Timing of Biomarker Changes in Alzheimer’s Disease

This is a summarized version of the full in-depth article on Relias Media.

By Makoto Ishii, MD, PhD

Recent advances in imaging techniques and fluid biomarkers have made it possible to identify Alzheimer’s disease (AD) pathology in individuals before clinical symptoms manifest. Despite the promise of these biomarkers in improving the accuracy of AD diagnosis, understanding how changes in these biomarkers relate to the onset of clinical symptoms remains challenging. Existing biomarker trajectory models, mostly based on autosomal dominant AD, do not fully capture the progression in sporadic AD, which constitutes the majority of cases. Sporadic AD progresses over many years or even decades, while current studies have mostly relied on cross-sectional or short-term longitudinal designs, limiting our understanding of the full course of the disease.

Study Overview

To address this gap, Jia and colleagues conducted a longitudinal, multicenter, nested case-control study involving cognitively normal participants from the China Cognition and Aging Study. The study aimed to chart the temporal changes in Alzheimer’s biomarkers in sporadic AD over nearly 20 years. A total of 648 participants who eventually developed AD were matched with 648 cognitively normal controls. The analysis focused on cerebrospinal fluid (CSF) biomarkers—such as amyloid-beta 42, amyloid-beta 42 to amyloid-beta 40 ratio, phosphorylated tau181, total tau, and neurofilament light chain—hippocampal volume via structural MRI, and cognitive testing over the course of the follow-up period.

Key Findings

The study revealed a clear timeline for the emergence of biomarker changes associated with AD, starting nearly two decades before clinical diagnosis:

• Amyloid-beta changes: The earliest biomarker shifts were detected in CSF amyloid-beta 42 levels, approximately 18 years before AD diagnosis. Four years later, changes in the CSF amyloid-beta 42 to amyloid-beta 40 ratio became evident.

• Tau pathology: Abnormal CSF levels of phosphorylated tau181 and total tau were observed at 11 and 10 years before AD diagnosis, respectively.

• Neurodegeneration and brain volume: Nine years before diagnosis, differences in CSF neurofilament light chain (a marker of neurodegeneration) were noted. At eight years prior to diagnosis, hippocampal atrophy became apparent.

• Cognitive decline: Objective cognitive impairments, as measured by the Clinical Dementia Rating Sum of Boxes, were detected around six years before the clinical diagnosis of AD.

Interestingly, the rate of biomarker changes appeared to accelerate early in the disease process before slowing down as cognitive function began to deteriorate.

Clinical and Research Implications

This study provides crucial insights into the long preclinical phase of Alzheimer’s disease and the sequence of biomarker changes, reinforcing earlier findings about the disease's progression. The early involvement of amyloid-beta accumulation, followed by tau pathology, neurodegeneration, and finally cognitive decline, mirrors the widely accepted amyloid cascade hypothesis.

• Clinical practice: These findings could pave the way for a precision medicine approach where a patient's specific biomarker profile could help estimate both their risk for AD and the likely timeline for developing clinical symptoms. This approach may also enhance patient counseling, providing them with clearer information about their prognosis.

• Future research and clinical trials: Understanding the sequence and timing of these biomarker changes will be invaluable in designing future clinical trials. It will enable researchers to track how therapeutic interventions may alter the disease's pathophysiological course and could help identify more effective treatment windows.

Strengths and Limitations

Strengths:

• Large sample size: The study involved a substantial cohort of 1,296 participants with repeated biomarker measurements.

• Length of follow-up: The nearly 20-year follow-up period is exceptionally long compared to many similar studies, allowing the researchers to capture the gradual progression of sporadic AD.

Limitations:

• Generalizability: Since the study cohort consisted solely of Chinese participants, the findings may not be fully applicable to other racial and ethnic groups. Although this study adds valuable data to the relatively underrepresented Asian population, further studies across diverse groups are essential.

• Family history exclusion: The study did not include individuals with a family history of AD to focus on sporadic cases. However, this reduces the number of apolipoprotein E (ApoE) e4 carriers in the study, limiting its relevance to those with a genetic predisposition to AD.

• Study participant bias: The participants who completed this lengthy study may have had better health or higher educational levels, potentially introducing bias.

• Accessibility of biomarkers: Many of the CSF biomarkers used in this study, though highly informative, may not be available in everyday clinical settings. Therefore, the development and validation of plasma biomarkers, which are less invasive and more readily available, will be crucial for broader applicability.

Summary

This study highlights the lengthy preclinical phase of Alzheimer’s disease and clarifies the sequence and timing of biomarker changes leading to clinical onset. These findings carry important implications for both clinical practice and the design of future AD trials, emphasizing the need for personalized approaches and long-term biomarker tracking in managing Alzheimer’s disease. However, the limitations, particularly concerning generalizability and biomarker accessibility, underscore the need for continued research across more diverse populations and the use of more practical biomarker tools.

Read the full in-depth article on Relias Media

We discuss the timing of biomarker changes in Alzheimer’s Disease in more detail and include detailed charts and tables in our full write-up on Relias Media.

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