We found distinct differences in cognitive decline, as measured by the MMSE, over time in residents with depression compared with residents without depression. The effect remained stable beyond the effect of dementia diagnosis alone and was sizable in that it reflected a 4-point decline in MMSE over about 3 years relative to residents without depression. Furthermore, there was a significant depression by dementia interaction, suggesting that the presence of comorbid depression in dementia further accelerates cognitive decline. Although residents suffering from dementia, on average, declined 13.7 points over about 3 years, the presence of depression in dementia led to an additional loss of ~2.7 points on the MMSE during the course of this study, showing that the presence of comorbid depression accelerates cognitive decline associated with dementia in old age. When restricting our analyses to cases with AD and vascular dementia only (N = 156), we found that patients with AD and comorbid depression exhibited an additional decline of ~2.2 points on the MMSE during the course of this study, suggesting that depression may exert specific effects on the course of cognitive decline in AD. Such an interaction could be mediated by effects of depression on AD neuropathology,23
which may be driven by depression-associated changes in the neurotrophin system,24
but we cannot characterize such neurobiological changes from the present data.
The assessment of major depression and depression history in dementia, as used in our study, is characterized by intrinsic methodological limitations. The reported point prevalence of depression in older nursing home residents ranges from 6% to 32%2
and is thus comparable with the prevalence of ~10% in our sample. However, clinical studies suggest that the prevalence of depression in dementia may be even higher, ranging from 30% to >50%,1
suggesting that the prevalence of depression in our sample may have been underestimated. Prior studies showed that, when informants and structured interviews are used, interrater reliability might not exceed 80%.39,40
Thus, the accuracy of the depression diagnoses in our sample may be limited. On the one hand, underestimating the incidence of depression is likely to have biased the results toward a reduced estimate of the influence of depression on cognitive function, raising the possibility that depression impacts the rate of progression of dementia more than that observed in this study. On the other hand, the diagnosis of depression in dementia is clinically difficult, and we may have missed depressed patients with dementia with our assessment that could have been detected using specific scales for the assessment of depression in dementia. Therefore, depression severity may have been a factor, with greater depressive symptoms leading to cognitive decline. However, because there was no measure of depression severity, this possibility cannot be tested. In addition, we cannot rule out that the effects of depression on cognitive decline in dementia are in part due to psychotropic medications prescribed, because we lack these data in our sample.
Furthermore, overall sample size made it difficult to examine effects of different types of depression and/or depression duration across the lifespan on cognitive decline in dementia. For example, we explored whether onset of depression (recurrent, early onset versus late onset) had a differential effect on cognitive decline, and model fit did not change when adding that variable (−2log likelihood = 61; χ2 = 1.98, df = 2, p = 0.64), but limited power prohibits further interpretation of that finding.
Despite these limitations, the results showed that the presence of depression in older adults suffering from dementia is associated with accelerated cognitive decline. Moreover, we analyzed longitudinal data from elderly with a wide, yet more or less normally distributed, range of educational attainment and a wide range of cognitive functioning. Our study points to an accelerated decline in patients with dementia and specifically patients with AD with comorbid depression. Our study is in line with two other studies showing accelerated cognitive decline in dementia as a function of depression,24,25
whereas most community-based studies did not find such an effect.11,22,23
In community-based studies, it has been shown that depression in itself may not be a risk factor for dementia.27
It may well be that detecting the comparably small additive effects of depression on cognitive decline in dementia is more likely when comparing patients diagnosed with depression to nondepressed patients with dementia, rather than using continuous measures of depression, and associated neurobiological changes may be especially pronounced in major depressive disorder, as has been shown, e.g., changes in the neurotrophin system.24
A key limitation in that context is that we did not investigate possible underlying neurobiological changes as a function of comorbid depression, and future longitudinal studies are needed to address this issue.
Recent studies suggests accelerated amyloid pathology in subjects with depression.31,32
Such an increase in amyloid pathology in persons with depression may provide another potential mechanism for the results observed in this study. This hypothesis is consistent with our earlier observation of increased neuritic plaque an neurofibrillary tangle pathology in persons with a lifetime history of depression and AD.25,30
However, we lack more detailed information on depression that could be of interest, such as disease duration, number of prior episodes, and medication treatment, that could help develop hypotheses on possible mechanisms of accelerated cognitive decline in depression and dementia. Conceptually, depressive symptoms may be an early manifestation rather than a risk factor for dementia and AD, in that the underlying neuropathological condition that causes dementia may also cause depressive symptoms.41
It is possible, albeit unproven in this study, that factors such as reduced cognitive42
or neurobiological reserve in dementia may have contributed to the greater impact of depression on cognitive decline. Comorbid depression in dementia often goes undetected in the clinical context and may result in higher rates of nursing home placement in patients with dementia by increasing their functional disability.43
To conclude, we showed that the presence of major depression leads to accelerated cognitive decline in dementia beyond age, gender, and level of education, suggesting a unique influence of depression on cognitive decline in dementia.