Background The rapidly progressive phenotype of Alzheimer’s disease (rpAD) remains a rare and less-studied entity. Therefore, the replication of key results from the rpAD brain and cerebrospinal fluid (CSF) is lacking. Methods A label-free quantitative LC-MS/MS analysis of proteins co-aggregating with core-amyloid<InlineEquation ID="IEq1"> <InlineMediaObject> <ImageObject Color="BlackWhite" FileRef="13195_2025_1767_Article_IEq1.gif" Format="GIF" Height="17" Rendition="HTML" Resolution="72" Type="Linedraw" Width="15" /> </InlineMediaObject> <EquationSource Format="TEX">$\beta$</EquationSource> <EquationSource Format="MATHML"><math> <mi>β</mi> </math></EquationSource> </InlineEquation> plaques in fresh frozen tissue (FFT) from medial temporal regions of rpAD (<InlineEquation ID="IEq2"> <InlineMediaObject> <ImageObject Color="BlackWhite" FileRef="13195_2025_1767_Article_IEq2.gif" Format="GIF" Height="14" Rendition="HTML" Resolution="72" Type="Linedraw" Width="42" /> </InlineMediaObject> <EquationSource Format="TEX">$n=8$</EquationSource> <EquationSource Format="MATHML"><math> <mrow> <mi>n</mi> <mo>=</mo> <mn>8</mn> </mrow> </math></EquationSource> </InlineEquation>) neuropathologically characterized at the National Prion Disease Pathology Surveillance Center (NPDPSC), compared with microdissected amyloid plaques from formalin-fixed, paraffin-embedded (FFPE) tissue blocks from patients with rpAD (<InlineEquation ID="IEq3"> <InlineMediaObject> <ImageObject Color="BlackWhite" FileRef="13195_2025_1767_Article_IEq3.gif" Format="GIF" Height="14" Rendition="HTML" Resolution="72" Type="Linedraw" Width="50" /> </InlineMediaObject> <EquationSource Format="TEX">$n=22$</EquationSource> <EquationSource Format="MATHML"><math> <mrow> <mi>n</mi> <mo>=</mo> <mn>22</mn> </mrow> </math></EquationSource> </InlineEquation>) previously published from the NPDPSC cohort, was performed. Matched rpAD CSF from the FFT cases were compared to a previously published proteomic evaluation of CSF in the AD subtype with rapid progression. Results A total of 1841 proteins were characterized in the FFT study, of which 463 were consistently identified in every rpAD patient analyzed. One thousand two hundred eighty-three proteins were shared between the FFT and the prior FFPE study. FFT offered a more comprehensive proteomic profile than the prior FFPE study and prominently included the immune system pathways. Thirty-five proteins were shared in the FFT brain tissue, matched CSF from the same subjects, in which biological processes related to immune response were again notable. These results were validated against prior published proteomic CSF AD data with a faster rate of progression to identify the top 5 potential protein biomarkers of rapid progression in AD CSF. Conclusions These results support a distinct immune-related proteomic profile in both the brain and the CSF that can be explored as potential biomarkers in the future for the clinical diagnosis of rpAD.

Protein co-aggregates of dense core amyloid plaques and CSF differ in rapidly progressive Alzheimer’s disease and slower sporadic Alzheimer’s disease

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2025年5月27日

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Gurkan Bebek,
Masaru Miyagi,
Xinglong Wang,
Brian S. Appleby,
James B. Leverenz,
Jagan A. Pillai

摘要

Background

The rapidly progressive phenotype of Alzheimer’s disease (rpAD) remains a rare and less-studied entity. Therefore, the replication of key results from the rpAD brain and cerebrospinal fluid (CSF) is lacking.

Methods

A label-free quantitative LC-MS/MS analysis of proteins co-aggregating with core-amyloid $\beta$ $β$ plaques in fresh frozen tissue (FFT) from medial temporal regions of rpAD ( $n=8$ $n = 8$ ) neuropathologically characterized at the National Prion Disease Pathology Surveillance Center (NPDPSC), compared with microdissected amyloid plaques from formalin-fixed, paraffin-embedded (FFPE) tissue blocks from patients with rpAD ( $n=22$ $n = 22$ ) previously published from the NPDPSC cohort, was performed. Matched rpAD CSF from the FFT cases were compared to a previously published proteomic evaluation of CSF in the AD subtype with rapid progression.

Results

A total of 1841 proteins were characterized in the FFT study, of which 463 were consistently identified in every rpAD patient analyzed. One thousand two hundred eighty-three proteins were shared between the FFT and the prior FFPE study. FFT offered a more comprehensive proteomic profile than the prior FFPE study and prominently included the immune system pathways. Thirty-five proteins were shared in the FFT brain tissue, matched CSF from the same subjects, in which biological processes related to immune response were again notable. These results were validated against prior published proteomic CSF AD data with a faster rate of progression to identify the top 5 potential protein biomarkers of rapid progression in AD CSF.

Conclusions

These results support a distinct immune-related proteomic profile in both the brain and the CSF that can be explored as potential biomarkers in the future for the clinical diagnosis of rpAD.