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July 2003

The Diagnosis of Alzheimer Disease Before It Is Alzheimer Dementia—Reply

Arch Neurol. 2003;60(7):1023-1024. doi:10.1001/archneur.60.7.1023-a

In reply

I appreciate that Frisoni and colleagues took our previous results, placed them into a clinical context, and concluded that detection of the biological fingerprint of AD in patients with MCI might be sufficiently accurate for clinical decisions.

In our exploratory study, we identified elevated tau protein and decreased Aβ42 protein concentrations at baseline in the CSF of patients with MCI who subsequently progressed to AD, yielding sensitivity and specificity values of 90% each. We also observed elevated CSF tau protein concentrations in subjects with MCI who showed a worsening of cognitive symptoms that was not severe enough to fulfill the diagnostic criteria of AD. Logistic regression analysis identified tau as the only variable among several others that predicted the progression of clinical symptoms. Therefore, elevated tau protein in CSF as a marker of neuronal degeneration and to a lesser extent decreased Aβ42 protein may be the most accurate tools to identify subjects with MCI who are at the greatest risk for progression to AD. From a functional view, this result is convincing because the formation of neurofibrillary tangles and plaques is known to occur several years before the onset of clinical symptoms and probably a decade before the onset of dementia.1 However, this view also supports the possibility that subjects at risk for developing AD might be detectable using CSF analysis even before entering the stage of MCI. This is also supported by the fact that CSF tau protein level is a stage-independent marker. The appropriate approach to prove this hypothesis would be a population-based study2 accompanied by clinical follow-up visits for several years. However, with an eye toward future therapies aimed at the modification of disease progression, a shifting of the diagnostic threshold is of paramount importance.

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