Revealing Individual Neuroanatomical Heterogeneity in Alzheimer Disease Using Neuroanatomical Normative Modeling

Alzheimer disease (AD) is highly heterogeneous, with marked individual differences in clinical presentation and neurobiology. To explore this, we used neuroanatomical normative modeling to index regional patterns of variability in cortical thickness. We aimed to characterize 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, β-amyloid, phosphorylated-tau, and ApoE genotype. Finally, we examined whether cortical thickness heterogeneity was predictive of conversion from MCI to AD. 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. Participants with MCI had reported memory complaints, and controls were cognitively normal. A neuroanatomical normative model indexed cortical thickness distributions using a separate healthy reference data set (n = 33,072), which used hierarchical Bayesian regression to predict cortical thickness per region using age and sex, while adjusting for site noise. -scores per region were calculated, resulting in a -score brain map per participant. Regions with -scores