Cell-weighted polygenic risk scores are associated with β-amyloid and tau biomarkers in Alzheimer's disease.

The molecular pathways influencing the build-up of β-amyloid and tau pathology in Alzheimer's disease are unclear. To investigate how the involvement of different cell types influences β-amyloid and tau, we utilized single-cell RNA-seq data to derive cell-weighted polygenic risk scores. We included participants from the BioFINDER-1 study, including cognitively unimpaired (N = 734) individuals and patients with mild cognitive impairment (N = 235), Alzheimer's diseasedementia (N = 97) or non-Alzheimer's disease neurodegenerative diseases (N = 227). We developed seven polygenic risk scores, including six cell-weighted (for astrocytes, excitatory neurons, inhibitory neurons, microglia, oligodendrocyte precursor cells and oligodendrocytes) and one full polygenic risk score without cell specificity. For each of the polygenic risk score models, we calculated seven scores (polygenic risk score 1-7) based on different P-value thresholds (ranging from P-value < 0.05 to P-value < 5e-08) of variants from an independent large Alzheimer's disease genome-wide association study. We tested associations between the polygenic risk scores with β-amyloid [using cerebrospinal fluid (CSF) β-amyloid_1-42/β-amyloid_1-40], tau (using CSF pTau217) and cognitive measures (Mini-Mental State Examination score and Preclinical Alzheimer Cognitive Composite) using regression models adjusting for age, sex and the top genotype principal components. We also replicated the polygenic risk score association with β-amyloid (CSF β-amyloid_1-42/β-amyloid_1-40) and tau (CSF pTau217) in an independent cohort (BioFINDER-2), including cognitively unimpaired (N = 773) individuals and patients with mild cognitive impairment (N = 358), Alzheimer's disease dementia (N = 286) or non-Alzheimer's disease neurodegenerative diseases (N = 319). We observed differential cellular effects on β-amyloid, pTau217 and cognitive measures. There are substantial effects of neuronal-specific polygenic risk scores on β-amyloid, pTau217 and cognitive measures. The microglial-polygenic risk scores showed more significant effects on pTau217 than on β-amyloid. β-Amyloid positivity partly mediated the associations between polygenic risk scores and pTau217, with the lowest mediation effect observed for the microglial-polygenic risk scores (on average 33%). Cell-weighted gene expression has differential effects on pathological β-amyloid and tau metabolism, as well as cognitive decline. Cell-weighted gene expression related to microglia is preferentially relevant for the metabolism of soluble phosphorylated tau through partly β-amyloid-independent mechanisms. Cell-weighted gene expression related to neurons shows the strongest associations with cognition. These findings inform further studies that address specific cell types for various aspects of Alzheimer's disease, including the development of novel treatment strategies.