Abstract
Lewy bodies (LBs) and limbic-predominant age-related TDP-43 encephalopathy neuropathologic change (LATE-NC) are common in older persons and associated with cognitive impairment. However, little is known about the relationship between LBs and LATE-NC and their combined roles in cognitive impairment and Alzheimer’s dementia in community-dwelling participants. The study included 1670 community-based participants (mean age-at-death, 89.5 years (SD = 6.65); 69% females) who underwent annual assessments of cognition to create summary measures of global cognition and cognitive domains and evaluation for Alzheimer’s dementia. Systematic neuropathologic evaluations were performed to assess LBs, LATE-NC, and Alzheimer’s disease (AD) pathology. We excluded cases with pathologically confirmed frontotemporal lobar degeneration in this study. Logistic and linear regression analyses were used, adjusted for demographics and AD pathology. LBs were present in 428 (25.6%) decedents (29 nigra-predominant, 165 limbic-type, and 234 neocortical-type) while 865 (51.7%) decedents exhibited LATE-NC (307 stage 1, 167 stage 2, and 391 stage 3). LBs combined with LATE-NC were common (15% of all participants) and in those with Alzheimer’s dementia (25%). Neocortical-type, but not nigral-predominant or limbic-type LBs increased the odds of stage 2/3 LATE-NC (odds ratio = 1.70; 95% confidence interval = 1.26–2.30). The association between neocortical-type LBs and stage 2/3 LATE-NC was stronger in those under 90 years of age and in women. In analyses of cognition and Alzheimer’s dementia, LATE-NC and neocortical-type LBs, separately, were related to lower global cognition, five specific cognitive domains, and an increased odds of Alzheimer’s dementia, above and beyond the AD pathology. Limbic-type LBs were related to lower global cognition, and the domains of episodic, working, and semantic memory, and increased odds of Alzheimer’s dementia. Furthermore, there was no interaction between limbic/neocortical-type LBs and LATE-NC on cognitive function, cognitive domains, or Alzheimer’s dementia. These findings suggest that neocortical-type LBs are associated with LATE-NC, specifically in the younger old and in women. Limbic/neocortical-type LBs and LATE-NC have separate and additive effects on cognitive function and odds of Alzheimer’s dementia.
Highlights
It is well recognized that the brains of older people who live in their communities have mixed or comorbid pathologies that account for most cases of Alzheimer’s dementia [37, 39, 42]
It is reported in the aging brain without other pathologies [27, 30, 31] Notably, Lewy bodies (LBs) have been reported as common comorbidity in persons with Limbic-predominant age-related TDP-43 encephalopathy neuropathologic change (LATENC) [3, 10, 27, 32], yet little is known about the relationship between limbic-predominant age-related TDP-43 encephalopathy neuropathologic change (LATE-NC) and LBs from community-based clinical-pathological studies
The interaction was not significant between limbic-type LBs and LATE-NC (p = 0.995; data not shown) as well as neocortical-type LBs and LATENC (p = 0.974; data not shown), suggesting that the effects of LATE-NC and limbic/neocortical-type LBs on the odds of Alzheimer’s dementia are in essence additive. In this clinical-pathological study of 1670 older participants, we found that neocortical LBs and LATE-NC are common and related proteinopathies in aging and Alzheimer’s dementia
Summary
It is well recognized that the brains of older people who live in their communities have mixed or comorbid pathologies that account for most cases of Alzheimer’s dementia [37, 39, 42]. It is reported in the aging brain without other pathologies [27, 30, 31] Notably, LBs have been reported as common comorbidity in persons with LATENC [3, 10, 27, 32], yet little is known about the relationship between LATE-NC and LBs from community-based clinical-pathological studies Given that these pathologies add variability, complexity, and heterogeneity to clinical phenotypes, it is important to understand the role of pathologic co-morbidities in aging and Alzheimer’s dementia; as they may provide clues to pathogenesis
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