Depression in the Prodromal Phase of Alzheimer Disease and the Reverse Causal Hypothesis

It was a pleasure reading the article of Wilson et al¹ dealing with changes of depressive symptoms in the prodromal phase of Alzheimer disease (AD) in a large cohort of elderly subjects. They tested the reverse causality hypothesis, arguing that depression would be a consequence of the disease rather than a risk factor. The hypothesis is plausible from a biological standpoint and worthy of consideration since there is a continuum between normality, mild cognitive impairment, and AD. The follow-up period was long enough to detect an increase of depressive symptoms in the early phases of the disease. However, Wilson et al were unable to verify their hypothesis as no increases in depressive symptoms were detected before the diagnosis of AD was made. Aside from the possibility of low sensitivity of the self-reported instrument used to measure depressive symptoms in AD, increases in depressive symptoms were not observed in determined subgroups according to determined variables (perceived memory dysfunction, personality traits, and vascular disease).

This finding looks at the odds of the high prevalence of depression in AD even in mild stages of the disease.^{2 - 3} Furthermore, a European longitudinal study with elderly people from a community-based sample in different phases of cognitive decline, including a group with AD, showed that depressive symptoms increased in early phases of cognitive decline.⁴

I think the major drawback of the study is the highly selected population of the cohort (nuns, priests, and monks), which lessens the ability to extrapolate the results to the general elderly population. Very homogeneous cohorts are ideal for analytical studies aimed at determining the association of determined risk factors and diseases because diet, habits, and lifestyle are similar or equal and biases can be avoided. However, these cohorts may not reflect the true strength of the association in the general population.

The relationship between religiosity and depression has been the focus of numerous reports, with intrinsic religiosity (personal feeling of the importance of spirituality and religion) being a highly protective factor for depression. An American study conducted in the Bible Belt region in elderly patients with medical diseases showed that religiosity hastened remission of depression after 1-year follow-up. Patients with high levels of religiosity were twice as likely to improve as those with low levels.⁵ In a cohort of women with a history of major depression followed up for 10 years, religiosity was related to a high degree of protection against recurrence.⁶ Religiosity was associated with less depression and better self-esteem in caregivers of people with mental illness.⁷ Personal devotion and institutional conservatism were protective against depression triggered by stressful events such as death and personal illness. This effect was found after adjusting for several demographic and personality variables. Although the association is complex, it was suggested that there may be a favorable influence of religiosity in the coping process.⁸

The cohort of Wilson et al is totally composed of religious people so it is understandable that high levels of religiosity must exist in these subjects. Thus, the perception of symptoms, the type of stressful events, and the manner in which they cope may be different from those of the general population. Taking into account the aim of the study and the protective effects of religiosity, this cohort could be to some extent biased in nature and the reverse causality hypothesis cannot be ruled out.

Correspondence: Dr Modrego, Department of Neurology, Miguel Serve University Hospital, 50009 Zaragoza, Spain (pmodrego@salud.aragon.es).

Financial Disclosure: None reported.