Biomarker Changes during 20 Years Preceding Alzheimer’s Disease

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Fascinating paper, published in the New England Journal of Medicine, about biomarker changes preceding a diagnosis of Alzheimer's Disease published in NEJM today. Based on a case-control study in Japan. The study examined changes in cerebrospinal fluid (CSF) biomarkers and other indicators in the years leading up to a diagnosis of Alzheimer's disease. The researchers conducted a long-term, multicenter study in China, following participants for up to 20 years to track how various biomarkers changed over time in those who eventually developed Alzheimer's compared to those who remained cognitively normal.

The study was a nested case-control study within the larger China Cognition and Aging Study (COAST). It included 648 participants who were eventually diagnosed with Alzheimer's disease and 648 matched controls who remained cognitively normal. Participants were enrolled between January and June 2000, aged 45-65 at baseline with no cognitive deficits. They underwent assessments every 2-3 years including CSF sampling, cognitive tests, and brain imaging. Where the median follow-up time was 19.9 years.

Key Biomarkers Examined:

- CSF amyloid-beta 42 (Aβ42)

- Ratio of Aβ42 to Aβ40

- CSF phosphorylated tau 181

- CSF total tau

- CSF neurofilament light chain (NfL)

- Hippocampal volume on MRI

- Cognitive assessments (CDR-SB, MMSE, Logical Memory Test)

The study found that biomarkers in those who developed Alzheimer's began diverging from the control group at different time points before clinical diagnosis:

1. CSF Aβ42: Diverged 18 years before diagnosis. Mean difference: -59.13 pg/mL (95% CI: -108.08 to -10.18)

2. Ratio of Aβ42 to Aβ40: Diverged 14 years before diagnosis. Mean difference: -0.01 (95% CI: -0.02 to -0.001)

3. CSF phosphorylated tau 181: Diverged 11 years before diagnosis. Mean difference: 7.10 pg/mL (95% CI: 1.10 to 13.10)

4. CSF total tau: Diverged 10 years before diagnosis. Mean difference: 87.10 pg/mL (95% CI: 45.10 to 129.10)

5. CSF neurofilament light chain: Diverged 9 years before diagnosis. Final mean difference: 228.29 pg/mL (95% CI: 122.42 to 334.16)

6. Hippocampal volume: Diverged 8 years before diagnosis. Mean difference: -358.94 mm3 (95% CI: -613.20 to -104.69)

7. Cognitive decline (CDR-SB): Diverged 6 years before diagnosis. The researchers also observed that the rate of change in CSF biomarkers in Alzheimer's patients appeared to initially accelerate and then slow down as cognitive impairment progressed. For example, CSF Aβ42 and Aβ42/40 ratio changes peaked when MMSE scores were around 25 and Logical Memory Test scores around 11. And total tau and phosphorylated tau 181 changes peaked at MMSE scores of about 27 and LMT scores of about 12-13.

The findings are generally consistent with previous studies on biomarker changes in Alzheimer's disease. Particularly, the overall sequence of biomarker changes aligns with the hypothetical model proposed by Jack et al. in 2010 and updated in 2013. The results are similar to studies on autosomal dominant Alzheimer's disease, though changes in Aβ42 appeared later in this sporadic Alzheimer's cohort.

The acceleration followed by deceleration of biomarker changes has been observed in other studies of sporadic Alzheimer's disease. However, this study provides a longer-term perspective and more precise estimates of when various biomarkers begin to diverge in sporadic Alzheimer's disease. The study suggests that CSF biomarkers, particularly Aβ42, may show changes up to 18 years before clinical diagnosis, potentially allowing for very early detection of Alzheimer's disease processes.

This 20-year longitudinal study provides valuable insights into the temporal evolution of biomarkers in sporadic Alzheimer's disease. It demonstrates that CSF biomarkers, particularly Aβ42, begin to change nearly two decades before clinical diagnosis, followed by changes in tau-related markers, neurofilament light chain, brain volume, and finally cognitive function. The study also reveals a pattern of accelerating then decelerating change in biomarkers as the disease progresses, with peak rates of change occurring at different stages of cognitive decline for different markers.

While the study has limitations, particularly in its focus on a Chinese population, it represents one of the longest and most comprehensive examinations of biomarker changes in sporadic Alzheimer's disease to date. The findings have significant implications for early detection, disease monitoring, and the development of therapeutic interventions for Alzheimer's disease.

https://www.nejm.org/doi/pdf/10.1056/NEJMoa2310168?articleTools=true