Basic Science and Pathogenesis - Part 1.

Abstract

Alzheimer's disease (AD) is a heterogeneous proteinopathy. Co-pathology with Lewy bodies (LB) is frequent and known to contribute to a differential pattern of executive cognitive impairment compared to typical AD. While primary age-related tauopathy (PART) presents with neurofibrillary tangles, mainly restricted to the temporal lobe and in the absence of amyloid-beta plaques, LB co-pathology is also present. However, it is still unknown how the combination of these proteinopathies affects patterns of brain atrophy, which might help clarify the clinical importance and pathophysiology of combined pathology within these groups. Here we investigated the influence of LB on patterns of brain atrophy in AD and PART. We selected 214 patients with AD neuropathological change (ADNC) with no LB (n = 102), ADNC with LB (ADNC+LB) (n = 77), PART with no LB (n = 22) and PART with LB (PART+LB) (n = 13) with ante-mortem volumetric MRI from the National Alzheimer's Coordinating Center, after exclusion of other neurodegenerative pathologies. Dementia severity was compared using Clinical Dementia Rating Scale Sum of Boxes (CDR-SB). Cortical and subcortical MRI volume residuals were compared between groups after correction for age. Statistical significance was considered at p-value < 0.05 after false discovery rate correction for multiple comparisons. We found that ADNC, ADNC+LB and PART+LB presented similar levels of dementia severity, whereas PART with no LB was the least affected group. MRI revealed higher atrophy of the right frontal operculum and amygdala in ADNC+LB compared to ADNC. ADNC and ADNC+LB showed increased atrophy in regions across all cortical lobes, hippocampus, amygdala and putamen compared to PART, but did not reveal significant differences compared to PART+LB. Interestingly, PART+LB showed higher atrophy of the frontal poles bilaterally, right superior frontal gyrus, left frontal operculum and right putamen compared to PART. Altogether, these results suggest that LB co-pathology contributes to frontal lobe regional atrophy in ADNC and likely drives it in PART. Particularly in PART+LB, it suggests that cognitive impairment might derive from alpha-synuclein pathology rather than tauopathy. These findings indicate that LB pathology determines disease severity within the PART- and AD-continuums.