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

Geut, H.; van den Berg, E.; Boon, B. D.; Hoozemans, J. J.; Tunold, J.-A.; Pihlstrom, L.; Jonkman, L. E.; Rozemuller, A. J.; Lemstra, E. A.; van de Berg, W. D. J.

doi:10.1101/2024.01.02.573857

bioRxiv · 10.1101/2024.01.02.573857

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

Geut, H.·van den Berg, E.·Boon, B. D.·Hoozemans, J. J.·Tunold, J.-A.·Pihlstrom, L.·Jonkman, L. E.·Rozemuller, A. J.·Lemstra, E. A.·van de Berg, W. D. J.

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Abstract

BackgroundIn dementia with Lewy bodies (DLB), co-existence of Alzheimers disease (AD) pathology, i.e. amyloid-{beta} 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 -synuclein pathology. Also, we compared regional load and morphology of AD copathology in DLB to pathology in AD. MethodsWe 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 - 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 - synuclein, amyloid-{beta} and phosphorylated tau (p-tau) pathology in fifteen neocortical, limbic and brainstem regions. ResultsMixed 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-{varepsilon}4 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, -synuclein-positive astrocytes and -synuclein-positive plaques in these regions. A-synuclein load was most strongly correlated to amyloid-{beta} 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-{beta} 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. ConclusionsIn DLB brains, AD copathology was associated with more neocortical -synuclein pathology, consisting not only of Lewy bodies and plaques, but also of astroglial -synuclein. AD pathology in DLB cases is less than in AD cases, reflecting less advanced pathological stages. Astroglial -synuclein and its relation with AD copathology in DLB should be further studied, as this may play a role in accelerating clinical decline.

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Geut, H., van den Berg, E., Boon, B. D., Hoozemans, J. J., Tunold, J.-A., Pihlstrom, L., Jonkman, L. E., Rozemuller, A. J., Lemstra, E. A., van de Berg, W. D. J.. 2024-01-02. Alzheimer's disease copathology in dementia with Lewy bodies is associated with astroglial α-synucleinopathy. https://doi.org/10.1101/2024.01.02.573857

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