Prediction of future Alzheimer’s disease dementia using plasma phospho-tau combined with other accessible measures

Abstract

A combination of plasma phospho-tau (P-tau) and other accessible biomarkers may provide accurate prediction about the risk of developing Alzheimer’s disease (AD) dementia. We examined this in patients with subjective cognitive decline (SCD) and mild cognitive impairment (MCI) who were consecutively recruited in the BioFINDER study (n=340). The results were validated in SCD/MCI participants in the ADNI study (n=543). Plasma P-tau, plasma Aβ42/Aβ40, plasma neurofilament light, APOE genotype, brief cognitive tests and MRI (cortical thickness in AD-specific regions) were examined as predictors of progression to AD dementia primarily within 4 years. The accuracy was determined using the area under the ROC curve (AUC) from logistic regression models. Within 4 years, plasma P-tau217 predicted AD dementia accurately (AUC 0.83) in BioFINDER. A model of plasma P-tau217, memory, executive function, and APOE had higher accuracy (AUC 0.91, p<0.001). In ADNI, this model produced a similar AUC (0.90) using plasma P-tau181 instead of P-tau217. A cross-validated version of this model was implemented online for prediction of the individual probability of progressing to AD dementia. Within 2 and 6 years, parsimonious models performed similar in both cohorts (AUCs 0.90-0.91). Using cerebrospinal fluid P-tau, Aβ42/Aβ40 and neurofilament light instead of plasma biomarkers did not improve the accuracy. The clinical prediction by memory clinic physicians had significantly lower accuracy than all models (4-year AUC 0.71). In summary, plasma P-tau in combination with brief cognitive tests and APOE genotyping may greatly improve the diagnostic prediction of AD dementia and facilitate recruitment for AD trials.

Blood-based biomarkers for Alzheimer's disease: towards clinical implementation

“…38,50 These associations were only observed in individuals with Aβ pathology 51 , which underpins its specificity for AD neuropathological changes. pTau181 also differentiated patients with mild cognitive impairment (MCI) who converted to AD from non-converters 39,44,52 and had better performance than Aβ42/40. 44 Similar results have been observed in non-demented individuals, with high pTau181 associated with higher risk of progressing to AD dementia.…”

Adaptive data-driven selection of sequences of biological and cognitive markers in pre-clinical diagnosis of dementia

“…This was further demonstrated in the time-to-event analyses in which the models with the most data consistently had highest odds ratio between the classes. The observed complementary information of different diagnostic markers has been shown and explored in the literature previously (17) and the performance achieved with all available data marks the maximum accuracy that can be expected from sequential algorithm with fewer variables or time points. However, under certain conditions, a single or very few markers may be sufficient for a definitive diagnosis and it's the objective of sequential neutral zone classifiers to balance misclassification and acquisition costs.…”

“…Motivated by a use case of pre-clinical diagnosis of AD-the most frequent cause of severe cognitive decline at old age, we developed a general statistical framework to objectify the selection of sequence and time of diagnostic markers to include in a decision process. As previous studies indicated the benefit of combining multiple, diverse markers (17), cognitive, brain anatomical, and molecular markers were included here. The performance of the non-sequential strategies consistently improved when multiple cross-sectional and multiple longitudinal measurements were combined.…”

Millipore xMap® Luminex (HATMAG-68K): An Accurate and Cost-Effective Method for Evaluating Alzheimer's Biomarkers in Cerebrospinal Fluid

“…Finally, plasma AD biomarkers represent a more convenient and less invasive alternative to CSF biomarkers. Previous studies showedplasma p-tau181 ( 50 , 51 ), p-tau217 ( 52 , 53 ), and p-tau231 ( 54 ) isoforms can correctly diagnose and predict AD in large studies. However, this is currently a very expensive technology and, unfortunately, it is not available in low and middle-income countries, where million people are living with dementia.”…”