Imagine being able to predict, not just treat, Alzheimer's. A recent study in collaboration with esteemed Chinese institutions, brings us closer than ever to that reality. Researchers from the Innovation Center for Neurological Disorders and collaborating with esteemed Chinese institutions, has completed a 20-year study. Their research offers unprecedented insights into the early changes occurring within the brain, even before Alzheimer's symptoms manifest clinically.
The Study's Journey
The study, initiated in January 2000, focused on identifying biomarkers in cerebrospinal fluid (CSF), cognitive assessments, and brain imaging in individuals who were cognitively normal at the start. It aimed to trace the changes occurring over years, leading to Alzheimer's diagnosis, providing a detailed map of the disease's onset and progression.
Key Findings: A Timeline of Changes
The researchers recorded the alterations in several key biomarkers, revealing a timeline of changes that precede the clinical diagnosis of Alzheimer's by up to 20 years:
Decrease in Amyloid-beta 42 Levels - 18 Years Before Diagnosis
Amyloid-beta (Aβ) 42 is a protein that, when accumulated in the brain, forms plaques that are a hallmark of Alzheimer's disease. The study found that levels of Aβ42 in the cerebrospinal fluid (CSF) begin to decrease approximately 18 years before Alzheimer's is clinically diagnosed. This decrease indicates the early stages of plaque formation.
This finding suggests that interventions aimed at reducing Aβ42 accumulation could potentially delay the onset of Alzheimer's symptoms if applied early enough in the preclinical phase.
Changes in the Ratio of Amyloid-beta 42 to Amyloid-beta 40 - 14 Years Before Diagnosis
Alongside Aβ42, Aβ40 is another form of amyloid-beta protein. The ratio of Aβ42 to Aβ40 in CSF decreases as Aβ42 levels drop more significantly than Aβ40 levels, which is indicative of plaque accumulation. This change was observed around 14 years before the clinical symptoms of Alzheimer’s disease appeared.
Implications: The Aβ42/Aβ40 ratio could serve as a more sensitive biomarker for early Alzheimer’s disease detection and monitoring, offering another potential target for early therapeutic intervention.
Alterations in Tau Proteins - 11 to 10 Years Before Diagnosis
Phosphorylated Tau 181 (11 Years Before): This form of tau protein becomes abnormally phosphorylated and begins to accumulate in the brain. The study observed an increase in CSF levels of phosphorylated tau 181 about 11 years before Alzheimer's diagnosis.
Total Tau (10 Years Before): The overall concentration of tau protein in CSF also increases as neurodegeneration progresses, observed around 10 years before clinical symptoms manifest.
Implications: Tau proteins play a crucial role in the neurodegenerative process of Alzheimer’s. Targeting tau pathology could be another strategic approach in developing treatments to slow or halt the disease's progression.
Increase in Neurofilament Light Chain (NfL) Levels - 9 Years Before Diagnosis
NfL is a marker of neuronal damage and neurodegeneration. An increase in CSF NfL levels was detected approximately 9 years before Alzheimer’s diagnosis, indicating early neuronal injury or loss.
Implications: This finding highlights the potential of NfL as a biomarker for detecting neurodegeneration before clinical symptoms of Alzheimer's disease appear, possibly guiding early intervention strategies.
Reduction in Hippocampal Volume - 8 Years Before Diagnosis
The hippocampus is a brain region crucial for memory and is one of the first areas to suffer damage in Alzheimer’s disease. The study observed a measurable reduction in hippocampal volume 8 years before the clinical onset of Alzheimer's, reflecting early brain atrophy.
Implications: Monitoring changes in hippocampal volume via imaging could help in the early diagnosis of Alzheimer's and in assessing the efficacy of interventions aimed at preserving cognitive function.
Cognitive Decline Begins - 6 Years Before Diagnosis
Six years before a clinical diagnosis of Alzheimer’s, participants in the study began to show signs of cognitive decline, as measured by specific cognitive assessments. This decline is likely a result of the cumulative effects of amyloid plaque accumulation, tau pathology, neuronal damage, and brain atrophy.
Implications: Early cognitive assessments could identify individuals at risk of developing Alzheimer's, enabling interventions that could potentially delay the progression of cognitive decline.
Future Research and Treatment
The findings from this study provide critical insights into the preclinical phase of Alzheimer's disease, offering potential targets for early intervention and treatment. Understanding the sequence of biomarker changes opens new avenues for developing diagnostic tools and therapeutic strategies aimed at delaying or preventing the onset of clinical symptoms.
Acknowledgments
This remarkable study was supported by the Key Project of the National Natural Science Foundation of China, among other contributors. It is published in The New England Journal of Medicine
