PHENOTYPING PROSPECTIVE COGNITIVE OUTCOMES OF LATE-LIFE DEPRESSION

Introduction It has long been known that major depressive disorder during later life (LDD) is associated with cognitive decline and development of Alzheimer's disease and other dementias. Less is known about the characteristics of LLD that contribute to individual cognitive outcomes, but identifying phenotypes of these outcomes could make important contributions to early detection and treatment. The current study explored clinical and neuroimaging phenotypes associated with normal and non-normal cognitive diagnostic outcomes in LLD. Methods The data were from a prospective study of individuals (N = 240) with acute depression at baseline and followed under treatment for a minimum of five years. Baseline assessment included clinical measures of mood, neuropsychological assessment, and neuroimaging. Mood was assessed during regular treatment over the course of each year, and neuropsychological assessment was obtained annually. A consensus review was held annually to assign clinical diagnoses based on cognitive status, which included categories of normal cognition; cognitive impairment, no dementia (CIND); dementia, with subtypes including Alzheimer's disease (AD). The current study analyzed diagnostic outcomes at five years from study entry, and the clinical characteristics that predict these outcomes. Results We found that 90% of cognitive diagnostic outcomes over five-years of follow-up were in three diagnostic categories: 1) cognitively normal, 2) persistent CIND, and 3) AD. The remaining 10% were non-AD dementias and various medical and neuropsychiatric diagnoses. Individuals with normal cognition were 50% of the sample, and this endpoint was associated with first depression onset before age 60 and indicators of heightened sensitivity to stress. Individuals with persistent CIND (22%) were not associated with age of depression onset, but were associated with clinical characteristics of frailty and indicators of cerebrovascular pathology on neuroimaging. Individuals with AD (18%) were associated with age of depression onset after age 60, depressive symptoms of appetite/weight loss, reduced hippocampal volume, and worse memory performance at study entry. Conclusions The current study found distinct clinical and neuroimaging profiles associated with the three major cognitive endpoints of LLD. Approximately half of individuals with LLD maintained normal cognition over five years, which appeared to be associated with a lifetime predisposition to depression and heightened sensitivity to stress. In contrast, nearly 20% of individuals with LLD converted to AD within five years of follow up, and results suggest a clinically detectable phenotype of prodromal AD based on appetitive disturbance, reduced hippocampal volume, and memory deficits. Individuals with persistent CIND demonstrated a profile consistent with physical decline and cerebrovascular pathology, which did not manifest as dementia over 5 years, but may represent a slower progress toward vascular dementia relative to those with AD. These clinical phenotypes reflect a starting point for mechanistic discovery while also improving current treatment of LLD by identifying individuals on distinct cognitive trajectories who many benefit from differentiated approaches to the treatment of mood and cognition. The current cohort is part of a collaborative project to further detect and characterize linkages between cognitive outcomes of LLD and their clinical and neuroimaging phenotypes. This research was funded by This research was supported by funding from the National Institute of Mental Health (R01MH108560), and the Leo and Anne Albert Charitable Trust. The authors have no industry or other conflicts to report.