**5. The pathogenesis of AD**

*Geriatric Medicine and Gerontology*

factors and/or aging.

**4.1 Role of cholesterol**

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

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

PUFAs and their oxylipins may affect the onset of AD [14]. The administration of omega-3 fatty acids may cause a dose-dependent reduction of triglyceridemia and cholesterolemia and exert an antiatherogenic effect [15]. With regard to mechanisms, in view of the proposed protective role of unsaturated fatty acids in phospholipids against the free radical-mediated injury of membrane proteins [9], it should be mentioned that the distribution of unsaturation (the trap for unpaired electrons) across the membrane leaflets is not uniform, and minima (the least protected areas from oxidative stress) were observed close to the C-6 site (i.e., very close to the membrane exterior, to the phosphorylable site of HMGCoAR, and to the vulnerable site of APP) and at the C-15 and C-17 levels (closer to the free radical conductor dolichol) [16]. Quite interestingly, signal might help focus free radicalmediated injury on the right target; more interestingly, in ad-libitum-fed (shorterlived) rats, is its recognizability that may fade on aging: the abundancy of double bonds near the C-6 site (but not at the C-15 and C-17) indeed appears to increase up to a doubling by age 24 months. Furthermore, this age-related change is prevented in part by nutritional anti-aging intervention [17]. Perhaps age-related changes in the production of Aβ1-42, in the activity of HMGCoA reductase, and in the PUFA content of membrane phospholipids are all somehow bound together and involved all in the risk of AD. As an additional comment, beneficial intervention on Aβ1-42 production may require the administration of antioxidants (e.g., polyphenols and resveratrol) to curb oxidative stress and of omega-3 fatty acids at a high dosage at the first good meal after fast (on the anabolic phase of metabolism) to counteract age-related changes in phospholipid unsaturated fatty acids and increase membrane

cause (a higher intramembrane oxidative stress) (see below).

**4.2 Role of polyunsaturated fatty acids (PUFAs)**

**22**

The hypothesis of the amyloid cascade attributes to beta-amyloid, the responsibility of all cases of AD, and considers the tau pathology and other degenerative changes secondary to the Aβ pathology. Indeed, the extracellular accumulation of Aβ, a hallmark of AD, produces ROS, including hydrogen peroxide (H2O2) in the presence of Fe3+or Cu2+ [19, 20]. The amyloid β-peptide responsible for AD is generated within the transmembrane domain (TMD) of a C-terminal fragment of the amyloid β protein-precursor (APP CTFβ) by the proteolytic action of the γ-secretase complex [21]. Very interestingly, it was shown that some mutation(s) that promote destabilization of TMD helix might affect the length of the accumulated Aβ species and the ratio of the toxic Aβ42 to the safer Aβ40 peptide and may result in a young-onset AD [22]. Hence, the speculation may be invited that a free radical-induced modification in (some) amino acids of APP close to the C-6 carbon of phospholipid fatty acids might have a similar effect and enhance amyloid deposition. With regard to disease progression, many different active factors in sequence would determine timing of neuronal damage and symptom development, such as: (1) an overproduction of the toxic Aβ peptide (1-42) for genetic reasons and/or decrease in the quality of the antioxidant device of the membranes, (2) an ensuing increase in Aβ excretion in the oligomeric form may concentrate the redoxactive copper at neuronal membranes before stacking in amyloid fibrils to form an ROS generating complex, (3) oxidative stress may be enhanced with an ensuing increase in lipid peroxidation and di-tyrosine formation, and (4) inflammation and activation of the microglia, which may further increase free radical generation, spread lytic enzymes, and cause cytotoxicity and anticipation of apoptotic neuronal death [23].
