Weekly fluctuations of plasma amyloid-beta in Alzheimer’s disease: implications for biomarker reliability

Alzheimer’s Disease (AD), the most prevalent age-related dementia, is characterized by accumulation of amyloid-beta (Aβ) and hyperphosphorylated tau proteins within the brain. Accurate monitoring of AD progression is crucial for patient management and the evaluation of clinical trials but often involves invasive and expensive methods like cerebrospinal fluid analysis and PET scans. Consequently, minimally invasive plasma biomarkers such as the ratio of Aβ42 and Aβ40 are often used as endpoints in clinical research. This study investigates the variability in plasma Aβ levels on a micro-longitudinal scale to determine if they remain stable over short periods of time. Aβ42 and Aβ40 peptides were quantified in plasma by enzyme-linked immunosorbent assay in a cohort of 73 AD patients with AD8 scores ≥ 3. Our cohort was 62% Black/African American and 38% White/Caucasian, 66% female and 34% male. Samples were collected weekly over a five-week micro-longitudinal study. We examined week-to-week Aβ peptide levels within-participant as well as between-patient variation. Impacts both of sex and race were examined as covariates. Significant week-to-week fluctuations were observed in the levels of Aβ40, Aβ42, and Aβ42/Aβ40. We observed Aβ42/40 ratio to shift by more than 50% in 60% of participants. Further participants had an average of 20–50% fluctuations in readings on a week-to-week basis. This week-to-week fluctuation appeared to be driven primarily by sudden episodic shifts in Aβ content with only a few individuals showing sustained shifts. We report no significant difference in fluctuations in Aβ content by sex or race of participants. However, we do find plasma amyloid content (Aβ42, Aβ40, and Aβ42/Aβ40) to be elevated in male participants. Finally, we show some participants to present higher levels of amyloid flux than others at least on a micro-longitudinal scale. These findings highlight the dynamic nature of plasma Aβ levels, contrasting with the expected stability over such a short period. The substantial levels of weekly variability in plasma Aβ levels we observed are comparable to the 18-month rate of change reported in recent pharmaceutical trials, and suggests that relying solely on these biomarkers for AD monitoring or outcome assessment could be misleading without considering their temporal fluctuations. This study emphasizes the need for frequent sampling and cautious interpretation when using plasma Aβ levels as an outcome measure.