Abstract
Those who identify within the geriatrics age group is currently the largest population in
the country and is also the population with the most need for medical attention and
individualized care. They tend to experience a wide range of diseases and disorders that can
significantly impact their longevity and quality of life. The relationship between depression and
Alzheimer’s Disease (AD) is closely associated in many older individuals due to the
neurochemical connection and biological cause that each disease presents. Both have distinct
etiology but also share similarities within their pathways. Previous research indicates that there is
a casual effect in terms of depression being a co-morbidity within individuals who are diagnosed
with Alzheimer’s disease and increases the progression as a result. Recent studies have proven
that there is more than a social cause that initiates the onset of depression; researchers have
examined the various pathways and identified similarities and processes that may possibly cause
the initiation of depression. This paper serves to examine these processes in depth and bring light
to the various chemical pathways to identify and solidify possible causes. The overall findings
for the onset of depression is caused by the interplay between neurotransmitters, neurotrophic
factors and neuronal damage caused by Alzheimer’s disease. Important neurotransmitters like
serotonin (5-HT), Brain-derived neurotrophic factors (BDNF), and other chemicals involved in
the processes are found to be at altered levels, showing signs of disruption, which has been
proven to cause the onset of AD- induced depression. Understanding the influential relationship
is vital for the treatment and reduction of the prevalence within this population to ensure the best
possible care delivery.
Introduction
The complex relationship between Depression and Alzheimer’s disease, commonly
referred to as AD, remains to be a challenge that is continuously explored today as both disorders
are likely to present itself simultaneously. Depression can occur throughout the life course
categorical identifies as a mental illness, whereas Alzheimer’s disease is a neurodegenerative
disease; both different diseases with different etiology and prognosis. Although their biological
pathways have distinct differences, they also have components that have similarities or influence
one another throughout their progression. It has been proven that both disorders can reciprocate a
causal relationship as individuals with prior depression in their adolescent years can develop
Alzheimer’s in later life and in addition to this, the development of Alzheimer’s in individuals
can cause the development of depression as well.
Many studies investigate this causal relationship and have proven that past experiences of
depression and other mental health issues can increase the chances of developing Alzheimer’s in
later life due to various biochemical impacts. However, depression is often predicted in
individuals with Alzheimer’s due to the social isolation and lifestyle changes that come with the
progression of the disease. Through research, many have discovered that there is very much a
pathological and biochemical cause that leads to the development of depression after the onset of
Alzheimer’s. The etiology of both depression and AD could be different but due to various
neurotransmitters involved in both diseases such as monoamines and amines, neurotrophic
factors and neuronal damage that is associated with the progression of Alzheimer’s diseases,
these factors have been proven to impact the development of AD-induced depression among the
elder population. This further complicates the longevity and significantly reduces the quality of
life for this particular population and can have a detrimental effect.
The impact of depression
Mental health has become a great economic burden for the country of Canada due to its
consistent prevalence among the various age groups and populations. Mental illnesses is
characterized by many different biological and mood disorders, including depression, which
causes a significant burden in various ways. It is found that the cost of combatting this disorder
costs up to about $51 billion annually for Canada and this includes the various health care costs
and compensation for unemployment. Since many seniors may not be able to travel for work,
compensation is required to make up for any physical illness or comorbidities that may
accompany the mental illness. The uptake and use of healthcare resources would only increase
when an individual has various comorbidities and therefore understanding how both of these
disorders can be treated simultaneously and dealt with, can reduce this burden overall. Not only
does this issue cause an economic burden, but it also causes something called the caregiver
burden. Care giver burden is known as something that is seen when a primary care giver within a
home setting, such as a family member, is the one giving primary care to the individual. Care
giver burden is quite common in AD patient’s families as their progression of the disease
requires constant assistance and care from their family members to fulfill the most basic daily
activities. These caregivers are not typically qualified to provide care but also are not given the
appropriate education to care for Alzheimer’s patients as the disease is quite complex and unique
to each individual. It has been displayed that caregivers experience an increase in chronic
diseases and there is a significant decrease in their overall health status when they become
fulltime caregivers. Caring for individuals who not only need medical treatment for AD itself,
but also would need alternative treatments with the onset of depression can impact the
caregivers as they themselves may experience a variety of chronic and mental health disorders
after being exposed to it for a long period of time.
Depression is a widely known psychiatric mood disorder presenting itself in many
different populations and can be experienced over the entire lifespan at multiple times during an
individual’s life. The prevalence of this disorder has significantly increased in present time, as it
has become a very common disorder among all age groups. It is claimed that 1 in 5 Canadians
will experience poor mental health in their lifetime and this, as a result, can stem through as a
social burden and a health care burden. More importantly, depression can be a very difficult
disorder to treat and cope with especially for the seniors population as it is proven that geriatric
depression is more commonly associated with a higher risk for suicide and increases the chances
of mortality in late-life.
It is said that about 50% of individuals who have Alzheimer’s disease, also develop
depression. There is a pre-existing idea that depression is common in the elder population due to
factors such as social isolation, lack of relationships, sense of belonging to a community or
family members and various other societal barriers. These factors can further establish a sense of
loneliness and sadness that can complicate already existing medical conditions and the overall
well-being of an individual. As mentioned previously, it has been proven that Alzheimer’s can
biologically trigger the onset of depression due to the various pathways and structural changes
that the brain experiences with the progression of Alzheimer’s. This is important because mental
health is a very important indicator of good health status and is also known to be an important
aspect of overall health apart from physical well-being, and therefore having this information can
act as an important indicator of predicting and combatting depression consecutively with AD.
Elder people usually have many other chronic diseases that impact their physical health, which
can be overwhelming to combat on a daily basis with added neurodegeneration and depression.
This sets them further away from optimal health, reduces the quality of life, and increases the
chances of mortality within this population. The etiology and symptoms are unique to the
disorder of depression and these symptoms may be classified into three categories: emotional,
neurovegetative and cognitive symptoms. Although these symptoms can be categorized, they are
classified as these symptoms when an individual is diagnosed, primarily with clinical depression
but when depression is simultaneously prognosed with other neurodegenerative and medical
disorders, a unique set of symptoms and treatment is required as one disorder can influence the
other in various ways, impacting the treatment, When a diagnosis for depression is conducted, a
medical professional has to ensure that the individual is presenting symptoms for at least two
weeks on a daily basis. As mentioned previously, these symptoms are unique to the disorder and
these include a persistent feeling of sadness or unhappiness, decreased or increased sleep, a gain
or loss in appetite or weight, loss of energy and a feeling of worthlessness or guilt. The figure
below shows an informative way to study the various symptoms and explains the timeline to
identify any possible symptoms that lead to depression.
*Insert figure*
Characterizing Alzheimer’s disease
Alzheimer’s disease is known as a progressively degenerative disease of the human brain.
It is the most common form of dementia and continues to affect the older population worldwide.
It is estimated by the World Health Organization that 47.5. million people around the world are
diagnosed with Alzheimer’s disease and these numbers will continue to grow over the years. In
fact, by the year 2059, it is estimated that 135 million individuals will be diagnosed with
dementia, making this disease a priority for health care.
The aging population is currently the largest population in Canada, who use the most
medical resources and need the most apt health care. This requires an increased need for medical
professionals, cost effective treatments, and individualized care as each individual may have
multiple co-morbidities and diseases they may be experiencing and in need of a variety of
different treatments. Therefore understanding the needs and interaction between various comorbidities is key to better treat individuals with the most effective care to ensure that health
care resources and expenses are used efficiently and wisely. The etiology of Alzheimer’s disease
involves the damage of various regions of the brain, where the death of neurons results in a
decline in memory and cognition. This results in a decreased level of synaptic proteins and
intraneural cytoskeletal abnormalities known as neurofibrillary tangles and amyloid plaques.
These tangles and plaques are known to have several toxic effects such as synaptic dysfunction,
mitochondrial damage, microglia activation, and tau phosphorylation which all impact optimal
brain functioning. Throughout the course of the disease, more plaques and tangles are produced
and affect various areas from normally functioning. These plaques and tangles can impact
important neurotransmitter pathways that are essential to conducting daily activities, ensuring
proper health status and are crucial for survival. These can be impacted with the onset of the
disease, but also harder to maintain or treat as the disease progresses due to its characteristic as a
slow and degenerative process.
The objective of this systematic review is to explore both these neurological diseases and
bring light to the awareness and education of both disorders and to provide a better
understanding of how a psychiatric disease such as depression, can biologically trigger a
neurogenerative disease like Alzheimer’s. Although it is known that depression can occur
through the development of Alzheimer’s due to the fact that cognition can disrupt daily
functioning and cause social isolation, this paper will examine several biological mechanisms
that can trigger depression apart from isolation. This paper discusses how dealing with both can
impact one’s vitality and longevity as it worsens the health status of an individual and can further
complicate their healthcare. This is explored by a series of peer reviewed articles that support the
etiology and causal effect of Alzheimer’s disease in compilation with mental disorder of
depression.
Discussion
From epidemiological observations, it is understood that there are several risk factors for
depression in persons with Alzheimer’s. These risk factors include family history of mood
disorder in first degree relatives, past history of depression, female gender, and early onset of
AD. Apart from these risk factors, the biological pathway consists of many chemical processes
that can be disrupted or altered to induce the onset of depression. To examine the neurogenetic
links between both diseases, it is vital to understand how each disease progresses biologically.
The etiology of Alzheimer’s is different from the etiology and pathology of depression, but
certain proteins, level of transmitters, inflammatory factors, neurotrophic factors and apoptotic
markers can be identified to understand the similarities. For example, the level of BDNF
neurotropic factors are shown to be at decreased levels in the brains of individuals with
depression and AD. This results in the hippocampal morphology being altered which affects
one’s mood and memory. Neurotrophic factors are highly important and quite essential for
survival as they are important for neurogenesis and neuroplasticity. AD is characterized by the
diminishing activity of neuroplasticity, which is found when the levels of neurotrophic factors
are decreased as well. Genetic studies have revealed that genetic polymorphisms can play a role
in developing depression or AD, as individuals who are heterozygous for polymorphisms in the
particular regions of receptors to have an increased risk for developing depression.
An important neurotrophic factor that is a prominent target in the studies of both AD and
depression is BDNF as it has been proven to act as a bridge between both disorders. Brainderived neurotrophic factor, also known as BDNF, is a neurotrophic factor that is found to be
decreased in both depression and AD. BDNF binds to a receptor called TrkB, which activates
intracellular signalling that sets off a cascade of events. This activates the mitogen activated
protein kinase (MAPK) pathway which phosphorylates cAMP response element binding protein
which is called CREB. CREB is a transcription factor that is involved in controlling
neuroplasticity and when there is decreased BDNF this activity is reduced and induces the
pathogenesis of depression. Many anti-depressants use the upregulation of CREB to treat chronic
depression in various studies, where increased activity of CREB was identified to produce antidepressant effects. As mentioned previously, neurotrophic factors are vital for survival. It has
been proven to play an important role in regulating the survival, growth, and maintenance of the
life of a neuronal cell. Through numerous animal studies, BDNF has been shown to display
neuroprotective properties and reserve synaptic loss, improve cell signalling and helps to correct
any cognitive impairments. That being said, the reduction in BDNF can act as an anchor for the
loss of neurons and contribute to the damage and cell death that is characterized in AD. Many
studies have supported this as they have measured the levels of BDNF and found that they have
been significantly reduced in the hippocampus as well as the frontal and parietal cortices. An
optimal level of BDNF can prevent neuronal death that is induced by damage and also reverse
neuronal atrophy, which was also proved through a study with primates and rats. This has also
been evaluated in subjects with and without Alzheimer’s to prove if the level of BDNF
influences mood disorders and many studies have proven that a reduction can cause depressive
symptoms, while other studies that involve the treatment of antidepressants with BDNF
expression, have significantly helped reverse depressive symptoms. An animal study was
conducted to force animals with less BDNF to act in inescapable situations and complete a
forced-swim test to prove that these animals had displayed depressive symptoms. Another study
has revealed that the disruption of BDNF can promote the amyloidogenic pathway in the
hippocampal neurons and this is believed to activate apoptosis which is essentially inducing cell
death. In a human study with two hundred and sixty-four patients who were diagnosed with AD,
the presence of behavioural symptoms was measured and evaluated. The results produced a
significant difference in those with polymorphisms in the BDNF where the BDNFVal66Met
functional polymorphism was exclusively associated with the severity of depression. This BDNF
allele presented abnormal hippocampal activation and hippocampal atrophy which explains the
depressive symptoms presented. This presented evidence that the hippocampus plays a vital role
in the development of depression, in regard to cognitive function. In addition, BDNF is
important for learning and maintaining memory but with reductions in BDNF, synaptic plasticity
is compromised, and memory and learning is impaired with those who battle AD.
There are important neurotransmitters that are vital for human life and one of those
neurotransmitters are serotonin. Serotonin, also known as 5- hydroxytryptamine (5-HT) is
produced in the neurons that are located in the raphe nucleus and the axons within these neurons
innervate cortical brain regions that regulate cognition, mood and behaviour. Serotonin is
essential for maintaining neural plasticity as well as the involvement in eating, sleeping and
regulating circadian rhythms. It has become a known fact that serotonin levels are significantly
decreased as part of the aging process but apart from old age, a depletion of this monoamine is
also seen in both depression and AD. Many rodent studies have proven that serotonin is involved
in memory, learning and cognition, depending on the subtype of 5-HT. 5-HT1A affects the
learning process whereas 5-HT2A and 5-HT2c are important for the formation of memory. That
being said, 5-HT levels can be used as excellent biomarkers for AD as decreased levels of 5-HT
and increased levels of 5-HT1A are signs that signify a decline in cognitive functioning. Just as
how BDNF promotes neural plasticity, 5-HT also has an important role in activating genes that
promote survival and through the treatment of serotonin selective reuptake inhibitors, also
referred to as SSRIs, have been proven to induce activity-related cytoskeletal-associated proteins
that promote neuroplasticity. 5-HT has also been proven to support brain development,
synaptogenesis and cell survival. A study with rats has proven that the reduction in 5-HT during
the aging process can be caused by oxidative stress and this can lead to the possible explanation
of the onset of depression as persons with depression tend to have higher levels of oxidative
stress. This provides information on how some of the biological outcomes of each pathway to
both disorders can have similarities or influence the progression of each.
Another important neurotransmitter is L-glutamic acid, commonly referred to as
glutamate or Glu. Glutamate is the most abundant neurotransmitter found in the human brain and
it is one of the most important neurotransmitters that has excitatory properties. Glutamate cannot
pass through the blood brain barrier due to its chemical properties and therefore they are
centrally produced within the neurons and glial cells. Glutamate acts on presynaptic neurons,
post-synaptic neurons and glia which are vital for neurotransmission. Although late-life
depression is known to be induced by monoamines like serotonin and neurotrophic factors,
through recent research, there has been discoveries of the glutamatergic system to play a role in
the pathogenesis of depression as it accounts for at least 50% of synapses in the brain. This has
been proven through various animal studies where discoveries of significantly higher levels of
plasma glutamate were found in patients with mood disorders. Many other studies have proven
that a disruption in the glutamatergic transmission system can significantly lower the levels of
NMDA receptors that are involved in the biological pathways of AD, as well as neurogenesis,
neurite outgrowth, synaptogenesis and cell death.
To understand the mechanisms of disease prognosis, it is important to understand the
glutamatergic system and how the neurotransmission process occurs. Glu is derived from
glucose and other sources but is packed into vesicles by the VGLUT transporters and is released
into the synapse after being stimulated, and once transmission is completed, it is removed by
excitatory amino acid transporters (EAAT). The receptors involved in this process play a key
role where they act as ion channels and are linked to second messenger systems which consist of
various subunits. These subunits can be expressed differently, and the various subunits can give
rise to different responses. For example, one of the subunits are the NMDA receptors, which
contain calcium channels to allow an influx of calcium and activate intracellular lipids, protein
kinases and other important molecules to mediate the characteristics and responses of the
synapses. An important factor to note is that an excess influx of calcium through the NMDA
receptors can cause neuronal cell death in terms of vascular or metabolic damage. Glu is part of
an important role in terms of regulating synaptic plasticity and memory but can be neurotoxic
through an agonist affect it has on NMDA, AMPA and other receptors. Receptors play a key role
in this pathway as they each contribute uniquely and have varying importance with the type of
neuron involved. Upstream neurotransmission of this pathway alters the downstream system and
Glu acts at the potential endpoint and these changes affect the depressive phenotype.
Glutamatergic system dysfunction is seen to lead to the development and progression of
depression in a number of ways. Recent studies show that decreased levels of Glu concentrations
in cerebrospinal fluid is found in persons with depression. low glutamatergic function has also
been associated with depression as the density of neurons and glia is seen at low levels in the
prefrontal cortex and anterior cingulate cortex of patients with mood disorders. This is a result of
glial dysfunction as there is a decreased uptake of Glu by astrocytes. Another reason why
dysfunction may occur is due to the activity of Gln which is the derivative of Glu as these Gln
synthetase transcripts are down-regulated in various parts of the brain in patients who are
diagnosed with major depressive disorder.
GABA is another important excitatory neurotransmitter involved and the dysfunction in
this pathway has also led to investigations on how it can cause depression. γ-aminobutyric acid,
also known as GABA has seen to be at significantly lower levels in many depressed patients in a
number of studies. GABA uses two receptor subtypes to mediate it’s function and these are
GABAA, which is involved in fast inhibitory synaptic transmission and GABAB which is a G
protein coupled receptor that carries out transmission through presynaptic inhibition. Decreased
levels of GABA in the occipital cortex of medication free depressed patients have been observed
in many studies as well as decreased levels in the anterior cingulated cortex and dorsal
medial/anterior PFC have been associated with melancholic traits in patients with depression.
The impairment of glutamatergic and GABA synapses is seen in AD when there is an imbalance
between both these systems. To understand the imbalance and relationship between these two
disorders, the role of Aβ must be examined as it is often assumed that significant levels of the it
causes the onset of depression. An animal study has proven that an increase in the levels of Aβ in
the hippocampus has resulted in morphological and functional development in the earlier stages
of maturation in granule cells and deficits in the later stages of maturation in granule cells as
these are important for plasticity. This provides strong evidence that the imbalance between
GABAergic and glutamatergic in terms of neurogenesis. The deposition of Aβ has also been
proven to induce the initiation of activating microglia and recruiting astrocytes to initiate a local
inflammatory response. Through investigation, it has been proven that there are inflammatory
mediators that may stimulate the amyloid precursor protein for amyloid and activated microglia
as well as astrocytes are responsible for clearing these. Due to hyperactivation of these microglia
and astrocytes, as well as an increased level of Glu release, this can increase plaque pathology
and influence hyperphosphorylation of tau and induce the development of neurofibrillary tangles,
causing the progression of disease.
Interplay among various receptors is known to be vital for synaptic activity in neurons.
Many of these interactions can also induce or influence the progression or onset of depression
within these individuals with AD and this is examined through several chemical processes found
within the glutamatergic system. Cannabinoid is a receptor that facilitates the release of GABA
and Glu with the help of endocannabinoid (EC), a lipid mediator that is important for synaptic
function. Cannabinoids influence PFC functions for example, working memory, emotional
learning, and sensory perception. Cannabinoids influence the GABAergic activity in the
hippocampus and conducts GABAergic transmission as endocannabinoids control the release of
neurotransmitters, but ECs have proven to have other effects where they can induce memory
impairments. Additionally, CB receptors have been found to influence hippocampal GABAergic
transmission by blocking reuptake and inhibiting transmission when needed. However, several
studies have shown that EC deficiency has been associated with the onset of depression. studies
have shown that chronic stress has reduced the levels of CB and downregulated EC activity
which resulted in presenting depressive symptoms. Another study has supported this theory as
the levels of EC were measured in those with major depressive disorder (MDD) and were shown
that the level of EC ligands were decreased. A genetic study has proven threat certain CB
receptors have also increased the chances of developing depression after a stressful life event.
These studies have supported the idea that decreased levels of EC activity and impairment in the
glutamatergic system as well as the GABA pathway has led to the formation of depressive
symptoms in individuals with AD. Interplay among the components within synaptic activity has
led us to believe that excitatory and inhibitory effects of the systems involved can influence one
another to contribute to the development of depression.