Joint Longitudinal Hazard Modeling Distinguishes Polygenic Effects on Dementia via Premorbid Cognitive Function and Aging-Related Decline

Multi-ancestry polygenic indices in 11,518 US adults are linked to dementia hazard through either faster aging-related cognitive decline or lower premorbid cognitive function, depending on the risk factor.

• Why it matters: AD/ADRD risk may reflect steeper cognitive aging or earlier-life cognitive disadvantage, but separating these pathways is needed to target interventions at the right life stage.
• What they did: Using joint longitudinal-hazard models on 26-year follow-up, the study estimated how multi-ancestry PGIs for established risk factors relate to dementia hazard and whether effects run through premorbid cognition versus longitudinal cognitive change.
• The result: APOE e4 and PGIs for ADRD, type 2 diabetes, stroke, LDL cholesterol, and hearing loss operated via rate of change, while PGIs for educational attainment, cognitive function, physical activity, BMI, smoking, loneliness, schizophrenia, and externalizing were linked to hazard via premorbid cognitive differences, with some ancestry-specific variation.

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