Cognitive Decline in Preclinical Alzheimer's Disease: Amyloid-Beta versus Tauopathy.

 We perform a large-scale meta-analysis of 51 peer-reviewed 3xTg-AD mouse publications to compare Alzheimer's disease (AD) quantitative clinical outcome measures, including amyloid-ß (Aß), total tau, and phosphorylated tau (pTau), with cognitive performance in Morris water maze (MWM) and Novel Object Recognition (NOR). "High" levels of Aß (Aß40, Aß42) showed significant but weak trends with cognitive decline (MWM: slope = 0.336, R2 = 0.149, n = 259, p < 0.001; NOR: slope = 0.156, R2 = 0.064, n = 116, p < 0.05); only soluble Aß or directly measured Aß meaningfully contribute. Tau expression in 3xTg-AD mice was within 10-20% of wild type and not associated with cognitive decline. In contrast, increased pTau is directly and significantly correlated with cognitive decline in MWM (slope = 0.408, R2 = 0.275, n = 371, p < < 0.01) and NOR (slope = 0.319, R2 = 0.176, n = 113, p < 0.05). While a variety of pTau epitopes (AT8, AT270, AT180, PHF-1) were examined, AT8 correlated most strongly with cognition (slope = 0.586, R2 = 0.521, n = 185, p < < 0.001). Multiple linear regression confirmed pTau is a stronger predictor of MWM performance than Aß. Despite pTau's lower physical concentration than Aß, pTau levels more directly and quantitatively correlate with 3xTg-AD cognitive decline. pTau's contribution to neurofibrillary tangles well after Aß levels plateau makes pTau a viable treatment target even in late-stage clinical AD. Principal component analysis, which included hyperphosphorylation induced by kinases (pGSK3ß, GSK3ß, CDK5), identified phosphorylated ser9 GSK3ß as the primary contributor to MWM variance. In summary, meta-analysis of cognitive decline in preclinical AD finds tauopathy more impactful than Aß. Nonetheless, complex AD interactions dictate successful therapeutics harness synergy between Aß and pTau, possibly through the GSK3 pathway.