Non-Alzheimer's contributions to dementia and cognitive resilience in The 90+ Study.

John L Robinson,Sharon X Xie,Virginia M.-Y Lee,Gabor G Kovacs,Carrie Caswell,Claudia H Kawas,Maria M Corrada,John Q Trojanowski,Myrna Dominique

doi:10.1007/s00401-018-1872-5

Abstract

The diagnosis of Alzheimer's disease (AD) in the oldest-old is complicated by the increasing prevalence of age-related neurofibrillary tangles, plaques and non-AD pathologies such as cerebrovascular disease (CVD), hippocampal sclerosis (HS), aging-related tau astrogliopathy (ARTAG), as well as TDP-43 and Lewy pathology. The contribution of these non-AD pathologies to dementia and cognitive resilience is unclear. We assessed the level of AD neuropathologic change (ADNPC) and non-AD pathology in 185 participants enrolled in The 90+ Study with available cognitive assessments and brain tissue. Logistic regression models-adjusting for age, sex and education-determined the association between each pathology and dementia or between subgroups. 53% had dementia, primarily AD or mixed AD; 23% had cognitive impairment without dementia (CIND); 23% were not impaired. Both AD and non-AD pathology was prevalent. 100% had tangles, 81% had plaques, and both tangles and plaques associated with dementia. ARTAG distributed across limbic (70%), brainstem (39%) and cortical regions (24%). 49% had possible CVD and 26% had definite CVD, while HS was noted in 15%. Cortical ARTAG, CVD and HS were each associated with dementia, but limbic and brainstem ARTAGs were not. TDP-43 and Lewy pathologies were found in 36 and 17% and both associated with dementia. No pathology distinguished CIND and the not impaired. By NIA-AA criteria and dementia status, the cohort was subdivided into four groups: those with minimal ADNPC included the not dementia (ND) and Not AD dementia groups; and those with significant ADNPC included the Resilient without dementia and AD dementia groups. Compared to the ND group, the Not AD dementia group had more HS, cortical ARTAG, TDP-43, and Lewy pathology. Compared to the AD dementia group, the Resilient group had less CVD, no HS and less cortical ARTAG, TDP-43 and Lewy pathology. Our findings imply that reductions in non-AD pathologies including CVD contribute to cognitive resilience in the oldest-old.

Highlights

The neuropathological diagnosis of Alzheimer’s disease (AD) in the oldest-old—those older than 90 years—is complicated by the increasing prevalence of aging-related neurofibrillary tangles (NFTs) and plaques in individuals without clinical dementia [5]
While AD pathology is common in the oldest-old, our study develops two lines of evidence implicating non-AD pathologies in the development of dementia in this age group
Dementia occurs in the absence of significant AD pathology when cerebrovascular disease (CVD), aging-related tau astrogliopathy (ARTAG), hippocampal sclerosis (HS), TDP-43 and Lewy pathology act as multiple insults on the aged brain

Summary

Introduction

The neuropathological diagnosis of AD in the oldest-old—those older than 90 years—is complicated by the increasing prevalence of aging-related neurofibrillary tangles (NFTs) and plaques in individuals without clinical dementia [5]. Those with AD pathology but no dementia may be pathologically indistinguishable from those with dementia who are vulnerable to a low burden of AD neuropathologic change (ADNPC). The decreasing correlation between AD pathology and dementia in the oldest-old may be the result of the increasing prevalence of non-AD pathology with advancing age. We use NIA-AA criteria to examine the hypothesis that non-AD pathology associates with dementia independent of AD pathology

Methods

Results

Discussion