Prediction models for dementia and neuropathology in the oldest old: The Vantaa 85+ cohort study

Background: We developed multifactorial models for predicting incident dementia and brain pathology in the oldest old using the Vantaa 85+ cohort. Methods: We included participants without dementia at baseline and at least 2 years of follow-up (N = 245) for dementia prediction or with autopsy data (N = 163) for pathology. A supervised machine learning method was used for model development, considering sociodemographic, cognitive, clinical, vascular, and lifestyle factors, as well as APOE genotype. Neuropathological assessments included β-amyloid, neurofibrillary tangles and neuritic plaques, cerebral amyloid angiopathy (CAA), macro- and microscopic infarcts, α-synuclein pathology, hippocampal sclerosis, and TDP-43. Results: Prediction model performance was evaluated using AUC for 10 × 10-fold cross-validation. Overall AUCs were 0.73 for dementia, 0.64-0.68 for Alzheimer's disease (AD)- or amyloid-related pathologies, 0.72 for macroinfarcts, and 0.61 for microinfarcts. Predictors for dementia were different from those in previous reports of younger populations; for example, age, sex, and vascular and lifestyle factors were not predictive. Predictors for dementia versus pathology were also different, because cognition and education predicted dementia but not AD- or amyloid-related pathologies. APOE genotype was most consistently present across all models. APOE alleles had a different impact: ϵ4 did not predict dementia, but it did predict all AD- or amyloid-related pathologies; ϵ2 predicted dementia, but it was protective against amyloid and neuropathological AD; and ϵ3ϵ3 was protective against dementia, neurofibrillary tangles, and CAA. Very few other factors were predictive of pathology. Conclusions: Differences between predictors for dementia in younger old versus oldest old populations, as well as for dementia versus pathology, should be considered more carefully in future studies.