Intraneuronal tau aggregation precedes diffuse plaque deposition, but amyloid-β changes occur before increases of tau in cerebrospinal fluid

In comparison to the levels in age and gender-matched controls, reduced levels of pathological amyloid-beta protein in cerebrospinal fluid routinely precede the onset of Alzheimer's disease-related symptoms by several years, whereas elevated soluble abnormal tau fractions (phosphorylated tau, total tau protein) in cerebrospinal fluid are detectable only with the onset and progression of clinical symptoms. This sequence of events in cerebrospinal fluid (amyloid-beta changes detectable prior to abnormal tau changes) contrasts with that in which both proteins develop in the brain, where intraneuronal tau inclusions (pretangles, neurofibrillary tangles, neuropil threads) appear decades before the deposition of amyloid-beta plaques (diffuse plaques, neuritic plaques). This viewpoint attempts to address questions arising in connection with this apparent sequential discrepancy-questions and issues for which there are currently no clear-cut answers.