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Current Medicinal Chemistry, 2016, 23, 1-6 1

REVIEW ARTICLE

Late-life Depression and Alzheimer Disease: A Potential Synergy of

the Underlying Mechanisms

Jerzy Leszek¹, Elżbieta Trypka¹, Euphrosyni Koutsouraki², Dimitrios Michmizos²,

Nagendra Sastry Yarla3, Vadim V. Tarasov4, Ghulam Md Ashraf 5 and Gjumrakch Aliev6,7,8*

¹Department of Psychiatry, Wroclaw Medical University, Pasteura 10, Str.,50-368 Wroclaw, Poland;
²Medical School, Aristotle University, Thessaloniki, Greece; 3Department of Biochemistry and Bioinformat-
ics, Institute of Science, GITAM University, Visakhapatnam, Andhra Pradesh, 530045, India; 4Institute of
Pharmacy and Translational Medicine, Sechenov First Moscow State Medical University, 2-4 Bolshaya Pi-
rogovskaya st., 119991 Moscow, Russia; 5King Fahd Medical Research Center, King Abdulaziz University,
Jeddah, Saudi Arabia; 6GALLY International Biomedical Research Consulting LLC., 7733 Louis Pasteur
Drive, #330, San Antonio, TX, 78229, USA; 7School of Health Science and Healthcare Administration, Uni-
versity of Atlanta, E. Johns Crossing, #175, Johns Creek, GA, USA 30097; 8Institute of Physiologically Active
Compounds Russian Academy of Sciences, Chernogolovka, 142432, Russia

Abstract: A number of biological and clinical characteristics typical of late

ARTICLE HISTORY
Received: April 23, 2016
Revised: June 25, 2016
Accepted: July 13, 2016
DOI: 10.2174/092986732366616090
2152829
life depression (LLD) have been suggested by recent research findings. The
close association of LLD with cognitive impairment is now well documented
and evidenced. However, it is still not clear whether it is depression that Please provide
corresponding author(s)
leads to cognitive decline, and in more severe cases, to dementia. The work photograph
size should be 4" x 4" inches
presented in this review article suggests that depression and dementia fre-
quently and strongly copresent, even if the causality remains largely opaque.

Keywords: Aging, Alzheimer disease, Depression, Dementia, BDNF.

1. INTRODUCTION pressed disposition should not be considered natural or

According to WHO global statistics, the incidence
of depression increases with age [1]. Almost 20% of
people above the age of 65 demonstrate depressive
symptoms, whereas 40% of the elderly above the age
of 85 become afflicted with some form of depression,
with the disorder appearing with the same frequency in
both males and females. The fact that only a small per-
centage, less than 20%, of elderly suffering from de-
pression receive proper medical treatment is even more
concerning. On the whole, it could be argued that de-
pression in the elderly population may well be one of
the most underdiagnosed and ignored diseases. Depres-
sion is not a characteristic of senescence and a de-
*Address correspondence to this author at the GALLY International
Biomedical Research Consulting LLC., 7733 Louis Pasteur Drive,
#330, San Antonio, TX, 78229, USA; Tel: +1(440) 263-7461;
E-mail: aliev03@gmail.com
expected for elderly people [2]. In most of the cases,
the elderly population adapts successfully to the life-
style changes that come with this stage in life. Thus,
symptoms such as the reduction in social contact and
activities, the decrease in opportunities to take the ini-
tiative, stress and general worrying are not the natural
consequences of senescence and, in numerous cases,
may be indicative of the presence of depression.
A good number of epidemiological studies propose
that the history of depressive episodes in patients can
be correlated to increased probability of developing
cognitive disorders [3, 4], more specifically Alz-
heimer’s disease (AD) in later stages [5, 6]. It is now
well known that during a depressive episode, especially
in the elderly, dementia-like cognitive dysfunctions
may also present themselves with the term “pseudode-
mentia” [7]. This term is used to describe the clinical
appearance characterized by depression combined with

0929-8673/16 $58.00+.00 © 2016 Bentham Science Publishers

2 Current Medicinal Chemistry, 2016, Vol. 23, No. 35
a decrease of the cognitive functions, a decrease which
responds positively to anti-depressant treatment and
recedes with the remission of the depression, in con-
trast with the classic dementia that has a progressive
manifestation [7, 8].
2. EPIDEMIOLOGICAL DATA
Epidemiological studies were performed to examine
the temporal correlation between the onset of AD and
the depressive episodes, in order to determine whether
and to what extent depression may be a precursor AD
symptom and/or functions as an independent risk fac-
tor. The systemic meta-analysis by Ownby et al. [6], in
which the results of ten epidemiological studies with a
combined sample size of 102,000 patients were exam-
ined, concluded the following:
• A depressive episode in patient’s history is corre-
lated to the enhanced probability of developing AD
later on. This result suggests that one could aim at
common therapeutic targets, as successful treatment
of depression today will probably prevent AD onset
in future.
• A positive temporal correlation between the onset
of a depressive episode and the probability of de-
veloping AD later on has been established. The
greater the time separating the AD onset and de-
pressive episode, the more pronounced this correla-
tion becomes. Moreover, data from some studies
suggest that the number of depressive episodes and
probability of AD development are correlated, and
that every new depressive episode that results in
admittance to a psychiatric clinic increases this
probability by 13% [4].
3. BIOCHEMICAL CORRELATIONS
The efforts to correlate the biochemical findings to-
gether as well as with stress, make up a good portion of
the relevant published studies. Both experimental [9,
10] and clinical [11, 12] studies have revealed a strong
correlation between stress triggers and the development
of depressive disorder [13-15]. The later is also con-
firmed by our everyday clinical experience, as it is un-
derstood that people under persistent stress are more
prone to depression; and the most recent studies dem-
onstrate that there is a causal correlation between stress
and neurodegenerative disorders, specifically AD [16-
18].
4. HYPOTHALAMIC-PITUITARY-ADRENAL
AXIS (HPA-AXIS)
The mechanisms triggered by stressful stimuli are
adaptable, and in this way, they facilitate or aim to re-
Leszek et al.
store normal balance. We know that the neuroendo-
crine pathway known as HPA-axis is triggered by
stress [19]. The stressful stimuli activates the hypo-
thalamus to release the corticotropic hormone releasing
factor (CRF agent), which acts on the pituitary to
stimulate the release of adrenocorticotropic hormone
(ACTH) [20]. In turn, the ACTH stimulates adrenal
glands to release glucocorticoids (GCs) through the
blood circulation. Together with epinephrine and nore-
pinephrine released by the sympathetic nervous system,
GCs stimulate the changes that occur in the body dur-
ing stressful situations to maximize our ability to deal
with various kinds of stressors [21].
These changes include sharpening of cognitive
functions, stimulation of the immune system, increased
cardiovascular tone, energy concentration in muscles,
increase in the rates of cerebral perfusion, and inhibi-
tion of the reproductive physiology and appetite [22].
The GCs pass through the blood-brain barrier and exert
a negative feedback loop to the hippocampus, the hy-
pothalamus and the pituitary, i.e., excess of GCs causes
an inhibition of the HPA axis. In major depression, as
well as AD, abnormalities can be observed in the se-
quence of the HPA axis resulting in the reduced effec-
tiveness of the negative feedback loop, which in turn
results in elevated GCs level in the brain [23-27]. Ex-
cess of these substances has been shown to play a cen-
tral pathophysiological role in depression [23] as well
as in AD [18], and this role is indeed related to reduced
activity of the GCs receptor network. In particular, high
concentrations of GCs in the blood circulation of brain
results in:
• Reduction of neurogenesis in the hippocampus [23].
• Collapse dendrites of hippocampus [28].
• Necrosis of hippocampal neurons [22, 29], through
the mechanism of apoptosis [30].
• Increase of the vulnerability of neurons to free oxy-
gen radicals and amyloid β (Aβ) [31, 32].
The end result is the reduction of hippocampal and
the prefrontal cortex (PFC) volumes, which is found in
AD as well as depressed patients [33]. The PFC, which
is also affected, is associated with the hippocampus and
structures important for regulating mood as well as
memory. Thus, the main argument presented so far is
that stress through the GCs causes a sequence, an ava-
lanche of events at the molecular and cellular level,
which culminates in both mood disorders (depression)
as well as cognitive disorders.
Late Life Depression and AD
5. INFLAMMATORY PROCESSES
The correlation between immune system and stress
is now well recognized, with cytokines being pro-
claimed to be contributing to depression and neurode-
generation as inflammatory agents [34, 35]. The in-
volvement of inflammatory process in AD has a pivotal
role, and it should be noted that some of these effects
have also been reported in depressed patients [14, 36].
Certain cytokines (IL-6, IL-1, TNF-α and TGF-1β),
whose levels are found to be elevated in depression,
have been found to be enhanced in dementia as well
[36, 37]. Moreover, these inflammatory molecules have
been reported to play an important role in AD patho-
genesis, thus suggesting that depression and dementia
may occur in a sequential manner [38]. Also, inflam-
mation medicated activation of the immune system
may be considered to induce cytokine mediated depres-
sion, which are either synthesized de novo in the CNS
or can enter the brain through the blood circulation and
stimulate processes similar to those induced by classi-
cal stressful stimuli [39]. It has also been suggested that
cytokines and stress can act synergistically to promote
the release of HPA-axis factors [40, 41]. HPA-axis
modification affects the serotonin level, which in turn
exerts direct or indirect effect on depression, through
the reduction of brain plasticity [42].
6. BRAIN DERIVED NEUROTROPHIC FACTOR
(BDNF)
Cytokines and stress could affect the development
of oxidative and apoptotic mechanisms through activa-
tion of other chemical agents like MAP protein and
kinases, thus resulting in decreased plasticity of brain
and depression and the deterioration of BDNF produc-
tion [26]. The decrease of BDNF production is some-
thing that is observed in AD as well, and indeed may
occur as a result of stress and increase of GCs [43].
GCs and stress can also trigger cell death through
apoptotic processes involving proteins associated with
cell life cycle (P53, p21) as well as pre-apoptotic fac-
tors of the Bcl-2 family, thus halting neurogenesis and
resulting in atrophy of neurons by Αβ production from
precursors and hyperphosphorylation of tau proteins
[18]. It seems that GCs induced chronic stress exerts a
clearly destructive effect, leading to the manifestation
of both depressive disorder as well as AD.
Recently a study by Naveen et al., [44] demon-
strated a significant improvement in depression scores
and serum BDNF levels in a group of patients with de-
pression, who perform yoga. The study suggests that
performing yoga may assist neuroplasticity through
Current Medicinal Chemistry, 2016, Vol. 23, No. 35 3
stress reduction in patients with depression. Very re-
cently a work by Fukuda et al. [45] found that TrkB
agonistic compound(s) exhibit(s) antidepressant effi-
cacy in mice. The study suggests that TrkB agonists
can be useful as antidepressants. Geniposide reduces
depression-like behavior in hippocampus of streptozo-
tocin-evoked mice by upregulating BDNF expression
[46]. Several antidepressants alleviate depression-like
behavior by enhancing or upregulating BDNF levels.
However, effect of antidepressants on memory of pa-
tients with AD is not well investigated.
Memory creation involves plasticity of dendritic
spines and synapses in the hippocampus and medial
PFC [44]. Throughout the female lifespan, memory
formation varies with estrogen levels [44]. In general,
elevated levels of estrogen are related to greater den-
dritic spine density on pyramidal cells in the hippo-
campus and PFC, and are also related to improved
memory function [44]. BDNF enhances memory func-
tion and increases dendritic spines, whereas, estrogens
elevate the BDNF level in the hippocampus and PFC
[45]. BDNF and estradiol may work in tandem to en-
hance cognition. Fluctuations in recognition memory of
adult females are accompanied by changes in the
BDNF levels, circulating estradiol, and spine density
alterations in the hippocampus and PFC in situations
like aging, pregnancy and ovariectomy and estradiol
replacement (during the estrous cycle) [46]. Both
BDNF and estradiol play role in slower transcriptional
regulation via the CREB pathway and spine plasticity
via rapid membrane effects [46]. Estradiol enhances
BDNF levels through action on nuclear receptors [44].
Elevation in BDNF protein or mRNA levels by estra-
diol were consistent with an earlier finding that the
gene encoding BDNF contained an estrogen response
element (ERE) which provides a mechanism for the
influence of estrogen on BDNF levels [47]. Circulating
estradiol enters the cell nucleus and binds to an ERE on
the BDNF gene thus resulting in an increase in BDNF
levels [44]. Estradiol can alter both the transcriptional
and translational products of BDNF as well as its re-
ceptor TrKB throughout the basal forebrain. Enhanced
BDNF level could thus exert powerful effects on cogni-
tive functions, including memory and learning, within
the basal forebrain and its targets. When estrogen lev-
els are high spine density and BDNF levels also in-
crease, and spatial as well as non-spatial memory is
enhanced [46]. Cytokines including TGF-1β and
BDNF are closely correlated in neurodegenerative dis-
eases. Increase in TGF-1β levels as well as decrease in
BDNF are observed in pathophysiological conditions
of several neurodegenerative disorders [51].
4 Current Medicinal Chemistry, 2016, Vol. 23, No. 35
7. FEMALE HORMONES
Another mechanism potentially associated with de-
pressive phenomena is the alteration in the level of fe-
male hormones, particularly estrogen. According to
epidemiological data women are more likely to suffer
from depression and AD [48]. This phenomenon can-
not be attributed solely on the longer expected lifespan
of women. In older women the risk of AD is 1.5-3
times higher than for their male counterparts [49]. Ac-
cording to The National Comorbidity Survey, older
women are more likely to meet diagnostic criteria for
clinical depression [48]. The menopausal transition is
associated with a different set of symptoms such as
weight gain, anxiety, depression, sexual dysfunction,
sleep disturbances to all of which impairment of cogni-
tive functions may be a contributing factor, especially
if premature menopause occurs. Some studies have in-
deed shown impairment of cognitive functions such as
verbal fluency, visual memory [50], semantic and epi-
sodic memory [51, 52] in late life in women with pre-
mature menopause. In the same study, it was noted that
premature menopause was associated with a 30% in-
creased risk of decline in psychomotor speeds and
global cognitive functions over 7 years [51, 52]. Possi-
ble mechanisms propose that estrogen may be associ-
ated with enhanced cell oxidative damage, reduction of
choline, and inhibition of formation and destruction of
Aβ [53]. There are two nuclear estrogen receptors, es-
trogen receptor alpha (ERα) and estrogen receptor beta
(ERβ), present in the brain [54]. Both receptors act as
nuclear transcription factors and the membrane-bound
receptor [G protein-coupled estrogen receptor 1
(GPER1)]. This genomic effect most likely underlies
changes in neural functions that occur during the men-
strual and estrous cycles, pregnancy, menopause and
aging. Some isoforms of ERα and ERβ are localized in
the plasma membrane. Activation of these receptors
can cause mobilization of intracellular calcium, stimu-
lation of adenylate cyclase activity, production of cy-
clic adenosine monophosphate (cAMP) and increase in
the cGMP levels. The ERα mediated effects on mem-
ory and the ERβ activation is effective in decreasing in
depressive-like behavior observed after a 12w ovariec-
tomy [55]. Genetic variation in the estrogen receptors
may therefore modify estrogen signaling, and, thus,
influence a woman’s susceptibility to developing de-
pression. Patients with Major Depressive Disorders
have reduced ERα messenger RNA (mRNA) levels in
the amygdala than controls [56] and the effects of es-
tradiol on the serotonin 1A receptor have been shown
to be mediated via ERα [57].
Leszek et al.
Decreased estrogen levels may reduce serotonin
levels, and thus upregulate the 5-HT2A receptor in the
hypothalamus. These changes are responsible for the
occurrence of hot flashes, a very common menopausal
symptom. Hot flashes can precipitate sleep disorders
which also lead to the development of depression and
cognitive decline [58].
CONCLUSION
Several studies suggest that LLD is closely associ-
ated with cognitive impairment. However, it is not
clearly known whether it is depression that leads to
cognitive decline and, in more severe cases, to demen-
tia. LLD and AD seems to be sharing a number of un-
derlying molecular mechanisms, both at the gene regu-
lation and transcription end as well as the structural
modification and functional one. LLD is considered as
a potential risk factor for AD and therefore better un-
derstanding of LLD-AD relationship is critical for the
treatment of the disease. Hence, further investigation is
needed for a better understanding of the presented
clinical phenomena and an improved medical treatment
at onset.
LIST OF ABBREVIATIONS
AD = Alzheimer disease
BDNF = Brain-derived Neurotrophic Factor
GCs = Glucocorticoids
HPA = Hypothalamic-pituitary-adrenal
PFC = Prefrontal cortex
CONFLICT OF INTEREST
The authors confirm that this article content has no
conflict of interest.
ACKNOWLEDGEMENTS
This work was partly supported by the Russian Sci-
entific Foundation (www.rscf.ru, Российский
Научный Фонд, Grant No.14-23-00160 for 2014-
2016: Directed design, synthesis, and study of biologi-
cal activity of multi-target compounds as innovative
drugs for treatment of neurodegenerative diseases).
Ghulam Md Ashraf gratefully acknowledges the facili-
ties provided by King Fahd Medical Research Center
(KFMRC) and Deanship of Scientific Research (DSR),
King Abdulaziz University, Jeddah, Saudi Arabia.
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