Association of Objective Subtle Cognitive Difficulties with Amyloid-β and Tau Deposition in Alzheimer's Disease

Neurology Geriatrics Medicine Medical Imaging
Objective subtle cognitive difficulties Subjective cognitive decline Alzheimer's disease Amyloid-β Tau protein Memory decline Neuroimaging

Research Progress on Early Alzheimer’s Stages: Focusing on Differences Between Objective Subtle Cognitive Difficulties and Subjective Cognitive Decline

Alzheimer’s disease (AD) is a critical topic in modern neuroscience and geriatric medicine research. Its pathological process begins years before the onset of clinical symptoms. Increasing evidence suggests that identifying the preclinical stage of AD and implementing early preventive interventions are crucial to slowing or halting disease progression. However, challenges remain in scientifically classifying and investigating these early stages. In recent years, “Subjective Cognitive Decline” (SCD) has drawn widespread attention as a tool for early AD detection due to its simplicity and ease of use. However, traditional reliance on patient self-reporting is susceptible to influences from factors such as emotional state, cultural background, and external conditions, limiting its diagnostic effectiveness.

To address this issue, researchers proposed the concept of “Objective Subtle Cognitive Difficulties” (Obj-SCD). Obj-SCD combines objective criteria with micro-level measurement of early cognitive changes to capture potential relationships with AD biomarkers. In AD’s pathological progression, amyloid-β (Aβ) deposition and tau protein neurofibrillary tangles are regarded as the most critical hallmark features. Investigating differences in these biomarkers between Obj-SCD and SCD, as well as their relationship with memory decline, is key to understanding AD’s early pathological mechanisms. This study builds upon this scientific context, aiming to analyze the Aβ and tau deposition levels, their dynamic changes, and their associations with early cognitive decline in Obj-SCD and SCD individuals.

This study was conducted collaboratively by researchers from Xiamen University, Huashan Hospital, and the Alzheimer’s Disease Neuroimaging Initiative (ADNI). The primary authors include Xiaoxie Mao, Anqi Li, and Ying Wang. The findings were published in the 2025 issue of the European Journal of Nuclear Medicine and Molecular Imaging.

Research Methods and Workflow

The study incorporated data from two independent cohorts, ADNI and Huashan Hospital, with a total of 501 participants. Participants were classified into Healthy Control (HC), SCD, and Obj-SCD groups. The research included the following key steps:

1. Participant Recruitment and Grouping Criteria

  • Huashan Cohort: Recruited 141 participants aged 50–80 from Shanghai communities. Through strict neuropsychological assessments, participants were classified into the HC group (102 individuals) and the Obj-SCD group (39 individuals). SCD screening was also conducted.
  • ADNI Cohort: Included 199 HC participants and 35 Obj-SCD participants. Additionally, for a specific subgroup, Subjective Memory Concern (SMC), 25 HC and 121 SMC participants’ data were collected.

2. Imaging Scanning and Data Processing

The study utilized [18F]Florbetapir PET for imaging Aβ deposition, [18F]MK6240 PET for imaging tau protein deposition, and high-resolution 3T MRI scanning for acquiring brain anatomical data. Data processing integrated multiple algorithms: - Calculated cortical Aβ Standardized Uptake Value Ratios (SUVRs) using Freesurfer software. - Normalized images to the Montreal Neurological Institute (MNI) coordinate space in ADNI and used SPM12 for spatial smoothing and Region of Interest (ROI) extraction. - Tau protein deposition analysis followed the Braak staging model, dividing the brain into six stages (I to VI) to distinguish deposition in different brain regions.

3. Data Analysis Methods

The study employed Generalized Linear Models (GLM) to explore baseline levels and annual change rates of Aβ and tau across groups. Mediation analysis evaluated Aβ deposition’s potential role in tau propagation and cognitive function changes.

Research Results

1. Differences in Baseline Aβ and Tau Levels

Obj-SCD participants exhibited significantly higher Aβ levels than the HC group (Cohen’s d = 0.73, p = 0.028, Huashan cohort; Cohen’s d = 1.56, p < 0.001, ADNI cohort). No significant differences were observed in Aβ levels between the SCD or SMC groups and the HC group. Similarly, Obj-SCD participants showed significantly elevated tau deposition at Braak stages I (Huashan: Cohen’s d = 0.88; ADNI: Cohen’s d = 0.55) and II.

2. Annual Changes in Aβ and Tau Accumulation

The Obj-SCD group exhibited significantly higher annual rates of Aβ accumulation compared to the HC group (Cohen’s d = 0.64, p = 0.029). Simultaneously, Obj-SCD participants demonstrated markedly accelerated annual tau accumulation rates at Braak stages III–IV (Cohen’s d = 1.36, p < 0.001), indicating particularly rapid progression in mid-stage pathology.

3. Relationship Between Aβ and Tau and Predictions for Cognition

  • Baseline Aβ showed significant positive correlations with the annual tau change rate, especially in Braak stages III–IV (standardized β = 0.714, p < 0.001) and Braak stages V–VI.
  • Baseline Aβ strongly predicted early memory decline, while baseline tau lacked significant predictive efficacy. Among Obj-SCD and SMC participants, baseline Aβ was negatively correlated with memory scores (ADNI-Mem) changes over time.

Conclusions and Significance

This study demonstrates that Obj-SCD participants show significantly higher levels of Aβ and tau deposition than HC participants. It also highlights Aβ’s potential role in tau pathology propagation and early memory function decline. The findings support considering Obj-SCD as a high-risk population for AD, paving the way for targeted interventions in the “ultra-early” stage of the disease. The study further elucidates the spatiotemporal distribution of Aβ and tau across different brain functional regions, particularly the propagation of tau from the entorhinal cortex to limbic and neocortical systems, identifying critical nodes in its pathological progression.

Highlights and Innovations

  • Cross-Cohort Validation: Consistent results across the Huashan and ADNI cohorts enhance the reliability and generalizability of the findings.
  • Advanced Tau Tracers: The use of the next-generation tracer [18F]MK6240 in the Huashan cohort improves specificity and enhances detection of early tau propagation.
  • Scientific Contributions: This study uniquely reveals the pathological features of the emerging classification Obj-SCD and highlights its significance in researching AD’s earliest stages.

Future research should aim to expand sample sizes, especially longitudinal data for the Obj-SCD subgroup, to solidify the foundation for ultra-early prevention and treatment strategies in Alzheimer’s disease.