The presence of Alzheimer’s disease pathology in dementia with Lewy bodies is related to increased neocortical α-synuclein load and different α-synuclein morphology

Background: The presence of Alzheimer’s disease (AD) type pathology in dementia with Lewy bodies (DLB) has been linked to a more rapid disease progression. We aimed to examine the relation between load of AD-type pathology and load and morphology of α-synuclein pathology in DLB brains.
Methods: We included 50 donors from the Netherlands Brain Bank fulfilling clinical criteria for ‘probable DLB’ and limbic or neocortical Lewy body disease. Levels of AD-type pathology according to NIA-AA guidelines were either absent to low (pure DLB, n=15), or intermediate to high (mixed DLB/AD, n=35). We visually rated α-synuclein-positive and amyloid-β-positive morphologies, and we quantitatively measured amyloid-β, hyperphosphorylated tau (HPF-tau) and α-synuclein load in fifteen brain regions. Regional amyloid-β and HPF-tau levels in DLB donors were compared to eight AD donors without α-synuclein pathology (pure AD).
Results: Mixed DLB/AD compared to pure DLB donors showed a shorter disease duration (6 ± 3 vs. 8 ± 3 years, p=0.021), more diffuse intraneuronal α-synuclein positivity (p=0.002) but not more glial α-synuclein positivity, and a higher overall α-synuclein load (F=25.7, p<0.001), specifically in the parietal (p=0.006), temporal (p=0.002) and occipital cortex (p=0.006). Mixed DLB/AD was related to more capillary cerebral amyloid angiopathy (CAA) (49% vs. 7%, p<0.001). Within cortical regions, α-synuclein load was most strongly related to amyloid-β and HPF-tau load in the temporal (Pearson’s r = 0.38 and 0.50 respectively) and occipital cortex (r=0.43 and 0.42 respectively). While controlling for age at death, mixed DLB/AD compared to pure AD showed lower HPF-tau load in frontal (p=0.043) and parietal cortices (p=0.002), but not in temporal cortex (p=0.48), and no differences in amyloid-β load in the frontal (p=0.57), parietal (p=0.56) and temporal cortex (p=0.10).
Conclusions: The presence of AD-type pathology in DLB was related to more diffuse intraneuronal α-synuclein positivity, a higher neocortical α-synuclein load and more capillary CAA. This study provides evidence for different neuropathological profiles in DLB, which may contribute to clinical heterogeneity in this disease.