Clinical and diagnostic implications of Alzheimer's disease copathology in Lewy body disease

: Concomitant Alzheimer's disease (AD) pathology is a frequent event in the context of Lewy body disease (LBD), occurring in approximately half of all cases. Evidence shows that LBD patients with AD copathology show an accelerated disease course, a greater risk of cognitive decline and an overall poorer prognosis. However, LBD-AD cases may show heterogeneous motor and non-motor phenotypes with higher risk of dementia, and, consequently, be not rarely misdiagnosed. In this review, we summarize the state-of-the-art on LBD-AD by discussing the synergistic effects between AD neuropathological changes and Lewy pathology and their clinical relevance. Furthermore, we provide an extensive overview of neuroimaging and fluid biomarkers under assessment in LBD-AD and their possible diagnostic and prognostic value. AD pathology can be suspected in vivo by means of CSF, MRI and PET markers, whereas α-synuclein seed amplification assays (SAAs) represent to date the most promising technique to identify Lewy pathology in different biological tissues. Pathological imaging and CSF AD biomarkers are associated with a higher likelihood of cognitive decline in LBD but do not always mirror the neuropathological severity like in pure AD. The implementation of blood-based biomarkers of AD might allow the fast screening of LBD patients for AD copathology, thus improving the overall diagnostic sensitivity for LBD-AD. Finally, we discuss the literature on novel candidate biomarkers being exploited in LBD-AD to investigate other aspects of neurodegeneration, such as neuroaxonal injury, glial activation and synaptic dysfunction. The thorough characterization of AD copathology in LBD should be taken into account for the differential diagnosis of dementia syndromes, for the prognostic evaluation on an individual level and for guiding symptomatic and disease-modifying therapies.