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

Abstract

AbstractBackgroundThe 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.MethodWe 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).ResultMixed 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).ConclusionThe 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.