International team's population study discovers 27 new proteins associated with Alzheimer’s

Researchers in the U.S., United Kingdom and Australia have found 27 additional proteins that may help identify individuals who are at risk for Alzheimer’s in middle age or earlier.

During the past decades, little progress has been made at stopping Alzheimer's progression once it is diagnosed. Many think this is because intervention is occurring too late, and that earlier treatment may be able to reduce the debilitating effect of the disease later in life. 

The results of the extensive new study appear in the peer-reviewed online journal PLOS Genetics, Sept. 1. 

Polygenic prediction and proteomic study

In this study the scientists used a two-part technique to identify potential biomarkers for Alzheimer’s. 

In the first phase, they used a statistical technique known as polygenic prediction to find associations of commonly found DNA variants in blood assays from 21,982 affected individuals and 41,944 controls in a European-wide study published in 2013. 

In the second phase, the results obtained, known as the polygenic score, were first applied to a different set of blood samples available from a large United Kingdom study of Alzheimer’s afflicted and non-afflicted control subjects. The comparison showed that the polygenic score was effective in predicting which subjects were likely to develop Alzheimer’s. 

The researchers then applied an advanced method for identifying circulating proteins to samples from a group of 3,175 blood donors in the UK Biobank. They used the level of apolipoprotein E, a known marker for the amyloid plaque deposition associated with Alzheimer’s, as a useful positive control to help identify likely at-risk samples. 

27 additional proteins showed link to Alzheimer risk

When the researchers then examined the samples for other circulating proteins, they found 27 additional proteins whose levels varied according to low versus high calculated polygenic score for Alzheimer’s disease. 

The strongest association was to a substance known as tubulin specific chaperone A, a protein that plays a role in preventing neurotoxicity caused by abnormal folding. “Individuals with a high polygenic score had substantially lower circulating levels of this protein, a mean score of 0.40 versus 1.2 for those in bottom versus top decile,” the authors report. 

Two other proteins with a notable association to inherited risk for Alzheimer’s, as calculated by the polygenic score, were the S100 calcium-binding protein A13, a member of a family known to interact with the advanced glycation end-product pathway, and leucine-rich repeat neuronal protein, known to regulate early neuronal progenitor cell signaling. Levels of these proteins were found to be substantially higher in individuals with higher inherited risk. 

The proteomic analysis was added by a technology known as SOMAscan, which allows for simultaneous, high accuracy measurement of thousands of proteins from small sample volumes of 15 microliters of serum or plasma. 

Limitations and cautions

Not detracting from the success of their polygenic scoring technique, the authors caution against its use “outside of a research setting.” 

One reason is that their data were based only on studies of European populations. They note that for most polygenic scores developed to date, the effect has been lower in non-European populations. 

“Second,” they warn, “current clinical guidelines do not yet support assessment of genetic risk for Alzheimer’s disease outside of suspected rare monogenic forms.” This, they note, is “largely due to concerns about implications for long-term-care or disability insurance, inducing anxiety, and relative absence of efficacious preventive measures.” 

–––––––––––––

Paranjpe MD, Chaffin M, Zahid S, Ritchie S, Rotter JI, Rich SS, et al. (2022) Neurocognitive trajectory and proteomic signature of inherited risk for Alzheimer’s disease. PLoS Genet 18(9): e1010294. 

DOI: https://doi.org/10.1371/journal.pgen.1010294