Alzheimer's Disease Genetics Research

Revised NINCDS-ADRDA research criteria incorporate biomarkers for the first time

Alzheimer’s Disease Biomarker Advances: Cerebrospinal Fluid

Specific proteins in cerebrospinal fluid (CSF), such as amyloid-beta and tau, also became increasingly recognized and validated as biomarkers for disease progression. Although these CSF biomarkers for Alzheimer’s disease were identified in the early 2000s, it was not until the mid-2000s that they became widely used in large clinical studies. In 2007, researchers demonstrated that CSF levels of tau and beta-amyloid42 could predict future Alzheimer’s disease in older adults with few or no cognitive symptoms.

These biomarkers were crucial for genetics studies—they could be used not only to confirm diagnosis, but also to explore their relationship with genetic risk factors, detect pathology in genetically high-risk individuals years before clinical signs appeared, and act as intermediate phenotypes. Subsequent research used these CSF biomarkers in combination with genetics to better understand gene-environment interactions and mechanisms for disease.

REFERENCES

  1. In 2007, a study published in Archives of Neurology demonstrated the power of CSF biomarker ratios for predicting future Alzheimer’s disease in older adults with preclinical cognitive decline.

Fagan AM, Roe CM, Xiong C, Mintun MA, Morris JC, Holtzman DM. Cerebrospinal fluid tau/beta-amyloid42 ratio as a prediction of cognitive decline in nondemented older adults. Arch Neurol. 2007;64(3):343–349. https://doi.org/10.1001/archneur.64.3.noc60123

  1. In 2023, a study published in Alzheimer’s Research & Therapy showed that DNA methylation in blood was associated with CSF biomarkers for Alzheimer’s disease, even in preclinical cases. This furthered the understanding of preclinical neuropathology and the underlying mechanisms of the disease.

Zhang W, Young JI, Gomez L, Schmidt MA, Lukacsovich D, Varma A, Chen XS, Martin ER, Wang L. Distinct CSF biomarker-associated DNA methylation in Alzheimer’s disease and cognitively normal subjects. Alzheimers Res Ther. 2023 Apr 10;15(1):78. https://doi.org/10.1186/s13195-023-01216-7