P2-008: dyrk1a: a novel biomarker for alzheimer's disease (ad) identified in plasma and lcls from ad and ds

Extensive brain amyloidosis, typically associated with dementia, has been noted at autopsy of older individuals who exhibited few or no cognitive complaints prior to death. Amyloid accumulates years before symptoms become apparent, and current tests depend on detection of either amyloid accumulation in brain or tau proteins in cerebrospinal fluid. Biomarkers that may help predict disease before onset or progression of symptoms are critically needed. We have previously shown in a peripheral organ that decreased expression of DYRK1A, a serine-threonine kinase active in brain and important for tau phosphorylation, induces NFkappa B activation and increased inflammation. Here, a two-hybrid screen for human DYRK1A extracellular interactants suggested the presence of DYRK1A in plasma. DYRK1A was subsequently detected by immunoblot in plasma from transgenic mouse models having different gene dosage of Dyrk1a and, consequently, different relative protein expression. We next measured plasma DYRK1A levels in individuals with Alzheimer's disease (AD) that present either mild cognitive impairment (MCI-AD) or dementia relative to plasma from control subjects. DYRK1A but not DYRK1B levels were significantly lower in plasma (p <0.0001) and in lymphoblastoid cell lines (LCLs) (p <0.05) from AD patients as compared to age-matched controls. Further, plasma levels of several markers related to AD and to DYRK1A expression in mouse models (BDNF, ApoD, and homocysteine) were altered in this AD cohort. AD-like dementia is also common in older individuals with Down syndrome (DS) though with a much earlier onset. We analysed DYRK1A levels in LCLs from patients with DS: we found a decreased level of DYRK1A in patients with DS and dementia. These findings suggest that reduced DYRK1A expression might be a novel plasma biomarker for AD.