Invited article

Depression, cognitive impairment and dementia: Why should clinicians

care about the web of causation?
Mary Ganguli
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Professor of Psychiatry, Neurology, and Epidemiology, University of Pittsburgh School of Medicine and Graduate School of
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Public Health, Pittsburgh, PA 15208, USA

ABSTRACT

Depression, cognitive impairment and dementia are all common in older adults. The relationship between them is
bi-directional and complex. The literature on the subject is growing and fascinating but also riddled with apparent
inconsistencies. This brief review attempts to clarify and integrate information from clinical, laboratory, and community
studies and to draw some inferences of potential relevance to clinicians.

Key words: Aging, Alzheimer’s disease, cognitive decline

RELEVANCE AND SCOPE neurochemistry, biomarkers, or neuroimaging.

As standards of living improve across the globe, people There are both broad similarities and wide discrepancies
are living longer, and the world’s population is aging among different studies of depression, dementia,
rapidly.[1] Although the proportions of people aged 60 and cognitive impairment and decline. A key issue in
or more years are smaller in the “developing” countries understanding the similarities and discrepancies is
than in the “developed” countries, the sheer numbers of that different studies use different measurements and
older adults will by 2020 be much larger in the low and definitions, and examine very different groups of people. In
middle-income countries of the world than in the affluent the clinical psychiatry setting, we might see something very
countries. Thus, depression and dementia will soon different in our own patients to what is seen in neurology or
become major public health problems in countries such as general practice, or what is reported in the literature from
India.[2,3] Depression and dementia are both common in older a population-based epidemiologic study. Cross-sectional
adults; cognitive functioning declines slightly with normal and longitudinal studies may appear to show different
aging; depression itself can be associated with cognitive relationships. Observational and interventional studies may
impairment and dementia. Increasingly, there are intriguing appear to have conflicting results. To avoid becoming cynical
reports that suggest depression might itself increase the and frustrated ourselves by all the apparent inconsistency,
risk of dementia.[4] This article will briefly and selectively it is helpful to gain a more integrated understanding of
review the evidence and draw some broad inferences about the literature and its implications for clinicians. A useful
the relationships among these conditions. This review is epidemiologic concept is the “web of causation,” meaning
not intended to be comprehensive or systematic, and will - in this case - that most mental disorders do not have a
not touch on several important, interesting, and relevant single cause but are rather the result of multiple factors
issues such as genetics, pharmacology, lifestyle factors, that interact with one another in different ways at different
points along the life course.
Address for correspondence: Dr. Mary Ganguli,
Western Psychiatric Institute and Clinic, DEFINITIONS
3811 O’Hara Street, Pittsburgh, PA 15213, USA.
E-mail: gangulim@upmc.edu
First, we must define what we mean by depression.
Psychiatrists usually mean a depressive illness, characterized
How to cite this article: Ganguli M. Depression, cognitive
impairment and dementia: Why should clinicians care about
by depressed or otherwise low mood, sustained over several
the web of causation?. Indian J Psychiatry 2009;51:S29-34. days. This mood change itself occurs in the presence of a
few other features, such as disturbed sleep and/or appetite,

Indian J Psychiatry 51: Supplement, January 2009 S29

 Ganguli: Depression, cognitive impairment and dementia

energy, interest, low self-regard, perhaps guilt, pessimism minimal cognitive changes of normal aging and those
or hopelessness, and thoughts of death. Depending on the of early dementia. Depression also has a negative effect
diagnostic classification system being used, a depressive on processing speed, in a way exaggerating the effect of
episode in ICD-10[5] or a major depression in DSM-IV-TR[6] normal aging.[8]
requires a certain number of these symptoms to be present
over a certain period of time, usually two weeks. However, Fortunately, most health care providers have the same
non-psychiatric practitioners may not follow these understanding of the term dementia; most of us today do not
definitions as strictly as we do. Patients and their relatives use the term “senility” or consider dementia to be simply a
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may speak of being depressed without consulting all these sign of old age. However, there is an unfortunate tendency
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books and criteria, while some who fulfill the criteria in much of the literature for authors to use the words
may not call themselves depressed. Further, obtaining a “dementia” and “Alzheimer’s disease” as though they mean
history of a previous depressive episode may be difficult the same thing. On the other hand, sometimes patients or
because precise details are not always easy to remember. families ask, “Do I have dementia or do I have Alzheimer’s
In many studies, cognitive impairment and dementia have disease?” According to current definitions, dementia
been examined in relation to well-defined episodes of refers to a syndrome of acquired cognitive impairment,
depressive illness established by expert clinical assessment occurring in clear consciousness, sufficient to interfere with
of patients presenting for treatment.[7-11] However, in many social and occupational functioning, and characterized by
other studies, especially of community-based samples, impairment in at least two cognitive domains.[6] For the past
depression has been measured by scores on symptom rating few decades, the definition has required that memory be
scales.[12,13] one of the domains that is impaired, but this requirement
may not persist in future revisions of diagnostic criteria.
Next, we should look at what we mean by cognitive For example, it is possible that, in the future, an individual
impairment. In most studies, the term refers to poor with significant impairments in executive functioning and
performance on one or more standardized tests of language functioning can be diagnosed as having dementia,
cognitive functioning. Sometimes these are general mental even if memory has not been affected.
status tests, and sometimes they are large, comprehensive
batteries of tests of different cognitive functions. We Alzheimer’s disease is a primary neurodegenerative disease
know of course that cognitive test performance is heavily which appears to be the single most common cause of the
influenced by age and education, and, in some cases, by dementia syndrome in older adults in most populations
gender.[14] In clinical practice, we find patients or their which have been studied around the world.[3] The definitive
families talking about cognitive impairment as reflected diagnosis of Alzheimer’s disease is made post-mortem on the
in impaired functioning, forgetfulness, repetitiveness, basis of classic neuropathology: cortical atrophy, amyloid
difficulty in carrying out tasks that would have been routine plaques, and neurofibrillary tangles, seen particularly in
in the past, getting lost in familiar places or becoming the temporoparietal regions. Ante-mortem diagnosis is
disoriented. In some patients who report no difficulties, made clinically[19,20] and many experts now believe that
we find deficits on objective testing, and in others with hippocampal atrophy can be seen on magnetic resonance
significant complaints, we find no objective deficits. Some imaging (MRI) brain scans very early in the disease.[21-23] The
clinicians, and some studies, examine subjective reports by high proportion of dementias caused by Alzheimer’s disease
individuals or their families, asking standardized questions; has contributed to the terms “dementia” and “Alzheimer’s”
others rely solely on objective measures. The term mild being used interchangeably. It has also led to the diagnostic
cognitive impairment (MCI) has been in use since the early criteria for the dementia syndrome being “Alzheimerized”
1990s but about a decade ago it acquired the more specific by the requirement of specific impairment in memory.[24]
meaning of a “transitional” or intermediate state between
normal cognition and dementia. The precise operational The next single most frequent cause of dementia is
definition of this term has varied across studies and over cerebrovascular disease; either cortical infarcts or white
time[15] with some authors claiming that it is simply early matter disease, or both, can lead to significant cognitive
Alzheimer’s disease and not a separate entity.[16] impairment and decline. However, particularly among the
very old, it is more common to see Alzheimer’s and vascular
Cognitive decline is more difficult to pin down. A certain pathology co-existing than to see pure vascular disease
amount of change, particularly in the speed of information with no concomitant degenerative disease. To complicate
processing, is seen with normal aging.[17] However, if given matters further, many vascular factors increase risk of
the same test year after year, we become practiced at it Alzheimer’s disease.[25] Cerebrovascular disease, whether or
and may show no change or even an initial improvement not an overt stroke has occurred, is also well-established
in performance; this learning effect may conceal the mild as a source of depression.[26,27] Other less frequent primary
loss of ability which is occurring in the background.[18] It brain disorders causing dementia include frontotemporal
can be quite challenging to differentiate between the dementia, dementia with Lewy bodies, Parkinson’s disease,

S30 Indian J Psychiatry 51: Supplement, January 2009

 Ganguli: Depression, cognitive impairment and dementia

progressive supranuclear palsy, etc. Each of these has as depression remits, there is a residual cognitive deficit that
distinctive clinical and pathological features and many of remains present.[10,11,31] One community-based prospective
them have behavioral manifestations including depression; study found that depression was associated with increased
however, these conditions, and non-CNS conditions that risk of subsequent MCI.[13] However, another similar study,
cause or contribute to dementia, are beyond the scope of which categorized participants into those who went on to
the current review. develop dementia and those who remained dementia-free,
found that the former group declined substantially while
The concept of “brain reserve” was introduced by Katzman[28] the latter group did not. Depression at baseline did not
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in the context of an autopsy series in which almost all the predict cognitive decline in either group. In other words,
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brains examined had evidence of Alzheimer-type pathology, substantial cognitive decline was a function of underlying/
but not all of the individuals had manifested dementia incipient dementing illness rather than of depression.[12]
during life. It appeared that those who did not dement
clinically, despite pathology being present, were those who Depression and dementia: Many patients with Alzheimer’s
had larger brain mass and better preserved large neurons. and other dementias have depressed mood and other
Katzman theorized that the brains of these individuals had behavioral symptoms.[32,33] Some studies have shown that
a reserve capacity that allowed them to compensate for the these patients report depression well before they report
pathology sufficiently that they could continue to function cognitive difficulties, raising the possibility that depression
within the normal range. Another autopsy study showed was a risk factor for dementia. Meta-analyses of the world
that individuals who remained non-demented despite literature suggested that history of depression was a
degenerative neuropathology were those who did not have risk factor for dementia[34] and Alzheimer’s disease in
concomitant subcortical cerebrovascular disease which particular.[35] To quote a recent, comprehensive review, “the
presumably disrupted circuits and further compromised temporal association between cognitive and depressive
their brain reserve.[29] A parallel concept is that of “cognitive symptoms in elderly patients varies widely, yet increasing
reserve” which may derive partly from brain reserve and evidence suggests that depressive illness contributes to the
partly from other factors that increase cognitive capacity, development of persistent or progressive cognitive deficits in
such as premorbid intelligence, education, and mental some patients”.[36] One population-based study that examined
stimulation.[30] While neither brain reserve nor cognitive the temporal sequence concluded that although depressive
reserve prevent the development of pathology, they might symptoms preceded the onset of dementia symptoms,
help to delay or mitigate the clinical symptoms of dementia. depression appeared to be a prodrome rather than an
It must be clearly emphasized that the above are only independent predictor of dementia.[37] Thus, depression
conceptual models. might be a prodromal or early sign of dementia rather than a
separate condition or risk factor for dementia.
Relationships of depression with
cognitive impairment, decline, and Depressive pseudodementia vs. pre-dementia: It had been
dementia observed by clinicians for decades that when undergoing
cognitive testing, depressed patients would make minimal
Depression and cognitive impairment: A profusion of effort; they would often lose points not by giving wrong
studies have demonstrated that the presence of depression answers but by responding, “I don’t know.” It was believed
is associated with worse performance on cognitive tests, that, in contrast, patients with dementia were more likely
both in clinical samples of patients with depressive illnesses to give wrong answers, and therefore that “don’t know”
and in population-based samples of older adults drawn from responses might provide a clue as to the true diagnosis.
the community.[4-13] Many older patients with depression When these patients recovered from their depressions, they
complain of difficulty in concentrating and remembering, would no longer respond in this way; they would perform
and this subjective phenomenon is borne out by objective better on tests and appear restored to their previous level
studies showing that cognitive deficits in depression are of cognitive functioning. The term “depressive pseudo-
mediated almost entirely by slowed processing speed and dementia” was introduced to describe this phenomenon,
working memory (executive functioning).[7-9] There is some implying that the temporary dementia-like syndrome was
variation in results as to which cognitive domains are in fact due entirely to depression. This was a comforting
associated with depression, related in part to the nature of concept that encouraged us to look harder for evidence of
the study population. depression in cognitively impaired patients, and to treat a lot
of depression that might otherwise have been left untreated.
Depression and cognitive decline: There is less agreement However, objective research has shown that patients with
in the literature about the relationship between depression dementia are as or more likely than depressed patients to
and continued (progressive) cognitive decline over time. say “I don’t know”.[38] Further, as depressed, cognitively
Some treatment trials of patients with late-life depression impaired patients were systematically studied and followed
have shown that, although cognitive functioning improves over time, a significant proportion continued to experience

Indian J Psychiatry 51: Supplement, January 2009 S31

 Ganguli: Depression, cognitive impairment and dementia

progressive cognitive decline even though they were no compromised to the extent that deficits become apparent.
longer depressed.[39] Thus, it appeared that the impairment This ability to compensate can be conceptualized as part
seen during the depression was not “pseudo” but a pre- of the cognitive reserve discussed earlier.[30] Depression
dementia harbinger of more permanent cognitive decline may compromise cognitive reserve and allow symptoms
in the future. As disappointing as this was to clinicians, it of dementia to be manifested earlier than they would
opened the door to new thinking about the relationship have been otherwise. This could create a false impression
between depression and dementia. that the cognitive impairment is “caused” (rather than
unmasked) by the depression. If the depression remits,
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Possible mechanisms compensatory ability could be restored and the patient

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may appear unimpaired for a while.

Depression could be a psychological response to the
individual’s self-awareness of mild cognitive deficits that Some unfortunate individuals may have two separate
have not yet begun to interfere with daily functioning. illnesses, a primary depressive disorder as well a dementing
Individuals experiencing the earliest signs of incipient disorder; this conclusion is usually drawn when the
dementia may realize that something has changed and is individual has suffered recurrent depressive episodes
not quite right, without necessarily being able to say what earlier in life, and now has a dementia as well. A question
exactly is wrong. Routine tasks become difficult and effortful, that has emerged over the past several years is whether
and previously enjoyed activities (e.g., reading, card games) major depression in earlier life is an independent risk
are no longer pleasurable. A natural response might be to factor for Alzheimer’s disease in later life. Originally, case-
withdraw from these activities, leading others to assume control studies in memory disorders clinics showed that
that the person is suffering primarily from depression patients with Alzheimer’s were significantly more likely
and anhedonia. Individuals with more advanced deficits than healthy control subjects to have had a previous history
might realize what is wrong; most people would become of major depression.[44,45] Similar findings were reported
sad at the prospect of having an incurable progressive from population-based studies.[46,47] Depression, like stress
disease leading to loss of autonomy in even the most basic generally, raises cortisol levels.[48] Animal studies have
functions. Other individuals whose dementia manifests in demonstrated that prolonged hypercortisolemia leads to
part as anosognosia, or loss of insight, might not react with hippocampal atrophy in rats. [49,50] Hypothalamic-pituitary-
depressed mood. adrenal axis dysfunction in depression and Alzheimer’s
disease has distinct MRI correlates.[51] Neuroimaging
Depressive symptoms might be manifestations of the same studies have shown that depressed older adults have
underlying disease that has caused the dementia, whether hippocampal atrophy proportional to the duration of
Alzheimer’s or Parkinson’s diseases or another condition.[40,41] untreated depression.[52] In animal studies, stress-induced
Along with cholinergic system disruptions causing memory neuronal atrophy in the hippocampus, as well as spatial
loss, it is entirely possible that the progressive brain disease memory deficits, are actually reversible.[53] In an autopsy
affects serotonergic and noradrenergic systems as well. In study of people who died with Alzheimer’s disease, those
addition, some dementia patients exhibit emotional liability with a previous history of major depression had greater
with tearfulness, which is often mistaken for depression. density of amyloid plaques and neurofibrillary tangles in the
Post-stroke depression is a well-known phenomenon which hippocampus than other people who died with Alzheimer’s
often does not respond well to standard antidepressant but did not previously have depression.[54]
treatment.[26] A broader phenomenon is “vascular
depression”[42,43] denoting the presence of cerebrovascular This theory suggests that depressive illness, particularly if
disease but not necessarily an overt stroke. It is hypothesized prolonged and inadequately treated, may result in sustained
to operate by disruption of prefrontal systems that mediate elevations of serum cortisol. Hypercortisolemia in turn may
both mood and executive functions. lead to hippocampal damage, reducing its ability to resist
or compensate for degenerative damage from Alzheimer’s
When individuals with progressive brain disease finally disease. Imagine two individuals with incipient Alzheimer’s
manifest a clinical dementia syndrome, subclinical disease pathology in their brains. One of them has also
pathology has likely been developing for at least a few years suffered with depression over the years while the other
before the onset of symptoms. Symptoms appear when the did not. Both will develop clinical symptoms of dementia,
individual can no longer compensate functionally for the if they live long enough, but the former will develop
underlying pathology. Symptom onset can be viewed as a symptoms earlier than the latter, because the former’s
tipping of the balance between the amount of pathology hippocampus was already damaged by the depression.
in the brain and the individual’s ability to compensate. Depression did not cause the dementia, but increased
Either the amount of pathology has increased till it crossed the individual’s susceptibility to the dementia caused by
the clinical threshold, holding compensatory ability Alzheimer’s disease. This theory holds out the hope that
constant, or the compensatory mechanisms have become early, effective detection and treatment of depression could

S32 Indian J Psychiatry 51: Supplement, January 2009

 Ganguli: Depression, cognitive impairment and dementia

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