The two patients described below visited the memory clinic. Both were referred by their GP for the evaluation of their cognitive complaints (Case B is adapted from Ramakers [1]).

Much research has focused on the differentiation between depression and dementia, but less on depression and MCI. This is remarkable, as in clinical practice the differentiation between depression and MCI might be more relevant. This is related to the fact that people with MCI are more prevalent than people with dementia and that most patients with dementia have gone through the stage of MCI, but, on the contrary, not all people with MCI will eventually fulfill the criteria of dementia.

Part of the problem of differentiation may be related to the partial overlap of symptoms described in the diagnostic criteria of both conditions. An important aspect is that both MCI and depression are defined as clinical syndromes, i.e., a group of symptoms, without reference to the underlying etiology. Although the concept of MCI is often used to describe the predementia stage of Alzheimer’s disease (AD), just having mild cognitive impairments in itself is not per se. Meta-analysis findings showed that the mean annual conversion rate to dementia in people with MCI is 10.2 % [3], compared to 1 % in the general population [4]. Contrary to what many clinicians think, a substantial proportion of people with MCI will not progress to dementia even after 10 years of follow-up, as was shown in a recent meta-analysis of the results of 41 robust cohort studies [5]. This has led to a further specification of the criteria, for instance, of MCI due to AD [6] or vascular cognitive impairment [7], in order to specify the underlying cause with use of biomarkers (such as brain imaging like CT, MRI or PET scan, or cerebrospinal fluid (CSF)).

Symptoms such as decreased mood, loss of interest, and loss of energy may occur both in the context of primary depression and MCI due to AD or other dementia disorders. It is often implicitly assumed that there is one uniform syndrome of depression in all patients with cognitive disorders. However, it can be doubted whether this is the case. Given the strong impact of cognitive deficits on the presentation of depressive illness, the severity and profile of cognitive symptoms should be taken into account when evaluating for depression. It is unlikely that depression in mildly cognitively impaired subjects share the same pathogenesis as we may find in dementia in later stages. Variance in nature and severity of neurobiological changes is likely to have consequences for the type of depression. Whereas the psychological impact of the disease is inevitable in the early stages, the situation may be different in more severe stages. A substantial part of depressive symptoms (e.g., loss of motivation) in the later stages of dementia might be better explained in neurobiological terms.

In addition, a mere categorical approach, in which symptoms are simply counted in order to make a syndrome diagnosis, often fails in the context of geriatric psychiatry, because it denies that depressive symptoms in primary depression and in MCI due to AD (or other forms of dementia) may differ qualitatively from each other. Clearly, a more qualitative, phenomenological approach is needed here in order to attribute symptoms to one disorder or the other [8]. Depressive mood in mildly cognitively impaired patients is usually less pervasive; patients may be distracted and be “cheered up” more easily than is the case in typical depression. The symptom “sleep disturbance” may have a different quality from a psychopathological viewpoint, for instance, problems with falling asleep due to mental rumination, compared to the same symptom in dementia, in which they may wake up and think that it is time to get out of bed due to disorientation in time. Likewise, the symptom “loss of interest” has a different meaning in depression (where the patient does not feel invited to otherwise pleasant events), compared to dementia (in which the patient is not aware anymore of this events due to memory loss).

This notion has led to the adaptation of specific criteria for depression in patients with AD dementia [9]. For instance, the DSM’s criterion “marked diminished interest or pleasure in (almost) all activities” is adapted for patients with AD dementia as follows: “Decreased positive affect or pleasure in response to social contacts and usual activities.” So far, there is no well-established set of criteria for depressive disorder in people with MCI, but it is likely that depression in MCI differs from depression in general.

In a longitudinal study that was performed by the authors and colleagues among 116 non-demented patients from our memory clinic, 13 out of the 25 patients who turned out to have AD dementia after follow-up of at least 2 years were initially diagnosed as depressed. Mild depression, but not major depression, was more common in those who became demented than those who did not. Multivariate analysis showed that patients with high age and more severe cognitive decline but less severe depression at baseline were at risk of developing dementia at follow-up [10]. The mean HDRS score at baseline in these subjects was 9.1, indicating mild depressive symptomatology. Patients with dementia at follow-up seemed at baseline emotionally more vulnerable for environmental circumstances than in depression. Typically, they demonstrated feelings of lowered mood, anxiety, and worrying in stressful situations. Relatively little stressing events were experienced as a major challenge, but when their circumstances were favorable and calm, they reported less depressive complaints. Thus, the picture of depressive symptoms in predementia differs from that of a classic depressive disorder. We have suggested elsewhere that the term “emotional vulnerability syndrome” describes their situation more appropriately [8]. Criteria for this condition are presented in Box 2.1 .

Due to the high frequency of depressive symptomatology, we advocate the use of depression rating scales in clinical practice for mental status examination as symptom checklists and to measure severity of symptoms in an individual patient. However, because the commonly used depression rating scales are not specifically designed to score the abovementioned symptoms that are prevalent in predementia, we cannot recommend the use of traditional cutoff scores in deciding whether a patient is depressed or not. With this in mind, we use the HDRS (17-item, clinician-based) [11], the Geriatric Depression Scale (15-item, self-rating) [12], and the Neuropsychiatric Inventory (12-item, informant-based) [13], which in our opinion is a good composition of well-known and validated scales for measuring depressive symptomatology from several perspectives in a memory clinic setting.

In both people with dementia and MCI, affective symptoms are very common and cause a severe burden for patients and their caregivers. Previous studies among people with AD dementia found that 80–90 % of the people reported neuropsychiatric symptoms. Findings from a large study of 12 centers from the European Alzheimer’s Disease Consortium found affective symptoms, such as depression and anxiety, to be very common in dementia [14].

In people with MCI, prevalence rates of neuropsychiatric symptoms range from 35 to 75 % [15], again with depression, anxiety, apathy, and irritability being most common. The large range in prevalence rates can be explained by several factors: a wide diversity in study characteristics, such as different sampling methods, different settings, differences in MCI definitions, or the sensitivity of the instruments used to measure neuropsychiatric symptomatology. Higher prevalence rates were found in hospital-based samples (median value 44 %) compared to population-based cohorts (median value 16 %) [16]. More specifically, Monastero et al. [17] found depressive symptoms to be present in 9–78 % of the MCI patients attending hospital-based settings, with highest prevalence rates for subjects directly attending a memory clinic. A recent study into social and demographic factors that might influence affective symptoms in MCI, including data from 3456 participants, showed that a higher presence of depressive symptoms in MCI was related to younger age, female gender, lower education, not being married, a Caucasian ethnicity, and more functional impairment [18]. Additionally, several studies investigated whether specific cognitive profiles, such as amnestic or non-amnestic subtypes of MCI, were related to specific affective symptoms, but results remained inconsistent [19–21].

On the other hand, cognitive deficits in people with depression are widespread and not limited to memory. Christensen et al. [22] found cognitive deficits in depressed people in almost every cognitive test, with an average deficit of 0.63 standard deviations compared to nondepressed people. However prevalence rates about MCI in people with depressive symptomatology remain unclear [23].

Affective symptoms have often been studied as a risk factor for developing dementia [24–26]. A recent study, in which the outcome of a review of epidemiological studies was in agreement which expert opinions, identified depression to be the strongest modifiable risk factor for dementia [27]. Whether depression also is an independent risk factor for dementia in people suffering from MCI yielded conflicting results. Based on 13 studies, a recent meta-analysis into predictors of dementia in people with MCI found that depression was a risk factor for developing dementia only in population-based studies [28]. Another recent in-depth meta-analysis by the authors of this chapter (Tan et al., unpublished data, submitted), resulting in 29 studies (including more than 10,000 people with MCI), confirmed the increased risk of depressive symptoms for developing dementia only in population-based studies. In clinical studies, the overall effect of depressive symptoms on the conversion rate to dementia was not significant, while the heterogeneity in study findings was large. This heterogeneity is probably related to the large diversity among memory clinics inside and outside hospitals, different patient populations (e.g., geriatrics, neurology, or psychiatry), or using different definitions or measuring qualitatively different aspects within the heterogeneity of depressive syndromes. Based on these findings, we conclude that depressive symptoms in cognitively impaired people are a risk factor for dementia, but also that, in clinical settings, depressive symptoms are of limited value for identifying MCI subjects at risk of dementia.

The direction of causality in the relationship between affective symptoms, cognitive impairments, and dementia remains poorly understood, as several mechanisms may be plausible. It should be noted that the increased risk of affective symptomatology for the development of dementia as mentioned before means no more than that affective symptoms are relatively more often present in subjects who convert to dementia, compared to the group of non-converters. It does not indicate any underlying causal relationships or etiological explanations for this complex interplay. Contradictory findings about these complex relationships maintain the discussion whether affective symptoms are a prodrome, or a risk factor of dementia, or both.