Amyloid Hypothesis: Is There a Role for Antiamyloid Treatment in Late-Life Depression?

Abstract

Antidepressants have modest efficacy in late-life depression, perhaps because various neurobiological processes compromise frontolimbic networks required for antidepressant response. We propose that amyloid accumulation is an etiological factor for frontolimbic compromise that predisposes to depression and increases treatment resistance in a subgroup of older adults. In patients without history of depression, amyloid accumulation during the preclinical phase of Alzheimer’s disease may result in the prodromal depression syndrome that precedes cognitive impairment. In patients with early-onset depression, pathophysiological changes during recurrent episodes may promote amyloid accumulation, further compromise neurocircuitry required for antidepressant response and increase treatment resistance during successive depressive episodes. The following findings support the amyloid hypothesis of late-life depression: a) Depression is a risk factor, a prodrome, and a common behavioral manifestation of Alzheimer’s disease; b) Amyloid deposition occurs during a long pre-dementia period when depression is prevalent; c) Patients with lifetime history of depression have significant amyloid accumulation in brain regions related to mood regulation; d) Amyloid deposition leads to neurobiological processes, including vascular damage, neurodeheneration, neuroinflammation, disrupted functional connectivity, that impair networks implicated in depression. The amyloid hypothesis of late-life depression is timely, because availability of ligands allows in vivo assessment of amyloid in the human brain, a number of anti-amyloid agents are relatively safe, and there is evidence that some antidepressants may reduce amyloid production. A model of late-life depression introducing the role of amyloid may guide the design of studies aiming to identify novel antidepressant approaches as well as prevention strategies of Alzheimer’s disease.

Vascular depression consensus report – a critical update

“…According to a recent clinical study, the presence of depressive symptoms in amnestic MCI patients is not predictive of conversion to dementia [92]. On the other hand, older, cognitively normal patients with depressive episodes were found more likely to have an underlying AD pathology, in particular β-amyloid deposition [33, 34]. However, there are inconsistent results for plasma and/or cerebrospinal fluid levels of soluble β-amyloid 42 in LLD [93].…”

“…Although immune and endocrine disorders affect vascular risk, they may also increase the risk of depression through independent mechanisms that require further study [167]. More recently, the amyloid hypothesis of LLD was discussed [33, 34]. …”

“…Individuals with VaDep are at greater risk to develop cognitive impairment, more likely related to vascular dementia than to Alzheimer’s disease (AD) [30]. However, recent data showed that VaDep is not a risk factor for AD [31, 32], although older cognitively unimpaired patients with depressive episodes may have more underlying AD pathology, in particular β-amyloid deposition [33, 34]. In general, depression in vascular dementia is clinically different from that in AD [30].…”

Chronic depressive symptomatology and CSF amyloid beta and tau levels in mild cognitive impairment

“…To date, the pathophysiological mechanisms linking depressive symptoms to cognitive dysfunction remain poorly defined. However, emerging data suggests that depressive symptoms may be associated with the accumulation of neuropathological proteins, amyloid beta and tau, in the brain . According to current biomarker models of Alzheimer's disease, amyloid deposition develops decades prior to dementia onset and propagates the dispersion of phosphorylated tau across the neocortex, inducing neuronal degeneration and synaptic dysfunction.…”

Late-Life Depression versus Amnestic Mild Cognitive Impairment: Alzheimer’s Disease Incidence in 4 Years of Follow-Up

“…In recent studies LLD has been considered a part of the preclinical course of Alzheimer’s disease (AD) [17, 18] and was associated with a 2- to 5-fold increased risk of developing AD compared with healthy aging individuals [19, 20]. Amnestic mild cognitive impairment (aMCI), characterized by memory deficit, is a transitional stage between normal aging and AD [21].…”