PET imaging and proteomics reveal distinct protein signatures in Alzheimer’s disease progression

Study: Proteomic changes in Alzheimer’s disease associated with progressive Aβ plaque and tau tangle pathologiesCredit: Kateryna Kon / Shutterstock

The study uses PET imaging and cerebrospinal fluid proteomics to identify 127 different proteins linked to Alzheimer’s disease, highlighting unique molecular features and potential therapeutic targets.

This is evident from a recent study published in the journal Nature Neuroscienceresearchers from Sweden and the United States used positron emission tomography (PET) imaging combined with proteomic analysis of cerebrospinal fluid samples from a large study population spanning the spectrum of Alzheimer’s disease to measure amyloid β and tau tangle burden and determine the molecular events understand underlying Alzheimer’s disease pathology.

Background

Alzheimer’s disease is characterized by the accumulation and aggregation of amyloid β and tau fibrils that form neurofibrillary tables in the brain. The neurodegeneration and cognitive decline that occur in Alzheimer’s disease are caused by the initial formation of amyloid β plaques, which facilitate the formation and proliferation of neurofibrillary tau tangles in the neocortex.

However, although the role of amyloid β-plaques and tau fibrils is well known, Alzheimer’s disease is multifactorial and involves numerous other proteins and biological pathways. Recent studies performing proteomic analyzes of cerebrospinal fluid have found significant variations in the levels of several proteins at different stages of the disease.

Furthermore, the use of advanced imaging techniques such as PET scans, compared to traditional biomarkers such as amyloid β and phosphorylated tau levels, has also provided more precise insights into brain pathology in Alzheimer’s disease.

About the study

In the current study, the researchers combined PET imaging techniques and cerebrospinal fluid proteomic analysis to measure the aggregation of amyloid β and tau tangles in a group of Alzheimer’s patients at different stages of the disease pathology. They focused on understanding the proteomic changes that occur at different pathological stages rather than on the changes in cognitive symptoms.

The study included 877 participants who had been phenotyped as part of the BioFINDER-2 study, which had conducted a proteomic analysis of cerebrospinal fluid samples from all participants. The researchers used the amyloid β and tau pathologies to divide the participants into different groups.

The ratio of amyloid β 42 to amyloid β 40 in the cerebrospinal fluid samples, which is typically used to detect amyloid β plaques in the brain, was used to identify amyloid β pathology. Tau pathology was determined using tau PET imaging, which can visualize insoluble tau fibrils in the cortex.

Participants were classified into four groups: those without amyloid β or tau pathologies, those who were amyloid β positive and tau negative, those who were positive for both amyloid β and tau, and those who had a neurodegenerative disease without amyloid β or tau pathologies.

To determine which proteins were differentially abundant in the early stages of Alzheimer’s disease, the scientists first compared protein levels between the only positive group for amyloid β and the negative group for both amyloid β and tau.

Next, comparisons between the group positive only for amyloid β and the group positive for both amyloid β and tau revealed the proteins associated with the more advanced stages of Alzheimer’s disease manifesting tau pathology.

Factors such as overall protein levels, gender and age were included as covariates in the study. Furthermore, the findings were validated using a separate cohort from the original study population. The Alzheimer’s Disease Neuroimaging Initiative was also used to further validate the findings.

Imaging transcriptomics also examined the relationship between amyloid β and tau accumulation and the early differentially expressed proteins. Comparisons of the proteins differentially expressed in Alzheimer’s disease with those of other neurodegenerative diseases not involving amyloid β and tau pathologies also helped determine the specificity of these proteins in Alzheimer’s disease.

Among all BioFINDER-2 participants with Olink CSF proteomic data, we first assessed DAPs in the different A/T categories. Based on these DAPs, we then evaluated whether: (1) they were independently related to Aβ plaques or the pathological burden of tau tangle (baseline PET) and the rate of change (longitudinal PET); (2) the regional gene expression of the proteins in the brain was consistent with the regional PET pattern; and (3) they were enriched in different cell types or biological processes using enrichment analyses. Finally, we derived protein co-expression modules to investigate the overlap between such modules and the DAPs.

Results

The study identified 127 differentially abundant proteins across the spectrum of Alzheimer’s disease pathology. The proteins associated with amyloid β pathology were mainly expressed in glial cells. The two predominant differentially abundant proteins were SMOC1, a modular calcium-binding protein 1, and integrin subunit alpha M (ITGAM).

Numerous proteins involved in adenosine triphosphate (ATP) metabolism showed independent associations with tau accumulation and tangles and were differentially abundant in the neurons. Furthermore, the Alzheimer’s disease proteome was identified as distinct, as the differentially abundant proteins showed only 20% overlap with those of other neurodegenerative diseases.

These differentially abundant proteins also showed links to various biological processes. The proteins that were differentially abundant in the early stages of Alzheimer’s disease were linked to cellular detoxification and transmission through synapses, while the proteins that were differentially abundant in the later stages of the disease were involved in cellular structure and metabolic processes .

Proteins such as fatty acid binding protein 3 and enolase 2 were found to be associated only with tau pathology and not with amyloid β pathology, indicating the potential to use these proteins as markers to detect tau-associated neurodegeneration in Alzheimer’s disease .

Conclusions

Overall, the findings comprehensively assessed the differential abundance of proteins at different stages of Alzheimer’s disease and highlighted the different molecular pathways involved in different disease stages. These findings highlight some of the protein signatures of the different pathologies of Alzheimer’s disease and provide potential targets for new therapeutic strategies.