"End-stage" neurofibrillary tangle pathology in preclinical Alzheimer's disease: fact or fiction?

Abstract

Among individuals who were cognitively intact before death, autopsies may reveal some Alzheimer's disease-type pathology. The presence of end-stage pathology in cognitively intact persons would support the hypothesis that pathological markers are epiphenomena. We assessed advanced neurofibrillary (Braak stages V and VI) pathology focusing on nondemented individuals. Data from the National Alzheimer's Coordinating Center database (n = 4,690 included initially) and from the Nun Study (n = 526 included initially) were analyzed, with antemortem information about global cognition and careful postmortem studies available from each case. Global cognition (final Mini-Mental State Examination scores (MMSE) and clinical 'dementia' status) was correlated with neuropathology, including the severity of neurofibrillary pathology (Braak stages and neurofibrillary tangle counts in cerebral neocortex). Analyses support three major findings: 1. Braak stage V cases and Braak VI cases are significantly different from each other in terms of associated antemortem cognition; 2. There is an appreciable range of pathology within the category of Braak stage VI based on tangle counts such that brains with the most neurofibrillary tangles in neocortex always had profound antemortem cognitive impairment; and 3. There was no nondemented case with final MMSE score of 30 within a year of life and Braak stage VI pathology. It may be inappropriate to combine Braak stages V and VI cases, particularly in patients with early cognitive dysfunction, since the two pathological stages appear to differ dramatically in terms of both pathological severity and antemortem cognitive status. There is no documented example of truly end-stage neurofibrillary pathology coexisting with intact cognition.

Fig. 1

NACC registry data: empirical distribution of final MMSE scores by Braak stage V and stage VI. Only cases with final MMSE tests administered within 3 years of death and with enough neuritic plaques in the brain to satisfy CERAD criteria of “possible”, “probable”, or “definite” Alzheimer's disease, were included (total n = 1,219). Note that the median MMSE is shifted 5 points between Braak V and Braak VI (p < 0.0001, Kolmogorov-Smirnov test).

Fig. 2

Combining Nun Study and NACC registry data to assess non-demented cases with final MMSE score of 30 within the last year of life (n = 89 cases). These cases were evaluated to assess the range of neurofibrillary pathologies seen in those individuals with the most rigorously documented intact cognition based on MMSE scores near death. There are no brains with Braak stage VI pathology in this group. Note that there are many cases in this category with Braak stages I–III. This clearly indicates that Braak stage III, in the context of preclinical disease, should not be considered “Intermediate likelihood” for AD.

Fig. 3

Nun Study data: Assessing the variation of neocortical neurofibrillary tangle (NFT) pathology at different disease stages. A) Final MMSE scores (± SEM) across Braak stages from the Nun Study autopsy cohort. Note that average final MMSE scores for Braak stage VI are dramatically lower than Braak stage V. B) Final MMSE scores are shown in correlation with NFTs counted in the cerebral neocortex stratified by Braak stage V or VI. Each data point represents one individual. Summed counts were used from inferior parietal lobule, superior and mid-temporal gyri, frontal (Brodmann Area 46), and occipital cortex (Brodmann Areas 17/18) as described in the Methods section. There is, as expected, a shift with increased counted neocortical NFTs in Braak VI cases. The correlation between NFTs counted postmortem, versus antemortem global cognitive status as defined by MMSE scores, is highly significant (p < 0.0001) but there is substantial variance (R² = 0.25). Above a particular threshold of counted neocortical NFTs (80 NFTs; see dashed orange vertical line), every patient had a final MMSE score under 15. 0% (0/44) of Braak stage IV cases (data not shown), 7.8% (5/64) of Braak stage V cases, and 60.4% (55/91) of Braak stage VI cases had neocortical NFT counts above this threshold.