Researchers have identified proteins and molecular pathways that can distinguish different forms of Alzheimer’s disease (AD).
The study in Science Translational Medicine was able to discriminate Alzheimer’s that has no specific familial link—known as its sporadic form—from inherited versions of the neurodegenerative disorder.
The analysis of more than 1000 proteins in brain, plasma, and cerebrospinal fluid (CSF) could lead to new disease biomarkers and increase the accuracy of prediction models critical for early diagnosis and monitoring.
“Although additional validation of some of our findings will be needed, these results highlight the need to combine brain tissue, CSF, and plasma proteomics to fully understand the biology of AD and to create prediction models for individuals with AD with specific genetic profiles,” reported the team.
Alzheimer’s is the most common form of dementia and is characterized by plaques containing amyloid β and tau neurofibrillary tangles in the brain that result in neuronal loss, neuroinflammation, and memory decline.
To investigate its proteomic profile further, Yun Ju Sung, PhD, an associate professor of psychiatry and biostatistics at Washington University School of Medicine in St Louis, and colleagues measured 1305 proteins in brain, CSF, and plasma from two cohorts who had different forms of the disease or who were healthy individuals.
The team identified a set of proteins that differed between sporadic Alzheimer’s and genetically defined forms of the condition.
Eight proteins in the brain, 40 in CSF, and nine from plasma created a molecular signature that was specific to the sporadic form, which accounts for 95% of cases and begins after 65 years of age.
These were successfully validated through several independent datasets and across brain tissue and fluids.
From this, the researchers were able to build highly accurate predictive models that could distinguish the sporadic form of Alzheimer’s from others.
A proteomic signature also distinguished carriers of rare coding variants in the microglia gene TREM2, which is linked with a two-fold increased risk of Alzheimer’s. This was able to delineate these individuals from those with the sporadic form of disease and healthy people.
Proteins linked with sporadic Alzheimer’s were also altered in people with the autosomal dominant form of the neurological condition, but with a greater size effect.
The autosomal dominant form usually shows before the age of 65 years and is only present in between 1% and 3% of Alzheimer’s cases, who carry pathogenic variants in genes such as amyloid precursor protein or presenilin-1 and -2.
Brain-derived proteins associated with this autosomal dominant form were replicated in additional samples of cerebrospinal fluid.
Further study highlighted several disease pathways. These involved calcineurin and Apo E in Alzheimer’s, α-Synuclein and leucine-rich repeat kinase 2 in Parkinson’s disease, and SHC-adaptor protein 1, extracellular signal–regulated kinase 1, and secreted phosphoprotein 1 in innate immune responses.
“In summary, we identified new proteins and pathways implicated in sporadic and genetically defined AD,” reports the team.
“We also demonstrated that, by leveraging proteins associated with AD status commonly across brain tissue, CSF, and plasma, one could validate and confirm potential new markers for AD.”
