emerged in some cases.35 Tau is considered today a novel attractive target in AD.36,37 While targeting tau production and aggregation is more theoretical, the possibility to a ect tau phosphorylation has been tested using GSK3b and other tau kinase inhibitors. Compounds able to regulate tau aggregation and folding, to stimulate its clearance and to stabilize microtubules are also being explored as therapeutic agents. Finally, tau immunotherapy has recently been considered and preclinical studies have provided some comforting data.35

Although much is on the way, available treatments are still poor and, in some cases, initial results from early phase clinical trials have been discouraging. Furthermore, there is no absolute certainty that the course of the disease can be modified simply by altering Ab concentrations and/or that results obtained in transgenic animal models of overproduction of Ab can be reproduced in patients with AD. In addition, as mentioned, early intervention may be critical for e cacy of treatment. This requires the development and identification of biomarkers that can be monitored even before the onset of clinical signs of AD. In this respect, according to Montine and co-authors,38 it appears necessary to broaden our current view of potential therapeutic/ preventive approaches to AD and cognitive impairments to include selection of specific biomarkers and a multi-faceted approach to these conditions. In this line, the possibility to place AD in a more global scenario and/or to relate

it to metabolic disorders such as diabetes, hyperinsulinemia, insulin resistance and obesity has to be taken into account.39,40

8.2 AD and Metabolic Dysfunction

8.2.1Impaired Glucose Metabolism

Although still debated, an association between diabetes and the risk of AD has recently found solid support from data provided by several studies with longer follow-up. The association based on several epidemiological studies mainly relates hyperinsulinemia and increased risk of AD. Hence, peripheral

hyperinsulinemia and insulin resistance represent the key elements of the increased risk of AD reported in patients with diabetes mellitus.39–43 Avail-

able epidemiological and clinical data have provided a solid support in this sense, underlying the potential connection between a peripheral metabolic disorder and a disease of the CNS. Under conditions of hyperinsulinemia, in fact, brain insulin levels are decreased due to the impaired transport of peripheral insulin across the blood-brain barrier (BBB).39 The concentrations of insulin in the cerebrospinal fluid are also low in AD patients and this correlates with a lower expression of insulin receptors and insulin receptor substrate (IRS). At the CNS, insulin is known to exert a physiological role in Ab production and clearance. Hence, low brain insulin concentrations result in Ab accumulation since low insulin and impaired insulin signaling a ect APP processing. At the same time, in the CNS, insulin becomes a substrate for insulin degrading enzyme (IDE), thus competing with Ab and decreasing its

clearance.31 Changes in Ab levels under these conditions are accompanied by increased tau phosphorylation due to reduced phosphatidylinositol-3-kinase (PI3K)/AKT signaling and increased glycogen synthase kinase 3b (GSK3b) activity. All these events contribute to AD pathogenesis. To confirm this hypothesis, increases in peripheral insulin levels produce a rise of Ab 1–42 in cerebrospinal fluid, and administration of intranasal insulin that reaches the CNS yields beneficial e ect in AD.

8.2.2Lipid Disorders

More recently, the view of AD in a context of metabolic disorders has been broadened including as a background scenario di erent aspects of disturbances in lipid metabolism. The first association in this regard comes from the demonstrated link between AD and apoE that, as mentioned, represents the main risk factor for the late onset form of the disease. In particular, the presence of two e4 alleles increases the risk of AD by approximately 12-fold and lowers the age of onset of the disease by about 15 years.19 ApoE is a 35 kDa protein that exists in three isoforms, E2, E3 and E4, di ering in only one amino acid. Cholesterol metabolism in the brain is regulated independently of peripheral cholesterol. It is synthesized mainly by astrocytes and microglia or recycled from degenerating neurons.44 Its transport in the brain depends on lipoproteins that are similar to HDL and contain mainly ApoE4 and to a lesser extent ApoE1.45 ApoE in brain is expressed in all types of glial cells, astrocytes, microglia and oligodendrocytes, and under conditions of neuronal damage its main role is the transport of cholesterol and phospholipids from glia to neurons where regeneration and remyelination occur.46,47 Although an exact correlation between the e4 allele and the risk of AD has not been clarified, ApoE is known to play a major role in modulating Ab production and clearance together with its receptors, LDL receptor (LDLR) and LDL receptor related protein (LRP). Accordingly, increased amyloid deposition and impaired cognitive behavior have been reported in transgenic mice lacking LDLR.48 ApoE co-localizes with amyloid deposits in the brain49 and its lipi-

dation state increases its ability to bind Ab.50 ApoE4 is more e cient in inducing Ab synthesis and fibrillogenesis19,51,52 and a ects Ab clearance

though several mechanisms. It causes retention of Ab within the brain, impeding its crossing the blood-brain barrier, thus reducing its tra cking toward the periphery.53,54 A correlation between the E4 isoform and increased tau hyperphosphorylation as well as the formation of neurofibrillary tangles has also been demonstrated.55 Although apoE4 has been mainly related to changes in Ab metabolism, the possibility that this isoform di erently a ects neuroinflammatory processes or altered brain blood flow and metabolic function that accompany AD have also to be considered.19

Although brain cholesterol is recognized to be regulated independently of the periphery, hyperlipidemia and midlife elevation of serum cholesterol (o6.5 mmol/l) significantly augment the risk of AD.56–58 Accordingly, studies