OBJECTIVE
Some individuals avoid Alzheimer's disease (AD) pathology as they age, or retain cognition despite substantial pathology, suggesting mechanisms of resistance or resilience to neurodegeneration. Educational attainment (EA) is associated with reduced risk of cognitive decline, although the underlying mechanisms remain unclear. We investigated whether genome-wide polygenic scores (GPS) based on cognitive and non-cognitive components of EA, reflecting intelligence and behavioral/social traits, respectively, show differential associations with AD diagnosis and neuropathology.
METHODS
Associations between GPS for cognitive and non-cognitive components of EA and AD outcomes were examined across four cohorts: two cohorts included living participants with biomarker assessments (BioHermes-1, n = 770; Alzheimer's Disease Neuroimaging Initiative [ADNI], n = 1,361), and two included postmortem neuropathological evaluations (Religious Orders Study and Rush Memory and Aging Project [ROSMAP], n = 841; Brain for Dementia Research [BDR], n = 511). Outcomes included clinical diagnosis, amyloid status, plasma neurodegenerative biomarkers, and neuropathological measurements.
RESULTS
We found a significant negative association between cognitive EA GPS and clinical diagnosis of AD across all four cohorts and with Braak stage in ROSMAP and BDR cohorts. In contrast, the GPS for non-cognitive component of EA showed no significant association with AD diagnosis, neurodegenerative plasma biomarkers or amyloid positron emission tomography (PET) status and the Consortium to Establish a Registry for Alzheimer's Disease (CERAD) scores.
INTERPRETATION
These results suggest a brain maintenance mechanism that supports the brain's ability to resist to changes in neuronal integrity. This indicates that interventions focused on increasing EA solely by additional years of schooling are unlikely to affect AD incidence, whereas alternative approaches targeting the cognitive component of EA (intelligence) may offer greater potential for prevention. ANN NEUROL 2026.
G. Leonenko, K. Mavromati, Lynn Hughes et al.· Annals of Neurology· 0 citations
INTRODUCTION: Accurately identifying risk of Alzheimers Dementia (AD) is essential for supporting people living with symptoms in clinical settings, as well as recruiting adults in prospective medical research. Various algorithms have been created to calculate AD risk based on evidenced risk factors which are weighted toward a total score. As daily life conditions determining risk change at scale, it remains unclear how effective gold standard algorithms remain in modern cohorts. METHODS: In the Bio-Hermes-001 diverse cohort, we assessed algorithm discrimination and calibration in six outcomes: classifying AB PET binary outcome (negative N = 603, positive N = 342); phosphorylated tau-217 binary outcome (pTau-217 negative N = 166, positive N = 469); participants with Healthy Cognition (N = 417) from probable AD (N = 272); HC from Mild Cognitive Impairment (N = 312), HC from pooled MCI or AD; and MCI from AD. Approximately a third of the cohort are individuals from populations typically underrepresented in dementia research (HC: 19%; MCI: 24%; AD: 33%). RESULTS: Hosmer-Lemeshow tests and Brier score demonstrate acceptable calibration of all algorithms except the oldest algorithm. However, Receiver Operating Characteristic (ROC) curves and the associated area under the curve (AUC) estimates evidenced that in this cohort only the BDSI exceeded conventional thresholds for good discrimination (.8 AUC in HC-AD classification, with AUC approximately .7 in the other clinical, AB PET, and pTau-217 comparisons). When the functional item is removed from the BDSI score, it remains acceptably calibrated, but DeLong tests reflect statistically significant reduction in discriminatory performance for all group comparisons. The two earliest published algorithms were only chance-level accurate. DISCUSSION: In a contemporary, diverse cohort, most established dementia risk algorithms had limited power in discriminating amyloid positivity, pTau-217 positivity, and current cognitive status despite acceptable calibration. Including a functional measure markedly improved discrimination across both clinical and biomarker-defined outcomes, suggesting that proximal indicators of cognitive vulnerability are critical for identifying individuals with underlying AD-related pathology.
K. Mavromati, A. Dibble, L. Tvrdá et al.· medRxiv· 0 citations
A multivariate blood-based framework integrating 19 molecular assays and six risk instruments in the Bio-Hermes-001 cohort supports resilience and resistance as molecularly distinct subgroups and provides a scalable framework for pathology-informed stratification and mechanistic investigation.
K. Mavromati, C. Dalby, A. Dibble et al.· medRxiv· 0 citations
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