Association of pulse pressure with presynaptic dysfunction in older adults with Alzheimer's disease: a cohort study

Vascular aging and synaptic dysfunction are closely related to Alzheimer's disease (AD) pathology, but the link between the two remains unclear. We aimed to investigate the relationship among pulse pressure (PP), presynaptic dysfunction, and in vivo AD pathologies, including amyloid beta (Aβ) deposition and cerebrospinal fluid (CSF) phosphorylated tau (p-tau). A total of 649 older adults, both cognitively normal and with mild cognitive impairment, were recruited from the Alzheimer's Disease Neuroimaging Initiative database. We investigated the associations of PP with CSF GAP-43, a marker of presynaptic dysfunction, and CSF p-tau. The mediation effect of presynaptic dysfunction on the association between PP and CSF p-tau was also examined. Elevated PP was significantly associated with greater presynaptic dysfunction (unstandardized B = 26.774, 95% confidence interval (CI) [12.102, 41.447], t = 3.583, p < 0.001) and elevated levels of CSF p-tau (B = 0.102, 95% CI [0.037, 0.168], t = 3.093, p = 0.002) and total tau (B = 0.927, 95% CI [0.331, 1.524], t = 3.052, p = 0.002). A positive interaction between PP and cortical Aβ deposition (F = 12.752, p < 0.001) indicated that PP resulted in severe presynaptic dysfunction as Aβ deposition increased. Further analyses revealed that presynaptic dysfunction mediated the association between PP and CSF p-tau. PP had no significant direct effect but had a significant indirect effect (81.6% of the total) on CSF p-tau. Elevated PP exacerbated presynaptic dysfunction in nondemented older adults, particularly those with AD pathology, and can lead to tau pathology. Further research on the mechanism underlying the relationship between PP and presynaptic dysfunction is warranted.