# Terpenes as Potential Anti-Alzheimer's Disease Agents
## 1 Introduction  
Alzheimer's disease (AD) was discovered in 1906 by Dr. [PERSON] [1]. At present, around 50 million persons are estimated to suffer from dementia worldwide, and this number is expected to increase up to 150 million in 2050, as a result of the increase in life expectancy [2]. Therefore, AD remains the subject of major ongoing research. There are two forms of AD development, called early-onset (EOAD) and late-onset (LOAD). EOAD occurs in people younger than 65 years old, and is associated with mutations in three genes, the amyloid precursor protein (APP) gene (_APP_) and the presenilin 1 and 2 genes (_PSEN1_ and _PSEN2_), which are involved in the production of the amyloid-\(\beta\) (A\(\beta\)) peptides in the brain. However, most of the cases diagnosed are associated with a LOAD form that occurs after the age of 65 [3,4], and has been consistently associated, across numerous studies, with only one gene, the apolipoprotein E (ApoE) gene (_APOE_). The _APOE_\(\varepsilon\)4 allele (_APOE_\(\varepsilon\)4) is a major genetic risk factor [5, 6], generating cognitive dysfunction and cerebral A\(\beta\) in aged individuals [7, 8]. In addition, _APOE_\(\varepsilon\)4 has been associated with tau (\(\tau\)) pathology [9]. Nevertheless, up to 75% of _APOE_\(\varepsilon\)4 homozygous carriers do notprogress to AD and 50% of AD patients are not _APOEe4_ carriers [5, 6]. In fact, the genetic tendency toward LOAD and the role of other risk factors remains unclear [4]. Although the mechanisms of action of the above-mentioned genes in AD pathogenesis have been studied extensively, those involved in AD progression are still not clear, suggesting that AD is driven by a complex combination of genetic and other risk factors, such as biological and environmental factors [10]. Owing to this complexity, there is currently no cure for AD [11], and this disease is becoming a major public health concern worldwide. In fact, the action against AD has mostly focused on symptom management. It is well established that the major clinical indications (CIs) of AD are extracellular plaques of A\(\beta\) protein, intracellular neurofibrillary tangles (NFTs) formed by hyperphosphorylated \(\tau\)-protein, uncommon neuroinflammatory response, oxidative stress, and synaptic and neuronal dysfunction [12, 13, 14]. A\(\beta\) plaques may cause cell death as they interfere with the communication at synapses between neurons, while NFTs block the axonal transport with neuropathological consequences [3]. Concerning A\(\beta\) plaques, their major building blocks are A\(\beta\) peptides having a length of 40-42 amino acids, that come from the cleavage of the transmembrane protein APP by the amyloidogenic pathway, involving the action of two enzymes: \(\beta\)-secretase (\(\beta\)-site APP-cleaving enzyme 1; BACE1) and \(\gamma\)-secretase. APP is first cleaved by BACE1, resulting in a soluble fragment, \(\beta\)-APP, and a longer peptide with 99 amino acids (C99). The C99 fragment is subsequently cleaved by \(\gamma\)-secretase to release A\(\beta\) peptides of varying length, including A\(\beta\)-40 and A\(\beta\)-42 [15]. The A\(\beta\) generation/clearance imbalance leads to cell death. Thus, one therapeutic strategy to combat AD is preventing the appearance of brain A\(\beta\) plaques by BACE1 inhibition. Regarding NFTs, their major constituent is a hyperphosphorylated form of \(\tau\)-protein, a microtubule (MT)-binding protein. Indeed, when hyperphosphorylated, \(\tau\)-protein aggregates into paired helical filaments (PHFs) and straight filaments (SFs), which result in formation of the NFTs, losing MTs that become destabilized [16, 17, 18]. MTs, crucial constituents of the eukaryotic cell cytoskeleton, are involved in several important structural and regulatory functions. These biopolymers, composed of \(\alpha/\beta\)-tubulin heterodimers [18], are always vibrating, alternating between growing (polymerization) and shrinking (depolymerization) phases [19].