AD: Shocked! The peak value of plasma Aβ42/Aβ40 began to decline 41 years before the deposition of brain Aβ! Alzheimer's diseases: New discovery on plasma Aβ42/Aβ40. AD: Shocked! The peak value of plasma Aβ42/Aβ40 began to decline 41 years before the deposition of brain Aβ! Amyloid β (Aβ) plaque deposition and phosphorylated tau (p-tau) protein tangles are two important pathological features of Alzheimer's disease (AD), and there are many kinds of AD biomarkers derived around them, Knowledge of the longitudinal trajectories of key markers could not only help improve the selection and monitoring of participants in clinical trials, but also help identify those at high risk for neurodegenerative changes and cognitive impairment. Although research on AD biomarkers has increased substantially in recent years, research on longitudinal changes in biomarkers is relatively limited. Studies have shown that the levels of plasma Aβ 42 /Aβ 40 , p-tau181 and glial fibrillary acidic...
AD: Shocked! The peak value of plasma Aβ42/Aβ40 began to decline 41 years before the deposition of brain Aβ!
AD: Shocked! The peak value of plasma Aβ42/Aβ40 began to decline 41 years before the deposition of brain Aβ!
Alzheimer's diseases: New discovery on plasma Aβ42/Aβ40.
AD: Shocked! The peak value of plasma Aβ42/Aβ40 began to decline 41 years before the deposition of brain Aβ!
Amyloid β (Aβ) plaque deposition and phosphorylated tau (p-tau) protein tangles are two important pathological features of Alzheimer's disease (AD), and there are many kinds of AD biomarkers derived around them, Knowledge of the longitudinal trajectories of key markers could not only help improve the selection and monitoring of participants in clinical trials, but also help identify those at high risk for neurodegenerative changes and cognitive impairment.
Although research on AD biomarkers has increased substantially in recent years, research on longitudinal changes in biomarkers is relatively limited. Studies have shown that the levels of plasma Aβ 42 /Aβ 40 , p-tau181 and glial fibrillary acidic protein (GFAP) in patients with mild cognitive impairment (MCI) change faster than in healthy people[1], while autosomal dominant Changes in plasma neurofilament light chain (NfL) and p-tau181 in AD mutation carriers start to “go off track” 16–17 years before symptom onset [2].
This suggests that changes in plasma biomarkers may begin in the preclinical stages of AD, or even earlier, although it is unclear how closely longitudinal changes in plasma biomarkers correlate with longitudinal changes in brain amyloid levels .
Recently, the journal Alzheimer's & Dementia published the latest results of the research team of the National Institute of Aging [3], they found that the strongest plasma biomarkers for predicting the amyloid load capacity in the brain are p-tau231 and Aβ 42 /Aβ 40 , there is also a very special finding that the relative decline in the peak value of plasma Aβ 42 /Aβ 40 began to appear 41 years before the positive detection of brain amyloid! The longitudinal changes of other markers, especially GFAP, were closer to the process of amyloid accumulation.
The study used amyloid PET and plasma biomarker data from participants in the Baltimore Longitudinal Study of Aging (BLSA). A total of 176 participants had results from at least two follow-up visits, and 21% of participants developed MCI or Dementia.
At the initial cognitively normal follow-up time point, PiB + participants were more likely to have APOE𝜀4+, Lower plasma Aβ 42 /Aβ 40 , higher Aβ 40 , p-tau181, p-tau231, p-tau181/Aβ 42 , p-tau231/Aβ 42 , GFAP, and NfL levels, and likely to maintain normal cognition Sex is lower.
In the univariate model, the most predictive markers for PiB PET results were p-tau231/Aβ 42 , p-tau181/Aβ 42 and p-tau231, with the area under the curve (AUC) ranging from 0.76 to 0.78. The predictive ability of the multivariate model was slightly stronger than that of the univariate model and the multivariate model based on demographic characteristics, with an AUC of 0.88, a specificity of 79%, and a sensitivity of 81%.
After calculation and analysis by the researchers, the two most important variables in this multivariate model are p-tau231 and Aβ 42 /Aβ 40 , and the AUC of the model established by using them alone is 0.89.
In predictive models, at the initial cognitively normal follow-up time point, PiB+ participants had lower Aβ 42 /Aβ 40 , higher p-tau181/Aβ 42 , p-tau231/Aβ 42 and GFAP, PiB+ and PiB - There was a significant difference in the rate of longitudinal change of Aβ42 /Aβ40 between the two groups (p=0.0073).
Changes in plasma marker levels in PiB+ and PiB- participants from the initial cognitively normal follow-up time point
Post hoc analysis showed that the longitudinal rate of Aβ42 /Aβ40 change was not significant in PiB+ participants but continued to decrease in PiB− participants. This may imply that Aβ42 /Aβ40 changes have already started before Aβ deposition .
Correlations were high (p<0.001) between p-tau181/Aβ42 and p-tau231/Aβ42 longitudinal rates of change, GFAP and NfL, and GFAP and cortical distribution volume ratio (cDVR, a measure of amyloid burden ) There was also a significant correlation (p<0.001) between the longitudinal rate of change.
The researchers estimated longitudinal trajectories of biomarker changes and progression scores (PS, assessing the temporal order of changes in plasma biomarkers and cDVR), as they expected, in patients with MCI and dementia compared with cognitively normal controls PS increased at last follow-up and for specific parameters over time.
Change trend of plasma markers with PS
To understand the relative order of change in biomarkers, the researchers calculated the relative percent change in the estimated change trajectory for each marker, and the timing of the relative change in the peak percentage change in the markers, showing that the earliest changes were in Aβ42 / Aβ40 , the peak relative decline (-1% per year) preceded the PiB+ result by 41 years, and the time intervals between the peak relative changes of the remaining plasma biomarkers and the PiB+ result were not statistically significant.
Collectively, the results of this study reveal the importance of plasma p-tau231 and Aβ42 / Aβ40 as biomarkers for predicting brain amyloid deposition, and the possible role of Aβ42 / Aβ40 in brain amyloid deposition. The off-track decline began in the first 41 years.
In the future, a simple and low-cost method for assessing brain amyloid based on plasma biomarkers can be applied to clinical trials and clinical diagnosis, changing the current landscape.
references:
[1] Chatterjee P, Pedrini S, Doecke JD, et al. Plasma Aβ42/40 ratio, p‐tau181, GFAP, and NfL across the Alzheimer's disease continuum: A cross‐sectional and longitudinal study in the AIBL cohort[J]. Alzheimer's & Dementia, 2023, 19(4): 1117-1134.
[2] O'Connor A, Karikari TK, Poole T, et al. Plasma phospho-tau181 in presymptomatic and symptomatic familial Alzheimer's disease: a longitudinal cohort study[J]. Molecular psychiatry, 2021, 26(10): 5967-597 6 .
[3] https://alz-journals.onlinelibrary.wiley.com/doi/10.1002/alz.13157
Alzheimer's diseases: New discovery on plasma Aβ42/Aβ40
(source:internet, reference only)