. Cognitive Decline in Preclinical Stage 2 Alzheimer Disease and Implications for Prevention Trials. JAMA Neurol. 2016 Jun 1;73(6):640-2. PubMed.


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  1. This is an interesting manuscript. The data fits with the diagnostic staging of preclinical AD proposed by the NIA-AA work group in 2011. This extends earlier findings that low CSF Aβ associates with eventual decline in amnestic MCI but that decline occurred sooner in MCI subjects with a combination of low Aβ and high tau (Buchhave et al., 2012). Baseline CSF tau and tau PET may be an important predictors of decline, and change in tau PET may be a key outcome

    A weakness of the  paper is the very wide age range and relatively low mean age of the sample. The young age of this cohort may explain why both stage 1 and ApoE4 were not associated with greater rates of decline.  

    To sum up: Alterations in baseline amyloid signify the presence of the AD disease process; elevated tau may be a good proximity marker for cognitive decline; and changes in tau PET with treatment may be a surrogate marker of clinical benefit.measure in AD clinical trials.


    . Cerebrospinal fluid levels of β-amyloid 1-42, but not of tau, are fully changed already 5 to 10 years before the onset of Alzheimer dementia. Arch Gen Psychiatry. 2012 Jan;69(1):98-106. PubMed.

    View all comments by Stephen Salloway
  2. This is an interesting and important paper on the core AD CSF biomarkers in cognitively normal elderly. Biomarkers are increasingly used for inclusion purposes in clinical trials, to enrich for patients or normal elderly with biomarker evidence of AD pathology. Based on the high concordance between CSF Aβ42 and amyloid PET (Blennow et al., 2015), these biomarkers may be used interchangeably to identify amyloid deposition and to enroll trial participants in anti-amyloid trials.

    Longitudinal biomarker studies in the MCI stage of disease suggest that the injury, or neurodegeneration, biomarkers CSF T-tau and P-tau add to Aβ42 by improving the prediction of progression of symptoms during a clinically relevant timeframe (Buchhave, 2012; van Rossum, 2012). For this and other reasons, the updated International Working Group criteria for AD advocate using the combination of low CSF Aβ42 together with either high T-tau or P-tau for the diagnosis of AD (Dubois et al., 2014). 

    In the present study, out of four hypothetical groups of cognitively normal elderly, only the group with both low CSF Aβ42 and high T-tau or P-tau showed cognitive decline during the clinical follow-up period of 11 years (Soldan, 2016). These findings on normal elderly thus corroborate results of previous studies on the MCI stage of the disease. Importantly, rate of progression was not associated with APOE genotype. As pointed out by the authors, these results are essential for trial design, and suggest that enrollment biomarker criteria should include both abnormal CSF Aβ42 and abnormal T-tau/P-tau levels since such individuals have the greatest likelihood of showing cognitive decline during the trial length. This would optimize the possibility of observing a treatment effect of a drug in trials enrolling cognitively normal individuals.

    Indeed, the novel diagnostic criteria for preclinical AD proposed by Dubois and co-workers make a distinction between the entities “preclinical AD,” meaning AD in the preclinical stage based on both Aβ and tau biomarkers being positive, and “asymptomatic at risk for AD,” meaning cognitively normal people with biomarker abnormalities insufficient to reach the definition of AD, e.g., only amyloid biomarkers being positive (Dubois et al., 2016). 


    . Amyloid biomarkers in Alzheimer's disease. Trends Pharmacol Sci. 2015 May;36(5):297-309. Epub 2015 Apr 1 PubMed.

    . Cerebrospinal fluid levels of β-amyloid 1-42, but not of tau, are fully changed already 5 to 10 years before the onset of Alzheimer dementia. Arch Gen Psychiatry. 2012 Jan;69(1):98-106. PubMed.

    . Advancing research diagnostic criteria for Alzheimer's disease: the IWG-2 criteria. Lancet Neurol. 2014 Jun;13(6):614-29. PubMed.

    . Preclinical Alzheimer's disease: Definition, natural history, and diagnostic criteria. Alzheimers Dement. 2016 Mar;12(3):292-323. PubMed.

    . Hypothetical Preclinical Alzheimer Disease Groups and Longitudinal Cognitive Change. JAMA Neurol. 2016 Jun 1;73(6):698-705. PubMed.

    . Injury markers predict time to dementia in subjects with MCI and amyloid pathology. Neurology. 2012 Oct 23;79(17):1809-16. Epub 2012 Sep 26 PubMed.

    View all comments by Kaj Blennow

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  1. CSF Tau Rivals Aβ for Predicting Cognitive Decline