Alzheimer’s disease copathology in dementia with Lewy bodies is associated with astroglial α-synucleinopathy

Background In dementia with Lewy bodies (DLB), co-existence of Alzheimer’s disease (AD) pathology, i.e. amyloid-β plaques and tau tangles, has been associated with a more rapid disease progression. In post-mortem DLB brains, we examined the association between AD copathology and regional load and morphology of α-synuclein pathology. Also, we compared regional load and morphology of AD copathology in DLB to pathology in AD. Methods We included 50 autopsy-confirmed DLB donors with a clinical DLB phenotype, categorized as having no/low levels of AD copathology (pure DLB, n = 15), or intermediate/high levels of AD copathology (mixed DLB+AD, n = 35), and autopsy-confirmed pure AD donors ( n = 14) without α- synuclein pathology. We used percentage area of immunopositivity for quantitative assessment of pathology load, and visual scores for semi-quantitative assessment of different morphologies of α- synuclein, amyloid-β and phosphorylated tau (p-tau) pathology in fifteen neocortical, limbic and brainstem regions. Results Mixed DLB+AD compared to pure DLB showed a shorter disease duration (6 ± 3 versus 8 ± 3 years, p = 0.021) and higher frequency of APOE -ε4 alleles. A-synuclein load was higher in neocortical regions (temporal, parietal and occipital), but not in brainstem and limbic regions, which was based upon an increase of Lewy bodies, α-synuclein-positive astrocytes and α-synuclein-positive plaques in these regions. A-synuclein load was most strongly correlated to amyloid-β and p-tau load in temporal ( r = 0.38 and r = 0.50 respectively) and occipital regions ( r = 0.43 and r = 0.42 respectively). Compared to pure AD, mixed DLB+AD showed a lower amyloid-β load in temporal cortex, CA3 and CA4 region, and lower p-tau loads in frontal and parietal cortex, based both upon presence of fewer neuritic plaques as well as neurofibrillary tangles. Conclusions In DLB brains, AD copathology was associated with more neocortical α-synuclein pathology, consisting not only of Lewy bodies and plaques, but also of astroglial α-synuclein. AD pathology in DLB cases is less than in AD cases, reflecting less advanced pathological stages. Astroglial α-synuclein and its relation with AD copathology in DLB should be further studied, as this may play a role in accelerating clinical decline. ### Competing Interest Statement The authors have declared no competing interest.