Brain pathology and cognitive scores prior to onset of late‐life depression

Abstract

Objectives: Understanding the biological changes that occur prior to onset of latelife depression (LLD) is key to its prevention. To investigate potential predictors of LLD, we assessed cognitive scores and neurodegenerative and vascular biomarkers in healthy older adults who later developed depression. Methods: Longitudinal data from the Alzheimer's Disease Neuroimaging Initiative of 241 cognitively unimpaired and non-depressed older adults aged 56-90 at baseline with at least 4 years of follow-up were included. Participants were classified based on whether they developed an incident depression (n = 96) or not (n = 145). Cognitive measures of memory, executive functioning, and language, and biomarkers proposed to be related to LLD: hippocampal volume, white matter hyperintensity volume (WMH), and cortical and cerebrospinal fluid (CSF) amyloid beta levels, were compared between the incident depression and the neverdepressed groups at four time points: at baseline, the visit prior to onset, at onset, and after the onset of depression.Results: In the incident depression group, there was a mild decline in cognitive scores from baseline to the visit before depression onset compared with the neverdepressed group. The cognitive differences between the groups became more marked after depression onset. Baseline cortical amyloid burden, CSF amyloid beta levels, and WMH were significant predictors of incident depression. Compared to the non-depressed group, hippocampal volume was not reduced before onset, but was reduced following depression.Conclusions: Amyloid pathology and WMH can predict future development of LLD in cognitively unimpaired individuals and may be involved in precipitating vulnerability for depression in older adults.

Age or age of onset: which is the best criterion to classify late-life depression?

“…In our sample, there were several cognitive differences between LOD and EOD groups: although most of them were related to chronological age rather than to the age of onset, suggesting they could simply reflect the impact of brain ageing ( Diniz et al , 2021 ), memory dysfunction has emerged as a true feature of LOD. This finding was consistent with prior studies such as Mackin et al (2014 ), who reported a correlation between memory impairment and LOD in older adults with depression and executive dysfunction and, more recently, a study of healthy older individuals who later developed depression, among whom mild cognitive impairment preceded depression onset ( Almdahl et al , 2022 ). Another characteristic that was associated with LOD in our sample was an increased risk of developing dyskinesias, notwithstanding the assumption of lower antidepressant doses.…”

Distinguishing features of depression in dementia from primary psychiatric disease

“…However, some studies have added nuance to this conclusion. When studying cognitively normal populations with LLD, some associations with pathological forms of Aβ have been found [104][105][106][107][108][109], while some studies still find no correlation [110][111][112]. Though interpretation of these results is challenging, one explanation could be that early AD pathological hallmarks are associated with depression-onset in some individuals because these early symptoms are actually prodromal for AD.…”

The heterogeneity of late-life depression and its pathobiology: a brain network dysfunction disorder

“…This group showed mild cognitive decline before depression onset. Cerebrospinal fluid (CSF) β-amyloid (Aβ) levels and white matter hyperintensities (WMH) suggested that subtle cognitive changes that occur prior to LLD may be explained by the underlying pathological aging process, disrupting brain networks involved in emotional and cognitive processing, thus disposing older adults to depression (Almdahl et al 2022 ). In older age bipolar disorder, cognitive dysfunction is more severe than in LLD, but in the same domains as in LLD, which cannot be fully explained by the severity of depressive symptoms (Orhan et al 2023 ).…”

“…A longitudinal study of older adults showed that baseline cortical Aβ burden, CSF amyloid levels and WMH were significant predictors of incipient depression. Compared to the non-depressed group, hippocampal volume was not reduced before onset, but was reduced following depression (Almdahl et al 2022 ). Conversely, two other studies showed that LLD was associated with reduced cortical Aβ burden.…”