**6. AD-associated changes in cholesterol metabolism**

Abnormal cholesterol metabolism is an established feature of AD: levels of cholesterol are increased in MCI subjects and levels of 24-hydroxycholesterol and 27-hydroxycholesterol are elevated compared to controls both in AD and MCI subjects [24]. It appears that the rate of cholesterol production may be boosted by a free radical attack via a constitutive activation of HMGCoA-reductase, the rate-limiting step in sterol biosynthesis. Mechanism was clarified by Bergamini group in Pisa in cooperation with Trentalance group in Rome: in the rat, a free radical attack may prevent AMP-dependent protein kinase from phosphorylating a serine residue close to the C-terminus of HMGCoA reductase, Ser 872 with human enzyme [25, 26]. It has been proposed by several authors that higher cholesterol may disturb the lipid raft domains in various membrane organelles and affect the functioning of α, β, and γ secretases as well as APP itself and the production of Aβ 42; and that by converse, the toxicity of Aβ may be produced, in part, by disturbing the composition of the lipid raft domains in which they reside [27, 28]. Both with in vitro experiments and with animal models, statins strongly lowered blood cholesterol and reduced the levels of Aβ peptides, Aβ 42 and A β40 [29, 30]. However, a statistically significant correlation between two events does not necessarily imply the existence of a causal link: an alternative explanation is that the events share a common cause. This might

be the case here: aging is known to lower antioxidant defenses, and any increase in oxidative stress either in vitro (e.g., by UV radiation of isolated rat liver cells) or in vivo (by chronic deprivation either of vitamin E or PUFA) may cause the constitutive increase in HMGCoA reductase and deregulate cholesterol synthesis [26, 31].

### **7. Alzheimer's disease: treatment or prevention strategies?**

The pharmacological treatments for AD can be divided into two categories: symptomatic treatments such as acetylcholinesterase inhibitors and N-methyl-D-aspartate (NMDA) receptor antagonists and etiology-based treatments such as secretase inhibitors, amyloid binders, and tau therapies [32].

Despite significant investments in therapeutic drug discovery programs, no drugs to alter the course of disease have been found so far. Only four drugs with cholinergic (donepezil, galantamine, rivastigmine) or glutamatergic activity (Memantine) are currently approved and marketed for the treatment of AD-associated dementia, and their utility is very limited; several trials on inhibitors of γ-secretase and β-secretase have been discontinued; the available drug treatments of AD are merely symptomatic and unsatisfactory, and only minor benefits are obtained even if therapy is started at a very early time [33]. By the way, the physiological function of the amyloidogenic peptide has not been clarified yet, though it may be synchronized with life history [34].

In conclusion, no effective therapy is available to cure AD so far, and attention had to be shifted to the primary prevention of the disease. It was realized indeed that there is an extremely long, symptom-free prodromal phase in the path toward dementia in which deficits in synaptic density and plasticity are the principal alteration [35]. As an additional comment, better diagnostic tools and earlier diagnosis are needed (earlier timing is an important factor for the success rate of intervention), and novel strategies toward primary intervention may be wanted [36].

Problems in primary prevention were tackled recently. Qiu et al. [37] stressed the potential risk roles of vascular risk factors and disorders (e.g., cigarette smoking, midlife high blood pressure and obesity, diabetes, and cerebrovascular lesions) and the possible beneficial roles of psychosocial factors (e.g., high education, active social engagement, physical exercise, and mentally stimulating activity) in the pathogenetic process and clinical manifestation of the dementing disorders. Paillard-Borg et al. [38] showed that the participation in activities (mental, physical, or social activity) can retard the onset of dementia significantly (a 17 months' delay was seen in mean age at dementia onset between an inactive group and the most active group).

It may be worthwhile to remind here that the primary risk factor for AD is old age and that the prevalence of AD and other age-related dementias increases with increasing age [2]. It is very surprising, indeed, that little attention has been given so far to benefits from the most effective antiaging interventions (dietary restriction and physical activity) on the age of onset of neurodegeneration [39].

Antiaging diet restriction is known to be the most effective intervention that retards aging and extends lifespan and health span. Effects are known to involve the activation of macroautophagy, a cell repair mechanism [40] that can be intensified by the administration of antilipolytic agents during fasting to safely improve cell housekeeping and boost the benefits of caloric restriction [41]. Physical exercise, which is available at low cost and largely free of adverse effects, is another powerful antiaging strategy that can influence, at least partly, most of the hallmarks of biological aging [42]. It is known that greater levels of physical activity are associated with decreased risk of a future diagnosis of MCI or AD [43], extend longevity, and

**25**

and death.

*Primary Prevention of Alzheimer's Disease (AD) DOI: http://dx.doi.org/10.5772/intechopen.85418*

logical treatment of AD [44].

misfunctioning and death [45].

brain insults of different etiology and anatomy [49].

relevant neuroprotective trophic factors, such as IGF-I [49].

**in the city of Volterra (Tuscany, Italy)**

aging on human body and brain.

reduce the risk of physical disability and may be an important adjunct to pharmaco-

Looking at mechanisms, it appears that dietary restriction and physical exercise share common neuroprotective mechanisms and should be included both in primary prevention of AD to increase the quality of nerve cells and oppose neurodegeneration and apoptosis (the third item in the **Table 1**, a repair mechanism harmful to brain) and give synergic support in a "train body and brain" program aimed to enhance neurotrophic antiapoptotic signals and defer or suppress neuron

Antiaging diet restriction improves metabolism and promotes rejuvenation (by stimulating autophagy) of visceral organs that talk to brain via the vagus nerve and spinal afferent nerves [46]. Physical exercise improves metabolism and promotes rejuvenation of the lean body mass by the process of autophagy, which is very active in skeletal muscle and more intense when strenuous exercise is performed in the fasted state [47] and helps communication of the exercising muscle with the brain via increase in the discharge frequency of thinly myelinated (Group III) and unmyelinated (Group IV) nerve fibers [48]. Under these conditions, physical exercise is good both for physical health and mental health and abilities, and constitutes a practical neuroprotective strategy that provides a remarkable protection against

Quite interesting, it has been clarified that dietary restriction and physical exercise share also common neuroprotective metabolic mechanism: the increased availability to brain of 3-hydroxybutyrate and an ensuing endogenous production of the brain-derived-neurotrophic-factor BDNF [50], and thus, both shelter the aging brain from memory loss and neurodegeneration, ameliorate mitochondrial function, and reduce the expression of apoptotic and inflammatory mediators [51]. As an additional evidence: both treatments safely modulate the endogenous production of BDNF, a neurotrophin that is vital to the survival, growth, and maintenance of neurons in key brain circuits involved in emotional and cognitive function [52, 53]. As an additional benefit, sustained levels of physical exercise together with dietary intervention may increase brain uptake of physiologically

In conclusion, both (dietary and physical) interventions should be included in primary prevention of AD to increase quality of nerve cells and oppose neurodegeneration and apoptosis to implement reported programs aimed to enhance neurotrophic antiapoptotic signals and defer or suppress neuron misfunctioning

**8. The "train body and brain" protocol for a primary intervention on AD** 

In view of the continuing increase in the prevalence of dementia to a magnitude growing to emergency [54, 55], a free of charge program to train people at higher risk of disease has been started in the Italian city of Volterra. Since AD is an agingassociated multifaceted disease that is hard to treat by single-modal treatment, a corresponding multifaceted preventive approach was included in a teaching program on how to counteract in practice the effects of biological and pathological

Program includes activation of the global antioxidant defense system in order to attenuate the AD-causative oxidative stress, improvement of the function of the free radical conducting mechanism responsible for membrane resistance to oxidative stress, reinforcement of cell repair mechanisms at the molecular and subcellular

#### *Primary Prevention of Alzheimer's Disease (AD) DOI: http://dx.doi.org/10.5772/intechopen.85418*

*Geriatric Medicine and Gerontology*

be the case here: aging is known to lower antioxidant defenses, and any increase in oxidative stress either in vitro (e.g., by UV radiation of isolated rat liver cells) or in vivo (by chronic deprivation either of vitamin E or PUFA) may cause the constitutive increase in HMGCoA reductase and deregulate cholesterol synthesis [26, 31].

The pharmacological treatments for AD can be divided into two categories: symptomatic treatments such as acetylcholinesterase inhibitors and N-methyl-D-aspartate (NMDA) receptor antagonists and etiology-based treatments such as

Despite significant investments in therapeutic drug discovery programs, no drugs to alter the course of disease have been found so far. Only four drugs with cholinergic (donepezil, galantamine, rivastigmine) or glutamatergic activity (Memantine) are currently approved and marketed for the treatment of

AD-associated dementia, and their utility is very limited; several trials on inhibitors of γ-secretase and β-secretase have been discontinued; the available drug treatments of AD are merely symptomatic and unsatisfactory, and only minor benefits are obtained even if therapy is started at a very early time [33]. By the way, the physiological function of the amyloidogenic peptide has not been clarified yet,

In conclusion, no effective therapy is available to cure AD so far, and attention had to be shifted to the primary prevention of the disease. It was realized indeed that there is an extremely long, symptom-free prodromal phase in the path toward dementia in which deficits in synaptic density and plasticity are the principal alteration [35]. As an additional comment, better diagnostic tools and earlier diagnosis are needed (earlier timing is an important factor for the success rate of intervention), and novel strategies toward primary intervention may be wanted [36].

Problems in primary prevention were tackled recently. Qiu et al. [37] stressed the potential risk roles of vascular risk factors and disorders (e.g., cigarette smoking, midlife high blood pressure and obesity, diabetes, and cerebrovascular lesions) and the possible beneficial roles of psychosocial factors (e.g., high education, active social engagement, physical exercise, and mentally stimulating activity) in the pathogenetic process and clinical manifestation of the dementing disorders. Paillard-Borg et al. [38] showed that the participation in activities (mental, physical, or social activity) can retard the onset of dementia significantly (a 17 months' delay was seen in mean age at dementia onset between an inactive group and the

It may be worthwhile to remind here that the primary risk factor for AD is old age and that the prevalence of AD and other age-related dementias increases with increasing age [2]. It is very surprising, indeed, that little attention has been given so far to benefits from the most effective antiaging interventions (dietary restriction

Antiaging diet restriction is known to be the most effective intervention that retards aging and extends lifespan and health span. Effects are known to involve the activation of macroautophagy, a cell repair mechanism [40] that can be intensified by the administration of antilipolytic agents during fasting to safely improve cell housekeeping and boost the benefits of caloric restriction [41]. Physical exercise, which is available at low cost and largely free of adverse effects, is another powerful antiaging strategy that can influence, at least partly, most of the hallmarks of biological aging [42]. It is known that greater levels of physical activity are associated with decreased risk of a future diagnosis of MCI or AD [43], extend longevity, and

and physical activity) on the age of onset of neurodegeneration [39].

**7. Alzheimer's disease: treatment or prevention strategies?**

secretase inhibitors, amyloid binders, and tau therapies [32].

though it may be synchronized with life history [34].

**24**

most active group).

reduce the risk of physical disability and may be an important adjunct to pharmacological treatment of AD [44].

Looking at mechanisms, it appears that dietary restriction and physical exercise share common neuroprotective mechanisms and should be included both in primary prevention of AD to increase the quality of nerve cells and oppose neurodegeneration and apoptosis (the third item in the **Table 1**, a repair mechanism harmful to brain) and give synergic support in a "train body and brain" program aimed to enhance neurotrophic antiapoptotic signals and defer or suppress neuron misfunctioning and death [45].

Antiaging diet restriction improves metabolism and promotes rejuvenation (by stimulating autophagy) of visceral organs that talk to brain via the vagus nerve and spinal afferent nerves [46]. Physical exercise improves metabolism and promotes rejuvenation of the lean body mass by the process of autophagy, which is very active in skeletal muscle and more intense when strenuous exercise is performed in the fasted state [47] and helps communication of the exercising muscle with the brain via increase in the discharge frequency of thinly myelinated (Group III) and unmyelinated (Group IV) nerve fibers [48]. Under these conditions, physical exercise is good both for physical health and mental health and abilities, and constitutes a practical neuroprotective strategy that provides a remarkable protection against brain insults of different etiology and anatomy [49].

Quite interesting, it has been clarified that dietary restriction and physical exercise share also common neuroprotective metabolic mechanism: the increased availability to brain of 3-hydroxybutyrate and an ensuing endogenous production of the brain-derived-neurotrophic-factor BDNF [50], and thus, both shelter the aging brain from memory loss and neurodegeneration, ameliorate mitochondrial function, and reduce the expression of apoptotic and inflammatory mediators [51]. As an additional evidence: both treatments safely modulate the endogenous production of BDNF, a neurotrophin that is vital to the survival, growth, and maintenance of neurons in key brain circuits involved in emotional and cognitive function [52, 53]. As an additional benefit, sustained levels of physical exercise together with dietary intervention may increase brain uptake of physiologically relevant neuroprotective trophic factors, such as IGF-I [49].

In conclusion, both (dietary and physical) interventions should be included in primary prevention of AD to increase quality of nerve cells and oppose neurodegeneration and apoptosis to implement reported programs aimed to enhance neurotrophic antiapoptotic signals and defer or suppress neuron misfunctioning and death.
