxide dismutase-2 (Sod2), reduced ROS production in cardiomyocytes, and ameliorated cardiac tissue injury [86] [87] . In the brain of aging mice, FGF21could inhibit D-galactose-induced ROS production in a dose dependent manner [87] , through preventing NF-κB nuclear translation and IκBα degradation [88] . Hence, as showed in Figure 2, FGF21 may ameliorate the oxidative stress of AD by enhancing the activities of SOD and reducing the production of ROS.

Increasing evidences demonstrated that inflammatory process play a critical role in AD progression [89] [90] [91] . However, FGF21 was demonstrated a modulatory role in the inflammatory processes [61] [73] . As demonstrated in Figure 3, it acted as a positive acute phase response (APR) protein and protected mice from the challenge of LPS and sepsis [61] . The inflammatory genes such as interleukin-6 (IL-6), and monocyte chemoattractant protein-1 (MCP-1) were significantly higher in FGF21 knockout mice [86] . While in db/db mice models, FGF21 treatment significantly reduced the mRNA expression level of TNFα [92] . FGF21 inhibited macrophage-mediated inflammation, by activating the nuclear transcription factor-E2-related factor 2 (Nrf2) and suppressing the NF-κB signaling pathway [93] .

A growing body of findings suggests that insulin resistance is closely related with the pathologic process of AD [2] [50] [51] . FGF21 acts as one of the metabolic regulators. It has been demonstrated as a potent regulator of glycemia, lipid metabolism and energy homeostasis [94] [95] . Recombinant FGF21 treatment can improve whole-body insulin sensitivity and reduce plasma levels of glucose and triglycerides in diabetic mice [94] , while loss of endogenous FGF21 in vivo led to increased insulin resistance and pancreatic islet hyperplasia and dysfunction [95] . As presented in Figure 4, FGF21 can potentially ameliorate cognition through improving insulin resistance and cerebral glucose hypometabolism.