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. 2024 Jun 6;24(1):501.
doi: 10.1186/s12877-024-05104-z.

Potential prognostic value of CSF-targeted proteomics across the Alzheimer's disease continuum

Bingdong Xu #  1 , Yitong Ling #  1 , Leiyuan Liu #  1 , Yujun Liu  1 , Yingze Lin  1 , Jun Lyu  2   3 , Yusheng Zhang  4
Affiliations

Potential prognostic value of CSF-targeted proteomics across the Alzheimer's disease continuum

Bingdong Xu et al. BMC Geriatr. .

Abstract

Background: Core biomarkers for Alzheimer's disease (AD), such as Aβ42 and tau, have demonstrated high prognostic accuracy but do not fully capture the complex pathophysiology of AD. In this study, our objective was to identify novel cerebrospinal fluid (CSF) biomarkers using proteomics across the entire AD continuum to predict conversion to AD and explore their involvement in AD pathogenesis.

Methods: A cohort of 186 cognitively normal (CN), 127 subjective memory complaint (SMC), 79 early mild cognitive impairment (EMCI), 249 late MCI (LMCI), and 132 AD individuals was analyzed, with a follow-up period of over 3 years for non-AD participants. CSF 65 peptides, as well as hippocampal and entorhinal volumes were analyzed, and cognitive function was evaluated using the 13-item cognitive subscale of the Alzheimer's Disease Assessment Scale (ADAS-Cog 13). Cox proportional hazards models and mediation analysis were performed to investigate associations and causal relationships.

Results: During the follow-up, approximately one-fourth (146/580) of the non-AD participants progressed to AD. After adjusting for baseline diagnosis (CN to LMCI) and other variables, multivariable Cox regression analysis identified three peptides (VAELEDEK, VSFELFADK, and VVSSIEQK) as significant predictors of conversion to AD. Incorporating these three peptides into the initial model significantly improved the C-statistic from 0.82 to 0.85 for predicting AD conversion, surpassing the predictive ability of Aβ42 and P-tau. Moreover, hippocampal and entorhinal volumes mediated 30.3-53.8% of the association between the three peptides and ADAS-Cog 13 scores.

Conclusions: These findings underscore the potential of these three peptides as robust prognostic biomarker candidates for AD conversion across the entire AD continuum, with a mechanism involving the mediation of hippocampal and entorhinal volumes.

Keywords: Alzheimer’s disease; Biomarkers; Cognitive function; Prognosis; Proteomics.

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Conflict of interest statement

The authors declare no competing interests.

Figures

Fig. 1
Fig. 1
Volcano plots of differential protein expression between every two groups. Blue dots represented peptides with low expression, red dots represented peptides with high expression, and gray dots represented peptides with no differential expression. Nine peptides that showed differential expression were presented across the AD continuum. Abbreviations: CN, cognitively normal; SMC, subjective memory complaint; EMCI, early mild cognitive impairment; LMCI, late mild cognitive impairment; AD, Alzheimer’s disease
Fig. 2
Fig. 2
Kaplan-Meier survival curves of non-conversion to AD. There were statistically significant differences between the CN and SMC vs. EMCI, CN and SMC vs. LMCI, and EMCI vs. LMCI groups. Abbreviations: CN, cognitively normal; SMC, subjective memory complaint; EMCI, early mild cognitive impairment; LMCI, late mild cognitive impairment; AD, Alzheimer’s disease. ***P < 0.001
Fig. 3
Fig. 3
Mediation effects of peptides on cognitive function via hippocampal and entorhinal volumes. A VAELEDEK effect on ADAS-Cog 13 mediated by hippocampal volume. B VAELEDEK effect on ADAS-Cog 13 mediated by entorhinal volume. C VSFELFADK effect on ADAS-Cog 13 mediated by hippocampal volume. D VSFELFADK effect on ADAS-Cog 13 mediated by entorhinal volume. E VVSSIEQK effect on ADAS-Cog 13 mediated by hippocampal volume. F VVSSIEQK effect on ADAS-Cog 13 mediated by entorhinal volume. Abbreviations: ADAS-Cog 13, 13-item cognitive subscale of the Alzheimer’s Disease Assessment Scale
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