Alzheimer's Disease: A Review from the Pathophysiology to Diagnosis, New Perspectives for Pharmacological Treatment

Abstract

Dementia is characterized by the impairment of cognition and behavior of people over 65 years. Alzheimer's disease (AD) is the most prevalent neurodegenerative disorder in the world, as approximately 47 million people are affected by this disease and the tendency is that this number will increased 62% by 2030. Two microscopic features assist in the characterization of the disease, the amyloid plaques and neurofibrillary agglomerates. All these factors are responsible for the slow and gradual deterioration of memory that affect language, personality or cognitive control. For the AD diagnosis, neuropsychological tests are performed in different spheres of cognitive functions but since not all cognitive functions may be affected, cerebrospinal fluid biomarkers are used along with these tests. To date, cholinesterase inhibitors are used as treatment, they are the only drugs that have shown significant improvements in the cognitive functions of AD patients. Despite the proven effectiveness of cholinesterase inhibitors, an AD carrier, even while being treated, is continually subjected to progressive degeneration of the neuronal tissue. For this reason, other biochemical pathways associated with the pathophysiology of AD have been explored as alternatives to the treatment of this condition such as inhibition of β-secretase and glycogen synthase kinase-3β. The present study aims to conduct a review of the epidemiology, pathophysiology, symptoms, diagnosis and treatment of Alzheimer's disease, emphasizing the research and development of new therapeutic approaches.

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Alzheimer's Disease: A Review from the Pathophysiology to Diagnosis,
New Perspectives for Pharmacological Treatment
Leide Caroline dos Santos Picançoa,*, Priscilla Farias Ozelaa, Maiara de Fátima de Brito Britoa,
Abraão Alves Pinheiroa, Elias Carvalho Padilhab, Francinaldo Sarges Bragac,
Carlos Henrique Tomich de Paula da Silvad, Cleydson Breno Rodrigues dos Santosc,
Joaquín María Campos Rosad,e and Lorane Izabel da Silva Hage-Melima,*
aLaboratório de Química Farmacêutica e Medicinal (PharMedChem), Universidade Federal do Amapá, Ma-
capá, Brazil; bFaculdade de Ciências Farmacêuticas, Universidade Estadual Paulista (UNESP), Campus
Araraquara, Departamento de Princípios Ativos Naturais e Toxicologia, Araraquara, São Paulo, Brazil;
cLaboratório de Modelagem e Química Computacional, Universidade Federal do Amapá, Macapá, Brazil;
dLaboratório Computacional de Química Farmacêutica, Departamento de Ciencias Farmaceuticas, Facul-
dade de Ciências Farmacêuticas de Ribeirão Preto, Universidade de São Paulo, Ribeirão Preto, São Paulo,
Brazil; eChemical Department of Pharmaceutical and Organic. Faculty of Pharmacy. University Campus of
cartuja. University Granada, 18071, Espanha
A R T I C L E H I S T O R Y
Received: August 13, 2016
Revised: November 20, 2016
Accepted: December 02, 2016
DOI: 10.2174/09298673236661612131
01126
Abstract: Dementia is characterized by the impairment of cognition and behavior of people
over 65 years. Alzheimer's disease (AD) is the most prevalent neurodegenerative disorder in
the world, as approximately 47 million people are affected b y this disease and the tendency is
that this number will increase to 62% by 2030. Two microscopic features assist in the charac-
terization of the disease, the amyloid plaques and neurofibrillary agglomerates. All these fac-
tors are responsible for the slow and gradual deterioration of memory that affect language,
personality or cognitive control. For the AD diagnosis, neuropsychological tests are per-
formed in different spheres of cognitive functions but since not all cognitive functions may be
affected, cerebrospinal fluid biomarkers are used along with these tests. To date, cho linester-
ase inhibitors are used as treatment, they are the only drugs that have shown significant im-
provements in the cognitive functions of AD patients. Despite the proven effectiveness of
cholinesterase inhibitors, an AD carrier, even while being treated, is continually subjected to
progressive degeneration of the neuronal tissue. For this reason, other biochemical pathways
associated with the pathophysiology of AD have been explored as alternatives to the treatment
of this condition such as inhibition of β-secretase and glycogen synthase kinase-3β. The pre-
sent study aims to conduct a review of the epidemiology, pathophysiology, symptoms, diag-
nosis and treatment of Alzheimer's disease, emphasizing the research and development of new
therapeutic approaches.
Keywords: Alzheimer's disease, pathophysiology, treatment, acetylcholinesterase, β-secretase, glycogen synthase
kinase-3β.
1. INTRODUCTION
Dementia is characterized by impairment of cogni-
tion and behavior of people over 65 years of age. Alz-
*Address correspondence to this author at the Laboratório de Quí-
mica Farmacêutica e Medicinal, Universidade Federal do Amapá,
68902-280, Macapá, Brazil; Tel/Fax: +55 96 4009 2921;
E-mails: leidecaroline@outlook.com; lorane@unifap.br
heimer's disease (AD) is the neurodegenerative disor-
der most prevalent in the world, affecting about 24 mil-
lion people and it is estimated that by 2050 this number
will be quadrupled. Its main features are the deposit of
β-amyloid (Abeta) peptides in the extracellular surface
of neurons and the formation of neurofibrillary tangles
arising from the intracellular accumulation of hyper-
phosphorylated Tau protein.

2 Current Medicinal Chemistry, 2017, Vol. 24, No. 00 dos Santos Picanço et al.,
AD is also associated with the deficit of the neuro-
transmitter acetylcholine (ACh) and oxidative stress
caused by exacerbation of glutamatergic transmission
[1-5]. In this review we will discuss the epidemiology,
pathophysiology, diagnosis, symptoms and prospects
for new pharmacological treatments for AD.
2. EPIDEMIOLOGY
Estimates in 2015 showed that around 46.8 million
people are affected by dementia worldwide. This num-
ber of new cases is almost 30% (9.9 million new cases)
greater than the incidence presented in the report of the
World Health Organization (WHO) in 2010. The high-
est incidence rates were in Asia (49%), Europe (25%)
and America (18%) [6, 7].
The prediction is that, by the year 2030, the number
will reach 74.7 million people and 131.5 million in
2050. Also, according to the estimates by the World
Alzheimer Report 2015 [6], East Asia and Africa are
the regions with the largest number of people with de-
mentia (about 9.8 million people), followed by Western
Europe with 7.4 million affected [6].
According to the Diagnostic and Statistical Manual
of Mental Disorders (2014) [8], the AD has a progres-
sive increase proportional to aging. Thus, the age is
considered to be a prevalence factor. Epidemiologi-
cally, AD affects approximately 5% of individuals over
65 years and 20% of those over 80 years. This means
that the rate of prevalence doubles every 5 years [9].
The World Alzheimer Report (2015) [6] pointed out
that in Europe and the Americas the highest incidence
of AD is between 80-89 years, in Asia among those
aged 75-84 years and 65-74 years in Africa.
Each year, in the United States, there is an increase
in the prevalence of AD in military veterans who have
suffered traumatic brain injury (TBI), post-traumatic
stress disorder and/or injuries associated with military
service [10]. These increasing infirm military veterans
tend to exacerbate hospital costs because of the need
for medical care and/or hospitalization for long periods.
In the wars of Iraq and Afghanistan, about 23% of
cases of TBI were originated from improvisation with
explosives [11].
People who have had moderate to severe TBI have a
two- to four-time higher risk to develop AD at older
ages [12]. A correlation with dementia development in
boxers was also observed [13]. But other sports of
much contact and strength, such as American football
and hockey, lead such athletes to TBI (about 1.6 to 3.8
million affected annually) in the United States [14-16].
The census of 2012 indicated that the population ob-
tained a substantial increase in the elderly population.
One indicator in this regard is the aging index, which is
the ratio of the number of people aged over 60 for
every 100 people under 15 years old. The rate in Brazil
is around 51.8, therefore the data show that there is a
person aged 60 years or older for every two people un-
der 15 years old [17]. In Brazil, more concrete data on
the AD come from the 2000s, when the statistical bases
of the country compared with data from other regions
revealed the prevalence in the country of 1.2 million
cases, and the incidence of 100,000 new cases each
year [18]. However, there is need to improve the search
and registration of the data, since the AD may be un-
registered or underdiagnosed [19, 20].
According to the World Alzheimer Report 2015 [6],
the overall costs of the disease (medical care, social
care and informal care) were 818 billion dollars with an
increase of 35.4% compared to the same study in 2010
[7]. The trend of the cost with Alzheimer's disease for
2018 will be $ 1 trillion, rising to 2 trillion in 2030 [6].
3. PATHOPHYSIOLOGY
Even with over a hundred years of history, the AD
does not have full clarification regarding its pathogene-
sis and still lacks a therapy that induces a natural heal-
ing. Nevertheless, macroscopic and microscopic mark-
ers related to it are known and may help in its charac-
terization, in understanding of the disease pathogenesis
and in the development of possible strategies [21, 22].
At the macroscopic level (Fig. 1) there is the atro-
phy of the hippocampus and cerebral cortex, which in
AD appears more sharply due to age [23, 24]. Micro-
scopically it is possible to observe the formation of
amyloid plaques, or senile plaques, which are amor-
phous structures of Abeta, and accumulation of hyper-
phosphorylated Tau protein which implies the forma-
tion of neurofibrillary tangles, and extensive neuronal
loss [25-30].
Recent research showed other mechanisms are re-
lated to the formation of these AD markers, ranging
from genetic imprint factors [30, 32] as family heritage
[33], and mechanisms that involve apolipoprotein E
[27, 31, 34], the mechanism of oxidation processes [25,
35] culminating in the neurodegeneration process.
3.1. Genetic Mechanism
The vast majority of AD case occurrences are spo-
radic, i.e. where there is no dominant genetic cause, but
rare mutations may occur in the APP gene, originating

Alzheimer's Disease: A Review from the Pathophysiology to Diagnosis Current Medicinal Chemistry, 2017, Vol. 24, No. 00 3
the familiar AD [33], and allele ε4 of apolipoprotein E
(ApoE) that has been shown in recent studies as the
strongest genetic risk factor related to AD development
process [27, 31].
Fig. (1). Macroscopic changes. Atrophy of the hippocampus
and cerebral cortex.
The human carriers of ApoE are present in ap-
proximately 1 of every 5 individuals. The subsidy that
ApoE provides to the development of AD is realized
when it is observed that these individuals account for
about 65% of cases of the disease [31] and that carriers
of the ApoE have the risk of developing Alzheimer's
increased three fold [32]. The mechanisms that corre-
late the presence of ApoE with AD are not well under-
stood yet, however, it is being suggested that in such
cases there is a decrease in clearance of Abeta in the
brain [31, 36].
In addition to the mechanism involving ApoE, stud-
ies also demonstrate a strong correlation between the
presence of preselinin alleles (PSEN 1 and PSEN 2) in
AD-patients and in individuals with a tendency to be
carriers of AD or other related diseases [37, 38]. There
is precedence in literature of the identification of two
different types of mutation in this gene in patients with
familial AD [39, 40].
PSEN 1 and PSEN 2 genes are rare in individuals
with AD, although their relationship with ApoE is a
major factor when the disease is due to genetic causes.
They are involved in early-onset pathology, which is a
rare form of the disease [41]. Mutations in PSEN 1
(chromosome 14) account for 18% to 50% of these
early onset cases [42], mutations in PSEN 2 (chromo-
some 1) have been rarely reported and was mostly de-
tected in African populations and in European coun-
tries [43]. The mechanism of correlation between pre-
selinin and the control of APP cleavage has not yet
been fully elucidated [44].
3.2. Amyloid hypothesis and Protein Tau
As previously mentioned, the Abeta fragments and
neurofibrillary tangles are important markers for AD
[25-27] which characterize the amyloid hypothesis.
These deposits are the result of the wrong folding of
native proteins, i.e. forming after altered cleavage of
the amyloid precursor protein (APP) [45-47].
APP is a transmembrane glycoprotein with ap-
proximately 770 amino acids expressed by several
cells, including CNS neurons [47, 48]. The cleavage of
APP occurs through the enzymes α-, β- and ɣ-secretase
[44, 49], while the amyloid pathway has its cascade
unleashed when APP is cleaved by β-secretase thereby
forming insoluble peptides having 39 to 43 fragments
[47, 48, 50].
The Abeta fragments, especially the Abeta-42 iso-
form, have pronounced cytotoxic properties which are
related to the process of neurodegeneration, for facili-
tating the formation of oxiradicals [51], being or not
directly toxic to neuronal cells, by deregulating calcium
homeostasis due to lipidic dysregulation of the cell
membrane [26, 27, 36, 37, 52], these fragments form
the insoluble structures that characterize histopa-
thologically the AD (senile plaques) and this process
ends up leading to neuronal death [53, 54].
Tau protein promotes a kind of assembly of tubulin,
providing microtubule stability [33]. Neurofibrillary
tangles are the result of Tau protein hyperphosphoryla-
tion. According to the results presented in the work of
Stancu and co-workers, although mice models that ex-
press the mutant amyloid precursor protein without tau
overexpression did not show neurofibrillary tangles,
subtle changes in mice endogenous Tau were induced
by high concentrations of Abeta, resulting in the proc-
ess of hyperphosphorylation of Tau [27]. Research has
also found strong evidence of the interdependence be-
tween Aβ accumulation and tau protein aggregation,
which represents the final stage of disease pathogenesis
[55, 56].
3.3. Inflammatory Mechanism and Mitochondrial
Dysfunction
AD is a disease that is closely linked to inflamma-
tory processes [41, 57]. In addition, several studies
have shown that Tau pathologies are drastically exac-
erbated during the occurrence of acute and chronic in-
flammatory processes [27, 58-60]. Those inflammatory
processes are mediated or induced by microglial clus-
ters around the densest regions of Abeta plaques, by
high levels of pro-inflammatory cytokines and by mi-

4 Current Medicinal Chemistry, 2017, Vol. 24, No. 00 dos Santos Picanço et al.,
croglial activation that precedes the formation of neu-
rofibrillary tangles (Fig. 2) [41].
With regard to mitochondrial dysfunction, it is be-
lieved that the deposit of Abeta fragments and patho-
logical Tau protein affect mitochondrial function in
brain cells, specifically in regard to the impairment of
mitochondrial oxidative metabolism [27, 35, 61]. Stud-
ies related to the presence of Abeta peptides carried out
by Benevento enabled him to conclude, with more
specificity, that these peptides can be directly toxic to
neuronal mitochondria [61].
3.4. Oxidative Stress
Studies show that there is strong evidence that oxi-
dative stress induced by Abeta is crucial to the patho-
genesis and progress of AD [26], being present, both as
cause and consequence, of inflammatory processes in
general, which is characteristic of neurodegenerative
diseases [62].
The brain is an organ that has high energetic activ-
ity, this energy demand is supplied by mitochondrial
oxidative phosphorylation, and this process can lead to
the formation of highly reactive oxygen species [63]:
oxidative stress is a result of excessive production of
these species. In this case, the protective mechanisms
are compromised, the reactive oxygen species begin to
accumulate and the neurons become susceptible to the
excitotoxic lesion [47]. However, this mechanism de-
pends on Abeta fragments which, when accumulated,
promote the reduction of iron and brain copper, which
are key factors to trigger oxidative stress [64] which,
under these conditions, promotes DNA damage [25].
3.5. Cholinergic Hypothesis
Among the mechanisms related to the onset and
evolution of AD, a extremely studied hypothesis is the
cholinergic hypothesis, which was the first theory re-
lated to AD pathogenesis [54, 64].
In general, the brain of AD carriers presents, in ad-
dition to the histopathological markers previously de-
scribed, atrophy, synaptic loss and deficiency in central
neurotransmission. There is overall degeneration of
basal forebrain neurons [65]. In the beginning of the
disease there is loss of the cholinergic neurons in the
basal nucleus and in the entorhinal cortex, but in the
advanced stage of AD, more than 90% of the choliner-
gic neurons of the basal nucleus are lost [66].
Bartus and Emerich (1999) [67] point out that ac-
cording to the cholinergic hypothesis, the abnormal or
impaired functioning of the cholinergic system proves
Fig. (2). Amyloid cascade in AD.

Alzheimer's Disease: A Review from the Pathophysiology to Diagnosis Current Medicinal Chemistry, 2017, Vol. 24, No. 00 5
capable of inducing a memory deficiency in animal
models, similar to AD. According to this hypothesis,
the destruction of cholinergic neurons in the basal fore-
brain and the loss of central cholinergic transmission
leads to the appearance of cognitive and non-cognitive
symptoms in patients with AD [66].
It is also observed that the cholinergic hypothesis is
also characterized by: a marked decrease in acetyltrans-
ferase concentration responsible for the synthesis of
acetylcholine in the cortex and hippocampus; and due
to the loss of cholinergic neurons in the Meynert basal
nucleus [68]. The cholinergic hypothesis also corrobo-
rates that the dysfunction and cell death of neurons re-
sponsible for the maintenance of specific transmission
systems leads to the deficiency of Ach, noradrenaline
and serotonin [69].
4. SYMPTOMATOLOGY
AD is often a major cause of dementia in elderly
people, when the evolution of the symptoms becomes
severe, with slow and gradual deterioration of the
memory that affects language, personality and cogni-
tive control [70-74]. AD has major medical, economic
and social consequences due to problems such as de-
mentia, dependency and disability [75].
AD can be classified in three stages: the early
stage, where the loss of memory is discrete; cholinergic
neurons in the limbic system are affected, the hippo-
campus shrinks by approximately 25% of its volume.
The light declines in memory capacity are associated
with damaged neurons since they are responsible for
the short and long term memory; the intermediate
stage, which is characterized by difficulty in recogniz-
ing and communicating with people, is a long stage and
can last from two to ten years according to Seidl [76].
After that, there is a decline in the acetylcholine levels
of some neurons, among these are those located in the
ventral telencephalon, which under normal conditions
are involved in information storage and long-term
memory; and the final stage, in which the patient is
completely debilitated and there is total dependency
and inability to perform daily activities. Additionally,
no information recovery is possible due to the interfer-
ence of the disease in the limbic system. The destruc-
tion of stored memories are associated with degenera-
tion of cholinergic neurons throughout the cerebral cor-
tex. The person forgets his past, friends and family.
This phase lasts from one to three years on average and
ends with the death of the patient [77-82].
According to Petronilho, this condition is mainly as-
sociated to the reduction of acetylcholine (ACh) levels
in the synaptic process, since this neurotransmitter is
directly related to cognitive, motor and memory proc-
esses [83]. In the early stages of AD there are typical
behavioral changes such as irritability and indifference
in family affairs or entertainment [71]. Patients show
personality changes, confusion, anger, sadness, lack of
direction and difficulty in concentrating. Agitation is
associated with loss of volume in several specific areas
of the brain, including the frontal cortex, anterior cin-
gulate cortex (ACC), posterior cingulate cortex (PCC),
insula, amygdala and hippocampus. There are two dif-
ferent mechanisms that explain the agitation in AD,
one is due to emotional regulation deficits (emotional
responses) and another is due to executive function
deficits (problem solving). However, it is important to
state that their evolution may vary from patient to pa-
tient [84].
Over time, more than 90% of all patients feel
symptoms such as apathy, restlessness, anxiety, depres-
sion, hallucinations, delirium, motor activity abnormal-
ity, irritability, sleep disorders, eating disorders, eupho-
ria or disinhibition. Mood disorders affect a significant
percentage of individuals who develop AD at some
point in the evolution of dementia. Depressive symp-
toms are observed within 40-50% of patients, while
depressive disorders affect about 10- 20% of cases.
Depressive symptoms are very common in AD, major
depressive disorder has been extensively studied as a
possible neurocircuitry disorder, but there are still very
few neuroimaging data published involving depression
in AD [84-88].
AD patients develop a gradual and insidious cogni-
tive deficit that becomes disabling in advanced stages
of the disease. These devastating symptoms compro-
mise significantly the quality of life of patients, leading
to absolute dependence, hospitalization and inevitably
death [77, 89-91].
5. DIAGNOSIS
The diagnosis of AD performed in an initial stage of
the disease is essential to ensure that the patient has
good living conditions [92]. For this, the criteria of the
Diagnostic and Statistical Manual of Mental Disorders
(DSM IV) and established standards by the National
Institute of Neurological and Communicative Disorders
and Stroke (NINCDS) concomitant with Alzheimer's
Disease and Related Disorders Association (ADRDA)
are used [93]. These neuropsychological tests and psy-
chometric tests, in various fields, analyze the cognitive
functions of patients. In addition, blood tests, structural
neuroimaging, molecular and functional neuroimaging,

6 Current Medicinal Chemistry, 2017, Vol. 24, No. 00 dos Santos Picanço et al.,
cerebrospinal fluid, electroencephalogram (EEG) and
evoked potentials are performed. Genetic studies are
also important complementary tests that can integrate a
more complete diagnosis of the disease [94].
For global cognitive function, the main clinical ex-
amination established by NINCDS-ADRDA is the
Mini-Mental State Examination (MMSE). The MMSE
is one of the most used tests in the world. It was pre-
pared by Folstein et al., [94]. This test can be used
alone or coupled with other tools to assess the cogni-
tive level of the patient [95]. Nitrini and colleagues
[96] recommend the association of Information -
Memory - Concentration Test (IMC) of Blessed [97]
and The Cognitive Abilities Screening Instrument -
Shortform [98] for ratification of the reduction in
global cognitive framework.
In the memory assessment, delayed recall tests can
be used [99], the Rey Auditory Verbal Learning Test
(RAVLT) [100] or the memory logic of the Wechsler
Memory Scale (WMS) [101]. In this aspect, exams in
Brazil also use a battery of neuropsychological delayed
recall of the Consortium to Establish a Registry for
Alzheimer's Disease (CERAD) [102].
Analyzing the cognitive function of attention, the
most applied exams are random letter Test [103], Digit
Extension (direct and reverse) and the Trail Making
Test [104].
To check the cognitive framework of language the
instrument ADAS-cog is used, naming real objects
[105]; Boston Naming Test (BNT) that applies the
name of 15 figures in black and white [106] or desig-
nating eight figures in the Abbreviated Neuropsy-
chological battery test (NEUROPSI) [107].
Regarding conceptualization and abstraction, the
Cambridge Examination for Mental Disorders Similari-
ties Test of the Elderly (CAMDEX) [108] or NEU-
ROPSI [109] are tests that require the ability to relate
three pairs of nouns.
In constructive skills, the patient is examined by the
Clock Drawing Test (CDT) [110] and geometric de-
signs of CERAD [102].
However, these neuropsychological tests have be-
come deadlocked by the new proposals of clinical
manifestations, such as mild cognitive impairment
(MCI) [111]. Loss of timely memory and cognitive
changes in routine cases can be common and not nec-
essarily an early development of AD, as many activi-
ties are still preserved [111, 112]. From this context, it
is necessary that additional tests reinforce the diagnosis
of AD [113].
Laboratory blood tests for diagnosis of AD should
include the following parameters: complete blood
count, serum urea, creatinine, thyroxine (T4), thyroid
stimulating hormone (TSH), albumin, liver enzymes
(SGOT, SGPT, gamma GT), vitamin B12, calcium,
serologic tests for syphilis and in patients younger than
60 years, complete HIV serology [114].
Computed tomography (CT) and magnetic reso-
nance imaging (MRI) are important structural neuroi-
maging exams. CT reveals subdural hematomas, tu-
mors or normal pressure hydrocephalus. However, de-
pending on the clinical history of the patient, these may
be causes of reversible dementia [94]. Therefore, brain
MRI details more accurately change in areas of the
cerebral cortex and hippocampus [106].
Cerebrospinal fluid exams analyze the changes in
two biomarkers: reduced Abeta protein 1-42 (Abeta42)
which is a component of neuritic plaques and increased
levels of Tau protein (total and phosphorylated) that is
related to neuronal decay [115-117].
The positron emission tomography (PET) identifies
markers of β-amyloid plaques (pathological signature)
deposited in neuronal tissue [118]. The tomography
single photon emission computed tomography
(SPECT) is used for differential diagnosis of dementia,
including depression of the elderly and differential di-
agnosis of Alzheimer's disease and dementia through
Lewi bodies (generalized in the cortex) [119].
In addition, there are molecular diagnostics associ-
ated with magnetic resonance spectroscopy (MRS).
MicroRNAs (miRNA), small non-coding RNAs that
regulate gene expression at post-transcriptional level,
have been applied to the diagnosis of AD [120].
Changes in miRNA network caused by the disease,
contribute to deregulation of genes of the amyloi-
dogenic cascade (genes such as APP, BACE1 and
MAPT) [121].
6. PHARMACOLOGICAL TREATMENT
6.1. Acetylcholinesterase Inhibitors
To date, cholinesterase inhibitors (Table 1) are the
only drugs that have shown significant improvements
in the cognitive process of patients with AD, to reduce
their symptoms by improving the cholinergic function
in neuronal synapses [122,123]. These drugs act as in-
hibitors of cholinesterase (Acetylcholinesterase -
AChE, and butyrylcholinesterase - BChE), which are
enzymes responsible for degradation of the neuro-
transmitter acetylcholine (ACh) in the synapses, after
transmission of the nervous impulse. Thus, to inhibit

Alzheimer's Disease: A Review from the Pathophysiology to Diagnosis Current Medicinal Chemistry, 2017, Vol. 24, No. 00 7
them, cholinesterase inhibitors increase the availability
of these neurotransmitters in the synaptic cleft, reduc-
ing the symptoms of AD [123].
In this context, many studies have been conducted
in order to discover new drugs that act in this patho-
genic pathway. However, to date, only 4 drugs were
actually approved by regulatory agencies for the treat-
ment of AD, which are: Tacrine (Fig. 3a), Galantamine
(Fig. 3b), Rivastigmine (Fig. 3c) and Donepezil (Fig.
3d) [122].
N
NH2
O
O
O
N
O
O
N
HO
N
O
O
N
(a) (b)
(c) (d)
(e)
H2N
Fig. (3). FDA-approved drugs for the treatment of (a) tacrine, (b)
galantamine, (c) rivastigmine, (d) donepezil, (e) memantine [133,
134].
Tacrine was the first drug approved for the treat-
ment of AD. It is considered a non-competitive and
non-selective reversible inhibitor to acetylcho-
linesterase (AChE), which has a dose-dependent effi-
cacy, short half-life and high incidence of adverse ef-
fects and hepatotoxicity [124, 125].
Donepezil is a drug from the family of N-
benzylpiperidine; it was developed, synthesized and
evaluated by a Japanese pharmaceutical industry, and
was approved in 1996 for its use in the treatment
against AD. It is a highly selective reversible noncom-
petitive inhibitor of AChE, does not present serious
adverse effects and significantly improves the symp-
toms of AD [126, 128]. However, by using the cyto-
chrome P450 system in its metabolism, emerges the
development of drug interactions with other drugs, so
that their combination should be cautious [124].
Rivastigmine, a physostigmine derived-drug, is a
pseudo-selective irreversible inhibitor of AChE and
BChE. This drug shows good activity and tolerance in
patients with AD and does not involve the cytochrome
P450 system in its metabolism, reducing the possibility
of occurrence of drug-drug interactions, improving
cognition and generating neuroprotective effects [124,
129, 130].
Galantamine is a tertiary alkaloid extracted from
various species of Amaryllidaceae, accidentally dis-
covered in 1950. It is a selective, competitive and re-
versible inhibitor of AChE and contains a modulating
action on nicotinic receptors and low hepatotoxicity.
However, its association with other drugs requires cau-
tion since its metabolism uses the cytochrome P450
system. This drug was only approved in 2001 for the
treatment of AD, but it was used over the years for
various neurological disorders [124, 125, 131].
6.2. NMDA Antagonists
Memantine (l-amino-3,5-dimethyl adamantane)
(Fig. 3e) (Table 1) was approved in May 2002 by the
European Union and, in October 2003, was licensed by
the FDA (Food and Drug Administration). This drug
decreases excitotoxicity and neurodegeneration caused
by excessive action of glutamate [134, 135].
Memantine is a noncompetitive NMDA receptor an-
tagonist used for the treatment of AD in mild to severe
stages and presents a half-life less than 60 hours. Me-
mantine reduces excessive glutamatergic neurotrans-
mission, may decrease hyperphosphorylation of Tau
protein and protects against toxicity induced the Abeta
peptide [136, 139]. The blocking property of this recep-
tor was discovered by Kornhuber et al., [140] when
used as a selective inhibitor of the NMDA receptor, the
MK-801 compound.
In the 90s, the blocking action of memantine was
elucidated by Parsons et al., [141]. Memantine in vivo,
inhibits mitochondrial function, reduces both the cere-
bral blood flow and the toxic effects of the neuro-
inflammation, and the formation of Abeta peptide
[142]. Meta-analysis studies corroborate that the drug
reduces the neuropsychiatric symptoms of AD when
compared with a placebo [143]. However, Fox et al.,
[138] proved that the use of memantine does not sig-
nificantly improve the symptoms of agitation in people
with moderate to severe AD.
Hu et al., [144] found that in primary cultures of
granular neurons in the rat cerebellum, a derivative of
tacrine, such as bis(propyl)cognitin (B3C) (IC50 = 0.45
mM) proved to be 10 times more potent than mem-
antine (IC50 = 4.58 uM) to decrease the glutamate-
induced excitotoxicity. The B3C is a noncompetitive

8 Current Medicinal Chemistry, 2017, Vol. 24, No. 00 dos Santos Picanço et al.,
Table 1. Anti-Alzheimer agents and mechanism of action.
Agents
Mechanism
References
1
Tacrine
Non-competitive and non-selective reversible inhibitor
to acetylcholinesterase
[125, 126]
2
Donepezil
Highly selective reversible noncompetitive inhibitor of
AChE
[127-129]
3
Rivastigmine
Pseudo-selective irreversible inhibitor of AChE and
BChE
[125, 130, 131]
4
Galantamine
Selective, competitive and reversible inhibitor of
AChE
[125, 126, 132]
5
Memantine
[137-140]
6
Bis(propyl)cognitin (B3C)
Non-competitive NMDA receptor antagonist
[146]
7
LY2811376
Block the enzymes that cleave the amyloid precursor
protein (APP)
Non-peptide BACE1 inhibitor
8
2,2',4'-trihydroxichalcone (TDC)
9
Ginsenoside Rg1
BACE1 inhibitor
[156]
10
OM99-2
Potent peptide inhibitor of leucine and alanine
(BACE1 inhibitor)
[157]
11
hydroxyethylamine isosteres (HEA)
12
Isophthalamide
[158]
13
des(dimethylamino)
BACE1 inhibitor
[159]
14
LY45013A
γ-secretase inhibitor
[153]
15
Thiazolidinones (TZD)
ATP-non-competitive inhibito r
16
Bis-indole
[171]
17
Aniline
[173]
18
Maleimides, Kenpaullone
[174]
19
Indirubin
[175]
20
Hymenialdisin
GSK-3β inhibitor
[176]
21
SB216763 (3-[2,4-dichlorophenyl]-4-
[1-methyl-1H-indol-3-yl] -1H-pyrrole-
2,5-dione)
Highly selective inhibitor that possesses cell perme-
ability and acts by competing with ATP binding site
[162, 168]
22
SB415286
Blocks the glutamate induced apoptosis
[145]
23
Lithium
Deprive potassium or inhibits the enzyme competing
with magnesium ions (Mg2+)
[179-181]
24
Valproate sodium
Reduced the phosphorylation of the Tau protein
[184]
25
Mts-L803
Inhibits Abeta peptide accumulation and improve the
cognitive function
[185]
26
Piperazinyl sulfonamide analogs
GSK-3β inhibitor
[186]
27
derivatives of 6-amino-4-(pyrimidin-
4-yl)pyridone
[187]
28
2-(2-phenylmorpholin-4-yl)pyrimidin-
4(3H)-ones
Decreased phosphorylation of the Tau protein
[170]
29
1,3,4-oxadiazole derivatives
Highly selective inhibitors of GSK-3β
[188-191]

Alzheimer's Disease: A Review from the Pathophysiology to Diagnosis Current Medicinal Chemistry, 2017, Vol. 24, No. 00 9
(Table 1) contd….
Agents
Mechanism
References
30
Quinolone derivatives
Inhibitory activity against GSK-3β and neuroprotec-
tive action against the injury caused by the production
of Abeta peptide
[192]
31
Compounds C-7a and C-7b
Interfere with the neuronal death-induced accumula-
tion of Ab eta peptides and inhibits the phosphorylation
of the Tau protein
[194]
32
Pyrimidones
[195]
33
Np-1003
34
Methylthioninium chloride (TRx0237)
GSK-3β inhibitor
[196]
35
Indomethacin
36
Ibuprofen
Reduces formation of Abeta
[200]
37
Curcumine
Modulate eicosanoid biosynthesis and inhibits COX-1,
COX-2 and LOX
38
Magnolol
39
α-pinene
40
β-pinene
41
Carvacrol
42
Luteolin
43
Rosmarinic acid
44
Resveratrol
45
Apocynin
Inhibits COX
46
4’-O-metylhonokiol (MH)
Inhibits the induction of amyloidogenic
Inhibits the activation of astrocytes
[134, 197, 201, 202]
47
Quercetin
48
Myricetin
Antioxidant
[75]
49
AT-1792
Act on amyloid plaques
[198]
NMDA receptor antagonist that interacts only in patho-
logical situations as well as an AChE inhibitor and an-
tagonist of the γ-aminobutyric acid receptor subtype A
[145].
A rat model had their learning and memory func-
tions impaired by the okadaic acid, in this model the
impairment was reduced followed the administration of
memantine (10 mg/kg). It was assessed by the elapsed
time for the animal to find a submerged platform in the
Morris water maze (latency); it was significantly de-
creased after first session [146].
According Winblad et al., [147], memantine sho-
wed benefits for daily activities of patients with moder-
ate to severe DA when compared to a placebo, and thus
lead them to a dignified life. Patient groups (already
treated with acetylcholinesterase inhibitors) that re-
ceived only memantine or associated with tocopherol
showed no improvement in mild to moderate AD ac-
cording to Dysken et al., [148].
After 2 hours of memantine administration (50
mg/kg), there was increased phosphorylation at Ser9
residue from glycogen synthase kinase-3β (GSK-3β) in
the cerebral cortex of mice, thus inhibiting the enzyme
activity [137, 149]. In a study by Hellweg et al., [150]
in 2,506 patients with moderate to severe AD, indi-
viduals treated with memantine showed a significant
delay in worsening of clinical condition compared with
those who received placebo.
In the latency of the two-way avoidance response,
the mice treated with the drug memantine and the com-

10 Current Medicinal Chemistry, 2017, Vol. 24, No. 00 dos Santos Picanço et al.,
pound FTY720 had a longer latency to enter the dark
compartment and showed less time spent inside the
compartment that the untreated animals. Histological
analysis of hippocampal neurons, showed that the ani-
mals that received FTY720 and memantine had a sig-
nificant reduction in neuronal loss induced by Abeta
peptide [151].
In the study of 882 patients, who received a placebo
and 868 patients were treated with memantine an im-
provement of 1.99 in the Neuropsychiatric Inventory
scale was observed when compared with the placebo
group [143].
6.3. Secretases Inhibitors
The secretase inhibitors (Table 1) block the en-
zymes that cleave the amyloid precursor protein (APP),
thereby preventing the formation of insoluble Abeta
peptides that are responsible for the formation of senile
plaques. The main enzymes participating in this patho-
genic mechanism are the β-secretase (BACE1) and γ-
secretase [152].
According to Sinha and Liebenburg [153], the β-
secretase is an interesting therapeutic target for AD,
presenting an essential role in the production of Abeta.
Thus, Zhu et al., [154] report that subsequent to the
BACE1 identification, several researchers have sought
synthesizing and testing numerous inhibitors of this
enzyme with regard to their Abeta reduction properties,
in an attempt to retard the progression of AD in the
long term.
Zhang [155] reported the LY2811376 as the first
non-peptide BACE1 inhibitor drug available for oral
administration in clinical trials. However, the studies
had to cease when a significant increase in toxicity of
the retinal epithelial cells of the animals studied was
detected, thus suggesting the need for greater care dur-
ing the planning, use and safety assessment of this type
of drugs.
Among the compounds used for inhibition of
BACE1, there are some naturally occurring compounds
used in traditional Chinese medicine, such as 2,2',4'-
trihydroxichalcone (TDC) and ginsenoside Rg1 [155],
and other synthetic compounds such as OM99-2 [156],
hydroxyethylamine isosteres (HEA), the isophthala-
mide [157] and a des(dimethylamino) compound [158].
Regarding the natural origin BACE1 inhibitors, the
Rg1 ginsenoside is obtained from Panax notoinseng. It
has been used extensively over the years in traditional
medicine for improving the memory function and pre-
sented about 80% inhibitory activity against BACE1,
revealing its potential protection against the degenera-
tive effects of Abeta. Since the DCT is a family of fla-
vonoid chalcones extracted from the Glycyrrhiza
glabra, widely used as an emollient in stomach disor-
ders and respiratory problems. It presents anti-
inflammatory, antioxidant and anti-tumor activities;
while more recently it has been evaluated as a potential
candidate for the treatment of AD due to a surprising
inhibitory activity against BACE1, suppressing the
cleavage of the amyloid precursor protein and thereby
reducing the levels of toxic Abeta peptide in brain tis-
sue [155].
The OM99-2, a hydroxyethylene-containing potent
peptide inhibitor of leucine and alanine, was the first
compound to act effectively on the BACE1 [156, 159],
while other studies of Gosh et al., [157] found that in
terms of structure-activity relationship (SAR), the sizes
of structures and the choice of substituents in the hy-
droxyethylamine moiety was crucial for the inhibitory
potency of the drug against BACE1, just as some bioi-
sosteres of isophthalamide had better inhibitory poten-
tial, with good cell inhibitory activity and considerable
reduction in the production of toxic Abeta peptides,
such as the GRL-7234 and GRL-8234.
In 2009, Steele et al., [158] have identified the
aminopyrimidine-containing molecule (HTS) as a weak
inhibitor of BACE1 (IC50 = 317 µM), and only after
several optimization experiments, by molecular and
rational design modeling, the HTS originated the
des(dimethylamino) chemical structure, which in terms
of SAR showed an enzymatic activity superior to HTS.
In addition to the drugs mentioned above, Simers
and colleagues [160] obtained good results in clinical
trials of LY45013A, an inhibitor of γ-secretase, which
during the phase I studies showed a dose-dependent
reduction in plasma levels of Abeta without important
adverse effects [152].
6.4. Glycogen Synthase Kinase Inhibitors:
The Glycogen Synthase Kinase-3 is a ser-
ine/threonine kinase protein responsible for the phos-
phorylation and thus inactivation of glycogen synthase,
the control of glycogen metabolism, regulation of cell
proliferation and cell cycle. There are two isoforms of
GSK-3, GSK-3α and GSK-3β. The first presents the α-
aminoacid glycine in its N-terminal end, whereas the
second consists of two splice variants, in which the
shorter form (GSK-3β 1) is in several organs and the
longer form (GSK-3β2) is present in the central nerv-
ous system [161-164].

Alzheimer's Disease: A Review from the Pathophysiology to Diagnosis Current Medicinal Chemistry, 2017, Vol. 24, No. 00 11
GKS-3β activity is negatively regulated by phos-
phorylation of serine 9 (Ser9) and positively by phos-
phorylation of tyrosine 216 (Tyr216), i.e., the phos-
phorylation of Ser9 residue reduces the activity of this
enzyme, whereas the phosphorylation of Tyr216 resi-
due promotes activation [165-167].
The activation of GSK-3β causes the hyperphos-
phorylation of Tau protein which induces depolymeri-
zation of microtubules, leading to the formation of neu-
rofibrillary tangles and destabilization of the neuronal
processes. Microtubules are cytoskeletal components
that are involved in the maintenance of neuronal mor-
phology and axon and dendrite formation processes
[168, 169].
Thiazolidinones (TZD) were the first ATP-non-
competitive inhibitors (Table 1) with a potential to
originate drugs for the treatment of AD [170]. How-
ever, other compounds such as bis-indole [171], aniline
[172], maleimides, kenpaullone [173] indirubin [174]
and hymenialdisin [175] have been described as inhibi-
tors of GSK-3β.
The study by Hu et al., [161] corroborated the hy-
pothesis that hyperphosphorylation of the GKS-3 is
involved in the neurodegeneration-induced Abeta pep-
tide. In this study, SB216763 (3-[2,4-dichlorophenyl]-
4-[1-methyl-1H-indol-3-yl] -1H-pyrrole-2,5-dione)
inhibits the GSK-3 enzyme. The SB216763 is a highly
selective inhibitor that possesses cell permeability and
acts by competing with ATP binding site. The destabi-
lization of microtubules induced by rotenone, a toxin
that inhibits the mitochondrial complex I, was attenu-
ated by using the GSK-3β inhibitor SB216763 in hu-
man neuroblastoma cells SH-SY5Y [167]. According
to Wang et al., [176], the SB216763 is a potent imag-
ing agent that can be used in positron emission tomo-
graphy (PET) of GSK-3.
To determine the relationship via PI3-K/Akt/GSK-
3β with the NMDA receptor signaling pathway in glu-
tamate-induced excitotoxicity, the SB415286 inhibitor
was used (pre-treatment) in primary cultures of cere-
bellar granular neurons in rats and it was observed that
this compound blocks the glutamate induced apoptosis
[144]. Moreover, mice pretreated with inhibitors
SB216763 (0.6 mg/kg) and SB415286 (1 mg/kg) for 3
days before intracranial radiation of a single dose of 7
grays (Gy), improved their performance in the Morris
water maze platform [177].
Lithium was the first inhibitor of GSK-3 discovered
and presents two possible mechanisms of action: it may
cause deprivation of potassium or inhibit the enzyme
competing with magnesium ions (Mg2+). Lithium, be-
sides reducing hyperphosphorylation of the Tau pro-
tein, is capable of reducing the production of Abeta
peptide [178-180]. Noble et al., [181] observed a sig-
nificant reduction in GSK-3 activity and Tau protein
phosphorylation after administering intraperitoneally
lithium for 30 days in transgenic mice that overexpress
the Tau human protein.
Lithium and valproate are inhibitors of the enzyme
GSK-3β, and reduced the phosphorylation of the Tau
protein in animal models, according to Tariot and
Aisen [182]. However, divalproex sodium has acceler-
ated the loss of brain volume after one year of treat-
ment, in addition to a greater cognitive impairment ac-
cording to Fleisher et al., [183].
In transgenic mice treated with a peptide inhibitor of
GSK-3, the mts-L803, it was observed the inhibition of
Abeta peptide accumulation and improvement in cogni-
tive function [184]. According to Berg et al., [185],
piperazinyl sulfonamide analogs inhibit GSK-3β, be-
sides having good solubility and permeability through
the blood brain barrier and Caco-2 assays.
In a study by Coffman et al., [186], derivatives of 6-
amino-4-(pyrimidin-4-yl)pyridone showed inhibitory
activity against the GSK-3β enzyme in a cellular en-
zyme inhibition assay. Also, the 2-(2-phenylmorpholin-
4-yl)pyrimidin-4(3H)-ones decreased phosphorylation
of the Tau protein in mice when administered orally, by
inhibiting GSK-3β [169].
The 1,3,4-oxadiazole derivatives are potent and
highly selective inhibitors of GSK-3β, three of these
compounds (2-methyl-5-{3-[4-(methylsulfonyl)-, 2-
methyl-5-{3-[4-(methylsulfinyl)-, and 2-methyl-5-{3-
[4-(methylsulfonyl)-(3)-phenyl]-1-benzofuran-5-yl}-
1,3,4-oxadiazoles (MMBO), IC50 = 66, 35 and 42 nM,
respectively) showed good pharmacokinetic profiles
and high absorptions by the blood brain barrier. The
MMBO showed high selectivity for GSK-3 in inhibit-
ing the phosphorylation of the Tau protein in cultured
primary neural cells and normal rat brain, showing to
be a good drug candidate for the treatment of AD [187-
190].
Two quinolone derivatives (IC50 = 35 and 158 nM)
had inhibitory activity against GSK-3β and neuropro-
tective action against the injury caused by the produc-
tion of Abeta peptide in MC65 cells [191]. The prolyl
isomerase Pin1, an enzyme that controls the phos-
phorylation of proteins, inhibits GSK-3β activity and
decreased the PPA levels, which demonstrates a new
protection mechanism against AD [192].

12 Current Medicinal Chemistry, 2017, Vol. 24, No. 00 dos Santos Picanço et al.,
Compounds C-7a and C-7b (120-130 nM) were able
to interfere with the neuronal death-induced accumula-
tion of Abeta peptides and to inhibit the phosphoryla-
tion of the Tau protein (pThr231, pSer396, pThr181
and pSer202) in vitro. Furthermore, in vivo, 50 mg/kg
of C-7a decreased the phosphorylation of the Tau pro-
tein (Ser202) in the hippocampus of the brains of mice.
The C-7a may be considered a disease-modifying agent
and a potent candidate for the treatment of AD [193].
According Uehara et al., [194] pyrimidones showed
inhibitory activity against GSK-3β and good perme-
ability in mouse brains and reduction of the phosphory-
lation of the Tau protein. According Giacobini and
Gold [195] some GSK-3β inhibitors are in clinical
phase trials, such as Np-1003, developed by the
Noscira S.A., SAN-161 (Sanoimmune) and an inhibitor
of the aggregation of the Tau protein, methylthion-
inium chloride (TRx0237) studied at the University of
Aberdeen and TauRx Therapeutics.
6.5. Complementary Treatments Applied to AD
Regarding the pharmacological treatment of AD,
several authors state that, in addition to therapies al-
ready described in this article, there are other ap-
proaches that can collaborate in the process of stabili-
zation of the disease, such as the use of anti-
inflammatory, antioxidant, estrogenic replacement and
vaccine, among others [196-198].
The anti-inflammatory drugs (Table 1) act by reduc-
ing the inflammatory response in the brain tissue, as in
the studies conducted by Lim et al., (2001) [199],
which suggested that indomethacin and ibuprofen
would be able to reduce Abeta formation. However,
prolonged use can cause many unwanted side effects
such as kidney and stomach problems [200]. Other ex-
amples of anti-inflammatory drugs are: curcumin, ca-
pable of modulating eicosanoid biosynthesis and inhib-
iting COX-1, COX-2 and LOX; Ginkgolide B, which is
an antagonist of platelet activating factor; magnolol; Α-
pinene; Beta-pinene; carvacrol; luteolin; Rosmarinic
acid; resveratrol; and apocynin, which also act as in-
hibitors of COX. Furthermore, the compound 4'-O-
methylhonokiol (MH) has demonstrated an important
inhibitory capacity on the induction of amyloidogenesis
through anti-inflammatory mechanisms. It inhibits the
activation of astrocytes in brain tissue and several other
signaling cascades related to inflammation and oxida-
tive stress. Thus, all these activities favor the inhibition
of the inflammatory processes associated with the
physiology of AD and reduce the deleterious conse-
quences of this disease [133, 196, 200, 201].
Antioxidants prevent free radical formation, reduc-
ing oxidative stress on the cells and thus assisting in the
treatment of AD, exerting a probable neuroprotective
effect. The vitamin E demonstrated benefits on AD,
slowing the natural course of the disease [133]. Other
examples of antioxidants are resveratrol, apocynin
[196], and some flavonoids such as quercetin and
myricetin, which through their known antioxidant ac-
tivity prevent the inactivation of acetylcholine recep-
tors [74]. Similarly, the estrogen-replacement therapy
also acts through neuroprotective mechanisms in the
prevention of AD. Estrogens exert effects on various
receptors of the neuronal surface, promoting the release
of neurotransmitters and increasing the cerebral blood
flow. In addition, there are cases of estrogen reducing
the neurotoxicity promoted by Abeta [165]. Regarding
the anti-Alzheimer vaccine AT-1792, it was developed
to act on amyloid plaques but showed significant ad-
verse effects leading to a discontinuation of its use
[176].
CONCLUSION
The multifactorial character of AD's pathogenic
mechanism hinders the development of fully effective
drugs for its therapy. Thus, several researchers con-
tinue in the search for new drug candidates for the
treatment of AD. Nevertheless, all the drugs available
so far act only on the symptoms, which mean that these
treatments are often found to be unsatisfactory in view
of a permanent stabilization of the disease after the di-
agnosis. In addition, maintenance of the treatment from
the patient himself or caregiver is often difficult, since
this type of disease often requires drug combinations to
achieve better clinical outcomes. It is in this aspect that
the early diagnosis facilitates the maintenance of the
memory and cognitive functions of these patients. The
use of various drugs and drug candidates discussed in
this article may help to improve the prospects of the
anti-Alzheimer's therapy.
CONFLICT OF INTEREST
The authors confirm that this article content has no
conflict of interest.
ACKNOWLEDGEMENTS
We gratefully acknowledge the support provided by
the Postgraduate Program in Pharmaceutical Sciences
(UNIFAP), Laboratory of Modeling and Computational
Chemistry of Federal University of Amapá (UNIFAP)
and Computational Laboratory of Pharmaceutical
Chemistry of Faculty of Pharmaceutical Sciences of
Ribeirão Preto in University of São Paulo.

Alzheimer's Disease: A Review from the Pathophysiology to Diagnosis Current Medicinal Chemistry, 2017, Vol. 24, No. 00 13
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