Using Biological "Clocks" to Study Changes in Blood Biomarkers for Alzheimer's Disease

Alzheimer's Disease (AD) pathology can span decades before cognitive symptoms are recognized. Progression of this pathology follows a well known cascade of events, beginning with accumulation of beta-amyloid (Aβ) plaques, followed by tangles of tau proteins, neuronal atrophy, and finally cognitive impairment. Neuroimaging with PET MRI has become the gold standard in Alzheimer's research, allowing early, quantifiable detection and the opportunity for intervention. 

In recent years, researchers have been optimizing methods that may detect AD pathology in the early stages of Aβ and tau accumulation. A simple blood draw can now test for levels of AD biomarkers that can be statistically modeled to accurately predict eventual outcomes. High levels of biomarkers in the blood may indicate that they have not yet traveled to the brain where plaque and tangle accumulation occur. A recent study, led by Marta Milà-Alomà, compared blood-based biomarkers tested across six different company platforms. This data was then used to estimate the age at which participants would reach amyloid PET positivity, tau PET positivity, and the onset of AD symptoms. This "biological clock" approach can be used to align an individual's biomarker trajectories based on estimated years from key events in the cascade.

This key figure shows the timing of AD biomarker abnormality for Aβ, tau, and symptom onset where each outcome measure becomes abnormal compared to the reference group (PET). The earliest abnormalities were seen with Aβ peptides (Aβ42/Aβ40) and GFAP (glial fibrillary acidic protein), incredibly sensitive enough to detect up to 15 years before symptom onset.

Overall, Aβ42/Aβ40 reached a plateau over time while other biomarkers representing phosphorylated tau proteins (p-tau217, p-tau181), GFAP, and NfL (neurofilament light) increased steadily throughout the disease progression. Importantly, these results align with the pathway of AD disease progression. Amyloid accumulation occurs in the brain first as evidenced by Aβ peptide levels no longer increasing in the blood, but are thought to be moving to the brain where plaques will form. The levels of p-tau protein and secondary biomarkers for neuronal degeneration (GFAP, NfL) become abnormal after amyloid PET positivity. 

By measuring the timing of these changes in blood plasma, these amyloid PET and tau PET clocks can provide vital information for use in a clinical setting. The sensitivity of these tests will allow for accurate timing of pathology trajectories from a tailored, precision medicine approach.

This study was published in Annals of Neurology and can be accessed here. Marta and Dr Tosun worked with data from the Alzheimer's Disease Neuroimaging Initiative (ADNI) and the Foundation for the NIH (FNIH) Biomarkers Consortium Plasma Aβ and Phosphorylated Tau as Predictors of Amyloid and Tau Positivity in AD Project Team.