Dementia Risk Signals in Late-Onset Depression, With Lingfeng Xue, PhD

Late-onset depression may signal increased risk for cognitive impairment,

particularly when first depressive episodes occur after midlife, according to recent findings. The study identified deficits in fluid intelligence and visuospatial memory among individuals with late-onset depression, with these impairments partially mediating the association between depression onset and later dementia risk.

“These 2 [deficits] represent more…cognitive burden that involves multiple system[s],” Lingfeng Xue, PhD, from King’s College London, told HCPLive. “The factors behind it can be complicated, but these 2 deficits observed in late onset depression can say that the potential mechanism within late life depression can involve neurocognitive loss, or even…biological dysfunctions among people within mid to late age.”

The analysis evaluated adults aged ≥ 60 years using UK Biobank data with linked primary care records. Investigators categorized participants into depression-free controls, early-life depression, late-life depression with early onset, and late-life depression with late onset. At baseline, the team assessed cognitive performance across 5 domains and prospectively tracked incident dementia through clinical records until 2022.

Late-life depression with late onset was associated with worse performance in several cognitive domains compared with healthy controls, particularly fluid intelligence and visuospatial memory. Participants in this group also demonstrated worse fluid intelligence compared with individuals with late-life depression beginning earlier in life. During a median follow-up of 13.69 years, late-onset depression predicted incident dementia, with hazard ratios ranging from 1.41 to 1.52 across adjusted models. Deficits in fluid intelligence mediated 3.1% of the association (95% confidence interval [CI], 1.2% to 5.0%) and visuospatial memory mediated 1.4% (95% CI, 0.4% to 2.5%).

The results raise questions regarding earlier cognitive assessment in patients presenting with first-onset depression after midlife. Xue noted that cognitive testing may be feasible in routine care, particularly using low-cost screening tools, although broader implementation must consider resource constraints.

“When it comes to real world practice, it’s a matter of cost effectiveness,” he said. “In terms of cognitive testing, it might be easier…when it comes to paper and pen testing. It's cheaper and it's more accessible. Neuroimaging can be less accessible, and the findings can be harder to interpret, but in general, these are…recognized indicators or associates with the onset of late life depression. I would…definitely recommend it for both, but it really comes to cost effectiveness.”

The study also highlighted the potential influence of treatment. Although antidepressant exposure was not included in the primary analysis, Xue referenced additional work suggesting antidepressant use may modify cognitive outcomes and reduce dementia risk among individuals with late-life depression. He emphasized that treatment history represents an important factor requiring further investigation.

The trajectory of cognitive decline preceding dementia also informed interpretation of the findings. Gradual cognitive changes may begin years before clinical diagnosis.

“[Cognitive decline] can go back 15, even 20 years, before the actual [dementia] onset,” Xue said. “As this study suggests, it…warrants an earlier detection…of cognitive…or monitoring of cognitive trajectories in order to prevent later onset damage.”

Part 1 of the interview with Xue can be viewed here.

References

Xue L, Bocharova M, Young AH, Aarsland D. Late-onset depression predicts cognitive impairment and subsequent dementia among older adults with major depressive disorder: findings from UK Biobank and primary care linked data. BJPsych Open. 2026;12(2):e88. Published 2026 Mar 10. doi:10.1192/bjo.2026.10995