DOI: 10.1002/alz.077833 ISSN: 1552-5260

Association of hippocampal neuron loss, pTDP‐43, and Alzheimer’s disease pathology with the presence of cerebral Lewy bodies

Klara Gawor, Sandra O. Tomé, Alicja Ronisz, Simona Ospitalieri, Rik Vandenberghe, Christina von Arnim, Markus Otto, Dietmar Rudolf Thal
  • Psychiatry and Mental health
  • Cellular and Molecular Neuroscience
  • Geriatrics and Gerontology
  • Neurology (clinical)
  • Developmental Neuroscience
  • Health Policy
  • Epidemiology



The presence of multiple brain pathologies in patients with late‐onset dementia was shown to be a rule rather than an exception. Studies have shown that over half of the patients with Lewy bodies (LB) in the brain also have concurrent Alzheimer’s disease pathology (ADNC). The estimates of pTDP‐43 proteinopathy prevalence vary greatly between studies, ranging from 0‐50%. This disparity may be attributed to different patterns of LB distribution, including brainstem, limbic, and neocortical. In this study, we aimed to investigate the hypothesis that the severity of pTDP‐43 pathology and hippocampal neuronal loss vary depending on the distribution of LBs, independent of co‐existing ADNC.


Paraffin‐embedded sections from 270 brains of older adults with and without dementia were histologically evaluated for amyloid‐beta, pTau, pTDP‐43, and alpha‐synuclein. The severity of ADNC was assessed according to NIA‐AA guidelines. We differentiated cases positive for alpha‐synuclein in the amygdala or neocortex (cerebral LB) from those with pathology restricted to brainstem regions (brainstem LB). The CA1 region from the posterior hippocampus was quantitatively analyzed for pTDP‐43 pathology and overall neuronal density.


Our findings revealed that pTDP‐43 neuronal inclusions were present in the CA1 region in more than 80% of subjects with cerebral LB and high ADNC. The percentage of pTDP‐43 positive neurons was higher in the cerebral LB/AD group than in AD cases without LBs (β = 0.11, p<10−4). We detected a decreased neuronal density in the CA1 regions in cases with cerebral LBs regardless of AD status (β = ‐35.43, p<10−4). LB restricted to brainstem regions had no impact on pTDP‐43 pathology (β = 0, p = 0.99) and neuronal density in the hippocampus (β = ‐12.26, p = 0.15).


Our results support the existence of a distinct subgroup of late‐onset dementia cases characterized by cerebral LBs, ADNC, and severe pTDP‐43 pathology. This finding may explain the variability of pTDP‐43 prevalence estimations in LB patients. By identifying the association between cerebral LBs and neuronal loss in the hippocampus, we also emphasize the importance of stratifying dementia patients based on the pattern of LB distribution. Further research is needed to clarify the functional interactions between pTDP‐43, alpha‐synuclein (LB), and ADNC.

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