**2.4 Mitochondrial dysfunction**

Mitochondrial dysfunction has a significant function in brain aging and AD. Swerdlow and Kan suggested mitochondrial cascade hypothesis for sporadic form of AD in 2004 [13]. This hypothesis proposes that mitochondrial dysfunction exists early in disease pathogenesis and causes, NFT formation, Aβ deposition and synaptic loss, the mitochondria is vulnerable to oxidative stress because of lack of DNA repair activity and is the significant source of ROS in the central nervous system. Oxidation of mitochondrial DNA presents it vulnerable to somatic mutations which augments mitochondrial dysfunction. Mitochondrial dysfunction has been proposed to trigger onset of neuronal degeneration in AD. It is showed that Aβ accumulates in mitochondria from AD patients. Tau protein might also be included in mitochondrial dysfunction in synapse, indirectly.

#### **2.5 Brain insulin resistance and insulin deficiency**

Type 2 diabetes mellitus is a risk factor for AD and these two disorders share many common pathological pathways. Impaired glucose metabolism is related to rising oxidative stress and accumulated advanced glycation end products. Insulin is even produced in brain tissue itself. Insulin receptors are mostly located in the cerebral cortex, cerebellum, hypothalamus, hippocampus and olfactory bulb that are the cognition pertinent areas of the brain. Brain glucose utilization and insulin signaling are impaired in AD. AD is related to a reduction in the levels of insulin in the cerebrospinal fluid (CSF), in the ratio of CSF insulin/plasma insulin, a decline in the expression of insulin receptors and a rise in fasting plasma insulin levels. Impaired insulin signaling might influence AD pathogenesis via tau hyperphosphorylation, acetylcholine signaling and Aβ metabolism. Insulin stimulates the expression of choline acetyltransferase, the enzyme responsible for acetylcholine synthesis. Therefore, decreased insulin levels, as well as insulin resistance, can ultimately contribute to a decrease in acetylcholine in AD brains [14].

#### **2.6 Future therapeutic approaches and management of AD**

Alzheimer's disease [AD] is one of the most challenging threats to the healthcare system. The current therapeutic goals are to reduce amyloid levels, prevention of amyloid aggregation/toxicity and tau phosphorylation/aggregation. There is also a major improvement in understanding the role of cholinesterase [ChE] in the brain and the function of ChE inhibitors in AD Academic research has carried out on the system of a new generation of acetyl- and butyryl ChE inhibitors and test for AD in clinical experiments on human beings. Next to this alternative strategies for treating or slowing the progression of AD, like vaccination, anti-inflammatory agents, cholesterol-lowering agents, antioxidants and hormone therapy, are also studied. Although several anti-amyloid β compounds have been examined in clinical trials as potentially useful drugs, all of them have failed to show significant benefits so far. Tau-targeted drugs have been developed and have entered clinical trials recently. The improvements on early diagnostic biochemical markers will be useful to increase for better monitoring the course of the disease and to evaluate different therapeutic strategies [15].

Academic research of Alzheimer's disease consists three steps. The first one is to select a high-risk population with current evidence and to provide this population primary prevention. The goal of this first stage is to be able to manage modifiable risk factors. Second is to diagnose patients at the preclinical phase, which starts 10–20 years before symptoms occur. Researchers aim to find new and improve existing neuroimaging techniques, CSF investigations and laboratory and genetic studies. The third step is to discover disease-modifying molecules. Researchers are aiming to inhibit extracellular amyloid plaque accumulation and to inhibit intracellular tau-based neurofibrillary tangles accumulation [16].

#### *2.6.1 Anti-amyloid agents*

One of the main suggested pathophysiological processes is 'amyloid cascade hypothesis'. All autosomal dominant AD genetic forms are the result of mutations of amyloid metabolism encoding genes. Also clinical and experimental data indicates toxic effects of accumulated amyloid plaques. Amyloid directed therapies can be classified in three different classes: amyloid anti-aggregates, secretase modulators and immunotherapies [17].

#### *2.6.2 Secretase modulators*

To reduce Aβ production, researchers focused on modulate enzymes that breakdown amyloid precursor protein [by stimulating α secretase or inhibiting γ and β secretase activity]. While effective α secretase was infrequently, various γ and β secretase inhibitors improved. γ secretase plays a decisive role in Aβ generation but this enzyme has several cleavage actions including notch receptor signaling so that γ secretase inhibitors have significant side effects. β secretase inhibitors also failed to show disease-modifying effects but there are still ongoing studies [17].

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*Future Treatment of Alzheimer Disease DOI: http://dx.doi.org/10.5772/intechopen.85096*

*2.6.4 Amyloid removal [immunotherapy]*

ments ongoing about anti-tau vaccines at AD [19].

**3. Treatments that failed in clinical trials**

Another strategy is to prevent aggregation of amyloid in non-soluble forms. Although new studies report soluble form of Aβ also have toxic effects. It's known that Aβ forms oligomers, fibrils and then deposition of amyloid plaques exist. Tramiprosate, colostrinin, clioquinol are some of the studied anti-Aβ aggregation agents. There were no effects or minimal effects phase II and III anti-Aβ aggregation agents trials on cognition. There are ongoing projects to improve new molecules [18].

Although it is not proven (exactly) how immunotherapy might attenuate Aβ plaques in the brain, some mechanisms have postulated. Therapeutic goal is to induce a humoral immune response to fibrillary-Aβ42 or passive administration of anti-Aβ antibodies. First studies of active vaccination were halted because of the induction of serious side effects. There are ongoing phase I–III studies with active and passive immunization (CAD106, bapineuzumab, solanezumab, intravenous

Tau is a microtubule-associated protein and the MAPT gene encodes tau. Assembling microtubules and regulating axonal transport are various functions of tau. It is proven that hyperphosphorylated tau causes disruption of mitochondrial respiration and axonal transport. It should be emphasized that tau hyperphosphorylation is also considered as a pathologic sign of other neurodegenerative diseases, including, frontotemporal dementia with parkinsonism (FTD-P), corticobasal degeneration, progressive supranuclear palsy and Pick disease. Mutations of tau encoded MAPT1 gene causes FTD-P. Therefore neurodegeneration without amyloid deposition can be driven by tau dysfunction. Tau-based therapies are still at conceptual stages and include passive immunization against tau, preventing tau hyperphosphorylation and anti-aggregates of tau. Methylthioninium chloride and lithium are some of the elements with current studies. There are also some experi-

Only four cholinesterase inhibitors (tacrine, donepezil, rivastigmine, galantamine) and an *N*-methyl-d-aspartate (NMDA) receptor AD antagonist (memantine) are approved for the treatment of AD. These five drugs are all symptomatic treatments. No new drugs have been approved for treatment of AD since 2003. Disease modifying drugs (DMD) is the real goal in AD treatment. However, success rate is extremely low for Alzheimer treatment research. Until today, anti-inflammatory (NSAİD, steroids), antioxidant (selenium, vitamin E), anti-ischemic (statin, aspirin), cholinergic (lecithin), nutrients (Omega-3, vitamins B, folic acid), monoclonal antibody (bapineuzumab, solanezumab) treatments have failed (**Table 1**). The overall failure rate was 99.6% (0.4% success) in the decade spanning from 2002 to 2012 [20]. Many explanations have been proposed for the failures of trials of DMD for AD, including starting therapies at the late phase of disease, wrong or nonspecific treatment targets, incorrect doses, the lack of homogeneity of individuals (genetic, ethical, temporal and medical grounds), nonspecific or blunt trial design [21, 22]. On the other hand, pathological changes may not correlated with cognitive deficits

*2.6.3 Amyloid anti-aggregates*

immunoglobulin) [18].

*2.6.5 Tau-based therapies*
