Context A history of depression may increase risk for developing Alzheimer disease (AD) later in life. Clarifying this relation might improve understanding of risk factors for and disease mechanisms in AD. Objective To systematically review and complete a meta-analysis on the relation of depression and AD. Data sources We conducted electronic bibliographic searches of MEDLINE, PsychLit, EMBASE, and BIOSIS using search terms sensitive to studies of etiology combined with searches on terms related to depression and AD and reviewed reference lists of articles. Study selection Studies with data contrasting depressed vs nondepressed patients who did and did not later develop AD were included. Studies that related continuous measures of depression and cognitive status were excluded. Data extraction Numerical data were independently extracted by 3 reviewers. They also rated studies on a scale that assessed quality indicators for observational studies. Data on the interval between observation of depression and the diagnosis of AD were collected when available. Data synthesis Meta-analytic evaluation with random-effects models resulted in pooled odds ratios of 2.03 (95% confidence interval, 1.73-2.38) for case-control and of 1.90 (95% confidence interval, 1.55-2.33) for cohort studies. Findings of increased risk were robust to sensitivity analyses. Interval between diagnoses of depression and AD was positively related to increased risk of developing AD, suggesting that rather than a prodrome, depression may be a risk factor for AD. Conclusions A history of depression may confer an increased risk for later developing AD. This relation may reflect an independent risk factor for the disease.

https://jamanetwork.com/journals/jamapsychiatry/articlepdf/209578/yoa50281.pdf

Depression and Risk for Alzheimer Disease: Systematic Review, Meta-analysis, and Metaregression Analysis

Context Cognitive impairment in late-life depression (LLD) is highly prevalent, disabling, poorly understood, and likely related to long-term outcome. Objectives To determine the characteristics and determinants of neuropsychological functioning LLD. Design Cross-sectional study of groups of LLD patients and control subjects. Setting Outpatient, university-based depression research clinic. Participants One hundred patients without dementia 60 years and older who met DSM-IV criteria for current episode of unipolar major depression (nonpsychotic) and 40 nondepressed, age- and education-equated control subjects. Main Outcome Measures A comprehensive neuropsychological battery. Results Relative to control subjects, LLD patients performed poorer in all cognitive domains. More than half exhibited significant impairment (performance below the 10th percentile of the control group). Information processing speed and visuospatial and executive abilities were the most broadly and frequently impaired. The neuropsychological impairments were mediated almost entirely by slowed information processing (β = .45-.80). Education (β = .32) and ventricular atrophy (β = .28) made additional modest contributions to variance in measures of language ability. Medical and vascular disease burden, apolipoprotein E genotype, and serum anticholinergicity did not contribute to variance in any cognitive domain. Conclusions Late-life depression is characterized by slowed information processing, which affects all realms of cognition. This supports the concept that frontostriatal dysfunction plays a key role in LLD. The putative role of some risk factors was validated (eg, advanced age, low education, depression severity), whereas others were not (eg, medical burden, age at onset of first depressive episode). Further studies of neuropsychological functioning in remitted LLD patients are needed to parse episode-related and persistent factors and to relate them to underlying neural dysfunction.

https://jamanetwork.com/journals/jamapsychiatry/articlepdf/482019/YOA30368.pdf

The nature and determinants of neuropsychological functioning in late-life depression.

Background: It remains unclear whether depression increases the risk for dementia in the elderly. We evaluated the relationship between depressed mood at baseline and the incidence of dementia, particularly Alzheimer's disease, in the elderly living in the community. Methods: A total of 1070 elderly individuals, aged 60 years or older, were identified as part of a registry for dementia in the Washington Heights community of North Manhattan, NY. In a prospective, longitudinal design with follow-up for 1 to 5 years, annual physician evaluation and neuropsychological testing were used to assess levels of cognitive impairment and to diagnose dementia. Depressive symptoms were evaluated with the 17-item Hamilton Rating Scale for Depression. Based on clinical considerations and a validity study, a positive score for the depressed mood item was used in statistical analyses. To confirm the results, the total Hamilton Rating Scale for Depression score was also evaluated as the "depression" variable. Results: Of the 1070 subjects, 218 met criteria for dementia at baseline evaluation. In the 852 subjects without dementia, depressed mood was more common in individuals with greater cognitive impairment. In a follow-up study of 478 of these subjects without dementia (mean±SD, 2.54±1.12 years of follow-up), the effect of baseline depressed mood on the end-point diagnosis of dementia (93% had possible or probable Alzheimer's disease) was evaluated in a Cox proportional hazards model. Depressed mood at baseline was associated with an increased risk of incident dementia (relative risk, 2.94; 95% confidence interval, 1.76 to 4.91;P Conclusions: Depressed mood moderately increased the risk of developing dementia, primarily Alzheimer's disease. Whether depressed mood is a very early manifestation of Alzheimer's disease, or increases susceptibility through another mechanism, remains to be determined.

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Depressed mood and the incidence of Alzheimer's disease in the elderly living in the community.

Clinical and epidemiologic research has focused on the identification of risk factors that may be modified in predementia syndromes, at a preclinical and early clinical stage of dementing disorders, with specific attention to the role of depression. Our goal was to provide an overview of these studies and more specifically to describe the prevalence and incidence of depression in individuals with mild cognitive impairment (MCI), the possible impact of depressive symptoms on incident MCI, or its progression to dementia and the possible mechanisms behind the observed associations. Prevalence and incidence of depressive symptoms or syndromes in MCI vary as a result of different diagnostic criteria and different sampling and assessment procedures. The prevalence of depression in individuals with MCI was higher in hospital-based studies (median: 44.3%, range: 9%–83%) than in population-based studies (median: 15.7%, range: 3%–63%), reflecting different referral patterns and selection criteria. Incidence of depressive symptoms varied from 11.7 to 26.6/100 person-years in hospital-based and population-based studies. For depressed normal subjects and depressed patients with MCI, the findings on increased risk of incident MCI or its progression to dementia were conflicting. These contrasting findings suggested that the length of the follow-up period, the study design, the sample population, and methodological differences may be central for detecting an association between baseline depression and subsequent development of MCI or its progression to dementia. Assuming that MCI may be the earliest identifiable clinical stage of dementia, depressive symptoms may be an early manifestation rather than a risk factor for dementia and Alzheimer disease, arguing that the underlying neuropathological condition that causes MCI or dementia also causes depressive symptoms. In this scenario, at least in certain subsets of elderly patients, late-life depression, MCI, and dementia could represent a possible clinical continuum.

Late-Life Depression, Mild Cognitive Impairment, and Dementia: Possible Continuum?

Background Depression symptoms may be associated with the development of Alzheimer disease (AD). Objectives To evaluate the association between depression symptoms and risk of AD, and to explore the temporal aspects of this association. Setting Academic institutions with specialized memory clinics. Design Cross-sectional, family-based, case-control study with standardized self- and proxy questionnaires to collect information on depression symptoms and other risk factors. Participants A total of 1953 subjects with AD and 2093 of their unaffected relatives enrolled in the Multi-institutional Research in Alzheimer's Genetic Epidemiology Study. Main Outcome Measures Odds ratios (ORs) of AD were estimated with and without depression symptoms, adjusted for age, sex, education, history of head trauma, and apolipoprotein E status. Results There was a significant association between depression symptoms and AD (adjusted OR, 2.13; 95% confidence interval [CI], 1.71-2.67). In families where depression symptoms first occurred within 1 year before the onset of AD, the association was higher (OR, 4.57; 95% CI, 2.87-7.31), while in the families where the depression symptoms first occurred more than 1 year before the onset of AD, the association was lower (OR, 1.38; 95% CI, 1.03-1.85). In families where depression symptoms first occurred more than 25 years before the onset of AD, there was still a modest association (OR, 1.71; 95% CI, 1.03-2.82). Conclusions Depression symptoms before the onset of AD are associated with the development of AD, even in families where first depression symptoms occurred more than 25 years before the onset of AD. These data suggest that depression symptoms are a risk factor for later development of AD.

/pdf/depression-as-a-risk-factor-for-alzheimer-disease-the-mirage-25qt3s491y.pdf

Depression as a risk factor for Alzheimer disease: the MIRAGE Study.

Data from case-control studies of Alzheimer's disease (AD) were pooled to examine the possible roles of history of depression, anti-depressant treatment and adverse life events as risk factors. History of depression was found to be associated with AD, although the effect was confined to late onset cases. The association held for episodes of depression more than 10 years before AD onset, as well as for episodes occurring within a decade of onset. No association was found with anti-depressant treatment. However, data were only available from two studies, limiting the power of the analysis. Also, no association was found with the three major life events considered in the pooled analysis: death of spouse, death of a child and divorce.

/pdf/psychiatric-history-and-related-exposures-as-risk-factors-2pf9tcbl9w.pdf

W.A. Rocca

Papers

Psychiatric History and Related Exposures as Risk Factors for Alzheimer's Disease: A Collaborative Re-Analysis of Case-Control Studies