Background: 
Early detection of brain amyloid pathology is critical for the timely intervention in Alzheimer’s disease (AD). Plasma Aβ biomarkers change early in the amyloid continuum, according to current evidence. The aim of this longitudinal study was to determine whether baseline plasma Aβ42/Aβ40 detects amyloid deposition before PET positivity.

Methods:
This study includes 164 Aβ-PET(−) (≤ 13.5 centiloids [CL]) individuals with subjective cognitive decline (SCD) from the Fundació ACE Healthy Brain Initiative (FACEHBI) cohort. Baseline plasma Aβ42/Aβ40 was measured using a mass-spectrometry based method (ABtest-MS, Araclon Biotech). Participants underwent 18F-Florbetaben PET at baseline, 2, 5, and 8 years, and annual clinical assessments up to 8 years. Participants were classified as plasma Aβ(+) or Aβ(−) using a cutoff value of 0.241 for plasma Aβ42/Aβ40. Differences in the rate of brain amyloid accumulation between plasma Aβ(+) and plasma Aβ(−) groups were assessed using linear mixed-effects models (LMEM). Progression to Aβ-PET positivity (cutoff 13.5 CL) or MCI due to AD (defined as incident MCI with concomitant Aβ-PET positivity) was evaluated based on plasma Aβ status using Kaplan-Meier and Cox proportional hazards models.

Results:
At baseline, plasma Aβ(+) (N=34) and plasma Aβ(−) (N=130) groups were comparable in MMSE score, APOE status, and CL values. Age and sex showed borderline differences between groups (Table 1). Among Aβ-PET(−) individuals, those with lower baseline Aβ42/Aβ40 ratio (plasma Aβ(+)) exhibited significantly higher rates of amyloid accumulation compared to plasma Aβ(−) subjects (interaction β = 1.99, 95% CI 1.12–2.86; P < 0.001), despite no significant differences in baseline CL values (Figure 1). Survival analyses confirmed earlier progression to Aβ-PET positivity (log-rank P = 0.015) and to MCI due to AD (log-rank P = 0.014) in plasma Aβ(+) participants (Figure 2). In Cox proportional hazards models adjusted for age, sex, APOE status, and baseline CL, plasma Aβ(+) status was associated with increased risk of conversion to Aβ-PET positivity (hazard ratio [HR] = 3.92, 95% CI 1.69–9.11, P = 0.001) and to MCI due to AD (HR = 7.11, 95% CI 1.67–30.29, P = 0.008). Integration of baseline ROC analysis1 and longitudinal findings in Aβ-PET(−) individuals illustrates a potential plasma-based trial enrichment strategy (Figure 3).

Conclusions:
In a population of SCD Aβ-PET(−) participants, plasma Aβ42/Aβ40 identified individuals with emerging amyloid pathology, supporting that plasma alterations may precede PET-detectable cortical deposition. Plasma Aβ(+)/Aβ-PET(−) individuals showed increased risk of subsequent amyloid accumulation and clinical progression, consistent with an early amyloid transitional stage not yet fully captured by PET. These findings highlight the potential of plasma Aβ42/Aβ40 as a first-step screening tool for clinical trial enrichment with important implications for primary prevention trials.