Background: Recent evidence from a prospective study in the UK Biobank suggests that multimorbidity is associated with an increased risk of dementia. However, adverse neurodegenerative and cerebrovascular changes in the brain start occurring much before a clinical diagnosis of dementia. To gain insight into the potential pathways underlying the previously observed relationships between multimorbidity and dementia, we investigated the association of multimorbidity and disease clusters with brain outcomes and cognition; and whether genetic risk for dementia modify these associations. Methods: We included 43,160 participants aged 45-83 years free from neurological conditions, who attended the UK Biobank (UKB) imaging assessment. Multimorbidity was defined as the presence of ≥2 long-term health conditions from a standardized criteria of 39 conditions. Latent class analyses were used to identify multimorbidity clusters. Brain outcomes were measured through magnetic resonance imaging (MRI), and cognition was assessed by seven tests measuring different cognitive domains. Linear regression models, adjusted for socio-demographic and neuroimaging confounders were used to test the association between multimorbidity and brain and cognitive outcomes. Genetic risk for dementia was determined using both apolipoprotein E (APOE) ε4 status and a polygenic risk score (PRS) based on 38 non- APOE single nucleotide polymorphisms. Results: Multimorbidity was present among 14,339 (33.2%) participants. In fully-adjusted models, multimorbidity was associated with several measures of poorer brain health and cognition, including lower volumes of grey matter (β: -0.03 standard deviation (SD); 95% confidence interval (CI): -0.04 to -0.02), total brain (β: -0.01 [-0.02 to -0.01]), left hippocampus (β: -0.03 [-0.05 to -0.01]), increased white matter hyperintensity volume (β: 0.09 [0.07 to 0.10]), diminished executive function (β: 0.04 [0.02 to 0.06]), poorer verbal declarative memory (β: -0.03 [-0.05 to -0.01]), and slower processing speed (β: -0.07 [-0.10 to -0.05]). A strong dose-response relationship was observed with the number of multimorbid conditions. There was no evidence of an interaction with genetic risk for dementia. Strength of associations varied across disease clusters, with the 'hypertension & diabetes' cluster showing the strongest associations to brain outcomes, executive function, non-verbal reasoning, and processing speed. The 'pain & dyspepsia' cluster exhibited the strongest association for verbal and numerical reasoning, and verbal declarative memory. Summary and next steps: Our findings suggest that multimorbidity is associated with poorer brain health and cognition, regardless of genetic risk. The associations varied among disease clusters, with cardiometabolic conditions showing the strongest associations. Future availability of repeat neuroimaging and cognitive data will help determine the temporality of these associations.