Dementing Disorders Lead to Affective Symptomatology.
Alternatively, dementing disorders might lead to depressive symptomatology by (a) inducing biological cascades, and (b) sharing common pathological processes, or (c) as a psychological reaction in the context of cognitive and functional loss.
First, AD-related pathology in itself might lead to both cognitive impairments and affective symptomatology. Evidence comes from studies that found significant degeneration of neurotransmitter systems in Alzheimer’s disease [35, 36]. Also significant AD-typical differences in amyloid-beta (Ap) metabolism in older people with depression in later life compared to nondepressed people were found .
Other studies however stated that depressive symptoms were not related to plaques and tangles burden  . Furthermore, depressive symptoms were not related to whole brain volume, hippocampal volume or white matter lesions in people with probable AD dementia . In addition, elderly depressed women had increased CSF Ap42 levels, whereas AD pathology leads to a decrease . In people with MCI, the authors and colleagues also did not found a relation between depressive symptoms and key in vivo biomarkers for AD in the CSF in a pooled cohort of the large European DESCRIPA study and the US ADNI study . In contrast, there was an association between anxiety and abnormal CSF biomarkers for AD. This finding was recently confirmed by a positive association between increased amyloid deposition on PET scans and symptoms of anxiety in the same ADNI cohort .
Both depressive symptoms and cognitive impairments can also be caused by other (non-AD specific) pathological processes, such as synaptic loss, neurochemical changes such as neurotransmitter dysfunctions, or vascular changes [43,44]. In the vascular depression hypothesis, depressive symptoms are explained by (micro) vascular pathology in the brain, mainly subcortical ischemic lesions. This is in line with studies that found depression to be more often present in people who developed vascular dementia . In older age cohorts, a combination of several AD-specific and nonspecific pathologies might be most likely to explain depressive symptomatology.
Another hypothesis for linking cognitive and affective symptomatology is that both conditions share common neurophysiologic features, such as HPA axis dys- regulations, chronic inflammation , cerebrovascular pathology, neuronal loss, neurotransmitter dysregulations (deficiencies in cholinergic, serotonergic and dopaminergic systems), and oxidative stress. In addition, an accumulation or synergy of these factors might be the explanation for both depressive and cognitive problems and might be most in line with an aging and increasingly frail population .
Depressive symptoms may also result from a psychological reaction to the awareness of cognitive decline and functional loss in daily life caused by an underlying pathological process in the brain . People may experience memory complaints and come across their routines more effortful, leading to a feeling of losing control of daily life. These worries about cognitive functioning and losing control might cause emotional imbalance including symptoms of depression, worrying, anxiety, and increased irritability. This psychological reaction can also account for higher prevalence rates of depressive symptoms in people with MCI who will develop dementia, but is not linked to pathophysiological processes per se.
All abovementioned hypotheses for explaining the relationship between depression and cognitive impairments are plausible, but none of them will be able to entirely explain it. Depression in itself is a very heterogeneous syndrome, with qualitatively different symptoms, and missing reliable biomarkers. Biomarker technologies for diagnostics in the early phases of AD pathology had strong improvements in the last decennia; however, atypical biomarker profiles are very common in clinical practice. In addition, AD biomarker profiles have a role in the explanation of cognitive impairments (e.g., the abovementioned mild medial temporal lobe atrophy of Mrs. A), but they cannot explain the causal or reactive role of comorbid depressive symptomatology. Butters et al. [29 ] proposed a role of the “reserve threshold” (consisting of an individual’s brain reserve and cognitive reserve) for explaining the highly variable clinical course of cognitive decline. In this concept, depression might be one of the threshold lowering factors, leading to an earlier clinical presentation of cognitive impairments.
The pathogenesis of depression will differ from case to case, due to the heterogeneity of depression itself (in which Mrs. A is feeling sad and had loss of initiative and lost control, while Mrs. B can be characterized by worrying and preoccupation), and in different stages of cognitive decline (e.g., the depressive symptoms of Mrs. A at baseline compared to the fifth-year visit). The onset of depressive symptoms (lifetime/recurrent episodes versus comorbid/current) might also have different pathogenic aspects. In addition, the variation in interval period between the onsets of depression and cognitive impairments may have other linking mechanisms (in which shorter periods might share more common pathways and in longer preceding periods depression might be a more true risk factor for cognitive decline or dementia) .