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CLINICAL PEARLS

The complex conundrum of geriatric depression and dementias: Revisiting the

clinical ambiguity
Sanchari Mukhopadhyay, Debanjan Banerjee1
Consultant Psychiatrist, Kolkata, Bangalore, 1Consultant Geriatric Psychiatrist, Kolkata, Member, International Psychogeriatric
Association, Bengaluru, Karnataka, India

ABSTRACT

Late‑life depression (LLD), mild cognitive impairment (MCI), and dementia are clinically distinct yet interrelated disease
constructs, wherein LLD can be a prodrome, risk factor, comorbidity, or consequence of MCI and dementia. There is considerable
prevalence of depression in those with MCI or dementia, and vice versa, with maximum evidence in Alzheimer’s disease.
These intersections often form one of the most confusing aspects of psychogeriatric practice, leading to under‑detection and
mismanagement of depression, thus leading to incomplete recovery in most cases. This article focuses on this clinical ambiguity
in daily practice, reviews the clinico‑investigative pointers for the LLD–dementia intersection, and puts forward clinical and
research recommendations in view of the available evidence. Although there is conflicting evidence regarding the cause–effect
relationship between LLD, MCI, and dementia, it is likely that these constructs share some common pathological processes
and are often associated with each other within a longitudinal clinical continuum. This is a linear yet complex bidirectional
association: either the comorbid depression exaggerates preexisting cognitive deficits or chronic persistent depression eventually
leads to major neurocognitive disorders, not to mention depression as a part of behavioral and psychological symptoms of
dementia, which often impairs quality of life and psychosocial morbidity. Thus, a comprehensive approach, including tailored
history, neuropsychiatric examination, and relevant investigations, is necessary for assessing the differentials, with a sound
clinical understanding being vital to the process. Depression, if suspected, must be treated adequately with longitudinal
neuropsychological reviews. Future research warrants elucidating precision biomarkers unique to these clinicopathological
entities.

Key words: Alzheimer’s disease, cognitive deficits, dementia, geriatric depression, late‑life depression, late‑onset depression, mild
cognitive impairment

LATE‑LIFE DEPRESSION AND DEMENTIA:
INTER‑RELATIONSHIPS
Late‑life depression (LLD) is a clinical construct describing
depressive symptoms in persons aged 65 years and
above.[1] It consists of both early‑onset depression (EOD),
continuing into or recurring in old age, and late‑onset
depression (LOD) manifesting in the geriatric population
for the first time.[2] LOD constitutes almost 50% of all cases
with LLD.[3] The lifetime prevalence of major depression,
as per the National Comorbidity Survey‑Replication, in
people aged 60 years and above was found to be 10.6%,
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and the projected lifetime risk of the same in those aged
75 years and above was 23.2%.[4] Recent data from the
first wave of Longitudinal Aging Study in India showed
8.3% prevalence of depression in those above 60 years
of age, which is nearly ten times more than self‑reported
depressive complaints.[5] Considering both depressive
symptoms and minor depression, the prevalence went up
to 30%. These statistics are suggestive of significant disease
burden caused by LLD. Medical morbidities are high in the
old age, including cardiovascular, respiratory, endocrine,
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DOI: How to cite this article: Mukhopadhyay S, Banerjee D. The complex

10.4103/jgmh.jgmh_21_21 conundrum of geriatric depression and dementias: Revisiting the clinical
ambiguity. J Geriatr Ment Health 2021;8:93-106.

Corresponding Author:
Dr. Debanjan Banerjee, Consultant Geriatric Psychiatrist, Kolkata; Member, International Psychogeriatric Association, Bengaluru, Karnataka,
India. E‑mail: dr.Djan88@gmail.com
Submitted: 23-Mar-2021 Revised: 05-May-2021 Accepted: 04-Jun-2021 Published: 31-Jan-2022

© 2022 Journal of Geriatric Mental Health | Published by Wolters Kluwer - Medknow 93

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Mukhopadhyay and Banerjee: Clinical intersections of late‑life depression and dementias
and neurological conditions, increasing the risk of
depression.[2,6] Dementias are a group of neurodegenerative
disorders with global cognitive decline over the course of
illness.[6,7] The major types of neurodegenerative dementias
are Alzheimer’s dementia (AD), vascular dementia (VaD),
frontotemporal dementia (FTD), Parkinson’s disease (PD)
dementia, and Lewy body dementia.[8] Depression and
dementia are shown to be inter‑related across the literature
in bidirectional and complex ways. Depression may act
as a risk factor, prodrome, comorbidity, or consequence
of dementia.[9,10] It is seen to double the risk of dementia
in older persons.[6] On the other hand, depression is
known to be more common in all‑cause dementias than
in general population. Overall prevalence of depression
in neurodegenerative disorders may range from 15% to
50%, depending on the type of dementia. Almost 17% of
patients with AD and an even higher percentage of those
with subcortical dementias have major depression.[1]
There are several possible hypotheses to explain the mutual
relationship between these two illnesses. Sharing of the
same genetic or pathophysiological changes predisposing to
both the illnesses, reduction in hippocampal neurogenesis
in depression, high‑risk behaviors in depression increasing
vascular risk factors and leading to later cognitive
decline (e.g., smoking, alcohol use, less engagement in
cognitively and socially stimulating activities), medication
use (e.g., those with anticholinergic effect) are just some of
them.[2] Although AD, constituting about 50%–60% of the
late‑onset dementias, is most studied in the context of LOD,
depression is present as considerable comorbidity in other
dementias as well. Up to 50% with VaD, 40%–50% with PD,
40% with FTD, and 60% with dementia with hippocampal
sclerosis may have depression.[9,11‑13] Depending on the
diagnostic criteria and instrument use, the prevalence of
comorbid LOD in dementias and depressive symptoms
as a part of BPSD is seen to vary considerably across
studies.[2,6,14] Almost 60% of patients with MCI were found
to have depressive symptoms, both major and minor, as per
the Italian Longitudinal Study of Aging.[15] The cumulative
prevalence of depression in MCI across studies is seen to be
around 30%.[1,14,16] Subthreshold but clinically significant
depressive symptoms are nearly twice more prevalent
than major depression in the community, primary care,
nursing home population, as well as patients with mild
cognitive impairment or dementia,[6,14] further adding to
the disease burden. Butters et al. had proposed a multiple
model nonmutually exclusive pathway to explain the
links in the depression–cognitive impairment–dementia
continuum [Figure 1]. [17] The authors proposed that
depression increased the risk of neurocognitive disorders
through activation of the hypothalamo–pituitary–
adrenal (HPA) axis and cerebrovascular disease, which
eventually led to hippocampal atrophy and generalized
ischemia. This, in turn, influenced the cognitive
reserve which led to AD‑like presentation based on the
accumulation of AD pathological changes in the brain.
The clinical presentation and progression of cognitive
deficits over time depend upon a critical interaction
between vascular pathology, inflammation, frontolimbic
damage (implicated in depression) and beta‑amyloid, tau
94
pathology, as well as hippocampal atrophy (implicated
in AD). Frontostriatal abnormalities were considered to
be a hallmark of this pathway. Although there has been
more than a decade of further research in this field, this
hypothesis still holds good to understand this clinical
overlap between depression and neurocognitive disorders.
In routine clinical care, the psychiatrist faces several
ambiguities while dealing with this dementia–depression
overlap, leading to under‑detection of depression and
mismanagement. Approximately 5%–15% of patients
with LLD are mistaken to have dementia.[6] Discussion
in this paper reviews evidence to address some of these
clinical conundrums to facilitate better psychogeriatric
care. The authors would like to state that this is by no
means a detailed review of LLD as a clinical entity, as the
focus is more on clinical distinction within the dementia–
depression continuum based on the available evidence.
For the purpose of this review, dementia (International
Classification of Diseases [ICD‑10]) and major
neurocognitive disorder (Diagnostic and Statistical
Manual [DSM]‑5) will be considered synonymous. Besides,
though LOD forms a subpart of the LLD spectrum and there
exist clinical differences, for the purpose of simplification,
LLD will be used to denote all forms of late‑life depression
throughout the manuscript.
PATHOLOGICAL SUBTYPES OF LATE‑LIFE
DEPRESSION AND OVERLAP WITH DEMENTIAS
LOD differs from EOD in having more structural brain
changes (changes in white matter, brain ventricles),
vascular changes, neurosensory and neuropsychological
impairments, prevalence and incidence of dementia,
and less frequent family history of mood disorders and
lesser prevalence of psychiatric comorbidity other than
dementia.[1,3] There are several clinicopathological models
or subtypes of LLD. They can be enumerated as: [6,18]
1. Depression executive dysfunction (DED)
2. Vascular depression
3. Depression with reversible dementia
4. LOD (as mentioned above).
DED model is based on the hypothesis that frontolimbic
disruption, manifested by executive dysfunction,
predisposes to the development of LLD. The clinical
features resemble those of medial frontal lobe syndrome,
including executive dysfunction, apathy, psychomotor
retardation, severe behavioral disability, reduced interest,
and poor insight. DED presents with less of depressive
cognition and vegetative symptoms. It shows poor and
unfavorable response to antidepressant treatment with
early relapse. Neurobiologically, there are white matter
integrity disruption, white matter hyperintensities (WMHs)
in executive function‑related networks, reduced functional
connectivity (FC) in cognitive control network (CCN),
increased FC in default mode network (DMN), and lowered
dorsolateral prefrontal cortex (DLPFC) activation on task
challenging CCN.[3,6,18]
Vascular depression refers to the depressive syndrome
developing in relation to some vascular event. This model
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Mukhopadhyay and Banerjee: Clinical intersections of late‑life depression and dementias

Figure 1: Pathways linking depression to predominant cognitive outcomes (Butters et al., 2008). Copyright information: This is an open‑access article
distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by‑nc‑nd/3.0/), which permits unrestricted
use, distribution, and reproduction in any medium, provided the original work is properly cited

originates from the finding that cerebrovascular events may
precede, precipitate, or worsen LLD or maybe comorbid
with it. Evidence of a preceding cerebrovascular disease,
a temporal relation between the incident depression and
vascular event, and the presence of vascular risk factors
are required for this construct. The clinical features of
depression include apathy, retardation, higher disability,
and poor insight. Guilt is less commonly seen. Executive
dysfunction is also common. This, too, responds poorly
to antidepressant treatment. Neurobiologically, there
are WMHs in subcortex, periventricular areas, and deep
white matter, evidence of limbic hyperactivation, low
FC in subgenual anterior cingulate cortex (ACC), high
FC in dorsomedial PFC (DMPFC), reduced task‑related
DLPFC activation, perfusion deficits in the PFC, subcortex,
and frontostriatocingulate areas, evidence of endothelial
dysfunction, increased arterial thickness and endothelial
stiffening, and persistently increased HPA axis activity.[1,6,18]
“Pseudodementia” or reversible dementia is commonly
encountered in LLD, wherein the symptoms of cognitive
impairment often reduce with improvement in depression.
However, approximately 40% of patients having depression
with reversible dementia are seen to develop irreversible
dementias in 3 years. Thus, this construct calls for a detailed
diagnostic workup, including neurological evaluation.[1,6]
This has however been debated as the cognitive deficits
associated with LLD may not really be “pseudo” in all
cases and tend to be persistent, often evolving into a
neurocognitive disorder.[18]
Some dubious entities of geriatric depression proposed
are masked depression, depletion syndrome, and
subsyndromal symptomatic depression with and without
mood disturbances. They lack sufficient evidence to
justify individual diagnostic categories. Due to clinical
heterogeneity in older persons, these entities are often on
the “gray border” of depression–dementia overlap. Masked
depression refers to the prominent presentation of somatic
symptoms without active reporting of low mood by older
adults. However, it has been attributed to cohort effect
rather than actual diagnostic value.[19] Depletion syndrome
is the group of symptoms of hopelessness, thoughts of
death, lack of interest, and reduced appetite. Feelings of
exhaustion, dysphoria, and sleep disturbances are also seen
in the older cohort more than the younger adults.[14,20,21]
Subsyndromal symptomatic depression with and without
mood disturbances was suggested by Judd et al. in a
study of samples taken from National Institute of Mental
Health (NIMH) Epidemiological Catchment Area study.
They proposed this entity to be characterized by any two
or more symptoms of depression, simultaneously present
for the majority of time, for at least 2 weeks, associated
with the evidence of social dysfunction, in individuals
not meeting the criteria for major or minor depression or
dysthymia, leading to significant disability.[22]
Other pathophysiological models of LLD include
inflammatory and genetic hypotheses. The
inflammatory hypothesis states that there are increases
in proinflammatory cytokines and chemokines with
aging (e.g. interleukin‑6 [IL‑6], IL‑1β, IL‑1Ra, tumor necrosis
factor [TNF]‑α), with microglial activation, oxidative
stress, and metabolic changes, enhancing vulnerability to
develop LLD. There is evidence of differential response to
antidepressants with inflammation status.[6,18] Inflammation
is often considered to be the “missing link” deciding the
outcome of the LLD–MCI–AD continuum. [23] Genetic
models of LLD are not definitive. Some roles of C677T
mutation of methyl tetrahydrofolate reductase gene (related
to risk of cerebrovascular lesions), serotonin 5HT2A
receptor‑A/A genotype (LLD in females), C1166 allele of
type‑I angiotensin receptor gene (white matter lesions), and
ApoE4 allele (association with more severe depression)

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Mukhopadhyay and Banerjee: Clinical intersections of late‑life depression and dementias
have been found.[1,3,6,24] In addition, psychosocial factors
such as personality attributes (neuroticism, hopelessness),
cognitive distortions, low mastery, poor self‑efficacy, low
socioeconomic status, low education, cumulative stressful
life events, bereavement, and perceived poor social support
contribute to the development of LLD.[3,8,25]
The main diagnostic challenge encountered in the geriatric
population is the differentiation between LLD and dementia
because of symptomatic overlap.[2] As discussed before,
cognitive impairment, particularly executive dysfunction
as well as apathy, retardation, sleep disturbances, and
bradyphrenia, are common findings in the LLD models
of DED and vascular depression. Subjective memory
impairment or reversible dementia often accompanies
depression. Moreover, depression may be comorbid with
dementia and depressive symptoms can be a part of
behavioral and psychiatric symptoms in dementia (BPSD).
LLD may not present with all the classical depressive
symptoms of adult diagnostic criteria, thereby making
the diagnosis difficult.[25] In this article for the purpose
of clinical differentials, dementia will mainly encompass
AD and VaD as these have the maximum evidence base
in this regard.
DEPRESSION AS A PART OF BEHAVIORAL AND
PSYCHOLOGICAL SYMPTOMS OF DEMENTIA:
HOW IS IT DIFFERENT?
Depression in dementia may be a component of BPSD or
a prodrome preceding cognitive decline for many years. It
has been studied the most in AD, and hence, our discussion
here will be majorly in the context of AD.[1,2,8,14] Risk factors
for developing depression in AD include vascular changes
such as history of cerebrovascular disease, leukoaraiosis,
leukoencephalopathy in frontostriatal and frontolimbic
circuits, female sex, past history of depression, family
history of depression, ApoE4 carrier status, and
contributory medication use.[14] BPSD can also develop
due, in addition to biological risk factors, to psychosocial
and environmental issues such as sensory overstimulation
or understimulation, unfavorable housing conditions,
and poor caregiver support, including abuse and neglect
and insight into cognitive decline.[26‑29] Depression in
patients with dementia poses a difficulty in diagnosis
due to the cognitive decline present in the patients, as
well as atypical presentation of mood symptoms.[2] There
may be acute deterioration in the cognitive status or
physical condition with onset of depression in patients
having dementia.[30] Apathy, decreased energy, decreased
interest in activities, psychomotor abnormality, reduced
attention, and concentration may be present in dementia,
independent of depression. However, persistent sadness
of mood with morning worsening, sense of worthlessness,
guilt, recurrent thought of death, or suicidal ideation (as
compared to vegetative symptoms) are more seen in
dementia with depression than dementia alone. [6]
Differentiating features of depression in dementia from
depression alone are gradual and progressive course of
symptoms, presence of cognitive decline, lack of concern
for or denial of cognitive decline, situational mood changes
96
including lability (in VaD), psychomotor agitation, less
frequent guilt, suicidality, sleep disturbances, vegetative
symptoms, and greater prevalence of anhedonia, rejection
sensitivity, as well as self‑pity.[2,3,14,31] The neurobiological
changes in AD with depression include more severe
tau, amyloid pathology, vascular burden, and loss of
serotonin receptors and transporter binding, as compared
to only dementia. The reduction in regional cerebral
blood flow in the amygdala and hippocampus is also
higher in those with depression and dementia than
either alone.[14] White matter lesions and temporal lobe
atrophy are found to predict future development of both
depression and dementia.[14] The NIMH developed a set
of diagnostic criteria for depression in AD, wherein the
DSM‑4 depression criteria had been modified [Table 1].
Number of symptoms required for diagnosis was made
to three instead of five (out of ten), with decreased
positive affect and decreased pleasure merged into one,
and addition of social withdrawal, irritability, and social
isolation as symptoms.[32] Coming to depression in VaD,
the neuropathology is often the same for both. Depression
is more prevalent in VaD than AD and has a longer
duration and higher severity. However, the symptomatic
similarities in psychomotor retardation, decreased
attention and concentration, as well as vegetative
symptoms pose difficulty in differentiating vascular
depression from VaD. These clinical and neurobiological
overlaps are attributed by some researchers to a unified
entity of vascular depression and VaD which involve
arterial stiffness, vascular remodeling, intimal thickening,
endothelial dysfunction, and inflammation.[33]
Table 1: National Institute of Mental Health Provisional Diagnostic
Criteria for Depression in Alzheimer’s Disease (adapted from Olin
et al., 2002)[32]
Three (or more) of the following symptoms must be present during
the same 2‑week period and represent a change from previous
functioning. At least one of the symptoms must either be (1) depressed
mood or (2) decreased positive affect or pleasure
Clinically significant depressed mood
Decreased positive affect or pleasure in response to social contacts
and usual activities
Social isolation or withdrawal
Disruption in appetite
Disruption in sleep
Psychomotor changes
Irritability
Fatigue or loss of energy
Feelings of worthlessness, hopelessness, or excessive or
inappropriate guilt
Recurrent thoughts of death, suicidal ideation, plan, or attempt
All criteria are met for Dementia of the Alzheimer Type as per the
Diagnostic and Statistical Manual‑4
The symptoms cause clinically significant distress or disruption in
functioning
The symptoms do not occur exclusively in the course of delirium
The symptoms are not due to the direct physiological effects of a
substance
The symptoms are not better accounted for by other conditions
such as major depressive disorder, bipolar disorder, bereavement,
schizophrenia, schizoaffective disorder, psychosis of AD, anxiety
disorders, or substance‑related disorders
AD: Alzheimer’s dementia
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Mukhopadhyay and Banerjee: Clinical intersections of late‑life depression and dementias
CLINICAL DIFFERENTIALS: DECODING THE
AMBIGUITY
There is a lack of consensus regarding the differentiating
features of LLD and depression in young adults. Some
researchers have proposed that there is no unique
symptom characteristic of old‑age depression, though
some depressive symptoms occur more frequently in the
elderly than in the younger adults.[8] However, considering
the unique biopsychosocial underpinnings of LLD, it has
often been proposed as a separate clinical entity altogether.
The challenge while differentiating LLD from dementia is
mostly due to the notable presence of cognitive impairment
and apathy. This distinction is vital as it can have several
important management implications.
In an elderly presenting with cognitive complaints, based
on the onset and course, three “D”s need to be evaluated
for delirium, dementia, and depression. A basic evaluation
framework to exclude these conditions is depicted in
Figure 2.
In general, it is worthwhile to keep in mind certain
considerations while assessing any individual with
LLD [Table 2]. In many cases, a preexisting major or minor
neurocognitive disorder may present when the comorbid
depression leads to an exacerbation of the cognitive deficits
and added disability. Subjective memory complaints may
be more marked in LLD and early stage of dementia as well
as MCI. Depressive ideations and vegetative symptoms are
less common in LLD than young‑onset depression but more
prevalent compared to depression in dementia. Deficits in
attention, processing speed, and verbal and visual memory
are associated with LLD, while an individual with dementia
can have all the preexisting cognitive deficits increased due
to comorbid depression. The temporality of onset of mood
and cognitive complaints provides an important clue as
to whether the depressive diathesis has led to or is a part
of the dementia syndrome, though such distinction is
often not possible. In general, apathy, irritability, fatigue,
and anhedonia with increased dependence are seen in
depression/anxiety in dementia. Suicidality can be more,
and insight is often impaired compared to either LLD or
dementia alone.[14,18,34,35]
The classic concept of depressive pseudodementia may
manifest in LLD, especially with comorbid chronic medical
illness and frailty. This is often confused with the clinical
phenotype of “depression with reversible dementia.”
Ideally, such pseudodementia is characterized by: [34]
• More subjective cognitive complaints
• Higher difficulties with attention, concentration, and
recent memory
• Discordance of memory and activity reports between
patients and caregivers
• Poor efforts during cognitive testing
• “I do not know” or “I cannot remember” answers
• Sequential assessments show inconsistent
performances in cognitive tests.
Important to understand, that it is always necessary to grasp
a holistic clinical picture and supplement it with tailored
investigations rather than prelabeling an individual with
Journal of Geriatric Mental Health | Volume 8 | Issue 2 | July‑December 2021
cognitive deficits as “dementia,” as that brings in distress
to the patient and his/her family, a guarded prognosis, and
therapeutic nihilism. There is no substitute for a systematic
history from multiple sources and detailed physical as well
as neurocognitive examination.
We attempt to lay down some pointers to clinically
differentiate between LLD, dementia, and depression (BPSD)
in AD [Table 3]. In some cases, however, these symptoms
occur on a continuum, and there are no water‑tight
categories.[1‑3,8,14,31]
Let us look at a couple of case vignettes to have a practical
idea of the possible clinical conundrums [Table 4].
While Case Vignette 1 depicts how a possible MCI appeared
clinically as mild dementia due to the overshadowing LLD,
Case Vignette 2 highlights how a chronic and recurrent
depressive syndrome can eventually lead to AD over the
longitudinal course. These examples are common in the
practice of geriatric psychiatry and are only few of the
numerous similar confusing scenarios that can arise in
the depression–dementia overlap.
ASSESSMENTS TO CLINICALLY DIFFERENTIATE
In geriatric patients presenting with symptoms of depression
with or without cognitive impairment, a detailed evaluation
needs to be carried out, including psychiatric, medical,
surgical, cognitive, social, environmental, and treatment
history, thorough physical, especially neurological,
examination, cognitive status evaluation, and laboratory
investigations and neuroimaging to rule out contributory
factors and other investigations as indicated (The readers
are encouraged to go through the clinical psychiatry
guidelines of comprehensive geriatric assessment by the
Indian Psychiatric Society [IPS]).[36] In this article, we shall
specifically focus on the intersections of LLD, dementia,
and depression in dementia.
Although the most commonly used assessment tools for
depression (Hamilton depression rating scale [HAM‑D],
Montgomery Asberg Depression Rating Scale (MADRS),
and Beck Depression Inventory [BDI]) were developed
in the context of adults and not the geriatric age group,
several screening and diagnostic instruments have become
available to assess depression in the older population
with or without cognitive impairment [Table 5]. These
are the most studied and well validated in the geriatric
age group.[37‑43] In addition, scales such as HAM‑D, BDI‑II,
MADRS, and Patient Health Questionnaire‑9 can be used
for assessment.[31] Validated inventories are there to assess
depression as a part of BPSD, such as neuropsychiatric
inventory, behavioral pathology in AD rating scale,
Manchester and Oxford Universities Scale for the
psychopathological assessment of dementia, and Columbia
University Scale to assess psychopathology in AD.[3,8]
Geriatric depression scale is commonly used as a screener
for depression in the elderly and has been validated in the
Indian setting. However, it is not sensitive to pain, somatic
complaints, and health‑related preoccupations which
are common in LLD and is also not used for assessing
depression in dementia.[1,14]
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Mukhopadhyay and Banerjee: Clinical intersections of late‑life depression and dementias

Figure 2: Schematic depiction of diagnostic differentials in an elderly presenting with cognitive complaints (prime considerations: 3 “D”s, Delirium, Dementia,
Depression). AD: Alzheimer’s disease

In the neuropsychological assessment, the classical finding
reported in depression is the reduction of processing speed,
thinking capacity, attention, and concentration, termed
debatably as “pseudodementia.” More answers such as “I
do not know” or “I cannot do” are observed on structured
cognitive assessment, suggestive of poor motivation.
However, persistent dysfunctions of other domains of
cognition, including memory and executive function,
are also seen in depression.[45] LLD, especially LOD, may
present with more cognitive deficits than young‑age
depression. The deficits usually, however, do not amount
to the extent observable in dementia. In depression with
AD, the cognitive impairment may be higher than in either
alone, and often, the pattern of cognitive deficit in LLD
with or without MCI (say, episodic memory impairment)
predicts future development of dementia. In addition,
there may be cognitive deficits as noted in the pathological
LLD models, such as executive dysfunction and profound
impairments in attention and concentration.[18,46,47]
Research in LLD and dementias in the recent past has
focused on laboratory and neuroimaging biomarkers. Some
useful investigations needed in assessment of LLD (also in
dementia) are: [3]
• Complete blood count– to rule out anemia
• Thyroid function test – T3, T4, thyroid‑stimulating
hormone, radioactive iodine uptake

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Mukhopadhyay and Banerjee: Clinical intersections of late‑life depression and dementias

• Vitamin B12 and folate levels differentiation)

• Routine blood biochemistry
• Electrocardiograph (for antidepressant use)
• Computerized tomography (CT) scan or magnetic
resonance imaging (MRI) of the brain for excluding
structural/vascular/infective lesions (MRI is preferred
over CT for better resolution and gray‑white matter
Table 2: Considerations in history and physical examination while
evaluating late‑life depression
Detailed history of the evolution of depressive symptoms (from patient
and reliable sources)
Association with physical factors (locomotor impairment, pain, etc.)
and medical conditions
Evolution of cognitive complaints (if present), timeline, domains
affected, and influence on instrumental/daily activities of living
Amnestic versus nonamnestic (executive, visuospatial, language,
social cognition) cognitive complaints
Gait, processing speed, and motor activities
Look for thyroid swelling, bradycardia, skin lesions, signs of
malnutrition, liver or kidney disease
Review of medications, treatment history, and polypharmacy
Exclude bipolarity
Psychosocial details (perceived social support, disability,
postretirement life, interests and hobbies, family relationships,
attention and support of caregivers, dynamics with spouse, lifestyle,
spirituality, coping patterns, substance use, etc.)
Symptom severity and subtypes of depression
Clinical phenotype (vascular/depression executive dysfunction
syndrome/depression with reversible dementia)
Suicide risk and ideations
Vascular risk factors (diabetes, hypertension, dyslipidemia, sedentary
lifestyle, obesity, etc.)
Closely monitor cognitive status after clinical improvement of depression
Changes in functioning and social participation
Knowledge, attitude, and practice of the family/caregivers toward the
illness and care provided
• Polysomnography (PSG) (for persistent unexplained
sleep disturbance and rapid eye movement‑sleep
behavior disorder)
• Electromyography (EMG) and nerve conduction
study (NCV) (if peroneal nerve palsy is suspected,
which may occur in the depressed elderly due to
weight loss and psychomotor retardation).
PSG, EMG, and NCV are used rarely only in certain
selected cases.
However, it is difficult to point out any one diagnostic
investigation to differentiate LLD from dementia. The
composite clinical understanding is dependent on the
holistic picture rather than a single investigation in
vacuum. It is proposed that certain brain changes in
LLD may be predictive of later development of dementia,
particularly AD. Overall, neuroimaging and cerebrospinal
fluid (CSF) biomarkers findings relevant to LLD–dementia
discrimination are mentioned below. Neuroimaging
modalities may be useful in day‑to‑day clinical practice,
with structural MRI being a preferred baseline evaluative
tool for a diagnostic confusion.
Structural neuroimaging[3,8,14]
• Volumetric reduction and cortical thinning
of several brain structures such as PFC,
orbitofrontal cortex, anterior cingulate
cortex (ACC), amygdala, thalamus, basal ganglia,
hippocampus, and parahippocampal gyrus are
seen in LLD (hippocampal atrophy and ventricular
enlargement are shared by LLD and AD)
• WMH, microinfarcts, and microhemorrhages may be
present in frontal subcortical circuits in LLD (vascular

Table 3: Clinical differentials between late‑life depression, dementia, and depression in Alzheimer’s dementia
Clinical signs/symptoms LLD Dementia Depression in AD
Subjective memory complaints ++ +/− +
Subjective complaints of sadness + − +/−
Depressive ideations + − +/−
Vegetative symptoms ++ − +
Psychomotor agitation/retardation ++ − +/−
Somatic symptoms ++ − +
Cognitive deficits Attention, processing speed, Episodic memory (AD), executive Exaggerated preexisting memory
verbal memory functions (subcortical dementias), symptoms (cognitive deficits
language (PNFA, SD) precede depressive symptoms)
Suicidality ++ − +
Irritability + +/− ++
Disability +/− + ++
Sleep duration Reduced May or may not be due to night‑time Not affected more than usual
behavioral problems
Sleep disruption (REM) ++ +/− +
Eating behavior Reduced Reduced/hyperorality May be affected significantly
Psychotic symptoms Delusions of guilt/nihilism/sin/ Delusions of persecution/phantom Lower; nihilistic delusions
hypochondriacal delusion boarder/misidentification
Fatigue ++ − ++
Apathy + +/− ++
Sundowning − + +/−
Characteristic symptoms Guilt, vague physical symptoms, Global worsening of cognition with Fatigue, apathy, irritability,
vegetative symptoms, decreased intact consciousness (±behavioral and anhedonia, rejection sensitivity
psychomotor activity psychiatric symptoms of dementia)
AD: Alzheimer’s dementia; REM: Rapid eye movement; PNFA: Progressive nonfluent aphasias; SD: Semantic dementia; LLD: Late‑life depression; + : present, ++ :
frequently present, +/- : may or may not be present, - : not present

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Table 4: Case vignettes

Case vignette 1
A 67‑year‑old married lady, schoolteacher by profession, presented with her husband with 6‑month complaints of slowness in all activities,
difficulty in thinking and concentrating, inability to remember daily TV shows, decreased social interaction, and fragmented night‑time sleep. Her
husband mentioned that she made frequent mistakes in cooking, minor errors in naming and remembering daily activities. She has no subjective
complaints of sadness or anhedonia. Over time, she had totally restricted outdoor activities and IADL were dependent. Self‑care was normal but
tool a lot of time. Hypothyroidism and hypertension were under control. There were financial difficulties on socio‑environmental evaluation.
Family history revealed similar complaints (untreated) in mother and past history was not significant. Physical examination was normal apart
from generalized slowness, staggered slow gait, and mild action tremors. MSE showed nonspontaneous minimal speech, bradyphrenia, health
anxiety, preoccupations with memory, impaired attention, concentration, and recent memory deficits. HMSE score was 23/31. She did not
complete HAM‑D. GDS score was 4. There was no history of earlier psychotropic exposure. Laboratory investigations showed TSH of 7.2,
ESR 40, and hemoglobin 9.2. Rest of the parameters were normal. CT scan (plain) of brain done 2 months back showed age‑related cerebral
atrophy (frontal predominant) and extensive cortical/subcortical white‑matter change. She had a failed trial of escitalopram. Initial diagnosis
was major neurocognitive disorder (with a differential of MDD). An adequate trial of Sertraline was initiated considering the same. With a
further augmentation of Bupropion XL 150 mg, her symptoms improved in next 3 months, especially in domains of sleep, attention, and daily
functioning. Thyroid supplements and hematinics were administered. The elevated ESR was likely due to osteoarthritis, which was managed with
symptomatic pain control and physiotherapy. A review showed HMSE to be 28/31, GDS of 2, and HAM‑D (was cooperative) of 8. She continues
to maintain improvement till date with IADLs being mostly independent and occasional minor lapses in naming and recall. A diagnosis of MDD
was finalized, with an added differential of possible MCI. Cognitive symptoms improved at follow‑up visits with some persisting deficits in recall
not interfering with IADL
Case vignette 2
A 60‑year‑old widowed farmer presented with his son and daughter‑in‑law with complaints of anhedonia, decreased appetite, weight loss,
difficulties in taking care of cattle, insomnia, and out‑of‑proportion anxiety about financial concerns. His symptoms had started a year back after
his wife’s sudden demise due to a stroke and increased over the last 3 months. His self‑care had markedly decreased. History revealed a similar
episode 5 years back which was untreated (much details unavailable). Family history was insignificant. He used to consume country liquor
in a dependence pattern for >30 years, completely abstinent since wife’s death. Physical examination showed frailty, hypertension (first‑time
diagnosis), and bilateral mild‑moderate sensorineural hearing loss. Apathy, anhedonia, ideas of hopelessness, death anxiety, preoccupations
over family’s well‑being, and partial insight were obtained on MSE. There were deficits in attention, immediate and recent recall. GDS was 12,
HAM‑D was 29, and HMSE was 25/31. Investigations revealed dyslipidemia and Vitamin B12 deficiency. After being diagnosed as recurrent
depressive disorder (severe depression without psychotic symptoms), he was treated with escitalopram up to 15 mg with which he developed
hyponatremia and then was switched to mirtazapine 15 mg. Antihypertensive medications were also initiated with Vitamin B12 supplementation.
There was some improvement in his sleep and anhedonia over the next 6 months, but he persisted to have anxiety, hopelessness, and difficulty
in independent functioning. Mirtazapine was changed to amitriptyline up to 75 mg with which he had intolerable anticholinergic side effects and
was eventually maintained on mirtazapine and venlafaxine combination for 6 more months. After almost a year, his memory problems worsened
with deficits in naming, expressive speech, apraxia, and visuospatial deficits, which were gradually progressive. MRI brain (plain) showed
bilateral temporoparietal atrophy consistent with AD pattern. A repeat HMSE was 21/31. GDS and HAM‑D scores were 3 and 8, respectively.
A diagnosis of mild AD was further considered, and the family was psychoeducated about the same. In the course, he also developed visual
hallucinations and sundowning, and is presently being maintained on mirtazapine 7.5 mg, donepezil 10 mg, and quetiapine 12.5 mg
IADL: Instrumental activities of daily living; MSE: Mental status examination, HMSE: Hindi Mental State Examination; HAM‑D: Hamilton Depression Rating Scale;
GDS: Geriatric Depression Scale; TSH: Thyroid‑stimulating hormone; ESR: Erythrocyte sedimentation rate; CD: Computerized tomography; MDD: Major depressive
disorder; MCI: Mild cognitive impairment; MRI: Magnetic resonance imaging; AD: Alzheimer’s dementia

changes may be shared by vascular depression and
VaD, but not as obvious in AD), compared to more of
periventricular WMH in normal aging
• Ischemic deep white matter lesions are found more in
DLPFC in LLD (compared to nondepressed elderly).
These can be visualized best with T2 sequences and
FLAIR
• Structural connectivity: Diffusion tensor imaging (DTI)
has shown disruption of microstructural integrity in the
superior longitudinal fasciculus, uncinate fasciculus,
cingulum, and corpus callosum as important markers
of vascular depression, which in turn predicts
progression to vascular dementia.[48] Processing speed,
verbal fluency, and working memory are the main
neuropsychological correlates of the same. Further,
DTI findings are also correlated with WMH in genu,
hippocampus, dorsal ACC, precuneus, hypothalamus,
amygdala, and other paralimbic regions. The white
matter lesion burden and lesion severity are the
two most important parameters deciding executive
function deficits and response to treatment.[49] AD
Neuroimaging Initiative findings show that early DMN
involvement in LLD can be a predictor of progression
of dementia. On the other hand, vascular pathology so
common in LLD can affect progression of preexisting
AD pathology both through amyloid‑beta (Aβ)
dependent and independent mechanisms.[50]
Functional neuroimaging[6,14]
• LLD is usually conceptualized as a disorder affecting
reward, cognitive, and salience networks[1]
• Higher regional cerebral blood flow is noted
in amygdala and hippocampus in LLD (versus
dementia) on single‑photon emission computed
tomography (SPECT) (diagnostic accuracy of SPECT
in distinguishing between LLD and dementia is 86%)
• There is an absence or a relative lack of identifiable
Aβ pathology on [18F]‑flutemetamol amyloid
positron‑emission tomography (PET) in LLD (versus AD)
• Significantly reduced uptake is seen in temporoparietal
regions on [18F]‑fluorodeoxyglucose PET in
AD (versus LLD); glucose uptake patterns in LLD are
more non‑specific and heterogenous across cortex and
subcortex
• Fu n c t i o n a l M R I ( f M R I ) s h o w s D M N
overactivity (associated with negative self‑referential

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Table 5: Commonly used screening and diagnostic assessment tools for geriatric depression and depression in dementia
Scale Salient features
GDS[37]* Screening tool; short form available (developed in 1986), Long form has 30 items
Short form: 15 items
Time to administer: 4‑5 min
Score >5 is suggestive of depression
Score 0‑4: Normal
Score 5‑8: Mild depression
Score 9‑11: Moderate depression
Score 12‑15: Severe depression
Avoids somatic symptoms
Available in Hindi, Urdu, Bengali
CES‑D[38] Used widely in community settings, to screen for geriatric depression
Assesses symptoms for the past 1 week
20 items on behaviors and feelings evaluated
Each item scored from 0 (rarely) to 3 (most of the time); maximum score 60: Higher score suggestive of more symptoms
Four factors: Somatic symptoms (correlated to melancholic depression), positive affect (correlated with life satisfaction),
negative affect, and interpersonal relationship
CSDD[39] Measures depression in context of cognitive impairment
Better for mild to moderate dementia than severe
Information is collected from both patient and caregiver, combined with clinician’s assessment
Assesses symptoms in the past 1 week
Time to administer: 30 min
Domains evaluated ‑ mood‑related signs (4 items), behavioral disturbances (4 items), disturbances, physical signs (3
items), cyclic functions (4 items), and ideational disturbances (4 items)
Each item scored from 0‑2 or N/A (unable to evaluate)
Score >10: Probable depression, score >18: Definite depression, score <5: No depression/treated depression/
depression in remission
In disabled or medically ill elderly, physical signs may not reliable
DMAS[40] Modeled after HAM‑D, without the subjective components
Assesses symptoms in the past 1 week
Trained clinician‑rated, with inputs from caregiver (nursing staff for in‑patient)
24 items; 1‑17 to assess the depression severity and 18‑24 to assess the severity of dementia
Each item rated on a 6‑point severity scale
Reliable for assessing depression severity in mild‑to‑moderate dementia
BASDEC[41] Screening tool to identify patients at risk for depression
19 cards; true/false questionnaire; maximum score 21
“Caseness” cutoff: 7
Especially applicable in those with hearing impairment
NPI[42,43]* Assessment of BPSD; frequency and severity of neuropsychiatric symptoms
NPI‑nursing home version also rates occupational disruption (a measure of caregiver burden)
12 behavioral clusters measured (last two added later): Delusion, hallucination, agitation/aggression, dysphoria/
depression, apathy, anxiety, euphoria, disinhibition, lability/irritability, aberrant motor activity, night‑time behavioral
disturbances, and abnormality in appetite and eating
Useful in screening for BPSD in all types of dementias
Administered to caregivers: Screening, followed by frequency, severity of and distress caused by symptoms
BEHAVE‑AD[44]* Measures BPSD in persons with AD
Rating is done based on informant interview
Two parts: First assesses symptoms and second measures severity
Domains: Paranoid and delusional ideation, hallucinations, activity disturbances, aggression, diurnal variation, mood,
and anxieties and phobias
Useful in prospective studies and pharmacological trials
*Scale validated in the Indian population. BPSD: Behavioral and psychiatric symptoms in dementia; AD: Alzheimer’s disease; GDS: Geriatric Depression Scale; CES‑D:
Centre for Epidemiologic Studies‑Depression scale; CSDD: Cornell Scale for Depression in Dementia; DMAS: Dementia Mood Assessment Scale; BASDEC: Brief
Assessment Schedule Depression Cards; NPI: Neuropsychiatric Inventory; BEHAVE‑AD: Behavioral Pathology in Alzheimer’s Disease; HAM‑D: Hamilton Depression
Rating Scale; NA: Not applicable

ruminations) and increased FC between DMN and
subgenual PFC in LLD (versus moderate decrease of
DMN‑FC between posterior cingulate cortex and right
hippocampus and global reduction of DMN‑multiscale
entropy in AD).[14,51] Some typical fMRI findings in
depression are DMN dominance over the Central
Executive Network (CEN), dysfunction of salience
network‑mediated switching between the DMN and
CEN, and reduced CEN modulation of the DMN.[52]
Insular hypometabolism, task‑based deactivation of
the DMN, decreased FC between limbic and dorsal
cortical structures, and DMN–CEN disconnection
have been posited as possible functional biomarkers
of the “network dysfunction” in LLD.[53] Cerebellar
FC differences (at vermis) with DMN, CEN, and
Salience Network (SN) are seen more often in LLD
than dementia.[54] Functional disconnection between
anterior and posterior DMN regions and reduced

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global connectivity has been studied to be markers of
persistent cognitive deficits in LLD, hence increasing
the risk of dementias[53]
• Increased left hippocampal and decreased right
hippocampal FC with other brain regions involved
in mood regulation is present in LLD (as compared to
a globally reduced connectivity in amnestic MCI)[55]
• Nondemented depressed older persons have reduced
bilateral activation of dorsal ACC and hippocampus
on word‑activation task.
Cerebrospinal fluid markers[6,14]
• CSF Aβ‑42 is significantly higher in LLD versus AD
• CSF phosphorylated tau and total tau levels are
significantly higher in AD versus LLD
• CSF Aβ‑42 and tau levels in LLD are comparable to
controls.
From the above discussion, it is apparent that we still
have a long way to go in determining an unequivocal
biomarker for LLD differentiating it from dementias, and
as of now, the differentiation depends on a sound clinical
understanding. Moreover, other dementias are not as much
studied as AD in this light. The presence of certain unique
investigative pointers however encourages future research
in this direction.
DIFFERENCES IN THE MANAGEMENT
STRATEGIES
Treatment of LLD follows the line of treatment in young
adults, with certain restrictions regarding the choice of
medication, dose, and duration. The clinical course of
LLD is much like that in young adults, though relapse
and recurrence are said to be higher.[3,18,56] Poorer outcome,
including mortality, is noted with comorbid chronic
medical diseases and functional impairment. Further,
low‑grade depression and incomplete remission may
be chronic in older persons even after treatment that
leads to subsyndromal depressive symptoms, common
in the community. Depression in AD may often resolve
spontaneously or with less intensive treatment, whereas that
in VaD is more chronic and often refractory to treatment.[3]
Severity of depression, nonmelancholic features, history of
long duration of episode (past or current episode), presence
of delusion, poor self‑rated health, and poor social support
are predictors of chronicity in LLD. Relapse and recurrence
are predicted by history of frequent episodes, late age of
onset, history of dysthymia, intercurrent medical illness,
and high severity and chronicity of the index episode.[6]
The consensus on treatment is that a combination of
psychotherapy and pharmacotherapy is often better than
either alone in LLD. It is suggested that LLD responds
less well to antidepressants and has a high relapse risk
as compared to young adult depression.[18] The details of
LLD treatment guidelines are beyond the scope of this
chapter. The readers are suggested to go through the IPS
Clinical Practice Guidelines for treatment of depression
in the elderly, which provides a detailed discussion on
treatment algorithms and antidepressant considerations
in LLD.[31] However, a brief overview is provided below.
102
The pharmacological treatment options include selective
serotonin reuptake inhibitors (SSRIs) (citalopram,
escitalopram, sertraline, and fluoxetine), serotonin
noradrenaline reuptake inhibitors (venlafaxine, duloxetine,
and levomilnacipran), mirtazapine, bupropion, and
tricyclic antidepressants (desipramine and nortriptyline).
SSRIs are usually the first‑line unless contraindicated.
M o n o a m i n e ox i d a s e i n h i b i t o r s ( p h e n e l z i n e ,
tranylcypromine) are sometimes used in a very restricted
number of cases where other treatments are ineffective
or not tolerated.[3,6,31] The psychotherapeutic options are
problem‑solving therapy (PST; more rational in the context of
executive dysfunction), cognitive behavioral therapy (CBT;
for cognitively intact depressed elderly), behavioral
activation (BA), interpersonal therapy (useful due to high
prevalence of bereavement in this age group), problem
adaptation therapy (PATH; in depression and moderate
cognitive impairment), brief dynamic psychotherapy, and
ecosystem‑focused therapy (EFT; developed in poststroke
depression).[6] CBT, BA, and brief dynamic psychotherapy
are found equally efficacious in LLD.[3] Research domain
criteria group, NIMH, has proposed “Engage” psychotherapy
based on the neurobiological domains affected in LLD. It
focuses on assessing and targeting negativity bias, apathy,
or emotional dysregulation in response to reward exposure
in depressed individuals via psychotherapy.[57]
In treatment‑resistant depression (TRD), catatonia,
comorbid PD, inability to tolerate antidepressants, or acute
suicidality, electroconvulsive stimulation treatment (ECT)
can be administered. Right unilateral, ultra‑brief pulse,
high‑dose ECT is a common and safe choice in the elderly.
Other neurostimulation methods such as vagal nerve
stimulation and transcranial magnetic stimulation are not
mainly studied in LLD, and the efficacy results are usually
extrapolations of findings of adult study.[6] Maintenance
ECT with continued pharmacotherapy has been found
more efficacious in preventing relapse.[58] Treatment is
suggested to be continued in LLD for at least 6 months
after symptom remission and usually 2 years due to higher
risk of relapse.[6,59] Essential to note, retrograde amnesia
caused by ECT can be more pronounced in older adults
and persistent cognitive deficits may be seen in some
cases, especially in someone with preexisting mild or major
neurocognitive disorder.
Treatments targeting the models of LLD have insufficient
evidence as of now (dopamine D2/D3 agonists and
computerized cognitive remediation in DED, modification
of risk factors in vascular depression with possible role
of angiotensin receptor blockers and calcium channel
inhibitors, and anti‑inflammatory agents and cytokine
inhibitors, such as celecoxib and infliximab, in LLD with
increased inflammatory markers).[18]
Role of antidepressants in treating depression in AD is
doubtful. Some studies have found mild‑to‑moderate
short‑term efficacy though not sustained in the long run.
Depression in AD trial (DIADS)‑1 found significantly
more benefit with sertraline than placebo, given for
12 weeks, in depression in AD, whereas DIADS‑2,
continued on the remitted individuals for 12 more weeks,
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Mukhopadhyay and Banerjee: Clinical intersections of late‑life depression and dementias
found no superior efficacy for sertraline.[60,61] Similarly,
Health Technology Assessment Study of the Use of
Antidepressants for Depression in Dementia found no
more benefit with sertraline or mirtazapine than placebo
in treating depression in AD.[62] The National Institute of
Health and Care Excellence 2018 guidelines recommend
psychological treatments for mild‑to‑moderate depression/
anxiety in people living with mild–moderate dementias.[63]
Routine use of antidepressants is specifically discouraged
unless indicated for a preexisting severe mental illness.
Further, personalized multicomponent interventions
are recommended for sleep problems with or without
depression, which includes routine exercises and exposure
to sunlight.
In view of the evidence, the suggested first‑line treatment
for depression in AD is usually psychological, such
as PATH, caregiver‑focused treatment, PST, and brief
supportive therapy. Lifetime reminiscence and validation
therapy have also shown to help depression in AD.[14]
Neuroplasticity‑based computerized cognitive remediation
therapy targeting specific neurobiological deficits has
modest evidence in treatment‑resistant LLD (more in DDS
phenotype) and subcortical dementias. This again is an
evidence for the underlying common network abnormalities
in executive dysfunction and late‑life depressive
syndromes.[64] Depending on response to psychotherapy,
severity of depression, imminent risk of harm, functional
impairment and disability due to depression, and patient
and/or caregiver preference, judicial use of antidepressant
can be permitted. There is some evidence of reduction in
brain amyloid load with antidepressants in AD. However,
the duration of use of antidepressant in context of AD is not
very well formulated, and it is usually recommended to use
the drugs for a short term.[6,18] Certain specific management
considerations while dealing with depression in dementia
are highlighted in Table 6.
Finally, the primary preventive strategies of both all‑cause
dementia and LLD overlap significantly due to the common
risk factors. Recently, the 2020 Lancet Commission
Report on “Dementia Prevention, Intervention, and
Care” mentioned about 12 modifiable risk factors based
on a life‑course approach which accounts for 40%
theoretical risk of worldwide dementias.[65] Most of the
mid‑life (hypertension, alcohol consumption >21 units/
week) and late‑life risk factors (smoking, diabetes, obesity,
and physical inactivity) are related to lifestyle modification
and vascular vulnerabilities, which if modified are
also hypothesized to help depression.[18] Primary care
screening for depression, early detection, infection
control, collaborative care, and adequate management
are known to reduce cognitive decline in older adults.[66]
Especially in low‑resource countries, novel and large
depression prevention trials such as “Depression in late
life” conducted in Goa, India, involving nonspecialist lay
health workers have been shown to improve quality of life
and disability in the community geriatric population.[67]
Whether such interventions have a long‑term effect in
reducing the progression to dementia stays as a question
of further longitudinal research.
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Table 6: Specific considerations for depression in dementia
syndromes[14,31,63]
Assessment using adequate rating scales (e.g., CSDD)
Temporal correlation of the onset of cognitive and depressive symptoms
Apathy, anhedonia, fatigue and irritability are predominant
Worsening of preexisting cognitive functions/exacerbation of other
BPSD symptom clusters
Marked disability
Depressive cognitions and vegetative symptoms can be minimal to absent
Psychological treatments are best in mild‑moderate depression
Environmental modifications, controlling pain, and caregiver
education are vital
Check for the possibility of abuse/loneliness/other psychosocial triggers
Antidepressants with lowest propensity of anticholinergic burden and
least
pharmacological interactions are to be used (avoid TCAs, paroxetine)
Low dose stimulants (e.g., MPH) are beneficial both for depression
and cognition (modest effects)
Psychotic symptoms should be carefully evaluated (may be part of
BPSD): Routine use of antipsychotics is discouraged
ECT can be used safely for treatment resistant depression/suicidality
(extra caution for monitoring cognitive deficits)
CSDD: Cornell Scale for Depression in Dementia; BPSD: Behavioral and
psychological symptoms of dementia; TCA: Tricyclic antidepressants;
MPH: Methylphenidate; ECT: Emission computed tomography
The bottom‑line remains: In diagnostic doubt of whether
comorbid depression exists with a neurocognitive disorder,
it is always recommended to adequately treat the depression
and then assess the cognitive status at least 6 months
after remission of depressive symptoms.[59] Overtreatment
of depression in this regard is often suggested as the
underlying cognitive deficits may be reversible and may
have been exaggerated by the coexisting LLD. Appreciation
of this bidirectional relationship is vital.
A COMPLEX‑CONTINUOUS CONUNDRUM
Depression is frequently comorbid with both MCI and
dementias, as already mentioned earlier. These three
constructs of LLD, MCI, and dementia (especially AD)
are often argued as not being categorically distinct.
EOD and LOD, according to some authors, are known
to increase the risk of incident dementia.[2,14,16] There is
disagreement among researchers regarding LLD being a
predictor of conversion of MCI into dementia.[68,69] In one
study, patients with MCI, who developed AD, were found
to have more apathy and anxiety over 2 years.[70] MCI
and LLD are considered to share the pathogenic pathway
in two possible ways. The first is the accumulation of
AD neuropathology with concurrent cerebrovascular
disease burden over years, leading to manifestation of
MCI, on being coupled with depressed mood and reduced
brain reserve. The other is the role of cerebrovascular
diseases in causing LLD and MCI, more in the domains of
vascular cognitive impairment (e.g. executive dysfunction).
Vascular depression is in fact often comorbid with
recurrent strokes which in turn can lead to vascular
dementia. Other mechanisms include depression being an
early sign of MCI, sometimes unmasking and sometimes
overlapping it.[16] Similarly, high but varying incidence of
depression, from 11.7 to 26.6/100 person‑years, is found
in several studies in patients with MCI.[15,16] The variation
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is mostly attributed to different diagnostic tool use. The
depression–MCI–dementia continuum is not linear. Often,
someone who presents with a first episode of LLD (Case
Vignette 2) undergoes incomplete remissions, psychosocial
stressors, polypharmacy, side effects of medications,
chronic subsyndromal depressive symptoms, fluctuating
cognitive deficits, and impaired independent functioning
and then eventually slides into the spectrum of a major
neurocognitive disorder.
It has been shown that hippocampal atrophy and episodic
memory impairment, when observed in LLD (with or
without MCI), predict long‑term risk of development of
AD. Depression may lead to dysfunctional glucocorticoid
cascade, leading to serotonin and noradrenaline
dysfunction, hippocampal atrophy, and further, cognitive
impairment.[16] Persistent sleep disturbance in LLD has
a deleterious effect on neuronal activity, leading to a
chronic increase in soluble Aβ further increasing the risk of
amyloid plaque formation, a pathological process noted in
AD. Depression with sleep disturbance is seen to increase
the risk of AD by about threefold. This interconnection
among LLD, sleep disturbance, and dementia is stronger
in those with ApoE4 carrier status.[14] DMN hyperactivity,
as noted in depression, is also found to increase neuronal
activity and Aβ release (link with tau release is doubtful)
on amyloid‑PET imaging with Pittsburgh compound‑B.
On the other hand, Aβ deposition is seen to be associated
with significantly reduced FC between precuneus and
hippocampus. These findings point at a bidirectional
relationship between DMN activity and the risk of AD.[14,71]
LLD and dementia are thought to share another possible
pathogenetic mechanism. White matter changes and
temporal lobe atrophy are predictive of development
of both depression and dementia, as mentioned earlier
in the text. Worsening WMH is prognosticative of
nonremission in LLD over 2 years and of cognitive decline
over 5 years.[6] It is also noticed that older depressed adults
with moderate‑to‑severe treatment resistance have higher
amyloid burden, than milder and treatment‑responsive
depression, in parietal, temporal, occipital cortices, and
precuneus. The amyloid‑PET studies have shown amyloid
pathology in TRD to be typically similar to AD pathology.[14]
This argues for treatment‑resistant LLD to be a prodrome or
pointer of AD. Despite the presence of some distinguishing
features between LLD and AD on SPECT, the changes
often overlap. Clinically, two kinds of trajectories are
seen. Some patients with LLD develop MCI or AD over
the course of time, as discussed earlier. However, there
are up to 30% of those diagnosed with LLD who continue
to have chronic major depression over 1–6 years and
almost 40% stay in partial remission.[6] All these findings
suggest that LLD, MCI, and dementia possibly persist on a
clinicopathological continuum though further research is
warranted to elucidate more definitive biomarkers unique
to each pathological state.
CONCLUSION
This paper essentially tries to simplify the depression–
dementia conundrum for facilitating clinical management
and monitoring. Few related reviews/discussions related
to the subject are included in Table 7 to guide the readers
for additional information. To summarize, LLD, MCI, and
AD are interdependent entities, one often begetting the
other throughout the course. LLD can be conceptualized
as a prodrome or risk factor of MCI and dementia or may
be comorbid with the same. Although there is conflicting
evidence regarding the precise cause–effect relationship
between these three, it is likely that these constructs share
some common pathological processes and are more often
associated with each other than not. A recent systematic
review by Brzezinska et al. highlights that genetic

Table 7: Suggested reads on depression‑dementia conundrum for further study

Article title Authors Type Journal and year
The clinical interface of depression and dementia Raskind[72] Review J Clin Psychiatry, 1998
Pathways linking LLD to persistent cognitive impairment Butters et al.[17] Review Dialogues Clin Neurosci., 2008
and dementia
Depression versus dementia: How do we assess? Thorpe[2] Clinical approach The Canadian review of AD and
discussion other dementias, 2009
LLD, MCI, and dementia: Possible continuum? Panza et al.[16] Review Am J Geriatr Psychiatry, 2010
The complex relationship between depression and dementia Muliyala and Varghese[34] Review Ann Indian Acad Neurol, 2010
Depression and risk of developing dementia Byers and Yaffe[9] Review Nat Rev Neurol., 2011
The association between LLD, MCI and dementia: Is Hermida et al.[23] Review Expert Rev Neurother., 2012
inflammation the missing link?
Depression and dementia: Cause, consequence or Bennett and Thomas[73] Review Maturitas, 2014
coincidence?
Depression versus dementia: Is this construct still relevant? Ismail et al.[74] Review Neurodegener Dis Manag., 2014
LLD and the prodromes of dementia Steffens[10] Commentary JAMA Psychiatry, 2017
Clinical practice guidelines for management of depression Avasthi and Grover[31] Review and clinical Indian J Psychiatry, 2018
in elderly practice guidelines
Diagnosing and treating depression in patients with AD Burke[14] Review Neurol Ther., 2019
Depression in dementia or dementia in depression? Brzezińska et al.[75] Review Curr Alzheimer Res., 2020
systematic review of studies and hypotheses
Pathways connecting LLD and dementia Linnemann and Lang[76] Review Front Pharmacol., 2020
Depression in AD: A Delphi consensus on etiology, risk Agüera‑Ortiz et al.[77] Expert survey Front Psychiatry, 2021
factors, and clinical management
LLD: Late‑life depression; MCI: Mild cognitive impairment; AD: Alzheimer’s disease

104 Journal of Geriatric Mental Health | Volume 8 | Issue 2 | July‑December 2021

[Downloaded free from http://www.jgmh.org on Wednesday, February 9, 2022, IP: 200.89.66.6]
Mukhopadhyay and Banerjee: Clinical intersections of late‑life depression and dementias
polymorphisms are likely to explain the “variances in
shared phenomenology” between these three conditions.[75]
The authors also hypothesize that when these clinical
entities occur together, the order in which they present
clinically or are detected depending on individual physical
condition, neurocognitive reserves, medical history,
inflammatory diathesis, and frailty. Thus, it is preferable
to direct the clinical management and research in this
arena in a comprehensive way rather than pigeonholing
the diagnoses. Patients presenting with LLD must undergo
a comprehensive cognitive and mental status examination
cross‑sectionally and longitudinally with special emphasis
on social functioning, family support, instrumental
activities, and temporal evolution of symptoms. Similarly,
those with MCI should be evaluated for neuropsychiatric
symptoms, especially, depression, anxiety, and apathy,
for a better management and prognostication. Comorbid
depression often exaggerates the cognitive deficits making
MCI appear as mild AD or mild dementias appearing as
moderate (Case Vignette 1). Hence, in clinical ambiguity, it
is always better to treat the depression adequately and then
monitor for the cognitive status, change in functioning, and
quality of life. Research needs to be aimed at identifying
an accurate clinical and pathological relationship among
LLD, MCI, and all‑cause dementias, thereby paving the
path toward better clinical distinction, prevention, and
treatment.
Financial support and sponsorship
Nil.
Conflicts of interest
There are no conflicts of interest.
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