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The clinical spectrum of Alzheimer’s disease (AD) ranges dynamically from asymptomatic and mild cognitive impairment (MCI) to mild, moderate, or severe AD. Although a few disease-modifying treatments, such as lecanemab and donanemab, have been developed, current therapies can only delay disease progression rather than halt it entirely. Therefore, the early detection of MCI and the identification of MCI patients at high risk of progression to AD remain urgent unmet needs in the super-aged era. This study utilized transcriptomics data from cognitively unimpaired (CU) individuals, MCI, and AD patients in the Alzheimer’s Disease Neuroimaging Initiative (ADNI) cohort and leveraged machine learning models to identify biomarkers that differentiate MCI from CU and also distinguish AD from MCI individuals. Furthermore, Cox proportional hazards analysis was conducted to identify biomarkers predictive of the progression from MCI to AD. Our machine learning models identified a unique set of gene expression profiles capable of achieving an area under the curve (AUC) of 0.98 in distinguishing those with MCI from CU individuals. A subset of these biomarkers was also found to be significantly associated with the risk of progression from MCI to AD. A linear mixed model demonstrated that plasma tau phosphorylated at threonine 181 (pTau181) and neurofilament light chain (NFL) exhibit the prognostic value in predicting cognitive decline longitudinally. These findings underscore the potential of integrating machine learning (ML) with transcriptomic profiling in the early detection and prognostication of AD. This integrated approach could facilitate the development of novel diagnostic tools and therapeutic strategies aimed at delaying or preventing the onset of AD in at-risk individuals. Future studies should focus on validating these biomarkers in larger, independent cohorts and further investigating their roles in AD pathogenesis.

The increasing burden of Alzheimer’s disease (AD) emphasizes the need for effective diagnostic and therapeutic strategies. Despite available treatments targeting amyloid beta (Aβ) plaques, disease-modifying therapies remain elusive. Early detection of mild cognitive impairment (MCI) patients at risk for AD conversion is crucial, especially with anti-Aβ therapy. While plasma biomarkers hold promise in differentiating AD from MCI, evidence on predicting cognitive decline is lacking. This study’s objectives were to evaluate whether plasma protein biomarkers could predict both cognitive decline in non-demented individuals and the conversion to AD in patients with MCI. This study was conducted as part of the Korean Longitudinal Study on Cognitive Aging and Dementia (KLOSCAD), a prospective, community-based cohort. Participants were based on plasma biomarker availability and clinical diagnosis at baseline. The study included MCI (n = 50), MCI-to-AD (n = 21), and cognitively unimpaired (CU, n = 40) participants. Baseline plasma concentrations of six proteins—total tau (tTau), phosphorylated tau at residue 181 (pTau181), amyloid beta 42 (Aβ42), amyloid beta 40 (Aβ40), neurofilament light chain (NFL), and glial fibrillary acidic protein (GFAP)—along with three derivative ratios (pTau181/tTau, Aβ42/Aβ40, pTau181/Aβ42) were analyzed to predict cognitive decline over a six-year follow-up period. Baseline protein biomarkers were stratified into tertiles (low, intermediate, and high) and analyzed using a linear mixed model (LMM) to predict longitudinal cognitive changes. In addition, Kaplan–Meier analysis was performed to discern whether protein biomarkers could predict AD conversion in the MCI subgroup. This prospective cohort study revealed that plasma NFL may predict longitudinal declines in Mini-Mental State Examination (MMSE) scores. In participants categorized as amyloid positive, the NFL biomarker demonstrated predictive performance for both MMSE and total scores of the Korean version of the Consortium to Establish a Registry for Alzheimer’s Disease Assessment Packet (CERAD-TS) longitudinally. Additionally, as a baseline predictor, GFAP exhibited a significant association with cross-sectional cognitive impairment in the CERAD-TS measure, particularly in amyloid positive participants. Kaplan–Meier curve analysis indicated predictive performance of NFL, GFAP, tTau, and Aβ42/Aβ40 on MCI-to-AD conversion. This study suggests that plasma GFAP in non-demented participants may reflect baseline cross-sectional CERAD-TS scores, a measure of global cognitive function. Conversely, plasma NFL may predict longitudinal decline in MMSE and CERAD-TS scores in participants categorized as amyloid positive. Kaplan–Meier curve analysis suggests that NFL, GFAP, tTau, and Aβ42/Aβ40 are potentially robust predictors of future AD conversion.