ABSTRACT
Dementia is an umbrella term for a broad group of age-associated
neurodegenerative diseases. It is estimated that dementia affects 50
million people worldwide and that Alzheimer’s disease (AD) is
responsible for up to 75% of cases. Small extracellular senile plaques
composed of filamentous aggregates of amyloid β (Aβ) protein tend to
bind to neuronal receptors, affecting cholinergic, serotonergic,
dopaminergic, and noradrenergic neurotransmission, leading to
neuroinflammation, among other pathophysiologic processes, and
subsequent neuronal death, followed by dementia. The amyloid cascade
hypothesis points to a pathological process in the cleavage of the
amyloid precursor protein (APP), resulting in pathological Aβ. There is
a close relationship between the pathologies that lead to dementia and
depression. It is estimated that depression is prevalent in up to 90%
of individuals diagnosed with Parkinson’s disease, with varying
severity, and in 20 to 30% of cases of Alzheimer’s disease. The
hypothalamic pituitary adrenal (HPA) axis is the great intermediary
between the pathophysiological mechanisms in neurodegenerative diseases
and depression. This review discusses the role of Aβ protein in the
pathophysiological mechanisms of dementia and depression, considering
the HPA axis, neuroinflammation, oxidative stress, signaling pathways,
and neurotransmission.
Keywords: Dementia, Depression, Amyloid β protein, Hypothalamic
pituitary adrenal axis, Neurodegeneration.
Introduction
Dementia encompasses a wide range of neurodegenerative diseases linked
to aging. It is a medical condition in which there is a deterioration in
a person’s cognitive abilities compared to a previous period over
several months or years. It mainly affects memory but can also impair
other functions such as language, attention, orientation, judgment, and
planning. Age is directly related to the risk of developing dementia,
with a rate of 5 to 10 cases per 1,000 person-years between the ages of
64 and 69. It can increase significantly to 40 to 60 cases per 1,000
person-years in the 80 to 84 age
group.1
On a global scale, around 50 million people face the challenge of
dementia today. Alzheimer’s disease (AD) accounts for up to 75% of
dementia
cases2and is predicted to grow to 152 million by 2050. This increase will be
particularly pronounced in countries with low- and middle-income
families, home to approximately two-thirds of the population affected by
dementia. Dementia affects the individuals directly involved, their
families, and the global economy, generating costs estimated at around 1
trillion dollars
annually.3
The relationship between depression and dementia is complex and not yet
fully understood. There are divergent hypotheses about how these
conditions are related and the neurobiological mechanisms involved.
However, there is compelling evidence that depression early in life can
increase the risk of dementia later in life and that late-life
depression can be a precursor to dementia. Furthermore, both conditions
present similarities in terms of neurobiological changes. It is
suggested that white matter impairments may involve shared risk factors
or typical patterns of neuronal damage between depression and
dementia.4
Both depression and dementia, although considered distinct clinical
entities, have some common characteristics. Among these similarities are
attention and working memory impairments, sleep pattern disturbances,
and social and occupational function impairments. Furthermore, there are
potential changes in biological mechanisms that link depression to
dementia. Among the biological changes are vascular diseases,
dysfunctions in the hypothalamic-pituitary-adrenal (HPA) axis,
dysregulating glucocorticoid hormones, hippocampal atrophy, accumulation
of β-amyloid plaques, inflammatory changes and deficiencies in neural
growth
factors.5These connections may help clarify the complex relationship between
these two clinical conditions.
Hippocampal atrophy and the presence of β-amyloid plaques in the central
nervous system (CNS) are considered diagnostic indicators of AD. This
condition is characterized by the accumulation of β-amyloid and
tubulin-associated unit (TAU) proteins, constituting the main components
of neuritic plaques and neurofibrillary tangles (NFTs) in AD
pathology.6Studies have shown that both β-amyloid protein plaques and TAU protein
tangles accumulate in more significant quantities in the hippocampus of
AD patients who also suffer from depression compared to those AD
patients who have no history of
depression.7Furthermore, β-amyloid appears to be considered the leading triggering
agent of the sequence of events that culminates in the death of neurons
and the development of AD. Therefore, a plausible mechanism connecting
depression to AD involves the formation of β-amyloid
plaques.8
Amyloid and TAU Proteins
The scientific literature identifies the amyloid protein as a biomarker
for staging AD severity and helps investigate clinical prognosis. Other
neurodegenerative pathologies also have amyloid protein as a causal
background. Neurodegeneration after ischemic stroke has similarities
with neurodegeneration in AD, as both pathologies have risk factors in
common, such as age, hyperlipidemia, hypertension and diabetes, the
presence of neuroinflammation, and the presence of amyloid
protein.9
Amyloid protein is described as the main protein found in diseases
related to aging, such as AD and Parkinson’s disease (PD), dementia with
Lewy bodies (DLB), Huntington’s disease (HD), vascular dementia (VaD)
and frontotemporal dementia ( FTD). The ”Amyloid Cascade Hypothesis”
(figure 1) predicts the formation of extracellular senile plaques with
NFTs, composed of filamentous aggregates of amyloid-β protein (Aβ) as a
possible initial pathological event of dementia and consistent treatment
route for the
disease.2These small plaques tend to bind to neuronal receptors affecting
cholinergic, serotonergic, dopaminergic, and noradrenergic
neurotransmission, leading to neuroinflammation and subsequent neuronal
death, followed by
dementia.10
Aβ, composed of 39-42 amino acids, is expressed physiologically in the
body and results from the digestion of amyloid precursor protein (APP),
which performs physiological functions in neuroplasticity. The amyloid
cascade hypothesis points to a pathological process in the cleavage of
APP that results in pathological Aβ. APP is cleaved near the cell
membrane by a protease called α-secretase . This action releases a
soluble extracellular fragment, sAPPα. Crossing the membrane, a second
cut is made by a protein complex called γ-secretase , releasing a
second intracellular peptide known as amyloid intracellular domain
(AICD), a residual fragment between α-secretase and γ-secretase.11
The cutting carried out by α-secretase is physiological. Still, in
pathological situations, APP cleavage occurs further away from the cell
membrane by the β-secretase enzyme, followed byγ-secretase cleavage. The Aβ fragment can have 40 or 42 residues,
Aβ1-40 and Aβ1-42. The amino acid that lies between β (pathological) and
γ (physiological) cleavage is in the constitution of β-amyloidpeptides (Aβ), which aggregate to form oligomers (oAβ), distinct
misfolded proteins that mediate synaptic dysregulation, hyperactivity of
microglia and astrocyte
reactivity.11
The gradual accumulation and aggregation of Aβ peptides will initiate a
cascade that will lead to synaptic changes in microglial and astrocytic
activation, culminating in the release of cytokines and, consequently,
an inflammatory response, TAU modification and progressive neuronal
losses associated with neurotransmitter deficiencies and cognitive
impairments.12The cytoskeleton structurally organizes neurons, a component partially
formed by microtubules. The TAU protein is present on the microtubules’
surface and helps stabilize them. Composed of 3 or 4 semi-homologous
repeats of 31 or 32 amino acids, TAU undergoes a hyperphosphorylation
process and receives a phosphate group, leaving the microtubule and
becoming insoluble. Phosphorylated TAU units form small polymers called
helical filaments, resulting in NFTs in more significant quantities.
Without the TAU protein to stabilize microtubules, their breakdown and
subsequent cell death or apoptosis
occur.13
Hypothalamus Pituitary Adrenal (HPA) Axis and Amyloid Protein
The activity of the HPA axis occurs primarily in response to stress
through the secretion of corticotropin-releasing hormone (CRH) by
neurons in the paraventricular nucleus in the hypothalamus, which
stimulates the anterior pituitary gland to produce adrenocorticotropic
hormone (ACTH). ACTH activates receptors in the adrenal gland,
stimulating the release of glucocorticoids (GC) into the
circulation.14
GCs can cross the blood-brain barrier and bind to their respective
receptors in the CNS, which are predominant in the prefrontal cortex
(PFC), hippocampus, and amygdala and, through mechanisms that still
require further elucidation, induce amyloid protein accumulation and
cognitive
impairment.14Cortisol has even been shown to have a significant relationship as a
risk predictor for AD development, showing an average increase three
years before the clinical manifestations of the
disease.15
The greater availability of soluble Aβ proteins results in a stressful
state, a more excellent production of CRH, and increased GC levels in
response, positively feedbacking the HPA axis. It has been shown that
the HPA axis is the great intermediary between pathological mechanisms
of depression and neurodegenerative diseases, mainly due to the
distribution and activation of low-affinity glucocorticoid (GR) and
mineralocorticoid (MR) receptors, whose action and greater prevalence it
is strongly associated with both cognitive and memory processes and
psychiatric disorders such as depression, including in individuals who
have suicidal
ideation.16
A preclinical trial in rats used a selective GR blocker and found a
reduction in neurotoxic effects in several molecular mechanisms inherent
to the central regulation of the HPA axis, correlating with improved
emotional and cognitive behaviors in AD. The authors suggest the
presence of a vicious cycle based on the persistent activation of GR,
deregulating the negative feedback pathways of the HPA axis, as well as
culminating in structural changes in the PFC and hypothalamus, which are
important regions for the accessory control of CRH
production.14
A study showed that Aβ1-42 oligomers can impair learning and memory
capacity in mice, associated with elevated levels of CRH,
corticosterone, and greater expression of GR in the PFC and hippocampus.
Due to this induced hyperactivity of the HPA axis, there is a negative
regulation in the levels of cyclic adenosine monophosphate (cAMP),
causing a lower phosphorylation of neuroprotective factors such as cAMP
response element-binding protein (pCREB) and brain-derived neurotrophic
factor (BDNF), which reinforces the cognitive impairment of
AD.17
Another analysis carried out with cerebroventricular injection of
Aβ25-35 oligomers observed an increase in depressive and anxiety
symptoms in rats, as well as being associated with an increase in
corticosterone induced by stress and hyperactivity of the HPA axis
through GR in the hippocampal
region.18Furthermore, a prospective cohort study showed that individuals with Aβ
aggregates in imaging tests and high plasma cortisol levels have more
pronounced and accelerated effects on scores of cognitive decline,
episodic memory, and executive
function.19
Neuroinflammation and Amyloid Protein
Neuroinflammation is inherent to the pathophysiology of depression and
dementia. The literature has indicated that the inflammatory process in
nervous tissue is mediated mainly by the gradual increase in β-amyloid
load and the deregulated activity of microglia. The primary function of
microglia is to promote neuroprotection, primarily through the
phagocytosis of oAβ and, therefore, the loss of this capacity can
accentuate the formation of amyloid aggregates which, when recognized by
Toll-like receptors (TLR), induce inflammation, guided by the formation
of NLR family pyrin domain containing 3 (NLRP3) inflammasomes, with loss
of synaptic communication and diffuse neuronal
damage.20
The presence of NLRP3 inflammasome was associated with prolonged
exposure to corticosterone and consequent greater activation of the HPA
axis in mice with depressive
behaviors.21Specific inhibition of NLRP3 reduced local neuronal injury and exerted
control over Aβ accumulation and TAU protein hyperphosphorylation,
alleviating depressive behavior and cognitive decline in
rodents.22
Tumor necrosis factor alpha (TNF-α), in the context of neurodegenerative
diseases, plays a role in mediating the processes of necroptosis, a
pathway of cell death programmed by the activation of receptors
interacting serine/threonine kinase 1 and 3 (RIPK1 and RIPK3) and mixed
lineage kinase domain-like (MLKL). This process is responsible for the
massive release of other classes of cytokines, such as C-X-C motif
chemokine ligands 8 and 1 (CXCL8 and
CXCL1).23
The pronounced presence of pro-inflammatory proteins implies toxic
effects on neural tissue, mainly due to the activation of the kynurenine
(KP) pathway in specific regions important for cognitive and emotional
control. Cytokines, especially interleukin-1 (IL-1) and interferon-gamma
(IFN-γ), in addition to the presence of Aβ, stimulate the enzyme
indoleamine-2,3-dioxygenase (IDO). The enzyme tryptophan-2,3-dioxygenase
(TDO) functionality is positively influenced by corticosteroids,
considering that corticosteroids such as cortisol act as signals to
increase TDO activity. When TDO is more active, more tryptophan is
converted into neurotoxic metabolites through the KP. This increase in
TDO activity contributes to the deposition of harmful metabolites
derived from tryptophan, affecting neural tissue and specific areas
necessary for cognitive and emotional
control.24
Oxidative Stress and Amyloid Protein
The etiological process of AD is associated with oxidative imbalance.
The histopathological characteristic of the disease is related to NFTs
and senile plaques composed of Aβ that have metallic aggregates such as
copper, iron, or zinc ions. When these ions are part of the redox
reaction, their aggregation into the amyloid protein can trigger the
formation of reactive oxygen species (ROS). Increased oxidative stress
and consequent changes in metabolism cause local damage through lipid
deperoxidation, mitochondrial dysfunction, and damage to protein
structure and
function.25
Imaging methods showed increased oxidative damage due to Aβ deposition
associated with lower glutathione and superoxide dismutase (SOD)
activity in mice with
AD.26Gene expression mapping in AD patients showed a profile highly
associated with oxidative stress, with genes related to immune
exhaustion, damage to transcription factors, and mutations in genes
promoting protective
responses.27
It has been reported that rats with depressive-like behaviors induced by
Aβ have decreased levels of serotonin (5-HT) and norepinephrine (NA)
and, in contrast, increased levels of tryptophan (TRP) and kynurenine
(KYN) and high concentrations of ROS in the PFC, and consequent
establishment of a neuroinflammatory state with local tissue damage
(Figure 2). Pharmacotherapy aimed at inhibiting IDO has demonstrated
efficacy in controlling depression, reversing 5-HT levels, and oxidative
stress in animal models exposed to the accumulation of β-amyloid
protein.28
Associated with the neuroinflammatory state and depressive behavior,
producing metabolites by KP such as 3-hydroxy kynurenine (3-HK) and KYN
interfere with cellular respiration, inhibiting mitochondrial complexes
and, consequently, leading to energy losses. The inhibition of glutamine
synthesis, resulting in glutamate accumulation, aggravates oxidative
stress by hyperactivating NMDA and AMPA receptors, disrupting
intracellular Ca2+ homeostasis. These glutamatergic
events destabilize the cell membrane, causing cytotoxicity and inducing
neuronal
death.29
Excessive ROS production by dysregulated mitochondrial activity is
directly associated with increased expression of AMPA and NMDA receptors
and impaired glutamatergic signaling with Ca2+overload and excitotoxicity in cell cultures with frontotemporal
dementia (FTD) induced invitro .30A test in mice demonstrated that Aβ neurotoxicity is due to the high
microglial sensitivity to the presence of this protein. Aβ1-42 oligomers
led to increased mitochondrial ROS production, high extracellular
glutamate levels, and neuronal death due to the rapid increase in
calcium.31
Amyloid β Protein, Signaling Pathways, and Neurotransmission
Aβ accumulation interferes with complex intracellular signaling
pathways, including those essential for the inflammatory response.
Increased Aβ in the CNS can trigger a chronic inflammatory response,
which is closely linked to the activation of glial cells and the
production of pro-inflammatory
cytokines.32
This disturbance in intracellular signaling pathways and interference
with calcium homeostasis in nerve cells causes adverse effects on
synaptic function. The accumulation of Aβ impairs communication between
neurons at synapses, resulting in dysfunctions in neurotransmission.
Such synaptic changes are intrinsically related to the cognitive
deficits characteristic of AD since effective communication between
neurons is fundamental for adequate cognitive
functioning.33
Aβ impairs synaptic plasticity, inhibiting long-term potentiation (LTP)
and facilitating long-term depression (LTD). These synaptic changes
caused impairments in object recognition memory. Furthermore, Aβ leads
to the loss of dopaminergic terminals, reducing cortical dopamine
levels. Administration of catecholamine reuptake blockers can reverse
Aβ-induced synaptic dysfunction, restoring the ability to induce LTP
after high-frequency stimulation (HFS) and improving
memory.34
The complex relationship between APP, GABAergic neurotransmission, and
synaptic plasticity was also investigated. The absence of APP in mouse
models results in deficiencies in synaptic plasticity, including the
formation of LTP, as well as behavioral and learning deficits. This is
related to the reduction in GABA-mediated inhibitory postsynaptic
current. APP also interacts with potassium-chloride cotransporter 2
(KCC2), affecting the levels of this protein and the intracellular
concentration of chloride ions, which influences GABA-mediated
inhibitory transmission. The absence of APP alters the
post-translational regulation of KCC2, including its tyrosine
phosphorylation and ubiquitination, resulting in changes in the
inhibitory function of
GABA.35
APP also interacts with the presynaptic GABAB receptor
(GABABR), influencing the release of excitatory
neurotransmitters and regulating synaptic plasticity. This interaction
between APP and GABABR plays an essential role in
modulating neurotransmission. It may have implications for understanding
the normal mechanisms of the nervous system and in pathological
conditions, such as AD, in which APP plays a crucial role in
beta-amyloid production. These findings highlight the complexity of
interactions between neuronal components and open promising perspectives
for developing therapeutic strategies targeting neurological disorders,
such as AD, and for interfering with GABAergic transmission and synaptic
plasticity.35
Another cellular signaling pathway that has been extensively studied as
a possible mechanism involved in neurodegenerative and psychiatric
diseases is the mammalian target of the rapamycin (mTOR) pathway. mTOR
is a serine/threonine protein kinase complex that plays a crucial role
in protein synthesis and degradation, cytoskeleton formation, and
several diseases. Although the mechanism of mTOR is not entirely
understood, there is evidence that points to the influence of subsets of
NMDA receptors on GABAergic neurons, which reverse glutamate inhibition,
stimulating mTOR and increasing synaptic signaling in several brain
areas.36
An analysis of the expression levels of mTOR and its upstream and
downstream components in hippocampal brain tissues obtained from control
subjects and AD patients at different stages revealed a significant
increase in the expression of RagC, an upstream component of mTOR, in AD
patients in the initial, moderate and severe stages. Furthermore, in the
severe stage of AD, there was a notable increase in the levels of mTORC1
and its downstream targets, S6 kinase 1, and regulatory associated
protein of mTOR
(Raptor).37These findings suggest that the impact of mTOR on the aging process may
begin with forming of free radicals during aging, resulting in the
presence of ROS that cause damage to DNA, proteins, lipids, and
mitochondrial organelles. This culminates in a reduction in adenosine
triphosphate (ATP) production, activating the ATP-sensitive
AMP-activated protein kinase (AMPK) and inhibiting the mTOR pathway.
These events culminate in the negative regulation of protein synthesis,
as synthesis consumes ATP. Thus, there is a proportional increase in
damaged proteins concerning healthy
proteins.38
Furthermore, post-mortem studies have identified deficits in mTOR
signaling in the limbic system structures of depressive
individuals.39Drugs with NMDA receptor antagonist function stimulate mTOR and increase
synapses.22A study involving liquiritigenin, a natural compound, in mice with
chronic stress-induced depression showed that both liquiritigenin and
the antidepressant fluoxetine improved depressive symptoms.
Liquiritigenin restored neurotransmitter levels and activated the
phosphatidylinositol-3-kinase (PI3K)/serine-threonine protein kinase
family (AKT)/mTOR (PI3K/AKT/mTOR) cell signaling pathway, suggesting
that liquiritigenin may have an effect antidepressant through this
route. Therefore, the study indicates that liquiritigenin may be helpful
in treating chronic depression and suggests a potential role for the
mTOR pathway in suppressing neurodegenerative
diseases.40
These mechanisms play a fundamental role in dementia and thus represent
essential components in elucidating the underlying mechanisms.
Understanding these findings brings to light the intricate neuronal
processes involved in neurodegeneration and opens promising perspectives
for designing future therapeutic strategies and interventions targeting
neurological disorders. This, in turn, instills hope in the continued
search for effective treatments for AD and other related conditions.
Dementia, Depression and Amyloid Protein
A close relationship between depression and pathologies associated with
dementia is widely documented. Depression is estimated to be prevalent
in approximately 20 to 30% of individuals diagnosed with
AD.11Depression and cognitive impairment related to dementia are common
disorders in the elderly. The literature provides evidence that
depression is a risk factor for the development of dementia and, in old
age, is related to a prodrome of
dementia.4A meta-analysis encompassing 32 studies with 62,598 participants and a
follow-up period ranging from 2 to 17 years revealed that having
experienced a depressive episode represents a significant risk factor
for developing
dementia.41
Studies focusing on late-life depression provide complementary evidence
on the development of dementia. According to Saczynska et
al.,42depression was associated with a significantly increased risk of
incident dementia and AD in older men and women. Depression nearly
doubled the risk of dementia and AD, even after controlling for factors
such as age and sex. It is estimated that between 10% and 15% of AD
cases are preceded by episodes of
depression.43
Other research suggests that depression may be a psychological response
to AD and the difficulties of coping with the diagnosis. Depression is
also described as a consequence of AD, with a higher incidence in
patients with early-onset AD than those with late-onset AD, possibly
related to lifestyle changes. In later stages, the evolution of AD is
accompanied by a reduction in depressive symptoms due to the reduction
of emotions and their expression resulting from cognitive
impairment.44
Several mechanisms have been associated with the relationship between
depression and neuronal damage, including inflammatory processes,
increased production of glucocorticoids, accumulation of β-amyloid
protein, and formation of NFTs. These mechanisms can result in damage to
brain regions such as the hippocampus. These connections between
depression and neuronal damage not only directly contribute to the
development of dementia but also decrease cognitive reserve, which can
lead to the early and frequent emergence of cognitive
impairment.7
In this context, the hypothesis that hyperperfusion and atrophy of brain
areas, such as the anterior cingulate cortex, precuneus, and parietal
lobule, as well as changes in receptors, such as N-methyl-D-aspartate
(NMDAr), may be related to depressive symptoms and the progression of
AD.44NMDAr is a receptor for the neurotransmitter glutamate that plays a
fundamental role in synaptic plasticity, memory formation, and
excitotoxicity, which has been associated with the pathophysiology of
several diseases, including
AD.45
Antidepressant medications may slow the progression of dementia in
people with mild cognitive impairment (MCI) and depression. A 2017 study
showed that long-term use of the antidepressant citalopram, a selective
serotonin reuptake inhibitor (SSRI), for more than four years was
associated with a delay of about three years in the progression of MCI
to
AD.46
Studies have found changes in glutamate levels in depression and AD,
indicating a dysfunction in the NMDA receptor signaling pathway. The
presence of Aβ in AD affects glutamatergic signaling via NMDAr,
suggesting the possibility of developing NMDAr-modulating drugs with
potential anti-dementia
effects.47
Depression is frequently diagnosed in patients with cognitive and
affective disorders, with cognitive impairments related to brain amyloid
deposits and NFTs. In research involving young (2.5 months) and old (13
months) Brattleboro rats to evaluate the transcription of specific genes
related to neurodegenerative diseases, a link between dementia and
neurodegeneration was found with the APP and the mitogen-activated
protein kinase gene (MAPK1), associated with NFTs formed by the TAU
protein, and the beta-actin gene that highlighted changes in increased
cortical activity in elderly rats, indicating that age-dependent
transcriptional changes can influence development of AD and other
neurodegenerative
disorders.48
In correlating depression as a significant risk factor for dementia,
mainly due to the accumulation of Aβ peptide in the brain, a pivotal
study involving elderly male mice carrying specific gene variants
related to AD, Aβ load, and cognitive impairment yielded crucial
insights. The study revealed a notable accumulation of Aβ in these mice,
forming aggregated amyloid plaques. This accumulation not only indicated
a direct link between depression and altered monoaminergic systems but
also served as a vital indicator of changed functionality associated
with the early stages of AD-related
diseases.49
AD transgenic mice showed depressive and anxiety-like behaviors,
parallel with increased Aβ deposition, TAU hyperphosphorylation,
oxidative damage, inflammatory cytokines increase, and microgliosis in
hippocampal and cortical tissue. A long-term exercise protocol
significantly reduced anxious and depressive-like behaviors and brain
biological
damage.50
Final Considerations and Conclusions
Dementia is a degenerative disease characterized by the accumulation of
Aβ proteins and is clinically manifested through global cognitive
decline. These aggregates mediate the pathophysiology of several
diseases where there is damage to nervous tissue through
neuroinflammation and oxidative stress processes. In this article, we
showed that Aβ accumulation causes failures in synapses and,
consequently, in the activation of microglial cells, causing an
uncoordinated inflammatory response with a large concentration of
cytokines, inflammasomes, and cell migration. Furthermore, we point to
dysfunctions of the HPA axis, in response to chronic systemic stress, as
an intermediary in the biological processes of both diseases, especially
in the neurotoxic effect induced by excess GC in essential areas of
cognitive and emotional regulation, such as the PFC and hippocampus.
Likewise, neuronal communication is impaired, emphasizing the decrease
in synaptic plasticity mediated by GABAergic signaling and the mTOR
pathway. Despite the findings described in the literature, the
association between depression and dementia requires further
elucidation, especially in aspects that delimit epigenetic regulation
and intracellular response mechanisms to chronic stress induced by Aβ
accumulation. Therefore, we suggest conducting new studies that seek to
investigate this association and produce more assertive and specific
potential therapeutic targets for these disorders.
Acknowledgements : Zuleide Maria Ignácio is supported by
research grants from the Santa Catarina State Research and Innovation
Support Foundation - FAPESC, and Federal University of Southern Frontier
- UFFS
Conflicts of interest : None