Cognitive impairment due to neurodegenerative diseases is often multifactorial and co-pathologies may contribute to the clinical phenotype, disease progression and response to treatment. The second most common proteinopathy in dementias is LB pathology, which is characterized by intracellular aggregates of misfolded α-synuclein (α-syn) forming LBs and Lewy dystrophic neurites that can manifest as both dementia with LB (DLB) and Parkinson’s disease (PD), collectively referred to as Lewy body disease (LBD) 1, 2. Neurodegeneration is often characterized by accumulation of misfolded proteins, where the most common are amyloid-β (Aβ) and neurofibrillary tau pathology in AD, the leading cause of dementia worldwide. The development of biomarkers allowing the in vivo detection of the different neurodegenerative pathologies underlying cognitive or motor decline is a crucial step for a timely diagnosis, accurate prediction of disease progression and the stratification of patients for clinical trials 1. Neurodegenerative diseases are a leading health problem, given their devastating effects on quality of life, their high prevalence and the progressive global increase in life expectancy, which will increase their prevalence even more. LB status provides a better precision-medicine approach to predict clinical trajectories independent of AD biomarkers and a clinical diagnosis, which could have implications for the clinical management of cognitive impairment and the design of AD and LB drug trials. LB pathology was also associated with faster longitudinal decline in all examined cognitive functions, independent of amyloid-β, tau, cognitive stage and a baseline diagnosis of dementia with Lewy bodies/Parkinson’s disease. When examining independent cross-sectional effects, LB pathology but not amyloid-β or tau, was associated with hallucinations and worse attention/executive, visuospatial and motor function. Fifty-four percent had AD pathology in the whole sample (17% of mild cognitive impairment and 24% of patients with dementia were also LB-positive). Among these LB-positive patients, 48% had AD pathology. Twenty-three percent had LB pathology, of which only 21% fulfilled clinical criteria of Parkinson’s disease or dementia with Lewy bodies at baseline. Using a seed amplification assay, we analyzed cerebrospinal fluid for misfolded LB-associated α-synuclein in 883 memory clinic patients with mild cognitive impairment or dementia from the BioFINDER study. There is poor knowledge about the clinical effects of Lewy body (LB) pathology in patients with cognitive impairment, especially when coexisting with Alzheimer’s disease (AD) pathology (amyloid-β and tau).

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