2022 Alzheimer’s Association Investigator Initiated Award (AAIIA)

Molecular Dissection of TDP-43 Proteinopathy in AD and its Subtypes

How are proteins, not specific to Alzheimer’s, involved in the progression of types of Alzheimer’s?

Dietmar Thal, M.D., Ph.D.
Katholieke Universiteit Leuven, KU Leuven
Leuven, Belgium

Background

A hallmark brain change associated with Alzheimer’s is the accumulation of the proteins tau and beta-amyloid into clumps called tangles and plaques, respectively. About half of the individuals with Alzheimer’s also have clumps of another protein, called TAR DNA-binding protein 43 (TDP-43), in their brains. Studies have shown that increases in TDP-43 may be connected to brain shrinkage (due to brain cell death) and accelerated cognitive decline in individuals with Alzheimer’s. The mechanisms by which TDP-43 protein promotes brain changes associated with Alzheimer’s are not yet fully understood.

Research Plan

Dr. Dietmar Thal and colleagues will study differences associated with a build-up of TDP-43 using brain tissue from individuals who had Alzheimer’s and those that were cognitively unimpaired. They will divide the Alzheimer’s brain sample into two groups: brains with TDP-43 clumps in their brains and those without. Using  mass spectrometry, an analytical method that identifies unknown molecules, the researchers will be able to determine whether there are differences in the proteins made in the brains of individuals who had Alzheimer’s with TDP-43, Alzheimer’s without TDP-43, and no cognitive impairment. 

Next, Dr. Thal and team will measure levels of biological markers (biomarkers) of Alzheimer’s, including levels of tau and beta-amyloid, from blood samples. Using this data, the researchers will determine whether biomarkers for Alzheimer’s vary among individuals with Alzheimer’s with and without TDP-43 in the brain. The researchers will also perform genetic analyses on brain tissue to identify any genetic variations associated specifically with Alzheimer’s with TDP-43 compared to other groups. 

Finally, Dr. Thal and team will use the data they collect to make prediction models that can determine genetic risk using Alzheimer’s biomarkers to group individuals with Alzheimer’s and TDP-43, with Alzheimer’s and no TDP-43, and with no cognitive impairment. The models will clarify whether it is possible to predict the presence or absence of TDP-43 clumps in Alzheimer’s.

Impact

The findings may contribute to our understanding of underlying brain changes in cases of Alzheimer’s with differing underlying biology. The results may help in the development of new diagnostics or therapeutics for Alzheimer’s targeting different abnormal brain proteins.