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Author Notes:

Correspondence to: Cassie S. Mitchell, PhD, Assistant Professor, Biomedical Engineering, Georgia Institute of Technology and Emory University, 313 Ferst Drive, Atlanta, GA 30332, USA. Tel.: +1 404 276 8475; E-mail: cassie.mitchell@bme.gatech.edu

Authors’ disclosures available online (http://j-alz.com/manuscript-disclosures/17-0490r2)


Research Funding:

Funding provided by the National Institute of Health Grants NS069616, NS098228, and NS081426 to CSM.


  • 3xTg-AD
  • amyloid-β
  • meta-analysis
  • phosphorylated tau
  • total tau

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


Journal Title:

Journal of Alzheimer's Disease


Volume 61, Number 1


, Pages 265-281

Type of Work:

Article | Final Publisher PDF


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-β (Aβ), total tau, and phosphorylated tau (pTau), with cognitive performance in Morris water maze (MWM) and Novel Object Recognition (NOR). "High" levels of Aβ (Aβ 40 , Aβ 42 ) showed significant but weak trends with cognitive decline (MWM: slope = 0.336, R 2 = 0.149, n = 259, p < 0.001; NOR: slope = 0.156, R 2 = 0.064, n = 116, p < 0.05); only soluble Aβ or directly measured Aβ 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, R 2 = 0.275, n = 371, p < < 0.01) and NOR (slope = 0.319, R 2 = 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, R 2 = 0.521, n = 185, p < < 0.001). Multiple linear regression confirmed pTau is a stronger predictor of MWM performance than Aβ. Despite pTau's lower physical concentration than Aβ, pTau levels more directly and quantitatively correlate with 3xTg-AD cognitive decline. pTau's contribution to neurofibrillary tangles well after Aβ levels plateau makes pTau a viable treatment target even in late-stage clinical AD. Principal component analysis, which included hyperphosphorylation induced by kinases (pGSK3β, GSK3β, CDK5), identified phosphorylated ser9 GSK3β as the primary contributor to MWM variance. In summary, meta-analysis of cognitive decline in preclinical AD finds tauopathy more impactful than Aβ. Nonetheless, complex AD interactions dictate successful therapeutics harness synergy between Aβ and pTau, possibly through the GSK3 pathway.

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