The relationship between multimorbidity, particularly disease clusters, with neuroimaging and cognitive outcomes that typically manifest prior to clinical diagnosis of dementia, remains understudied. This study investigated whether multimorbidity is associated with dementia-related neuroimaging and cognitive outcomes in the UK Biobank cohort.

This cross-sectional study used data from UK Biobank participants who attended imaging assessments between 2014–2023, and were free from neurological conditions, including dementia. Multimorbidity was defined as the coexistence of two or more long-term conditions, selected from a standardised criteria of 39 conditions. Latent class analyses were used to identify disease clusters. Neuroimaging outcomes were measured using magnetic resonance imaging, and cognition was assessed by seven tests measuring different cognitive domains. Multivariable linear regression was used to assess the association between multimorbidity and disease clusters with neuroimaging and cognitive outcomes.

A total of 43,160 participants were included (mean [standard deviation] age, 64.2 [7.7] years, 53.1 % female). Multimorbidity was present among 14,339 (33.2 %) participants, and was associated with reduced grey matter volume, total brain volume, left hippocampal volume, increased cerebrovascular pathology as well as reduced domain-specific cognitive function. A strong dose-response relationship was observed with the increasing number of multimorbid conditions across these outcomes. A disease cluster driven by cardiometabolic conditions was consistently associated with poorer brain health across all outcomes. Disease clusters driven by respiratory, mental health and other conditions showed less consistent associations.

Multimorbidity was strongly associated with poorer brain health, particularly within the cardiometabolic disease cluster. Given that UK Biobank participants are, on average, healthier than the general population, future studies in more diverse and representative cohorts would be valuable.