**4. The primary cause of AD and the roles of cholesterol and unsaturated fatty acids**


It is obvious that native APP cannot be the ultimate substrate for γ-secretase trimming. Hence, both with the earlier and the later form of AD, the rate of Aβ

*There is evidence that the above-mentioned repair mechanisms are responsible for cleaning cells from any produced waste and for getting tissues rid of irreversibly altered cells. In younger persons, functions are redundant but progressively decline with increasing age, and may gradually fail in older persons resulting in the accumulation of "waste" in cells and tissues. On a healthy life, "waste" is the limiting factor for cell and tissue "cleaning" activities, but waste recognition-acuity co-varies with cell and body request for nutrients and repair. Function of all repair mechanisms are inducible (or suppressible) depending on life style. Benefits from healthy life style, diet restriction, and physical activity depend at least in part from the induction of repair mechanisms.*

**Table 1.**

*Effects of failure of repair mechanisms at the molecular, subcellular, and cellular level.*

free

production from APP should depend on a higher production of the ultimate substrate, possibly by a posttranslational modification of the APP molecules, likely to be secondary to oxidative stress. Age-related changes in the machinery that protects membrane proteins from free radical-mediated injury might help to account for age dependency [9]. With regard to the higher production of Aβ (1-42) in AD patients, a displacement of the free radical-mediated attack from the wanted site in the APP molecule might account for the higher involvement of the β and γ secretase pathways and the higher yield in Aβ 1-42. The effect may be favored either by genetic factors and/or aging.

## **4.1 Role of cholesterol**

Elevated cholesterol levels may be associated with a higher risk of AD [10]. Evidence was found suggesting an intimate connection between APP processing and lipid rafts [11]. An age-related increase in cholesterol and oxidized cholesterol products (namely 24-hydroxycholesterol and 27-hydroxycholesterol) was shown indeed to be increasingly associated with AD progression (brain levels are higher in AD patients, and levels of 24-hydroxycholesterol, 27-hydroxycholesterol and cholesterol in the cerebrospinal fluid appear to be useful biomarkers for the evaluation of mild cognitive impairment (MCI) and AD, together with Aβ42, total tau, and phospho-tau) [12]. It has been shown recently that higher total cholesterol levels in the blood are observed long before the clinical manifestation of MCI and AD in patients without psychiatric or somatic comorbidities and are independent of APOE genotype [13]. However, evidence was produced that changes in cholesterol metabolism in AD may not be the primary cause of the disease (see below): they may simply be a tightly associated sign with Aβ production by sharing a common cause (a higher intramembrane oxidative stress) (see below).
