Anxiety and depression in Alzheimer's disease: a systematic review of pathogenetic mechanisms and relation to cognitive decline

Objectives To explore the pathogenetic hypothesis provided to explain the comorbidity of anxious and depressive symptomatology and AD and to assess the association between anxious and depressive symptoms and the AD-related cognitive impairment.Methods In October 2020 and March 2021, PsycINFO, Embase, Ovid, and CINAHL were searched for peer-reviewed original articles investigating anxiety and/or depression in AD.Results A total of 14,760 studies were identified and 34 papers on AD patients were included in the review. Suggested biological causes of depression and anxiety in AD include higher strychnine-sensitive glycine receptor (GlyRS) functioning and selective reduction of N-methyl-D-aspartate (NMDA) receptor NR2A density, cortical and limbic atrophy, lower resting cortical metabolism, lower CSF A beta 42 and higher t-tau and p-tau levels, and neuritic plaques. At the same time, dysthymia arises in the early stages of AD as an emotional reaction to the progressive cognitive decline and can cause it; anxiety can appear as an initial compensating behaviour; and depression might be related to AD awareness and loss of functional abilities. Affective symptoms and the expression of the depressive symptoms tend to reduce as AD progresses.Conclusion The neurodegeneration of areas and circuits dealing with emotions can elicit anxiety and depression in AD. In the early stages of the disease, anxiety and depression could arise as a psychological reaction to AD and due to coping difficulties. In late AD stages, the cognitive impairment reduces the emotional responses and their expression. Anxiety and depression are more intense in early-onset AD, due to the major impact of AD on the individual.