New research uncovers biomarker changes preceding sporadic AD: Guidance for clinicians

By Katie Robinson | Fact-checked by Barbara Bekiesz
Published April 4, 2024

Key Takeaways

  • A study spanning 20 years found that changes in Alzheimer’s disease (AD) biomarkers may occur 18 years before a diagnosis.

  •  According to the authors, the timing of certain biomarker changes may differ between sporadic and autosomal dominant AD.

  • As cognitive decline progressed, the cerebrospinal fluid (CSF) biomarker level changes initially accelerated and then slowed.

In patients with sporadic Alzheimer’s disease (AD), biomarker changes occurred 6 to 18 years before their AD diagnosis. This is according to a study, published in the NEJM,[] which assessed biomarker changes over 20 years and then compared the timeline of changes in two groups of individuals: those who were later diagnosed with AD and those who remained cognitively healthy.

Changes in the biomarkers in sporadic AD were “similar in most respects” to the temporal sequence of biomarker changes seen in studies of autosomal dominant AD, wrote the authors of the study.

However, the alterations in amyloid-beta 42 (Aβ42) concentration “became evident nearly a decade later in our study. Therefore, the timing of the appearance of changes in biomarkers may differ” between sporadic and autosomal dominant AD, they added.

Specific biomarker changes

The nested case-control study included participants with normal cognition who were enrolled in the China Cognition and Aging Study (COAST) from 2000 to 2020.[] To assess AD biomarker changes, a subset of participants underwent CSF testing, cognitive assessments, and brain imaging every 2 to 3 years. 

The researchers excluded individuals with a family history of AD. In total, 648 adults developed AD (mean age, 61 years; 50.5% male; APOE ε4 carrier, 37.2%); for analysis, these were matched by age, sex, and education to 648 adults who remained cognitively normal (mean age, 61 years; 50.6% male; APOE ε4 carrier, 20.4%). The participants were followed for a median of 19.9 years.

In the participants who developed AD, CSF Aβ42 levels and the Aβ42-to-Aβ40 ratio diverged from those with normal cognition at 18 years and 14 years preceding an AD diagnosis, respectively. 

CSF levels of phosphorylated tau 181 (p-tau181) increased at 11 years, total tau rose at 10 years, and neurofilament light chain (NfL) levels increased at 9 years before an AD diagnosis. Hippocampal atrophy followed at 8 years and cognitive decline occurred at 6 years prior to an AD diagnosis. As this cognitive decline progressed, the CSF biomarker level changes initially accelerated and then slowed.

In discussing their results, the authors noted that “an apparent accelerated change in concentrations of CSF biomarkers followed by a slowing of this change up to the time of diagnosis [of AD was] consistent with results from previous studies [of sporadic AD]. 

“We explored associations between the rates of biomarker changes with cognitive function and found that the most rapid change in rate occurs in persons who have MMSE [Mini–Mental State Examination] scores in the range of 25 to 27,” they wrote.

Because the participants were of Han Chinese ancestry, the results may not be generalizable to other populations. The exclusion of individuals with a family history of AD diminished the proportion of APOE ε4 carriers, as the authors acknowledged, which may have reduced the influence of this genetic factor on the biomarkers. Finally, the study relied on the use of convenience sampling, as not all participants consented to repeated lumbar punctures, and this potentially lowered the accuracy of the results, per the authors.

Clinical use of biomarkers

In an accompanying editorial,[] Richard Mayeux, MD, of Columbia University noted that while the study included only individuals of Han Chinese ancestry, longitudinal studies that have involved a wide span of individuals of Asian, European, African, and Hispanic descent “have shown similar trends”—but in plasma biomarker changes preceding the onset of AD.

Dr. Mayeux noted that the accuracy of the clinical diagnosis of AD is controversial, as existing methods have their limitations. Amyloid positron emission tomography imaging is expensive, and most asymptomatic individuals do not willingly accept lumbar punctures for CSF testing.

“Assessment of plasma biomarkers are more practical, acceptable, and less expensive,” Dr. Mayeux wrote.

“The importance of [this work] cannot be overstated,” he asserted. “Knowledge of the timing of these physiological events is critical to provide clinicians with useful starting points for prevention and therapeutic strategies.”

What this means for you

CSF biomarker changes may occur 18 years before a diagnosis of sporadic AD, and may initially accelerate and then slow as cognitive decline progresses. While CSF testing and the use of imaging biomarkers may help diagnose AD, plasma biomarker testing may be more practical and less expensive.

Read Next: New study provides first evidence of environmentally acquired Alzheimer’s disease
Share with emailShare to FacebookShare to LinkedInShare to Twitter