Print This PostIn the more than a decade since scientists at Washington University and the Mayo Clinic first proposed the now well-known curves of biomarker change over the course of Alzheimer’s disease, researchers have filled in this framework with dozens of fluid and imaging biomarkers that reflect different aspects of AD progression. Data came mostly from cross-sectional, short-term, or familial AD cohorts. Now, two studies have deployed other methods to trace biomarkers longitudinally over the course of sporadic AD. They report surprisingly similar trajectories, which largely confirm prior analyses.
One, led by Suzanne Schindler at Washington University in St. Louis and published February 24 in the Annals of Neurology, used an “amyloid clock” she had previously developed to estimate years to symptom onset among almost 400 participants. With this proxy measure of time, the researchers charted the changes of multiple biomarkers reflecting amyloidosis, tauopathy, neuroinflammation, and neurodegeneration over a two-decade span.
- Using “amyloid clock” to estimate year of AD symptom onset, one study tracked biomarker changes over 20-year span.
- Biomarkers of amyloid changed first, followed by tau, neuroinflammation, and neurodegeneration.
- A large longitudinal study in China reported similar timing of AD biomarker changes.
The trajectories aligned closely with those among a large longitudinal cohort in China. That study, led by Jianping Jia at Capital Medical University in Beijing and published February 22 in the New England Journal of Medicine, tracked biomarker changes in some 1,700 people, nearly 700 of whom developed dementia over the 20+ year investigation, which began in 2000 with more than 50,000 people.
“These two papers describing the timeline of the trajectory from amyloid positivity to symptom onset are extremely important, with very practical implications for clinical trials and patient care,” commented Michael Weiner of the University of California, San Francisco. “What is so remarkable is how similar the results are in these two studies: a U.S., largely white population, and a Chinese population.”
Markers on the Clock. Differences in biomarkers plotted against estimated years from symptom onset. Biomarkers reflecting amyloidosis become abnormal first, followed by markers of tau pathology, hippocampal shrinkage, and cognitive decline. [Courtesy of Li et al., Annals of Neurology, 2024.]
In the current study, first author Yan Li and colleagues used this clock to place a slew of biomarkers along the amyloid-time trajectory. They included 395 participants who had undergone at least one amyloid-PET scan with a PiB tracer, of whom 118 had reached or surpassed the threshold for amyloid positivity. Volunteers averaged 70 years of age at the time of amyloid onset. Depending on the biomarker, between 40 and 60 participants had serial measurements over an average of five to seven years of follow-up. For each biomarker, the researchers tracked the difference in its levels between the amyloid-PET-negative and -positive groups, as a function of amyloid clock-based EYO.
Some key findings? First, at 19 to 15 years prior to symptoms, biomarkers reflecting amyloidosis changed. These included CSF and plasma Aβ42/40, CSF p-tau217/217, and amyloid-PET. Next, at 14 to 12 EYO, plasma p-tau217/217 rose, as did biomarkers of synaptic loss and neurodegeneration, such as CSF neurogranin, SNAP-25, and NfL. Neuroinflammation markers, including CSF sTREM2 and plasma GFAP, also ticked up at this time. Between nine to seven years before EYO, CSF p-tau205/205—thought to reflect tau pathology—started to climb, as did the neuroinflammatory indicator CSF YKL-40. Shortly thereafter, the hippocampus starting shrinking and cognitive scores faltered.
Alzheimer’s in China. In this graph, changes in biomarkers over two decades leading up to AD diagnoses were standardized to allow trajectories to be superimposed. [Courtesy of Jia et al., NEJM, 2024.]
What did this longitudinal data reveal? CSF Aβ42 was the first to change, becoming abnormal 18 years prior to diagnosis among those with AD. The ratio of Aβ42/40 changed 14 years prior to diagnosis, while CSF p-tau181 and total tau took off at 11 and 10 years out, respectively. CSF NfL started to rise nine years prior to diagnosis, followed closely by hippocampal shrinkage at seven and cognitive decline at six years.
Compared to Li et al, Jia et al. measured fewer biomarkers. Of those the two studies have in common, Li detected changes two to three years earlier. However, Jia plotted biomarker abnormality relative to actual AD diagnosis, not relative to EYO based on an amyloid clock. These different endpoints, in addition to assays used to measure the biomarkers, might explain some of the timing differences.
Even so, both studies tell a similar story, with biomarkers of amyloidosis followed by tauopathy, neurodegeneration, and cognitive decline. The number of biomarkers being studied in cohorts around the world is growing rapidly, hence more are going to be added to these diagrams before long.—Jessica Shugart.
Shared from the Alz Forum – find the original and more at https://www.alzforum.org/news/research-news/st-louis-beijing-ad-biomarkers-change-similarly-symptoms
Dementia Researcher
Alzheimer's Association