Braak stage and trajectory of cognitive decline in noncognitively impaired elders

doi:10.1016/j.neurobiolaging.2016.03.003

Neurobiology of Aging

Volume 43, July 2016, Pages 101-110

https://doi.org/10.1016/j.neurobiolaging.2016.03.003 Get rights and content

Abstract

In a previous cross-sectional study, we found that nondemented elderly participants from the Rush Religious Orders Study (RROS) displayed a wide range of Braak neurofibrillary tangle and amyloid plaque pathology similar to that seen in prodromal and frank Alzheimer's disease. Here, we examined longitudinal changes in cognitive domains in subjects from this cohort grouped by Braak stage using linear mixed effects models. We found that the trajectory of episodic memory composite (EMC), executive function composite (EFC), and global cognitive composite scores (GCS: average of EMC and EFC scores) was significantly associated with age at visit over time, but not with Braak stage, apolipoprotein E (APOE) ε4 status or plaque pathology alone. By contrast, the combined effects of Braak stage, APOE status, and age at visit were strongly correlated with the trajectory of EMC, EFC and GCS performance over time. These data suggest that age and APOE ε4 status, rather than Alzheimer's disease-related pathology, play a more prominent role in the trajectory of cognitive decline over time in this elderly nondemented population. However, the findings reported require confirmation in a larger cohort of cases.

Introduction

Older people without dementia display neurofibrillary tangles (NFTs) and beta amyloid (Aβ) plaques, the two neuropathology hallmarks of Alzheimer's disease (AD) (Bennett et al., 2002, Guillozet et al., 2003, Markesbery, 2010, Morris and Price, 2001, Morris et al., 2001, Mufson et al., 1999, Mufson et al., 2016, Price et al., 2009, Tomlinson et al., 1970, Wilson et al., 2006). However, there are relatively few prospective studies on the association between premortem cognitive function and AD pathology in people who died with a clinical diagnosis of no cognitive impairment (NCI) but display extensive NFT deposition within the medial temporal lobe (MTL) memory circuit. The Braaks (Braak and Braak, 1991) proposed a neuropathological staging to differentiate initial, intermediate, and advanced AD based on the spread of NFTs within the MTL memory circuit: Braak stage 0 corresponds to an absence of NFTs, stages I–II displays NFTs within the entorhinal-perirhinal cortex, stages III–IV shows NFTs additionally in hippocampus and, stages V–VI, NFTs are widely distributed in neocortical areas. Although previous studies evaluated the association between the Consortium to Establish a Registry in Alzheimer's Disease (CERAD; Mirra, 1997) and NIA-Reagan AD (The National Institute on Aging) pathologic criteria and clinical findings in older people without cognitive impairment (Bennett et al., 2002, Guillozet et al., 2003, Markesbery, 2010, Morris and Price, 2001, Morris et al., 2001), there is limited information on the relationship between Braak staging and longitudinal neurocognitive measure changes in this type of population (Bennett et al., 2002, Erten-Jones et al., 2009, Guillozet et al., 2003, Markesbery, 2010, Morris et al., 2001, Mufson et al., 1999, Nelson et al., 2009).

Previously, we performed clinical molecular pathobiological investigations regarding the onset of dementia in the elderly using tissue obtained from the Rush Religious Orders Study (RROS), a longitudinal clinic-pathologic investigation of aging and AD (Mufson et al., 1999, Mufson et al., 2008, Mufson et al., 2012b). In these studies, subjects with a premortem clinical diagnosis of NCI were classified postmortem with a wide range of Braak scores (I–V) (Gilmor et al., 1999, Mufson et al., 1999, Mufson et al., 2012b, Perez et al., 2015). Recently, we reported in a cross-section study that elderly RROS participants without dementia and free of other neurological disorders or pathologies who at autopsy were classified as Braak, NFT stages of I–V displayed preserved cognitive function (Mufson et al., 2016). Here, we extend this investigation to a longitudinal examination of changes in cognitive domains in this cohort of cases grouped by Braak stage. Linear mixed effects models were used to assess differences in the trajectory of change for cognitive composite scores between the Braak stage groups and to determine the association between amyloid load and neuritic and diffuse plaque counts with longitudinal changes in episodic memory and executive function.

Section snippets

Methods

Braak staging and cognitive status were examined in 106 older deceased and autopsied persons with no cognitive impairment and no coexisting clinical or neurological condition judged to contribute to cognitive impairment at the last clinical evaluation (Bennett et al., 2005, Mufson et al., 1999). The participants agreed to annual clinical evaluations and signed an informed consent and an Anatomic Gift Act donating their brains at time of death (see Table 1). Data from these subjects have been

Demographics

A total of 842 person-years were contributed by the 106 individuals in the sample. The average duration of follow-up was 7.94 ± 4.47 years, average age at death was 84.42 ± 6.97 years, and average postmortem interval was 5.64 ± 6.87 hours. The sample cohort had an average of 18.02 ± 3.57 years of education, average time between last clinical assessment and death was less than one year (0.70 ± 0.62 years) and had a relatively even gender distribution (51% male; see Table 1). Quantile-quantile

Discussion

The present study, found that changes in episodic memory, executive function, and global cognition are dependent upon the combined effects of age, NFT pathology, and APOE ε4 status in elderly noncognitively impaired individuals. Braak 0-II cases tended to display better longitudinal cognitive performance than Braak III and Braak IV-V subjects among the cognitive domains examined. APOE ε4 carrier status also effected the trajectories of cognitive performance within each Braak group. In this

Disclosure statement

None of the authors have any disclosures.

Acknowledgements

Supported by National Institute on Aging grants PO1AG14449, P30AG10161, P30AG019610, RO1AG43775 and Barrow Neurological Institute Barrow and Beyond. The authors thank the participants in the Religious Orders Study, the faculty and staff who work on this project at the Rush Alzheimer's Disease Center.

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Regular articleBraak stage and trajectory of cognitive decline in noncognitively impaired elders

Abstract

Introduction

Section snippets

Methods

Demographics

Discussion

Disclosure statement

Acknowledgements

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Braak stage and trajectory of cognitive decline in noncognitively impaired elders