Estimated Age of Amyloid Onset in Participants with Early‐ versus Late‐Onset Alzheimer’s Disease: Results from the LEADS & ADNI Studies
Ganna Blazhenets, Nidhi Mundada, JiaQie Lee, Susan M. Landau, Robert A. Koeppe, Maria C. Carrillo, Brad C. Dickerson, William J. Jagust, Liana G. Apostolova, Gil D. Rabinovici, Renaud La Joie- Psychiatry and Mental health
- Cellular and Molecular Neuroscience
- Geriatrics and Gerontology
- Neurology (clinical)
- Developmental Neuroscience
- Health Policy
- Epidemiology
Abstract
Background
Aß deposition is thought to start decades prior to symptom onset. Previous studies have shown that mathematical modeling enables reconstruction of Aß‐PET trajectory and age estimation at Aß‐PET positivity in Aß‐positive patients. We aimed to apply this approach to determine Aß duration and estimate age at Aß‐PET positivity in sporadic early‐ (<65yo) and late‐ ( = 65yo) onset AD (EOAD/LOAD).
Method
We combined PET data from the Longitudinal Early‐Onset AD Study (LEADS, n = 288) and ADNeuroimaging Initiative (ADNI, n = 915). First, we selected Aß+ (baseline Centiloids = 24) cognitively impaired patients with = 2 Florbetaben‐PET scans to compare baseline and longitudinal amyloid‐PET in EOAD versus LOAD using linear mixed effects regression (Figure 1). Then, we used ADNI participants with = 2 Florbetapir‐PET scans to assess the relationship between Aß‐PET Centiloids and time (Figure 2). We estimated the Aß temporal trajectory by integrating a reciprocal of the spline model from the accumulation rate and Centiloidmid‐point. Finally, we used the resulting Aß trajectory to estimate Aß duration and age at Aß‐PET positivity onset for patients with EOAD and LOAD (Figure 3).
Result
EOAD patients had higher baseline Aß burden than LOAD patients. Amyloid‐PET increased at similar rates in the two groups (Figure 1), allowing us to operate under the assumption that EOAD and LOAD follow the same Aß trajectory, with a temporal shift. Aß trajectory was estimated in ADNI Florbetapir‐PET, showing an almost linear dependency between Centiloids and Aß duration (Figure 2). The model suggests that Aß‐PET positivity (CL = 24) is reached after 7 years, and an additional 26 years are needed to reach 100 CL. When applied to the Florbetaben sample, we determined that 75yo LOAD patients became Aß‐PET positive around 52yo, while 60yo patients with EOAD dementia were Aß‐PET positive around age 31 (Figure 3).
Conclusion
Based on available data, the dynamic of Aß accumulation seems similar in EOAD and LOAD, with a temporal shift indicating that EOAD patients might transition to Aß‐PET‐positive in their early 30s. Prospective studies on early phases of Aß accumulation in EOAD patients will be important for validation of these findings since existing data is limited.