Logo image
Back
Neocortical tau burden determines the degree of cognitive impairment in individuals with Braak stage V neurofibrillary degeneration
Journal article   Open access   Peer reviewed

Neocortical tau burden determines the degree of cognitive impairment in individuals with Braak stage V neurofibrillary degeneration

Timothy E Richardson, Jonathan Cherry, Shrishtee Kandoi, Susan K Rohde, Madeline Uretsky, Fatima Tuz-Zahra, Kevin F Bieniek, Kurt Farrell, Marco M Hefti, Michael B Miller, …
Acta neuropathologica, Vol.151(1), 61
05/25/2026
DOI: 10.1007/s00401-026-03031-4
PMID: 42184025
url
https://doi.org/10.1007/s00401-026-03031-4View
Published (Version of record) Open Access

Abstract

Alzheimer disease neuropathologic change (ADNC) is considered to be the most common cause of cognitive decline and dementia worldwide. ADNC level is determined using the density of neuritic plaques in combination with the topographical distribution of β-amyloid (Aβ) plaques and hyperphosphorylated tau (p-tau)-positive neurofibrillary tangles (NFTs). While cognitive decline correlates with the level of ADNC, there remains a great deal of variation in cognitive outcomes between individuals that is unaccounted for by current neuropathologic evaluation metrics. We leveraged quantitative computer-assisted positive pixel assessments to establish the neocortical p-tau burden in the middle frontal and superior temporal gyri of 61 individuals with Braak NFT stage V who had a wide range of cognitive outcomes and trajectories. Frontal and temporal neocortical p-tau burden varied between 0.2% and 53.7%. Both frontal and temporal p-tau burden directly affected cognitive outcome and correlated with function of multiple cognitive domains, including measures of language/semantic memory and attention/working memory. In multivariable analysis, only p-tau burden and microinfarcts significantly impacted cognitive decline, while Aβ, limbic-predominant age-related TDP-43 encephalopathy, Lewy body pathology, and other measures of cerebrovascular disease did not. Additionally, individuals with low mean neocortical p-tau burden (≤ 13%) had significantly better longitudinal cognitive trajectories over the final 15 years of life compared to those with high burden (≥ 23.5%). These results suggest that while all individuals with Braak stage V have some degree of neurofibrillary degeneration in the neocortex, the significant variation in cognitive decline observed between these individuals can be partially understood as a reflection of the variation in quantitatively assessed neocortical p-tau burden, which had a greater impact on progression to dementia than common comorbid neuropathologies associated with dementia risk. This argues for the incorporation of the density of ADNC-related pathology, in addition to its regional location, as an adjunct to future staging systems for Alzheimer disease.
 Aged Aged, 80 and over Alzheimer Disease - metabolism Alzheimer Disease - pathology Cognitive Dysfunction - metabolism Cognitive Dysfunction - pathology Female Humans Male Middle Aged Neocortex - metabolism Neocortex - pathology Neurofibrillary Tangles - metabolism Neurofibrillary Tangles - pathology tau Proteins - metabolism

Details

Metrics

1 Record Views
Logo image