*2.3. Neurodegeneration*

One of the major challenges of current public health policy is the increasing prevalence of mental illness and neurodegenerative diseases, which is largely due to the rapid aging of the Western, i.e., European and American population. In socio-economic terms, this phenomenon is placing a heavy burden on national health care systems and on the overall population. Preventive strategies are indispensable and the most effective one is the early adoption of a healthy lifestyle and appropriate diet.

Epidemiological studies [23,24] have consistently associated olive oil consumption with better cognition. Moreover, several meta-analyses of observational studies sugges<sup>t</sup> that using olive oil as the main culinary fat can reduce the incidence of depression [25,26]. Even though these association might be casual, some ad hoc studies with olive biophenols are being undertaken. One example is that of HT, which was able to restore proper insulin signaling in an in vitro model of Alzheimer's disease (AD) [27]. It is also noteworthy that Qosa et al. tested the effects of EVOO [28] and of oleocanthal (OC) [29] in a transgenic mouse model of AD. They reported lower beta-amyloid deposition, which corroborates the scant in vitro data available thus far.

#### *2.4. Absorption, Distribution, Metabolism, and Elimination (ADME)*

As in traditional pharmacology, pharma-nutrition studies gain credibility and strength when they assess and elucidate absorption, distribution, metabolism, and elimination of the putative active compound. In the case of olive oil and its phenolic components, the first evidence of human absorption was published in the year 2000 [30]. At the time, there were no available techniques to evaluate plasma concentrations of biophenols. Therefore, only urinary metabolites were measured. Subsequent studies confirmed and expanded those findings [31]. To date, the most comprehensive and technologically-advanced study is that of Pastor et al. [32]. In that study, the authors report Cmax of HT of 2.8 10−<sup>6</sup> mol/L, following ingestion of EVOO. HT excretion can also be evaluated after the administration of an olive mill waste water (OMWW) preparation devoid of secoroidoids. Khymenets et al. measured HT urinary concentrations and reported HT-S-3' as the major metabolite [33]. Of note, Gonzalez-Santiago et al. [34] described the association of HT to LDL after intake of the pure molecule. This might be important in light of the purported activities of HT in reducing ox-LDL concentrations, as per the EFSA health claim.

In short, there is plenty of information available on the ADME of HT in humans and rats. Of note, D'Angelo et al. had access to tritiated HT and reported its accumulation in the rat brain (the only such piece of evidence thus far) [35]. In summary, accumulated research indicates the low bioavailability of HT (common to nearly all biophenols) and therefore, strategies are in place to create formulations to overcome this issue.
