AD is a typical disorder of senility whose risk increases exponentially with age. It is very rare under 60-65 years of age and the cases of early-onset AD are inherited forms following an autosomal dominant inheritance pattern, related to mutations in genes which influence Ab metabolism and expression like APP, PSEN1, and PSEN2. These inherited forms typically occur in the fifth decade or earlier and represent less than 1% of all the cases of AD.

One of the first and most important signs of the oncoming AD is memory impairment. This earliest manifestation is due to the damage of hippocampus, which has a pivotal role in storing information, and progresses very slowly and insidiously following a particular and distinctive pattern. The first stage of this pattern is the loss of memory regarding recent events, the so called “short-term memory”, subsequently followed by the memory of more distant facts and events in the past. The loss becomes of such an extent that the physician needs the assistance of family members to get information about the patient’s past. Afterwards, other memory problems emerge, such as problems regarding the semantic and procedural memory or even motor learning, together with a series of other cognitive impairments of language, visuospatial skills and executive functions.

Language dysfunction appears as an impaired verbal fluency which underlines a word-finding difficulty and a reduced vocabulary. The problem further progresses in agrammatism, paraphasic errors, impoverished speech content and impaired comprehension. Impaired visuospatial capability appears as the tendency to misplace items and the difficulty in navigating, first in unfamiliar terrains and then in familiar ones. The complication later progresses in visual agnosia (the inability to recognize objects) and prosopagnosia (the inability to recognize faces). The impairment in executive functions, instead, consists in a reduction of motivation, engagement, and abstract reasoning in the affected individuals who appear to be very apathetic. The problem later progresses in poor judgment, poor planning, the inability to perform complex tasks, and anosognosia (the inability to be aware of the existence of the disability itself) [50] [51], which is generally associated with depression and agitation [52] [53]. The impaired executive functions are usually accompanied with marked changes in personality involving apathy, social disengagement, and disinhibition, along with behavioral disturbances such as agitation, aggression, wandering, and psychosis.

Other important signs of AD include sleep disturbance, seizures and motor problems like apraxia (the difficulty in performing learned motor tasks), which later progresses to problems in daily activities such as dressing, feeding and incontinence. It is important to notice that AD can frequently occur with some other form of dementia, like dementia with Lewy bodies, frontotemporal dementia or vascular dementia, in a condition in which the clinical presentation and the course of the pathology is influenced by both disorders.

Perhaps we can better understand the presentation of the signs seen so far by giving a closer look at the course of the pathophysiology. From a pathological point of view AD is characterized by 4 main stages: preclinical, mild, moderate and severe stage. The preclinical AD begins with the pathological changes appearing in the entorhinal cortex, an area of the brain located near the hippocampus. These lesions soon move towards the hippocampus itself, essential for the formation of short- and long-term memories, slowly creating the condition for the following memory loss and mild cognitive impairment. The process occurs very early, even 10-20 years before the appearance of the first clinical signs, in a long period in which the patients appear completely normal and with no alteration in their judgment or their ability to perform daily tasks. The patients can also be divided in two groups: presymptomatic, including those carrying dominantly inherited mutations causing the disorder, who will almost certainly develop AD, and asymptomatic, including those not carrying these mutations and for whom the progress of the disorder remains uncertain.

In the mild AD, plaques and tangles begin to appear in the cerebral cortex as well, especially in those areas controlling memory, language and reasoning. In this stage, as memory loss continues, other forms of cognitive and physical inabilities start to emerge, to further worsen the patient’s conditions. Confusion on familiar places and faces becomes more and more frequent, together with compromised judgment, social disengagement, apathy, and changes in mood and personality, especially increased anxiety. The general situation is that of a person that, although apparently healthy, begins to experience more and more problems in making sense of the world around him. This situation might be very difficult to detect by the patient himself and by those surrounding him, because it is characterized by signs and changes that can frequently occur also in normal aging.

In the moderate AD the damage keeps spreading more deeply in the areas controlling language, reasoning, conscious thought and sensory processing, resulting in signs already seen in the previous stage but now much more pronounced and widespread. The patient no longer controls his behavioral problems and needs a more intensive supervision and care. The additional symptoms of this stage also include shortened attention span, marked problems in recognizing friends and family members, difficulty in reading, writing and working with numbers, problems in organizing thoughts coherently and inability to learn new things or cope with new and unexpected situations. The additional behavioral changes include restlessness, tearfulness, repetitive statements or movements, hallucinations and paranoia, which are usually accompanied with the loss of impulse control (for example, the patient might take his clothes off if he feels hot). Anger characterizes this stage, as a clear sign of the underlying confusion, anxiety and depression which increases enormously the risk of violent and homicidal behavior.

In the severe AD plaques and tangles are widespread throughout the brain, which appears seriously atrophied. The patients no longer recognize family members and loved ones, cannot communicate in any way and have no sense of self, in a situation in which they are completely dependent on others for care. Other classical symptoms appearing in this stage include weight loss, seizures, skin infections and difficulty in swallowing, together with moaning, increased sleeping and lack of bladder and bowel control. In the end, death comes as a result of other terminal-stage complications, the most frequent of which is aspiration pneumonia usually triggered by an incompetent swallowing mechanism.

The diagnosis of AD is based on four general clinical criteria: the family history of the subject, the progressive course of the disorder, the exclusion of other etiologies and especially the detection of impairments in one or more cognitive domains, without which an alternative diagnosis should be considered. Any diagnostic method chosen should serve to detect one of these underlined aspects.

Cognitive and mental status impairments can be detected using standardized scales designed to document the presence and the progression of any form of dementia. Particularly used by healthcare providers is the Montreal Cognitive Assessment (MoCA), freely accessible online in several languages and with superior sensitivity in detecting mild cognitive impairments and executive and language dysfunctions [54]. These neuropsychological tests can be useful for many purposes, like the evaluation of the cognitive impairment itself and the establishment of a baseline to follow the patient over the time, but not for the differentiation of the several forms of dementia, which substantially overlap in test performance [55].

The other clinical aspects defining the diagnosis of AD can be detected by using several methodological approaches like neuroimaging, blood studies or genetic testing. Neuroimaging includes major imaging studies today diagnostically available such as Computed Tomography (CT), Magnetic Resonance Imaging (MRI), Single-Photon Emission CT (SPECT) and Positron Emission Tomography (PET), which can be used to exclude other possible causes for dementia like cerebrovascular or thyroid disease. CT and MRI scans can provide precious structural information to detect lesions that might result in cognitive impairments, and rule out potentially treatable causes of progressive cognitive decline, like chronic subdural hematoma and normal pressure hydrocephalus . In particular, MRI can detect white matter lesions and generalized and focal atrophies, like the atrophy of the hippocampus, also known as medial temporal lobe atrophy [56] [57] [58] [59] [60]. It should be noted that hippocampal volume declines in normal aging as well, therefore it can be used as valid biomarker in clinical research but not as routine clinical criterion for the final diagnosis of AD.

PET and SPECT can be used as valuable tools for functional brain imaging. SPECT is a functional nuclear imaging technique used to evaluate cerebral perfusion by providing cross-sectional images of the brain. PET, instead, is another functional imaging technique, used to study functional processes in the body by providing three dimensional images that show the concentration of a tracer indicating the metabolic activity of the local tissue. When applied to the brain, PET can be very useful in detecting and measuring synaptic dysfunctions. Both techniques can reveal distinct spots of low metabolism and hypoperfusion, in regions such as the hippocampus and the posterior temporal cortex [61] [62] [63][64][65], which can be used to distinguish AD from other forms of dementia in those patients showing atypical presentations [66] [67] [68] [69]. SPECT and PET too are not indicated in the routine workup, apart from the cases of atypical presentation to rule out other forms of dementia. There are three major PET tracers for Ab, F18-Florbetapir (AMYViD), F18-Flutemetamol (Vizamyl), and F18-Florbetaben (Neuraceq), which attach to Ab in the brain and produce the PET image. The brain imaging techniques can be employed in combination with memory tests to identify the earliest stages of AD before the appearance of the first symptoms [70].

Other laboratory tests, like blood studies, can be helpful to rule out other conditions causing cognitive impairment, like hematologic, hepatic, and thyroid diseases. Other tests include electroencephalography, very useful to detect prion-related disorders, and lumbar puncture, which can reveal the presence of infection in the central nervous system like neurosyphilis. It is particular interesting to notice that in the cerebral spinal fluid can be found high levels of tau or phosphorylated tau, but low levels of Ab, perhaps because Ab tends to be deposited in the brain rather than in the spinal cord. Anyways, routine measurements of tau and Ab in the spinal fluid are now not recommended, and they will be so until the development of effective treatment methodologies to slow down the AD progression.

Genetic tests involve the study of the key genes involved in AD, especially APOE gene. In fact, the APOE genotyping has proved to be a valid research tool for determining the risk of AD in epidemiological studies, especially by considering the e4 allele. But some studies have revealed that the e4 plasma levels are associated with a high risk of developing AD, independently from the APOE genotype [71] [72]. For this reason, the genotyping of APOE is of little value, if not any, for the clinical diagnosis of AD, and many experts are even against its use [73]. Quite useful is also the genetic testing for the mutations occurring in APP, PSEN1 and PSEN2, especially in those patients with clear family history presenting one or more previous examples of early-onset autosomal dominant AD. But also in this case, the genetic testing of these genes is not recommended for routine evaluation, because of the marginal predictive value of this approach. Therefore, it should be used only in the cases of presenile dementia with clear family history, and always with an appropriate genetic counseling.

Unfortunately, there is no treatment now available capable of coping with the underlying causes of AD and reversing its progression. Therefore, the therapies used by caregivers are only symptomatic, aimed at slowing down and delaying the AD symptoms which are inevitable. These therapies are based on the use of drugs which modulate either the neurotransmitter acetylcholine or the neurotransmitter glutamate. The US Food and Drug Administration (FDA) has approved two major types of drugs: acetylcholinesterase inhibitors (AChEIs), used to treat mild to moderate AD, and partial N-Methyl-D-Aspartate (NMDA) antagonists [74] [75], used to treat the more severe and advanced AD.

Treatment of mild to moderate AD

The major goal of the treatment of mild to moderate AD is to preserve and maintain the cognitive levels and functional abilities as much as possible, delaying the deterioration of the patient’s conditions. This can be achieved by using cholinesterase inhibitors (ChEIs) and by having the patients practice mental exercises on a daily basis.

The principles of cholinesterase inhibition are based on the clinical observations, which reveal how the clinical manifestations of AD are due to the loss of cholinergic innervations in the cerebral cortex. ChELs prevent the breakdown of acetylcholine and thus delay the progress of AD. They do not address the underlying cause determining the neural degeneration, but undoubtedly slow it down delaying the cognitive and functional decline. ChEls were originally expected to be beneficial only in the early stages of AD, when there are still many cholinergic synapses intact, but there is now mounting clinical evidence suggesting that they might even be useful in later stages [76]. ChELs have several side effects, like nausea, vomiting, diarrhea and dizziness, which must be weighed against the benefits of taking this type of medications.

As for the mental exercises, it is still not known whether these might slow down the AD progress. There is not even a standardized approach in this regard, and plans of mental exercises are still customized according to the needs and conditions of each patient. In any case, these should be interactive and kept at a reasonable level of difficulty, so that the patient can constantly be engaged in them without being frustrated.

Treatment of moderate to severe AD

The treatment of moderate to severe AD, instead, is largely based on the use of partial N-Methyl-D-Aspartate (NMDA) antagonist called memantine. Approved by the FDA, the compound is believed to increase the signal-to-noise ratio at the NMDA receptors, and by doing so it should slow down the accumulation of intracellular calcium avoiding further damage of nerve cells. Many studies have demonstrated the security of the use of memantine when combined with ChELs [77] [78] [79].

Treatment of secondary symptoms

Dealing with the secondary symptoms of AD can be very problematic, because they are very frequent and might even exacerbate the cognitive and functional impairment characterizing the disorder. The psychotic medications used to cope with secondary symptoms include antidepressants, anxiolytics, antiparkinson agents, antiepileptics, beta-blockers and neuroleptics [80], many of them having serious side effects that should be carefully considered. Routine physical exercise can be very useful in dealing with stress and depression, and can even have a possible impact on the progress of the disorder and a protective effect on the health of the brain [81].

The prognosis of AD is characterized by three main stages. The first one consists in the appearance of memory impairment that progressively worsens with the advancement of the disorder. Generally, memory impairment is used as early-occurring sign of the forthcoming AD emergence. The second stages, instead, consists in the appearance of other dementia-connected signs such as anxiety, depression, insomnia, agitation, and paranoia, in a state that, although clinically serious, continues to see the patient as physically independent. But the physical conditions seriously worsen in the third stage, when the patient requires assistance with many basic daily activities, such as dressing, bathing, or toileting. At the end of the AD course the patient’s conditions become so grievous that feeding itself can only be possible through the use of gastrointestinal tubes.

The time elapsing from the diagnosis to death varies according to the case. The early-onset AD tends to have a more aggressive and rapid course, perhaps because of the genetic predisposition of the affected subjects which greatly favors the AD pathogenesis. In general, the time of survival from the moment of the diagnosis to the death of the individual lasts from as little as three years to as long as ten years. The patients usually die after succumbing to terminal-stage complications due to advanced debilitation, such as dehydration, malnutrition, and infections.

The etiology of AD is still unknown. However, the majority of the investigators now agree to see the disorder as the final outcome of a pathophysiologic cascade which ultimately leads to the pathology of AD or other forms of dementia. The process, which covers the span of many years, is triggered by several risk factors that include environmental, genetic and physiological elements [1] [2] [3] [4]. Based on the age in which signs begin to appear, AD is divided in two groups: If they begin to appear prior to 65 years of age the disorder is called early-onset AD, otherwise late-onset AD.

Genetic factors

The genetic basis of AD is much clear in the early-onset form, which follows an autosomal dominant inheritance pattern. This pattern is generally associated with a family history presenting at least three cases of AD of first degree relatives affected, in the span of one or more generations [5]. There are three key genes whose mutations are linked to AD development: amyloid precursor protein (APP) gene, presenilin 1 (PSEN1) gene and presenilin 2 (PSEN2) gene. These genes are directly or indirectly involved with the expression and production of amyloid beta (Ab), a peptide of 36-43 amino acids found as major component of the amyloid plaques in brain of AD patients. The mutations are highly penetrant, which means their carriers almost certainly develop AD during their life.

APP is an integral membrane protein present in great quantity in the synapses of neurons. Its primary role is unknown, but the fact that it is implicated in major functions such as synapse formation [6] and neural plasticity [7] might explain its involvement in the formation of AD neuronal lesions. In any case, APP is the precursor of Ab, which once released can aggregate in oligomers to perform its physiological functions. Any mutation affecting this molecular machine can result in the production of misfolded Ab aggregates that finally lead to the formation of AD neuronal lesions. There are several missense mutations in the APP gene which alter its proteolytic processing and cause the generation of amyloidogenic forms of Ab, especially the one with 43 amino acids which appears stickier and more prone to form misfolded oligomers. Interestingly enough, increased quantity of Ab with 42-43 amino acids have been found in the plasma of AD patients, regardless of age, sex, or clinical status, including sporadic cases.

Preselinins, instead, function as integral part of the gamma secretase complex, an intermembrane structure composed of four elements, preselinin, nicastrin, APH-1, and PEN-2, which characterizes itself for cleaving single-pass transmembrane proteins at the level of resides within their transmembrane domain. The best well known substrate of the gamma secretase is the amyloid precursor protein, which is cleaved to produce amyloid beta. The physiological role and pathogenic effects of preselinins are not yet understood, but it is known that mutations in the preselinin 1 and 2 genes, PSEN1 and PSEN 2, might result in the production of misfolded amyloidogenic forms of Ab. It is important to notice that these mutations account for just less than half of all cases of early-onset AD, and this indicates the presence of other mutations in other key genes which could favor the AD occurrence.

The genetic basis of late-onset AD is much more complex than that of the early-onset form, and its susceptibility might be the results of a number of genetic factors interacting with different environmental and epigenetic elements. The most well known genetic factor implicated in late-onset AD is the gene encoding cholesterol-carrying apolipoprotein E (APOE), a protein which packs cholesterol and other fats and carries them through the body. APOE gene has three alleles associate with a varying risk of developing late-onset AD: epsilon 2, epsilon 3, and epsilon 4. The risk is lowest with epsilon 2 and epsilon 3, the most common alleles, and highest with epsilon 4 (E4), with the carriers having two- to three-fold increased odds of developing AD compared with non-carriers if they have a single copy of the allele, or eight- to twelve-fold increased odds if they have two copies. The correlation between E4 and the development of AD is not yet understood, but since this allele is associated with hypertension it is believed that E4 might favor amyloid deposition in cognitively healthy middle-aged and older adults [8] by increasing their blood pressure. This suggests the existence of a primary etiological cardiovascular mechanism involving factors such as increased levels of cholesterol and cardiovascular diseases [9]. Hypertension, which has consistently been associated with the risk of dementia and AD [10] [11] [12] [13], must play a pivotal role in this cardiovascular mechanism, that must also involve elements like arterial stiffness, age, smoking, diabetes or obesity [14] [15] [16] [17].

Acquired risk factors

There is a variety of other polygenic or acquired factors influencing the risk of getting AD, which might involve up to one third of the cases worldwide. Particularly important among these is undoubtedly insulin resistance. Insulin is a hormone produced by the beta cells of the pancreas to regulate carbohydrates and fats metabolism, so that plasma levels are neither too high or too low but remain in the physiologically permitted normal ranges. Insulin performs it physiological role in three ways: by helping muscle, fat, and liver cells absorb glucose from the blood stream, by stimulating liver and muscle tissue to store glucose in excess, and by lowering glucose production in the liver itself. Insulin resistance is a condition in which the hormone is produced but not effectively used by the body, and this creates a buildup of glucose in the blood stream ultimately resulting in diabetes. Insulin resistance has been observed in AD patients as an early sign for the future development of this disorder, even before the appearance of mild cognitive impairment [18] [19]. It is now believed that insulin resistance is not responsible for the neurological changes observed in affected patients, but might effectively influence and accelerate them during the development of an early-onset AD.

Other acquired factors influencing the AD risk include infections, depression, and head trauma. Regarding infections, there is an emerging field of research which underlines the association between the occurrence of AD and chronic types of infections, especially those due to the species of spirochetes and herpes simplex virus type 1 [20]. Since Ab appears to have antimicrobial properties, it is now emerging the idea that Ab accumulation might be a type of response against viruses infiltration. Depression, instead, appears to be responsible for an up to 50% increase of AD development, especially when it comes out later in life [21] [22] [23] [24]. Head trauma have been documented to be a risk factor for many types of dementia, including AD [25] [26]. Many investigators are now of the opinion that head trauma might increase the intracellular production of Ab, which is then released from the injured axons and deposited into the extracellular plaques [27].

Epigenetic factors

Epigenetic factors involve variations in gene expression due to interactions between the genetic pool and the external environment, with no involvement of DNA sequence modifications. The major epigenetic variations include DNA methylation, RNA editing, and RNA interference. There are many elements underlining an epigenetic nature of the AD origin, like the fact that the majority of the cases are sporadic with no family history, or the fact that the AD onset frequently appears in advanced ages. This suggests that the occurrence of AD might be the final outcome of a long-term process triggered by the prolonged exposure of some element from the external environment.

The most important epigenetic factor now under investigation is undoubtedly oxidative stress, since it causes the accumulation of free radicals that directly alter the DNA methylation pattern, including the methylation pattern in the genes involved in the AD development [28]. Directly associated with this is the use of antioxidant supplements, since they might decrease long-term oxidative stress, thus reducing the incidence of AD together with cell damage and aging [29]. Other epigenetic factors for AD to remember are secondhand smoke [30], pesticides [31] [32], and especially air pollution, as suggested by the presence of diffuse amyloid plaques in the olfactory bulb, hippocampus, and frontal lobes of subjects living in highly polluted areas [33]. To date there are no conclusive data that might confirm one factor over another, and it cannot be excluded the possibility that these might work together, as single elements of a complex and multi-factorial process which finally leads to the development of AD.

According to a 2011 report, there are around 5.4 million people in USA today affected by AD, 200.000 of which being younger than 65 years of age. Considering the subjects showing mild cognitive impairment, which can easily evolve in full-blown dementia, experts expect to see from 11 to 16 millions of people affected by 2050 [34]. In other words, this is a major medical issue which is becoming an increasing cause of death in USA and all over the world second only to heart failure.

International statistics confirm the US trend, underlining a disorder which is now a world medical burden increasingly prevalent with the advancing age [35] [36] [37] [38] [39] [40]. The average global prevalence is 4,7% in people over 60 years of age, but the figure varies according to the local region considered. In general terms, the prevalence is particularly low in poor or developing countries, with an average of 2,6% in Africa and 4,0% in Asia, while much higher in industrialized ones, with an average of 6,2% in Europe and 6,9% in North America. These figures appear to confirm the existence of epidemiological factors in the development of AD which scientists have not properly focalized yet.
Both the prevalence and incidence of AD appear to increase with age, especially in people older than 60, as the physical conditions deteriorate. Interestingly enough, AD is sporadic in the 90% of the cases and this further confirms the pivotal role of acquired and epigenetic factors, which might slowly create the necessary conditions for the occurrence of AD in advanced ages. It is important to notice that for some studies the prevalence of AD appears to be declining over the time [41] [42] [43] [44], perhaps as consequence of improved educational levels and better prevention and treatment plans. Anyways, this trend might also be an artifact dependent on how dementia is defined, as progressive cognitive decline, or a higher tolerance for neuropathological changes by highly educated individuals [45].

The data coming from the studies about sexual differences in AD incidence appear largely contradictory. In fact, according to some studies the risk of developing AD is higher in females than men. This trend appears to be further confirmed by the trend in heterozygous individuals for APOE E4 allele, where the risk of AD is double in females [46]. According to some other studies, instead, there is no difference between the two genders, and the data telling otherwise are just the result of the sexual disparity in terms of life expectancy, which is much higher in women. Not clear are also the differences in incidence related to race. According to the data coming from the United States, the risk of developing AD is markedly higher in people of African origins than in Caucasians, with an incidence of 18,8% in black Americans against 7,8% in whites, but some experts claim that this trend might be the consequence of socioeconomic differences among the different strata of the American society [47].

The exact pathophysiology of AD still remains unclear, but from the data gathered so far it clearly involves two major proteins: amyloid beta (Ab) and tau. Amyloid beta is a 36-43 amino acids peptide produced from the proteolysis of the amyloid precursor protein (APP) by the gamma-secretase complex. The nature of the ultimate toxin is still debated, but the majority of the experts agree to see the toxic form of Ab in small aggregates commonly known as Ab oligomers. Soon after APP cleavage, Ab oligomers begin to form, together with other molecules and non-nerve cells, dense and mostly insoluble clumps known as amyloid senile plaques (SPs). The amyloid plaques mainly appear in the hippocampus and in the cerebral cortex.

Tau is a microtubule-associated protein involved in microtubule assembly and stabilization. Under pathological conditions, this protein becomes abnormally hyperphosphorylated and begins to aggregate in paired helical filaments as major components of the insoluble twisted fibers known as neurofibrillary tangles (NFTs). These are mostly present in the neurons of the medial aspect and of the poles of the temporal lobes, but can accumulate in other cortical regions as the disorder progresses. They spread following a stereotypical patterns of laminar distribution and this indicate the involvement of cortical connections in the AD pathophysiology.

These neuronal lesions follow a precise clinical pattern, with SPs appearing prior to AD clinical onset and NFTs, together with the loss of neurons and synapses, appearing with the progression of cognitive decline [48]. SPs and NFTs are not pathognomonic and might appear in other degenerative disorders, thus their presence is not sufficient to confirm the diagnosis of AD. The clinical consequence of the appearance of these lesions is the destruction and death of healthy cells which finally result into memory failure, personality changes, and problems in daily activities. There are also other less known lesions involved in the pathophysiology of AD. These include granulovacuolar degeneration, occurring almost exclusively in the hippocampus, and neuronal threads, which appear independently from plaques and tangles indicating an even more widespread damage to the cortical circuitry.

The relation between amyloid deposition and NFT formation is still controversial. Some experts back the “predominance” of amyloid deposition, as causative factor of NFTs. This thesis, known as “amyloid hypothesis”, is based on several important elements like the capacity of the fibrillary form of Ab to promote tau phosphorylation and the certain emergence of early-onset AD with the mutations of the genes influencing Ab production and expression. However, amyloid plaques might be undetectable in severe AD cases [49] and this indicates that they might not have a pivotal role in AD pathophysiology after all. On the other hand, the predominance of tau over amyloid plaques, a position known as “tau hypothesis”, appears to be sustained by the severity of AD correlated more with the number of NFTs than with the number of SPs, and by the important structural role of tau protein in the neuron cytoskeleton. Anyway, there are no conclusive data to support one position over the other.

There are no proven preventive strategies against the development of AD [82], although many data, especially epidemiological ones, suggest that a healthy life, together with routine physical activity [83] and cardiorespiratory fitness [84], can reduce the risk of getting the disorder. There are also no definitive recommendations for the dietary measures to adopt, although many physicians underline the benefits of the Mediterranean diet, rich in fruits, vegetables, fish, and omega-3 rich oils. In any case, two dietary measures appear to have a certain effect on the health of patients: calorie restriction, which results in an increased verbal memory correlated with higher levels of plasma insulin and C-reactive protein [85], and moderate alcohol consumption, linked to a reduced risk of developing AD, especially in those who do not carry the APOE e4 allele [86].

In 1901, Alois Alzheimer, a German psychiatrist working at the Frankfurt mental asylum, became intrigued by the case of a 51 years old woman named Mrs Auguste Deter, who showed the signs of a strange type of presenile dementia causing short-term memory loss and other behavioral symptoms, like delusions, temporary vegetative states and screaming without apparent reason. What most struck the psychiatrist was the age of the woman herself, much younger than other patients who usually began to show signs of dementia in their seventies. At Alzheimer’s questions, she replied with incoherent answers without relation with the questions themselves and making no sense at all. When asked about her name, she kept replying “I have lost myself”, an answer which proved she had no longer a sense of space and time but was aware of her helpless situation. Alzheimer kept observing the woman until her death in 1906, when he had the occasion of performing a series of dissections from her brain which he duly observed with the optic microscope. Thanks to the stained sections, Alzheimer was able to describe and identify numerous amyloid plaques and neurofibrillary tangles present in the brain of his dead patient. The case was then re-examined only in 1996, when the scientists of the university of Munich studied the samples left by Alzheimer using modern medical technologies. Their results underlined a mutation in the gene PSEN1 which caused an altered function of the gamma secretase, now known to be one of the causes of the early onset AD. Unwittingly, Alzheimer discovered the first sign of a disturbing acquired neurodegenerative disorder responsible of a severe cognitive and behavioral impairment considered, now considered one of the most common causes of dementia.

The typical sign of Alzheimer disease (AD) is the presence of plaques in the brain of the subjects concerned. The most affected area is the hippocampus, a region deep in the brain under the cerebral cortex, which is part of the limbic system and plays a pivotal role in the consolidation of short- and long-term memory and spatial navigation. Largely affected by the disorder is also the cerebral cortex itself, especially in all those regions implicated in thinking and decision-making. It is unknown whether the plaques are responsible for the AD occurrence or they are rather a consequence of it, in a disorder that still has no cure, apart from some treatments aimed at modulating the course of the disease itself and whose progress is long, progressive and unfortunately inevitable. Selective memory impairment is just one of the earliest manifestations of AD, which primarily affects the elderly as significant source of morbidity and mortality for this population.

Alzheimer disease (AD) is a neurodegenerative disorder with uncertain cause and pathogenesis which mainly presents itself as impaired selective memory resulting in serious problems for social and occupational life. The typical sign of AD is the presence of plaques in the brain of the subjects concerned. The most affected area is the hippocampus, a region deep in the brain under the cerebral cortex, which is part of the limbic system and plays a pivotal role in the consolidation of short- and long-term memory and spatial navigation. Largely affected by the disorder is also the cerebral cortex itself, especially in all those regions implicated in thinking and decision-making.

The etiology of AD is still unknown. However, the majority of the investigators now agree to see the disorder as the final outcome of a pathophysiologic cascade which ultimately leads to the pathology of AD or other forms of dementia. The process, which covers the span of many years, is triggered by several risk factors that include environmental, genetic and physiological elements. For its increasing prevalence and incidence, AD is now considered a major medical issue in the US and all over the world.

The exact pathophysiology of AD still remains unclear, but from the data gathered so far it clearly involves two major proteins: amyloid beta (Ab) and tau. Amyloid beta is a 36-43 amino acids peptide produced from the proteolysis of the amyloid precursor protein (APP) by the gamma-secretase complex. Outside the neuron, Ab oligomers begin to form dense and mostly insoluble clumps known as amyloid senile plaques (SPs), which mainly appear in the hippocampus and in the cerebral cortex. Tau, instead, is a microtubule-associated protein involved in microtubule assembly and stabilization. Under pathological conditions, this protein becomes abnormally hyperphosphorylated and begins to aggregate in paired helical filaments which are the major components of the insoluble twisted fibers known as neurofibrillary tangles (NFTs).

Memory impairment is one of the most important sign of AD. This earliest manifestation is due to the damage of hippocampus, which, as previously said, has a pivotal role in storing information, and progresses very slowly and insidiously following a particular and distinctive pattern. Afterwards, other memory problems emerge, such as problems regarding the semantic and procedural memory or even motor learning, together with a series of other cognitive impairments of language, visuospatial skills and executive functions.

The prognosis of AD is characterized by three main stages. The first one consists in the appearance of memory impairment that progressively worsens with the advancement of the disorder. The second stages, instead, consists in the appearance of other dementia-connected signs such as anxiety, depression, insomnia, agitation, and paranoia, in a state that, although clinically serious, continues to see the patient as physically independent. In the third and last stage, the patient is no longer independent and usually dies after succumbing to terminal-stage complications due to advanced debilitation, such as dehydration, malnutrition, and infections.

Unfortunately, there is no treatment now available capable of coping with the underlying causes of AD and reversing its progression. Therefore, the therapies used by caregivers are only symptomatic, aimed at slowing down and delaying the AD symptoms, which are inevitable. Moreover, there are no proven preventive strategies against the development of AD, although many data, especially epidemiological ones, suggest that a healthy life, together with routine physical activity and cardiorespiratory fitness, can reduce the risk of developing this disorder.

1. Rocchi A, Orsucci D, Tognoni G, Ceravolo R, Siciliano G. The role of vascular factors in late-onset sporadic Alzheimer's disease. Genetic and molecular aspects. Curr Alzheimer Res. Jun 2009;6(3):224-37. 
2. Roriz-Filho J, Sá-Roriz TM, Rosset I, Camozzato AL, Santos AC, Chaves ML, et al. (Pre)diabetes, brain aging, and cognition. Biochim Biophys Acta. May 2009;1792(5):432-43. 
3. Naderali EK, Ratcliffe SH, Dale MC. Obesity and Alzheimer's disease: a link between body weight and cognitive function in old age. Am J Alzheimers Dis Other Demen. Dec-2010 Jan 2009;24(6):445-9. 
4. de la Monte SM. Insulin resistance and Alzheimer's disease. BMB Rep. Aug 31 2009;42(8):475-81. 
5. Goldman JS, Hahn SE, Catania JW, LaRusse-Eckert S, Butson MB, Rumbaugh M, et al. Genetic counseling and testing for Alzheimer disease: joint practice guidelines of the American College of Medical Genetics and the National Society of Genetic Counselors. Genet Med. Jun 2011;13(6):597-605. 
6. Priller C, Bauer T, Mitteregger G, Krebs B, Kretzschmar HA, Herms J (July 2006). "Synapse formation and function is modulated by the amyloid precursor protein". J. Neurosci. 26 (27): 7212–21. 
7. Turner PR, O'Connor K, Tate WP, Abraham WC (May 2003). "Roles of amyloid precursor protein and its fragments in regulating neural activity, plasticity and memory". Prog. Neurobiol. 70 (1): 1–32. 
8. Anderson P. Hypertension Interacts With APOE Epsilon 4 to Increase Amyloid Load. Available at http://www.medscape.com/viewarticle/781430. Accessed April 8, 2013. 
9. de la Torre JC. Alzheimer disease as a vascular disorder: nosological evidence. Stroke 2002; 33:1152. 
10. Whitmer RA, Sidney S, Selby J, et al. Midlife cardiovascular risk factors and risk of dementia in late life. Neurology 2005; 64:277. 
11. Freitag MH, Peila R, Masaki K, et al. Midlife pulse pressure and incidence of dementia: the Honolulu Asia Aging Study. Stroke 2006; 37:33.
12. Alonso A, Mosley TH Jr, Gottesman RF, et al. Risk of dementia hospitalisation associated with cardiovascular risk factors in midlife and older age: the Atherosclerosis Risk in Communities (ARIC)study. J Neurol Neurosurg Psychiatry 2009; 80:1194.
13. Skoog I, Lernfelt B, Landahl S, et al. 15 year longitudinal study of blood pressure and dementia. Lancet 1996; 347:1141. 
14. Beason-Held LL, Thambisetty M, Deib G, et al. Baseline cardiovascular risk predicts subsequent changes in resting brain function. Stroke 2012; 43:1542.
15. Kaffashian S, Dugravot A, Elbaz A, et al. Predicting cognitive decline: a dementia risk score vs. the Framingham vascular risk scores. Neurology 2013; 80:1300.
16. Debette S, Seshadri S, Beiser A, et al. Midlife vascular risk factor exposure accelerates structural brain aging and cognitive decline. Neurology 2011; 77:461.
17. Profenno LA, Porsteinsson AP, Faraone SV. Metaanalysis of Alzheimer's disease risk with obesity, diabetes, and related disorders. Biol Psychiatry 2010; 67:505. 
18. Baker LD, Cross DJ, Minoshima S, Belongia D, Watson GS, Craft S. Insulin resistance and Alzheimer-like reductions in regional cerebral glucose metabolism for cognitively normal adults with prediabetes or early type 2 diabetes. Arch Neurol. Jan 2011;68(1):51-7.
19. Schrijvers JCM, Witteman EJG, Sijbrands, et al. Insulin metabolism and the risk of Alzheimer disease: The Rotterdam Study. Neurology. 2010;75:1982-1987. 
20. Miklossy J. Emerging roles of pathogens in Alzheimer disease. Expert Rev Mol Med. Sep 20 2011;13:e30. 
21. Saczynski JS, Beiser A, Seshadri S, Auerbach S, Wolf PA, Au R. Depressive symptoms and risk of dementia: the Framingham Heart Study. Neurology. Jul 6 2010;75(1):35-41.
22. Dotson VM, Beydoun MA, Zonderman AB. Recurrent depressive symptoms and the incidence of dementia and mild cognitive impairment. Neurology. Jul 6 2010;75(1):27-34.
23. Lowry F. Late-life depression linked to increased risk for dementia. Medscape Medical News [serial online]. May 7, 2013
24. Diniz BS, Butters MA, Albert SM, Dew MA, Reynolds CF 3rd. Late-life depression and risk of vascular dementia and Alzheimer's disease: systematic review and meta-analysis of community-based cohort studies. Br J Psychiatry. May 2013;202:329-35. 
25. Magnoni S, Brody DL. New perspectives on amyloid-beta dynamics after acute brain injury: moving between experimental approaches and studies in the human brain. Arch Neurol. Sep 2010;67(9):1068-73. 
26. Plassman BL, Havlik RJ, Steffens DC, Helms MJ, Newman TN, Drosdick D, et al. Documented head injury in early adulthood and risk of Alzheimer's disease and other dementias. Neurology. Oct 24 2000;55(8):1158-66. 
27. Chen XH, Siman R, Iwata A, Meaney DF, Trojanowski JQ, Smith DH. Long-term accumulation of amyloid-beta, beta-secretase, presenilin-1, and caspase-3 in damaged axons following brain trauma. Am J Pathol. Aug 2004;165(2):357-71. 
28. Dizdaroglu M, Jaruga P, Birincioglu M, Rodriguez H. Free radical-induced damage to DNA: mechanisms and measurement. Free Radic Biol Med. Jun 1 2002;32(11):1102-15. 
29. Harman D. Aging: a theory based on free radical and radiation chemistry. J Gerontol. 1956 11, 298-300. 
30. Chen R. Association of environmental tobacco smoke with dementia and Alzheimer's disease among never smokers. Alzheimers Dement 2012; 8:590. 
31. Hayden KM, Norton MC, Darcey D, et al. Occupational exposure to pesticides increases the risk of incident AD: the Cache County study. Neurology 2010; 74:1524. 
32. Richardson JR, Roy A, Shalat SL, et al. Elevated serum pesticide levels and risk for Alzheimer disease. JAMA Neurol 2014; 71:284.
33. Calderón Garcidueñas L, Reed W, Maronpot RR, et al. Brain inflammation and Alzheimer's like pathology in individuals exposed to severe air pollution. Toxicol Pathol 2004; 32:650. 
34. Alzheimer's Association. 2010 Alzheimer's disease facts and figures. Alzheimers Dement. Mar 2010;6(2):158-94. 
35. Rocca WA, Petersen RC, Knopman DS, et al. Trends in the incidence and prevalence of Alzheimer's disease, dementia, and cognitive impairment in the United States. Alzheimers Dement 2011; 7:80.
36. Ganguli M, Hendrie HC. Screening for cognitive impairment and depression in ethnically diverse older populations. Alzheimer Dis Assoc Disord 2005; 19:275. 
37. Llibre Rodriguez JJ, Ferri CP, Acosta D, et al. Prevalence of dementia in Latin America, India, and China: a population based cross sectional survey. Lancet 2008; 372:464.
38. Prince M, Bryce R, Albanese E, et al. The global prevalence of dementia: a systematic review and meta analysis. Alzheimers Dement 2013; 9:63. 
39. Sosa-Ortiz AL, Acosta-Castillo I, Prince MJ. Epidemiology of dementias and Alzheimer's disease. Arch Med Res 2012; 43:600.
40. Hebert LE, Weuve J, Scherr PA, Evans DA. Alzheimer disease in the United States (2010-2050) estimated using the 2010 census. Neurology 2013; 80:1778. 
41. Rocca WA, Petersen RC, Knopman DS, et al. Trends in the incidence and prevalence of Alzheimer's disease, dementia, and cognitive impairment in the United States. Alzheimers Dement 2011; 7:80. 
42. Larson EB, Yaffe K, Langa KM. New insights into the dementia epidemic. N Engl J Med 2013; 369:2275. 
43. Christensen K, Thinggaard M, Oksuzyan A, et al. Physical and cognitive functioning of people older than 90 years: a comparison of two Danish cohorts born 10 years apart. Lancet 2013; 382:1507.
44. Matthews FE, Arthur A, Barnes LE, et al. A two decade comparison of prevalence of dementia in individuals aged 65 years and older from three geographical areas of England: results of the Cognitive Function and Ageing Study I and II. Lancet 2013; 382:1405. 
45. Amieva H, Mokri H, Le Goff M, et al. Compensatory mechanisms in higher educated subjects with Alzheimer's disease: a study of 20 years of cognitive decline. Brain 2014; 137:1167. 
46. Payami H, Zareparsi S, Montee KR, et al. Gender difference in apolipoprotein E-associated risk for familial Alzheimer disease: a possible clue to the higher incidence of Alzheimer disease in women. Am J Hum Genet. Apr 1996;58(4):803-11. 
47. Yaffe K, Falvey C, Harris TB, et al. Effect of socioeconomic disparities on incidence of dementia among biracial older adults: prospective study. BMJ 2013; 347:f7051. 
48. Serrano-Pozo A, Frosch MP, Masliah E, Hyman BT. Neuropathological alterations in Alzheimer disease. Cold Spring Harb Perspect Biol. Sep 2011;3(9):a006189. 
49. Lippa CF, Duda JE, Grossman M, et al. DLB and PDD boundary issues: diagnosis, treatment, molecular pathology, and biomarkers. Neurology 2007; 68:812. 
50. Harwood DG, Sultzer DL, Feil D, et al. Frontal lobe hypometabolism and impaired insight in Alzheimer disease. Am J Geriatr Psychiatry 2005; 13:934.
51. Barrett AM, Eslinger PJ, Ballentine NH, Heilman KM. Unawareness of cognitive deficit (cognitive anosognosia) in probable AD and control subjects. Neurology 2005; 64:693. 
52. Harwood DG, Sultzer DL, Wheatley MV. Impaired insight in Alzheimer disease: association with cognitive deficits, psychiatric symptoms, and behavioral disturbances. Neuropsychiatry Neuropsychol Behav Neurol 2000; 13:83. 
53. Mizrahi R, Starkstein SE, Jorge R, Robinson RG. Phenomenology and clinical correlates of delusions in Alzheimer disease. Am J Geriatr Psychiatry 2006; 14:573. 
54. Nasreddine ZS, Phillips NA, Bédirian V, et al. The Montreal Cognitive Assessment, MoCA: a brief screening tool for mild cognitive impairment. J Am Geriatr Soc 2005; 53:695. 
55. Hutchinson AD, Mathias JL. Neuropsychological deficits in frontotemporal dementia and Alzheimer's disease: a metaanalytic review. J Neurol Neurosurg Psychiatry 2007; 8:917. 
56. Whitwell JL, Dickson DW, Murray ME, et al. Neuroimaging correlates of pathologically defined subtypes of Alzheimer's disease: a casecontrol study. Lancet Neurol 2012; 11:868. 
57. van de Pol LA, Hensel A, Barkhof F, et al. Hippocampal atrophy in Alzheimer disease: age matters. Neurology 2006; 66:236.
58. Barkhof F, Polvikoski TM, van Straaten EC, et al. The significance of medial temporal lobe atrophy: a postmortem MRI study in the very old. Neurology 2007; 69:1521. 
59. Whitwell JL, Josephs KA, Murray ME, et al. MRI correlates of neurofibrillary tangle pathology at autopsy: a voxelbased morphometry study. Neurology 2008; 71:743. 
60. Kantarci K, Avula R, Senjem ML, et al. Dementia with Lewy bodies and Alzheimer disease: neurodegenerative patterns characterized by DTI. Neurology 2010; 74:1814. 
61. Minoshima S, Giordani B, Berent S, et al. Metabolic reduction in the posterior cingulate cortex in very early Alzheimer's disease. Ann Neurol 1997; 42:85. 
62. Silverman DH, Small GW, Chang CY, et al. Positron emission tomography in evaluation of dementia: Regional brain metabolism and longterm outcome. JAMA 2001; 286:2120. 
63. Powers WJ, Perlmutter JS, Videen TO, et al. Blinded clinical evaluation of positron emission tomography for diagnosis of probable Alzheimer's disease. Neurology 1992; 42:765. 
64. Duara R, Grady C, Haxby J, et al. Positron emission tomography in Alzheimer's disease. Neurology 1986; 36:879.
65. Hu WT, Wang Z, Lee VM, et al. Distinct cerebral perfusion patterns in FTLD and AD. Neurology 2010; 75:881. 
66. Pickut BA, Saerens J, Mariën P, et al. Discriminative use of SPECT in frontal lobetype dementia versus (senile) dementia of the Alzheimer's type. J Nucl Med 1997; 38:929. 
67. Ishii K, Sakamoto S, Sasaki M, et al. Cerebral glucose metabolism in patients with frontotemporal dementia. J Nucl Med 1998; 39:1875. 
68. Foster NL, Heidebrink JL, Clark CM, et al. FDGPET improves accuracy in distinguishing frontotemporal dementia and Alzheimer's disease. Brain 2007; 130:2616. 
69. Rabinovici GD, Rosen HJ, Alkalay A, et al. Amyloid vs FDGPET in the differential diagnosis of AD and FTLD. Neurology 2011; 77:2034. 
70. Brooks M. Memory tests plus brain scans detect earliest stages of AD. Medscape Medical News [serial online]. July 15, 2013
71. Rasmussen KL, Tybjaerg-Hansen A, Nordestgaard BG, Frikke-Schmidt R. Apolipoprotein E plasma level and genotype -- risk of dementia in 76,000 individuals from the general population. Presented at: XXI World Congress of Neurology (WNC), 2013; September 24, 2013; Vienna, Austria. 
72. Keller DM. APOE plasma levels predict dementia independent of genotype. Medscape Medical News [serial online]. October 4, 2013
73. Goldman JS, Hahn SE, Catania JW, LaRusse-Eckert S, Butson MB, Rumbaugh M, et al. Genetic counseling and testing for Alzheimer disease: joint practice guidelines of the American College of Medical Genetics and the National Society of Genetic Counselors. Genet Med. Jun 2011;13(6):597-605. 
74. Winslow BT, Onysko MK, Stob CM, Hazlewood KA. Treatment of Alzheimer disease. Am Fam Physician. Jun 15 2011;83(12):1403-12. 
75. Massoud F, Léger GC. Pharmacological treatment of Alzheimer disease. Can J Psychiatry. Oct 2011;56(10):579-88. 
76. Farlow M, Veloso F, Moline M, et al. Safety and tolerability of donepezil 23 mg in moderate to severe Alzheimer's disease. BMC Neurol. May 25 2011;11:57. 
77. Schmitt FA, van Dyck CH, Wichems CH, Olin JT. Cognitive response to memantine in moderate to severe Alzheimer disease patients already receiving donepezil: an exploratory reanalysis. Alzheimer Dis Assoc Disord. Oct-Dec 2006;20(4):255-62. 
78. Porsteinsson AP, Grossberg GT, Mintzer J, Olin JT. Memantine treatment in patients with mild to moderate Alzheimer's disease already receiving a cholinesterase inhibitor: a randomized, double-blind, placebo-controlled trial. Curr Alzheimer Res. Feb 2008;5(1):83-9.
79. Schneider LS, Dagerman KS, Higgins JP, McShane R. Lack of evidence for the efficacy of memantine in mild Alzheimer disease. Arch Neurol. Aug 2011;68(8):991-8. 
80. Madhusoodanan S, Shah P, Brenner R, Gupta S. Pharmacological treatment of the psychosis of Alzheimer's disease: what is the best approach?. CNS Drugs. 2007;21(2):101-15. 
81. Rolland Y, Abellan van Kan G, Vellas B. Healthy brain aging: role of exercise and physical activity. Clin Geriatr Med. Feb 2010;26(1):75-87. 
82. Winslow BT, Onysko MK, Stob CM, Hazlewood KA. Treatment of Alzheimer disease. Am Fam Physician. Jun 15 2011;83(12):1403-12. 
83. Rolland Y, Abellan van Kan G, Vellas B. Healthy brain aging: role of exercise and physical activity. Clin Geriatr Med. Feb 2010;26(1):75-87. ) 
84. Honea RA, Thomas GP, Harsha A, Anderson HS, Donnelly JE, Brooks WM, et al. Cardiorespiratory fitness and preserved medial temporal lobe volume in Alzheimer disease. Alzheimer Dis Assoc Disord. Jul-Sep 2009;23(3):188-97. 
85. Witte AV, Fobker M, Gellner R, Knecht S, Flöel A. Caloric restriction improves memory in elderly humans. Proc Natl Acad Sci U S A. Jan 27 2009;106(4):1255-60. 
86. Anstey KJ, Mack HA, Cherbuin N. Alcohol consumption as a risk factor for dementia and cognitive decline: meta-analysis of prospective studies. Am J Geriatr Psychiatry. Jul 2009;17(7):542-55.