Lingfeng Xue, PhD, an old age psychiatry and clinical research assistant at King’s College London.

Lingfeng Xue, PhD

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

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

 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 

“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

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. 

. 2026;12(2):e88. Published 2026 Mar 10. 

Videos

Interview with Xue on UK Biobank data linking first-onset depression after age 50 to cognitive deficits and increased dementia risk.

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

Late-Onset Depression Linked to Increased Dementia Risk, With Lingfeng Xue, PhD

Late-onset depression was associated with poorer performance in fluid intelligence and visuospatial memory, as well as a greater risk of incident dementia, in older adults with 

, Lingfeng Xue, PhD, an old age psychiatry and clinical research assistant at King’s College London, discussed the implications of these findings.

“The relationship between late-onset depression and…dementia can be complicated,” Xue said. “The depressive symptoms [can represent a] prodrome of dementia or independently as a risk factor of dementia. These are 2 valid theories, and they both have evidence…there's no exclusive or established theory for 1 against another.”

The analysis evaluated 75,064 adults aged ≥ 60 years from the UK Biobank with linked primary care data, comparing cognitive outcomes and dementia incidence across depression subtypes defined by age at onset.1 Participants with late-life depression with late onset (LLD-LO), defined as the first depressive episode after age 50 years, demonstrated significantly worse performance in fluid intelligence and visuospatial memory compared with both depression-free controls and those with earlier-onset depression. Over a median follow-up of 13.69 years, LLD-LO was associated with an increased risk of incident dementia, with hazard ratios ranging from 1.42 to 1.52 across adjusted models.1

Impairments in fluid intelligence and visuospatial memory partially mediated dementia risk, accounting for 3.1% (95% CI, 1.2% to 5.0%) and 1.4% (95% CI, 0.4% to 2.5%) of the association, respectively.1 Xue noted that such deficits may be detectable in midlife and should prompt further evaluation.

“Any mid-age cognitive loss warrants attention in… real-world practice,” he said, referencing commonly used tools such as the Wechsler Adult Intelligence Scale for reasoning and computerized tasks for visuospatial assessment.

The reported hazard ratio of approximately 1.4 to 1.5 indicates a 40–50% relative increase in dementia risk among individuals with late-onset depression. Xue said this aligns with prior evidence identifying depression as a modifiable risk factor for dementia. He added that first-onset depression after 50 years old should prompt clinicians to consider additional cognitive assessment and longitudinal monitoring.

The study’s use of age 50 years as a cutoff for late-onset depression was intended to increase sensitivity for detecting early cognitive changes. Sensitivity analyses suggested this threshold captured associations with impairment more effectively than higher cutoffs.

Xue cautioned against rigid clinical interpretation of this boundary. Rather, the findings serve more as a reminder that mid-to late-life depression onset is associated with later cognitive decline.

The findings support integrating cognitive screening into the evaluation of patients presenting with first-onset depression in mid- to late life. Xue highlighted the importance of considering both psychiatric and neurological pathways when assessing these patients, particularly given the potential for early cognitive changes to precede clinically recognized dementia.

“The onset of depression after 50 is multi-driven, so the clinician should consider various factors from multiple dimensions into consideration,” Xue said.

Analysis of 75,064 UK Biobank participants found late-onset depression associated with worse fluid intelligence and visuospatial memory and a 42–52% increased dementia risk.


Lingfeng Xue, PhD

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