**1. Introduction**

Alzheimer is an age-dependent neurodegenerative process distinct from normal aging and characterized morphologically by the presence of senile plaques and neurofibrillary tangles, which progress from the brain stem and inner parts of the temporal lobes to most the telencephalon.

Senile plaques are mainly composed of different species of fibrillar β-amyloid (Aβ), a product of the cleavage of the β-amyloid precursor protein (APP), and they are surrounded by dystrophic neurites, reactive astrocytes and microglia. Aβ fibrillar deposits also occur in diffuse plaques, subpial deposits and in the wall of the cerebral and meningeal blood vessels in the form of amyloid angiopathy. A substantial part of β-amyloid is not fibrillar but soluble and forms oligomers of differing complexity which are toxic to nerve cells.

Neurofibrillary tangles are mainly composed of various isoforms of tau protein, which is hyper-phosphorylated and nitrated. It has an altered conformation and is truncated at different sites through the action of a combination of several proteolytic enzymes giving rise to species of low molecular weight which are toxic to nerve cells. Abnormal tau deposition also occurs in the dystrophic neurites of senile plaques and within the small neuronal processes, resulting in the formation of neuropil threads.

The mechanisms of disease progression are not completely understood but Aβ initiates the pathological process in the small percentage of familial cases due to mutations in genes encoding APP, presenilin 1 and presenilin 2, the latter involved in the cleavage of APP, and potentiates tau phosphorylation in sporadic cases that represent the majority of affected individuals (β-amyloid cascade hypothesis). Moreover, Aβ act as a seed of new β-amyloid production and deposition under appropriate settings, and abnormal tau promotes the

production and deposition of hyper-phosphorylated tau. Therefore, Aβ and hyper-phos‐ phorylated tau promote the progression of the process and this may occur in an exponential way once these abnormal proteins are accumulated in the brain.

provided by the neuropsychological examination. Unfortunately, these tests, at present, detect

Potential Therapeutic Strategies to Prevent the Progression of Alzheimer to Disease States

http://dx.doi.org/10.5772/54783

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It is very illustrating to visualize under the microscope how a brain at middle stages of the degenerative process has been working without apparent neurological deficits during life. The adaptive capacities of the brain in coping with current functions in spite of the decrepitude of composition and organization resulting from the chronic progression of the degenerative

Taking into consideration this scenario, it is compulsory to increase understanding of the first stages of the degenerative process and to act on selective targets before the appearance of

The present review is not a mere list of putative treatments of Alzheimer's disease (AD) but rather an approach to learning about observations made on experimental models and early stages of disease aimed at curbing or retarding disease progression on the basis of definite rationales. It is also our aim to encourage the consideration of Alzheimer as a degenerative process not necessarily leading to dementia [1]. This concept has important clinical implica‐ tions as it supports early preventive measures in the population at risk (i.e. persons over 50

**2. Experimental therapeutic strategies to prevent Alzheimer progression to**

Several reviews have focused on various aspects related to habits and dietary elements which may act as protective factors against AD, including physical and mental exercise, low caloric intake, various diets with low fat content, and vitamin complements [2, 3]. It is worth noting that neuropathological studies in old-aged individuals usually present combined pathologies, and combination of Alzheimer changes and vascular lesions are very common [4]. It is well documented that vascular pathology potentiates primary neurodegenerative pathology and that vascular factors may be causative of cognitive impairment and dementia [5]. Therefore, therapies geared to reduce vascular risk factors are also protective factors against AD clinical

Most of the current drug development for the prevention or treatment of AD is based on the β-amyloid cascade hypothesis and aims at reducing the levels of Aβ in the brain. Overpro‐ duction, aggregation and deposition of the Aβ peptide begin before the onset of symptoms and they are considered an essential early event in AD pathogenesis. Thus, targeting these early Aβ alterations is assumed to reduce the progression to disease states. The different strategies developed to achieve this objective include decreasing Aβ production through modulating secretase activity, interfering with Aβ aggregation, and promoting Aβ clearance.

relatively advanced stages of the process in pathological terms.

years) even in the absence of clinical symptoms.

**Alzheimer Disease (AD) states**

process are impressive.

clinical symptoms.

manifestations.

**2.1. Targeting Aβ**

In addition to these pathological hallmarks, multiple alterations play roles in the degen‐ erative process. Several genetic factors, such as apolipoprotein ε4 (APOE4), and external factors, such as vascular and circulatory alterations and repeated cerebral traumatisms, among others, facilitate disease progression in sporadic forms. Furthermore, metabolic components mainly, but not merely, associated with aging have a cardinal influence, in‐ cluding mitochondrial defects and energy production deficiencies, production of free rad‐ icals (oxidative and nitrosative reactive species: ROS and NOS) and oxidative and nitrosative damage, increased reticulum stress damage, altered composition of mem‐ branes, inflammatory responses and impaired function of degradation pathways such as autophagy and ubiquitin-proteasome system.

It has been proven that the degenerative process, at least the presence of neurofibrillary tangles, starts in middle age in selected nuclei of the brain stem and entorhinal cortex, and then progresses to other parts of the brain. Instrumental stages of Braak cover stages I and II with involvement of the entorhinal and transentorhinal cortices; stages II and IV also affect the hippocampus and limbic system together with the basal nucleus of Meynert; and stages V and VI involve the whole brain although neurofibrillary tangles are not found in selected regions such as the cerebellar cortex and the dentate gyrus. The distribution of senile plaques is a bit different as they first appear in the orbitofrontal cortex and temporal cortex and then progress to the whole convexity.

A concomitant decline in neuronal organization occurs most often in parallel with senile plaques and neurofibrillary tangles manifested as synaptic dysfunction and synaptic loss, and neuronal death and progressive isolation of remaining neurons.

An important observation is that about 80% of individuals aged 65 years have Alzheimerrelated changes, at least at stages I-III, whereas only 5% have cognitive impairment and dementia. About 25% of individuals aged 85 years suffer from cognitive impairment and dementia of Alzheimer type. Stages I-IV are often silent with no clinical symptoms. Cognitive impairment and dementia usually occur at stages V and VI when the neurodegenerative process is very advanced. Importantly, the progression from stage I to stage IV may last decades, whereas the progression to stages V and VI is much more rapid. Therefore, Alzheimer is a well-tolerated degenerative process during a relatively long period of time, but it may have devastating effects once thresholds are crossed. Moreover, clinical symptoms may be compli‐ cated by concomitant vascular pathology.

Several attempts have been made to predict the evolution to disease states. Neuroimaging, including high resolution and functional magnetic resonance imaging, positron emission tomography and the use of relative selective markers of β-amyloid and tau deposition in the brain, together with reduced levels of Aβ and increased index of phospho-tau/total tau in the cerebrospinal fluid, are common complementary probes (biomarkers) in addition to the data provided by the neuropsychological examination. Unfortunately, these tests, at present, detect relatively advanced stages of the process in pathological terms.

It is very illustrating to visualize under the microscope how a brain at middle stages of the degenerative process has been working without apparent neurological deficits during life. The adaptive capacities of the brain in coping with current functions in spite of the decrepitude of composition and organization resulting from the chronic progression of the degenerative process are impressive.

Taking into consideration this scenario, it is compulsory to increase understanding of the first stages of the degenerative process and to act on selective targets before the appearance of clinical symptoms.

The present review is not a mere list of putative treatments of Alzheimer's disease (AD) but rather an approach to learning about observations made on experimental models and early stages of disease aimed at curbing or retarding disease progression on the basis of definite rationales. It is also our aim to encourage the consideration of Alzheimer as a degenerative process not necessarily leading to dementia [1]. This concept has important clinical implica‐ tions as it supports early preventive measures in the population at risk (i.e. persons over 50 years) even in the absence of clinical symptoms.
