Inflammatory signaling in Alzheimer disease and depression

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To help define the relationships among inflammation, Alzheimer disease, and depression, the Texas Alzheimer’s Research Consortium analyzed an array of inflammatory biomarkers in a cohort of patients with Alzheimer disease and in controls. Inflammation severity was highly correlated with earlier age at onset of Alzheimer disease and was also associated with cognitive decline. The relationship between inflammation and depression was not as clear, and it varied with aspects of depression, gender, and the presence of Alzheimer disease.



The relationships among inflammation, Alzheimer disease, and depression have been the subject of recent research at several centers. Alzheimer disease and depression appear to be linked by several genetic and inflammatory processes, although the exact nature of the relationship is not clearly understood. The two disorders also share risk factors for vascular disease. This article reviews the current state of knowledge about inflammation and its implications for Alzheimer disease and depression, and it presents recent findings from the Texas Alzheimer’s Research Consortium, which assessed an array of inflammatory markers in a cohort of patients with Alzheimer disease.


Alzheimer disease and depression share several vascular disease risk factors and appear to be linked through complex and integrated processes. The link may be mediated by long-term inflammatory processes. Hypothalamic-pituitary-adrenal (HPA) axis dysfunction, chronic inflammation, and a deficit in neurotrophin signaling all may play roles in the pathogenesis of depression and Alzheimer disease.1 Excessive release of glucocorticoids subsequent to HPA-axis dysfunction in chronic depression appears to damage the hippocampus: hippocampal atrophy is a feature in both depression and dementia, and recurrent depression is associated with greater atrophy. The direction of influence—whether depression leads to the factors that increase the risk of Alzheimer disease or the other way around—remains a controversial topic.

Symptoms of depression tend to appear early in Alzheimer disease and increase as dementia progresses to moderate severity. In advanced dementia, depression symptoms tend to decline, although this may reflect the difficulty in assessing depression at advanced stages of dementia.2

Numerous reports have linked inflammation to cognitive dysfunction or decline, as well as to the development of Alzheimer disease.3–5 Evidence suggests that inflammation is a key mediator between cardiovascular risk factors and Alzheimer disease, although this is also still controversial.


The Texas Alzheimer’s Research Consortium, composed of five medical centers, is pursuing a longitudinal, multi-institutional study of Alzheimer disease. The group recently published the results of a study assessing whether inflammatory markers were over- or underexpressed in patients with Alzheimer disease, and whether biomarkers could predict Alzheimer disease status and the age at onset of the disease.4 The analysis included 197 patients with Alzheimer disease and 203 control subjects. The evaluation consisted of cognitive assessment, DNA analysis for human genome-wide association studies, and protein microarray analysis from blood. Cardiovascular risk factors were also measured, including serum lipids and blood factors for diabetes risk. The goal was to better understand the pathophysiology of cognitive decline and predict conversion of mild cognitive impairment to Alzheimer disease.

Researchers analyzed the levels of 34 inflammatory-related markers (Table) in the patient and control groups. Proteins were quantified by Rules-Based Medicine via Luminex, a multiplex fluorescent immunoassay using colored microspheres linked to protein-specific antibodies; this technology permits simultaneous measurement of several hundred proteins.

Significant differences were found in the study groups. For example, the median age in the Alzheimer group was significantly higher than in controls (79 vs 70 years, P < .0001), an issue that is being addressed as subjects are replaced due to attrition. The median educational level was higher in the control group (14 vs 16 years, P < .0001) than in the Alzheimer group. Subjects in the Alzheimer group were significantly more likely (P < .001) to carry at least one copy of the APOE ε4 allele.

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