Aquaporin-4 polymorphisms predict amyloid burden and clinical outcome in the Alzheimer's disease spectrum.

Clearance of amyloid-β (Aβ) from the brain is hypothesized to be mediated by the glymphatic system through aquaporin-4 (AQP4) water channels. Genetic variation of AQP4 may impact water channel function, Aβ clearance, and clinical outcomes. We examined whether single-nucleotide polymorphisms (SNPs) of the AQP4 gene were related to Aβ neuropathology on [18F]Florbetapir PET in 100 Aβ positive late mild cognitive impairment (LMCI) or Alzheimer's disease (AD) patients and were predictive of clinical outcome in prodromal AD patients. AQP4 SNP rs72878794 was associated with decreased Aβ uptake, whereas rs151244 was associated with increased Aβ uptake, increased risk of conversion from MCI and LMCI to AD, and an increased 4-year rate of cognitive decline in LMCI. AQP4 genetic variation was associated with Aβ accumulation, disease stage progression, and cognitive decline. This variation may correspond to changes in glymphatic system functioning and brain Aβ clearance and could be a useful biomarker in predicting disease burden for those on the dementia spectrum.