Plasma Aβ42/Aβ40 predicts longitudinal amyloid pathology and clinical progression in amyloid-PET negative individuals with subjective cognitive decline

Early detection of amyloid-β (Aβ) pathology is critical for timely intervention in Alzheimer’s disease (AD). Changes in plasma Aβ42/Aβ40 levels appear early in the AD continuum, but whether they precede amyloid deposition detected by Aβ-PET requires further research. Data from 164 Aβ-PET negative (Aβ-PET(−) ≤ 13.5 centiloids (CL)) individuals with subjective cognitive decline (SCD) from the Fundació ACE Healthy Brain Initiative (FACEHBI) study were included. Baseline plasma Aβ42/Aβ40 levels were quantified using mass spectrometry, and participants were classified as plasma Aβ( +) or Aβ( −) using a threshold of 0.241. Participants underwent florbetaben PET at baseline and 2, 5, and 8 years, with annual clinical assessments. Rates of brain amyloid accumulation (CL) and progression to Aβ-PET positive (Aβ-PET( +)) or mild cognitive impairment (MCI) due to AD (incident MCI with concomitant Aβ-PET( +)) were analyzed according to plasma Aβ status for two conversion thresholds: 22 CL and 13.5 CL. Plasma Aβ( +) participants (n = 34) at baseline exhibited faster amyloid accumulation than Aβ( −) individuals (n = 130) (β = 1.99, 95% CI 1.12–2.86; p < 0.001), despite no significant differences in baseline CL values. At the 22 CL threshold for Aβ-PET( +) conversion, significant group differences were observed in time to event (p = 0.003 for Aβ-PET( +); p = 0.002 for MCI due to AD). Plasma Aβ( +) status was associated with higher risk of conversion to Aβ-PET( +) (Hazard ratio (HR): 6.86, 95% CI 2.45–19.20, p < 0.001) and MCI due to AD (HR 9.50, 1.98–45.65, p = 0.005). Findings were consistent for the 13.5 CL threshold ( p = 0.015 and 0.014; HR 3.93, 1.69–9.11, p = 0.001 and HR 7.11, 1.67–30.29, p = 0.008, respectively). 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.