A quick look at our results would suggest that the association between depressive symptoms and cognitive deficit in late midlife is being driven by cross-sectional associations. However, this interpretation does not take into account the fact that depressive episodes tend to cluster in individuals. 49% of those with (distal) GHQ depression at Phases 1, 2 or 3 also had (proximal) depressive symptoms at Phases 5, 6 or 7. Furthermore, 43% of those with 2–3 episodes of ‘distal’ depressive symptoms also had 2–3 episodes of ‘proximal’ depressive symptoms. The persistence effect is stronger when looking at all 6 measures of GHQ depression over the 18-year period. In all, 250 participants reported depressive episodes between 4 and 6 times over the total follow-up period; out of these 210 (84%) had 2–3 episodes of ‘distal’ and 218 (87%) reported ‘proximal’ depressive symptoms. Thus, clearly a subgroup of individuals report persistent depressive symptoms and our results suggest that it is this group that has greater risk of cognitive deficits in late midlife.
The association between depressive symptoms and cognition, impaired cognition or dementia has been much examined in the research literature. There is a general consensus that it is important to examine the temporal aspect of this association in order to make sense of the three different explanations of this association: depression as a cause or a consequence of cognitive decline, plus the common cause hypothesis. Considerable attention has been paid to separating the cross-sectional from the longitudinal associations6;7
and examining either multiple waves of data on cognition10–14
. Less attention has been paid to measuring depression over the adult lifecourse. The exceptions are studies that assess history of depression20;27;28;49;49
. However, two of these studies measure depression history retrospectively, 24;27
and are likely to suffer from some recall bias, particularly as they are based on the elderly. The other two studies use medical data to show increased risk of cognitive deficit with increases in the number of episodes of depressive disorders28
or with recurrent depression49
. One of these used data on hospital admissions for affective disorders28
and the other was on an elderly sample and used data drawn from physician records49
A recent meta-analysis examined the association between depression and Alzheimer’s disease (AD) and reported an OR of 2.02 (95% CI=1.80–2.26) for AD among those with a history of depression36
. The review also found a positive association between a longer interval between the diagnosis of depression and an increased risk of AD, in the few studies where it was available. The conclusion reached by the review was that depression appears to be a risk factor rather than a prodrome of AD. However, subsequent work continues to show inconsistent results. Data from the Rush Religious Orders Study50
and the Rotterdam Scan study35
suggest no increase in depressive symptoms during the prodromal phase of dementia but a Swedish Twin study found the contrary.51
Finally, another study found only “severe” depression to be a risk factor for dementia.32
However, in studies on the elderly, when the risk factor being examined is influenced by early subclinical stages of disease, protopathic bias is a real concern. Studies like ours that shift the observation window to midlife are likely to be unbiased in this regard. Our results suggest that multiple or persistent episodes of depressive symptoms are associated with greater risk of cognitive deficits. The association of frequent proximal depressive episodes with cognition was somewhat more robust than that with frequent distal depressive episodes. However, in further analyses (not shown but available on request) we excluded all individuals with distal episodes and the associations for proximal episodes were much reduced. Thus, clearly it is persistent depressive symptoms that are either a risk factor or identify a group of individuals at risk of cognitive deficits.
Of the studies examining dementia as an outcome, a majority have focussed on AD11;17;21;22;24–27;29;30;36
, which implicates deficits in memory38;39
. Our results suggest a consistent effect of depressive symptoms (history, cross-sectional, distal, proximal and overall frequency) on memory deficits. One study on the elderly reported recurrent depression or history of depression to be characterized by deficits in memory49
, suggesting that memory might be particularly vulnerable domain. However, another study in which depressive symptoms were associated with an increased risk of mild cognitive impairment (MCI) showed stronger effects for the MCI subtype without memory impairment15
. In general terms, the mechanisms behind the association between depression and cognition remain little understood. It has been suggested that the link between depression and cognition can be attributed to vascular disease10;11;19;23;25;30;31
, reflecting the common cause hypothesis. In our data, as in other studies,52
statistical adjustment for vascular disease did not much change the association between persistent depressive symptoms and cognitive deficit.
Our study has several strengths and limitations. The strengths lie in the size of the study; the 6 measures of depressive symptoms over 18 years and multiple measures of cognition. A further strength is the examination of the link between depression and cognition in an age-group where incipient dementia is less likely to be a confounding factor. The limitations are mostly to do with the scale used to assess depression. The GHQ depression scale used is only a part of the seven item depression scale of the GHQ 28. GHQ depression is also best considered to be a measure of depressive symptoms, and should not be equated with clinically diagnosed depression42
. It is essentially a measure of self-reported depressive symptoms and although reliable, it does not indicate the severity of depression. There is some evidence to suggest that major depression has a stronger effect on cognitive impairment4;32
. Nevertheless, our six measures of depressive symptoms are a good measure of persistent depression. A further limitation is that no data were available for cognition at baseline and thus it remains unclear to what extent cognitive functioning at study entry determined subsequent trajectories of depression. Finally, the Whitehall II study is based on white-collar civil servants and is not representative of the general population, limiting the generalisability of our results.
In conclusion, our study of middle-aged adults from the Whitehall II cohort shows that persistent depressive symptoms are a risk factor for cognition in late midlife. This association is independent of vascular risk factors and appears to implicate memory in particular. Of the three hypotheses put forward to explain the association between depression and cognition – depression as a cause or a consequence and the common cause hypothesis – we did not examine the hypothesis that depression was a consequence of declining cognition. However, there was little evidence of vascular diseases explaining away the association between persistent depressive symptoms and cognition. Our results suggest an association between persistent depressive symptoms and poor cognitive function in late midlife. However, whether this association is causal remains unclear as the precise mechanisms linking depression to cognitive functioning remain to be elucidated.