Interactive Effects of Plasma Alzheimer Disease Biomarkers and White Matter Hyperintensities on Cognitive Decline and Clinical Progression in Nondemented Adults.
BACKGROUND Alzheimer disease pathology and cerebral small-vessel disease frequently coexist in older adults, yet how their interaction influences early clinical progression remains poorly understood, particularly in individuals without dementia. We aimed to investigate how plasma Alzheimer disease biomarkers and white matter hyperintensities (WMHs) interact to influence cognitive trajectories and the risk of progression to cognitive impairment and dementia. METHODS We studied 463 nondemented participants from the ADNI (Alzheimer's Disease Neuroimaging Initiative). Linear mixed-effects models assessed interactions between plasma biomarkers and WMHs on cognitive trajectories. Cox models examined incident cognitive impairment and dementia. Moderated mediation analyses explored potential biological pathways. RESULTS Among 463 participants, plasma phosphorylated tau 217 to β-amyloid 42 ratio was the only biomarker that consistently interacted with WMHs across multiple stages of disease progression, including cognitive decline (Mini-Mental State Examination: β=-0.05 [95% CI, -0.06 to -0.03]; executive function: β=-0.02 [95% CI, -0.03 to -0.01]; memory: β=-0.03 [95% CI, -0.04 to -0.02]; language: β=-0.03 [95% CI, -0.04 to -0.02]; visuospatial function: β=-0.02 [95% CI, -0.04 to -0.01]) and increased clinical risk (cognitive impairment: χ2=15.67, P=0.047; dementia: χ2=15.88, P=0.044). These interactive associations were most pronounced in cognitively normal individuals and men. Moderated mediation analyses indicated that plasma glial fibrillary acidic protein partially mediated the interaction between phosphorylated tau 217 to β-amyloid 42 ratio and WMHs for executive function and language performance. CONCLUSIONS These findings indicate that phosphorylated tau 217 to β-amyloid 42 ratio and WMHs jointly contribute to clinical progression in nondemented individuals, with astrocytic activation potentially involved in this process.