Blood test detects early Alzheimer’s signs in people with memory concerns

By Vijay Kumar MalesuReviewed by Susha Cheriyedath, M.Sc.Apr 21 2025

Researchers have shown that a simple blood test for plasma p-tau181 can flag subjective cognitive decline, an early but biologically distinct stage in Alzheimer’s, years before traditional symptoms appear.

Study: Blood biomarkers confirm subjective cognitive decline (SCD) as a distinct molecular and clinical stage within the NIA-AA framework of Alzheimer´s disease. Image Credit: Belight / Shutterstock

In a recent study published in the journal Molecular Psychiatry, a group of researchers evaluated whether blood biomarkers can distinguish subjective cognitive decline (SCD) as a distinct transitional stage in Alzheimer’s disease (AD) progression.

Background

What if a simple blood test could detect AD years before symptoms appear? AD begins long before memory loss, progressing silently through biological changes. The National Institute on Aging and Alzheimer’s Association (NIA-AA) defines six stages of AD, where Stage 2 represents a subtle shift from normal cognition, often experienced as SCD. Although individuals may feel their memory slipping, standard tests typically reveal no deficits. Identifying reliable molecular biomarkers for this stage could revolutionize early detection and intervention. However, it is important to note that while promising, current research suggests these biomarkers are best used for group-level prediction rather than individual clinical diagnosis. Further research is needed to validate these biomarkers and their predictive power for clinical progression at the individual level.

About the Study

Researchers used data from 457 participants in the Longitudinal Cognitive Impairment and Dementia Study (DELCODE), coordinated by the German Center for Neurodegenerative Diseases. All participants were aged 60 years or older and categorized into clinical groups based on cognitive status and cerebrospinal fluid (CSF) biomarkers. Amyloid positivity was determined using the CSF amyloid beta 42/40 (Aβ42/40) ratio, aligning with the NIA-AA criteria. This allowed classification into amyloid-positive cognitively unimpaired (A+ CU), amyloid-positive subjective cognitive decline (A+ SCD), and amyloid-positive mild cognitive impairment (A+ MCI). Amyloid-negative groups were also included for comparison: A– CU, A– SCD, and A– MCI.

Plasma samples were analyzed for levels of phosphorylated tau at threonine-181 (p181) and neurofilament light chain (NfL), representing tau pathology and neurodegeneration within the Amyloid-Tau-Neurodegeneration (ATN) framework. Cognitive performance was assessed annually using the Preclinical Alzheimer’s Cognitive Composite (PACC5), and hippocampal volume was tracked via magnetic resonance imaging. Longitudinal data analysis employed linear mixed-effects models to evaluate biomarker trajectories and their relationship with cognitive decline and structural brain changes. Kaplan-Meier survival analysis and Cox regression models were used to assess whether baseline biomarker levels predicted progression from A+ SCD to A+ MCI, and from A+ MCI to AD dementia. All analyses were adjusted for age, sex, and education. The study specifically noted that all participants provided informed consent and that the research was conducted in accordance with ethical standards.

Study Results

At baseline, plasma p181 levels were significantly elevated in A+ SCD compared to A+ CU. These levels in A+ SCD also increased more rapidly over time, resembling patterns seen in A+ MCI, suggesting a distinct biological profile in Stage 2 of AD. In contrast, NfL levels were higher in A+ SCD compared to A– SCD, but differences between A+ SCD and A+ CU were not statistically significant. However, NfL levels increased steadily across A+ CU, A+ SCD, and A+ MCI, reflecting progressive axonal degeneration along the continuum.

Cognitive decline, measured using the PACC5 composite, was significantly more pronounced in A+ SCD individuals over time. While A+ CU individuals showed stable performance, A+ SCD participants demonstrated a negative cognitive trajectory that worsened further in A+ MCI. High baseline plasma p181 levels were predictive of faster cognitive decline in A+ SCD, but not in A+ CU, and this relationship persisted into the MCI stage. NfL levels, however, predicted cognitive deterioration only at the MCI stage and not earlier.

Furthermore, higher baseline p181 levels in A+ SCD predicted transition to MCI during a three-year follow-up. Nearly 30% of A+ SCD individuals converted to MCI, compared to 17% of A– SCD participants. This risk was almost three times greater for those with elevated p181 levels. Similarly, among individuals with MCI, higher p181 levels at baseline also predicted progression to AD dementia. These findings support the potential of p181 as a stratification biomarker for identifying high-risk individuals early in the disease course. However, the authors caution that these findings are currently most robust at the group level, and further validation is needed before such predictions can be reliably applied to individual patients in a clinical setting.

Neuroimaging findings partially corroborated biomarker data. At baseline, A+ SCD participants had reduced hippocampal volume compared to cognitively unimpaired individuals. However, significant associations between hippocampal atrophy and plasma biomarkers were only evident in A+ MCI, suggesting structural changes lag behind molecular alterations in early disease stages. The study notes that the shorter follow-up period may have limited the ability to detect robust associations between MRI findings and blood biomarkers in earlier stages.

Together, these results validate A+ SCD as a biologically and clinically distinct stage within the AD continuum. Plasma p181 levels provide a valuable tool for identifying individuals at high risk of future cognitive decline and clinical progression, while NfL offers additional support for underlying neurodegeneration in Stage 2. The study also highlights the potential role of plasma p181 in enriching participant selection for future clinical trials targeting early intervention, by identifying those most likely to experience faster decline.

Conclusions

This study confirms that SCD in A+ individuals represents a distinct and detectable transitional stage (Stage 2) within the NIA-AA AD continuum. Plasma phosphorylated tau at p181 emerges as a reliable blood biomarker, capable of identifying those at increased risk of cognitive deterioration and clinical conversion to MCI or AD dementia. While NfL supports evidence of neurodegeneration, p181’s distinct trajectory highlights its central role in early AD pathology. Importantly, the authors emphasize that current biomarker predictions should be interpreted at the group level, and further research is needed for their application in individual diagnosis and care. These findings support blood-based biomarkers for early AD diagnostics and intervention.