AT(N) predicts near-term development of Alzheimer’s disease symptoms in unimpaired older adults
Bibliographic record
Abstract
Abstract Importance National Institute on Aging-Alzheimer’s Association (NIA-AA) workgroups have proposed biological research criteria intended to identify individuals with preclinical Alzheimer’s disease (AD). Objective Assess the clinical value of these biological criteria for prediction of near-term cognitive impairment in cognitively unimpaired older individuals. Design, Setting, and Participants We studied 580 cognitively unimpaired older adults from four independent cohorts (PREVENT-AD: 128; HABS: 153; AIBL: 48; Knight ADRC: 251) having ≥1 year of clinical observation following Aβ and tau PET (median follow-up: PREVENT-AD = 3.16 yrs [1.51-4.50]; HABS = 1.94yrs [1.13-5.42]; AIBL = 3.66yrs [1.72-5.98]); Knight ADRC = 3.01 yrs [1.04-6.20]). Exposures Based on binary assessment of global amyloid burden (A) and of a composite temporal region of tau PET uptake (T), we stratified participants into four groups (A+T+, A+T-, A-T+, A-T-). Presence (+) or absence (-) of neurodegeneration (N) was assessed using temporal cortical thickness. Main Outcomes and Measures We analyzed each cohort separately. Primary outcome was clinical progression to mild cognitive impairment (MCI). A secondary outcome was cognitive decline. We compared MCI progression and cognitive decline across the four biomarker groups. MCI was identified by consensus committee review in PREVENT-AD, HABS, and AIBL, and by a CDR ≥ 0.5 in Knight ADRC. Clinical raters were blinded to imaging, genetic, and fluid biomarker data. Using a composite measure, cognitive decline was identified by a slope >1 SD below that of A-T- ‘non-progressors’. Results Across cohorts, 32 - 83% of A+T+ participants progressed to MCI during follow-up (mean progression time 2.0 - 2.72 years), as compared with <12% of participants in other biomarker groups. In two cohorts, progression increased to 100% when A+T+ individuals were also (N+). Cox proportional hazard ratios for progression to MCI in the A+T+ group vs. other biomarker groups were >5. Many A+T+ ‘non-progressors’ nonetheless showed longitudinal cognitive decline, while cognitive trajectories in other groups remained predominantly stable. Conclusions and Relevance Clinical prognostic value of the NIA-AA research criteria was confirmed in four independent cohorts, with nearly all A+T+(N+) cognitively unimpaired older individuals developing AD symptoms within ∼2-3 years. Key Points Question What is the clinical relevance of the AT(N) biological classification of Alzheimer’s disease (AD) in unimpaired older adults? Findings In this prospective study of 580 cognitively unimpaired participants from four independent cohorts, between 31.58 and 100% of A+T+(N+) participants progressed to mild cognitive impairment (MCI) within 2-3 years after PET. The majority of A+T+ non-progressors also showed cognitive decline. Meaning Cognitively unimpaired older adults with biological AD are at imminent risk of developing MCI. These individuals may be ideal candidates for disease modifying therapies.
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.001 | 0.003 |
| Meta-epidemiology (narrow) | 0.001 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.001 |
| Bibliometrics | 0.001 | 0.000 |
| Science and technology studies | 0.001 | 0.000 |
| Scholarly communication | 0.001 | 0.001 |
| Open science | 0.001 | 0.001 |
| Research integrity | 0.001 | 0.001 |
| Insufficient payload (model declined to judge) | 0.002 | 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 itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".