# Flavonoids as Promising Multitarget Agents in Alzheimer's Disease Therapy
## 1 Introduction  
Alzheimer's disease (AD) is a common disease in geriatric patients. Currently 50 million people are diagnosed with dementia and this number is expected to increase by 60% in 2030 and up to 180% in 2050 [1]. AD is the most common cause of dementia, accounting for 60 to 80% of cases. It is most common in people over the age of 65. Indeed, the risk of AD and other types of dementia increases with age, affecting an estimated 1 in 14 people over the age of 65 and 1 in every 6 people over the age of 80 [1]. Deficient cholinergic function, behavioral disorders, memory and intellectual function loss and neuronal death are symptoms of this disease. Some of the AD risk factors were identified as family medical history, way of living and psychosocial factors, elderliness, the apolipoprotein E (APOE) \(\epsilon\)4 allele genotype and cardiovascular disease risk factors [2]. There are two subtypes of AD. The first one, called early onset of AD (EOAD), develops in people younger than 65 years old being associated with genetic mutations, especially of amyloid precursor protein (APP), presenilin 1 (PSEN1) and presenilin 2 (PSEN2) genes, that are involved in the production ofthe amyloid-beta (A\(\beta\)) peptides. The second one, called late onset of AD (LOAD), develops in people older than 65 years, being the most frequent AD, and has been consistently associated with only one gene, the APOE gene. The allele \(\varepsilon\)4 of APOE is a genetic risk factor [3; 4], causing cognitive decline and cerebral amyloid in aged individuals [5]. APOE is formed in the neuroglial cells, astrocytes, producing A\(\beta\) plaques and development of cerebral amyloid angiopathology [6]. Furthermore, APOE\(\varepsilon\)4 has been associated with tau pathology [7]. However, 50% of AD patients are not APOE\(\varepsilon\)4 carriers [3; 4], and up to 75% of APOE\(\varepsilon\)4 homozygous carriers do not progress to AD. In fact, the genetic tendency to LOAD and the role of other risk factors is still unknown [8]. Nevertheless, the detailed studies of the mechanisms of action of these genes in AD pathogenesis suggest that AD is also an environmental complex disease [9], which efficacious treatment still remains to be developed [10] and the actions taken have been concerned mostly with the reduction of AD clinical indications (CIs). Extracellular plaques formed by A\(\beta\) peptide aggregation, intracellular neurofibrillary tangles (NFTs) resulting from hyperphosphorylated \(\tau\)-protein, abnormal inflammatory response and neuron apoptosis and death caused by oxidative stress are the major CIs of AD [11; 12; 13]. Indeed, communication at synapses between neurons is impeded by cell death caused by A\(\beta\) plaques. Also, the transport of crucial molecules in neurons is hindered by NFTs [2]. The A\(\beta\) peptides result from APP cleavage and are the major components of A\(\beta\) plaques. Thus, the inhibition of APP cleavage will cause a decrease in A\(\beta\) plaques. APP can be cleaved by the amyloidogenic pathway involving the action of two enzymes, \(\beta\)-secretase (BACE1) and \(\gamma\)-secretase. BACE1 cleaves APP generating a soluble fragment, \(\beta\)-APP, and a longer 99-amino acids peptide fragment that is then cleaved by \(\gamma\)-secretase into amylogenic peptides of varying length, such as A\(\beta\)40, A\(\beta\)42, and A\(\beta\)43 [14]. The imbalance between these A\(\beta\) fragments generation and their clearance causes disequilibrium and consequently cell death. One way to combat AD is, therefore, to prevent the brain A\(\beta\) peptide deposition by the inhibition of BACE1. The microtubules (MTs), which are involved in several important structural and regulatory functions, are stabilized by \(\tau\)-protein. However, when hyperphosphorylated, they aggregate into paired helical and straight filaments resulting in the formation of the NFTs [15; 16; 17; 18; 19], losing MTs, which become destabilized.