*2.6.3 Amyloid anti-aggregates*

*Geriatric Medicine and Gerontology*

therapeutic strategies [15].

*2.6.1 Anti-amyloid agents*

and immunotherapies [17].

*2.6.2 Secretase modulators*

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

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

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 intracel-

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

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].

ultimately contribute to a decrease in acetylcholine in AD brains [14].

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

lular tau-based neurofibrillary tangles accumulation [16].

**86**

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].
