Domain-specific cognitive impairment is differentially affected by Alzheimer disease tau pathologic burden and spread
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Bibliographic record
Abstract
Abstract Tau pathology in Alzheimer disease (AD) is often evaluated in regions associated with episodic memory impairment. However, heterogeneous spreading patterns of tau are observed and correspond to impairment in different cognitive domains. We have previously developed a metric to quantify tau spread extent that is robustly sensitive to atypical spreading patterns. Here, we evaluate tau spread relative to domain-specific and general cognitive impairments during early stages of AD. In total, 529 participants with baseline tau positron emission tomography (PET) and neuropsychological testing were separated into disease-stage groups based on amyloid PET positivity and clinical status via Clinical Dementia Rating® (CDR®). General cognition was assessed using the Knight Preclinical Alzheimer Cognitive Composite (Knight PACC). Domain-specific composites were calculated for episodic memory, semantic memory, working memory, and attention/processing speed. Baseline tau burden, the average tau intensity across previously defined AD signature regions, and baseline tau spread extent, the proportion of the brain with elevated tau pathology, were quantified for each participant as Tau Index and Tau Spatial Spread, respectively. Tau burden and tau spread were evaluated relative to baseline and longitudinal cognitive performance, as well as longitudinal clinical progression. Tau burden and tau spread extent both significantly correlate with cognitive impairment in symptomatic AD. Tau burden is most strongly correlated with episodic (r = -0.37, p = 0.02) and semantic (r = -0.36, p = 0.02) memory. In contrast, tau spread extent is most strongly correlated with the Knight PACC (r = -0.37, p = 0.01) and attention/processing speed (r = -0.44, p < 0.01), especially in preclinical AD (r = -0.27, p < 0.01). Tau burden captures more variance than tau spread extent in longitudinal change in the Knight PACC, episodic memory, semantic memory, attention/processing speed, and clinical progression. Tau burden strongly relates to baseline episodic and semantic memory, which may reflect that it is heavily weighted by entorhinal tau, a region previously linked to memory processing. In contrast, stronger associations between tau spread extent and baseline attention/processing speed could reflect the inclusion of additional brain regions, particularly the frontal lobe, which support a wider range of cognitive processing. Additionally, tau spread extent is generally more sensitive to baseline preclinical deficits; however, tau burden better estimates future decline across all cognitive domains and clinical symptom onset. Together, these findings suggest complementary utility of evaluating both tau burden and tau spread extent in early AD progression.
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Full frame distilled prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. Learned from the 10,348 direct Codex labels and 10,348 direct Gemma labels. Candidate is the union of thresholded teacher heads; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels or direct frontier model labels.
Codex and Gemma teacher scores by category
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.001 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.000 |
| Insufficient payload (model declined to judge) | 0.000 | 0.000 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from it