Blood biomarker profiles to distinguish amyloid-first and tau-first molecular subtypes of Alzheimer’s disease: a personalized medicine approach

Alzheimer´s disease is characterized by brain accumulation of amyloid-beta and tau aggregates. Recently, I developed simple blood tests that effectively reflect these brain changes.

I have shown that very small quantities of these markers (p-tau181, 217 and 231) are released from brain to blood in disease. However, the order in which brain-derived p-tau forms become available in blood is unknown.

Moreover, blood p-tau are increased in response to both amyloid and tau pathologies (unlike cerebrospinal fluid p-tau that is specific to tau).

Hence, blood p-tau are increased in both amyloid-first (A + T-) and tau-first (AT +) subtypes of AD.I hypothesize that the accuracy of blood p-tau to monitor brain amyloid and / or tau will be dictated by the underlying pathophysiology regarding disease stage and subtype.

However, since the amyloid-first phenotype is more clinically established, amyloid-negatives showing increased blood p-tau are likely to be initially diagnosed as non-AD, resulting in false negatives.

I aim to determine concordance and heterogeneity between in vivo brain and blood p-tau in AD subtypes and stages, and apply this novel information to establish the ideal clinical context of use of each p-tau biomarker.The results will show limitations of the one-size-fits-all (amyloid-first) approach, and present an evidence-based model targeting specific blood biomarkers to disease stages / subtypes to support directed use in screening, diagnosis, prognosis, and progression .