Revealing Individual Neuroanatomical Heterogeneity in Alzheimer Disease Using Neuroanatomical Normative Modeling
Bibliographic record
Abstract
Background and Objectives: Alzheimer’s Disease (AD) is highly heterogeneous, with marked individual differences in clinical presentation and neurobiology. To explore this, we employed neuroanatomical normative modelling to index regional patterns of variability in cortical thickness. We aimed to characterise individual differences and outliers in cortical thickness in patients with AD, people with mild cognitive impairment (MCI) and controls. Furthermore, we assessed the relationships between cortical thickness heterogeneity and cognitive function, amyloid-beta, phosphor-tau, ApoE genotype. Finally, we examined whether cortical thickness heterogeneity was predictive of conversion from MCI to AD. Methods: Cortical thickness measurements across 148 brain regions were obtained from T1-weighted MRI scans from 62 sites of the Alzheimer’s Disease Neuroimaging Initiative. AD was determined by clinical and neuropsychological examination with no comorbidities present. MCI participants had reported memory complaints, and controls were cognitively normal. A neuroanatomical normative model indexed cortical thickness distributions using a separate healthy reference dataset (n= 33,072), employing hierarchical Bayesian regression to predict cortical thickness per region using age and sex, whilst adjusting for site noise. Z-scores per region were calculated, resulting in a z-score ‘brain map’ per participant. Regions with z-scores <-1.96 were classified as outliers. Results: Patients with AD (n=206) had a median of 12 outlier regions (out of a possible 148), with the highest proportion of outliers (47%) in the parahippocampal gyrus. For 62 regions, over 90% of these patients had cortical thicknesses within the normal range. Patients with AD had more outlier regions than people with MCI (n=662) or controls (n=159) [F(2, 1022) = 95.39), P = 2.0×10-16]. They were also more dissimilar to each other than people with MCI or controls [F(2, 1024) = 209.42, P = 2.2×10-16]. A greater number of outlier regions was associated with worse cognitive function, CSF protein concentrations and an increased risk of converting from MCI to AD within three years (HR = 1.028, 95% CI[1.016,1.039], P =1.8×10-16). Discussion: Individualised normative maps of cortical thickness highlight the heterogeneous impact of AD on the brain. Regional outlier estimates have the potential to be a marker of disease and could be used to track an individual’s disease progression or treatment response in clinical trials.
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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 | 0.005 | 0.010 |
| Meta-epidemiology (narrow) | 0.001 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.001 |
| Bibliometrics | 0.002 | 0.001 |
| Science and technology studies | 0.000 | 0.001 |
| Scholarly communication | 0.001 | 0.001 |
| Open science | 0.001 | 0.001 |
| Research integrity | 0.001 | 0.000 |
| Insufficient payload (model declined to judge) | 0.001 | 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".