Objective: To determine the long-term association of haemoglobin levels and anaemia with risk of dementia, and explore underlying substrates on brain MRI in the general population. Methods: Serum haemoglobin was measured in 12,305 non-demented participants of the population-based Rotterdam Study (mean age 64.6 years, 57.7% women). We determined risk of dementia and Alzheimer’s disease (until 2016) in relation to haemoglobin and anaemia. Among 5,267 non-demented participants with brain MRI, we assessed haemoglobin in relation to vascular brain disease, structural connectivity, and global cerebral perfusion. Results: During a mean follow-up of 12.1 years, 1,520 individuals developed dementia, of whom 1,194 had Alzheimer’s disease. We observed a U-shaped association between haemoglobin levels and dementia (P=0.005), such that both low and high haemoglobin levels were associated with increased dementia risk (hazard ratio [95% confidence interval]– lowest versus middle quintile 1.29 [1.09-1.52]; highest versus middle quintile 1.20 [1.00-1.44]). Overall prevalence of anaemia was 6.1%, and anaemia was associated with a 34% increased risk of dementia (95%CI: 11-62%) and 41% (15-74%) for Alzheimer’s disease. Among non-demented individuals with brain MRI, similar U-shaped associations were seen of haemoglobin with white matter hyperintensity volume (P=0.03), and structural connectivity (for mean diffusivity, P<0.0001), but not with presence of cortical and lacunar infarcts. Cerebral microbleeds were more common with anaemia. Haemoglobin levels inversely correlated to cerebral perfusion (P<0.0001). Conclusion: Low and high levels of haemoglobin are associated with an increased risk of dementia, including Alzheimer’s disease, which may relate to differences in white matter integrity and cerebral perfusion.nn