Gene-variant specific effects of plasma amyloid-β levels in Swedish autosomal dominant Alzheimer disease.
APP
Alzheimer disease
Amyloid-β
Autosomal dominant
Plasma biomarkers
Journal
Alzheimer's research & therapy
ISSN: 1758-9193
Titre abrégé: Alzheimers Res Ther
Pays: England
ID NLM: 101511643
Informations de publication
Date de publication:
25 Sep 2024
25 Sep 2024
Historique:
received:
24
05
2024
accepted:
11
09
2024
medline:
26
9
2024
pubmed:
26
9
2024
entrez:
25
9
2024
Statut:
epublish
Résumé
Several blood-based biomarkers offer the opportunity of in vivo detection of brain pathology and neurodegeneration in Alzheimer disease with high specificity and sensitivity, but the performance of amyloid-β (Aβ) measurements remains under evaluation. Autosomal dominant Alzheimer disease (ADAD) with mutations in PSEN1, PSEN2 and APP can be studied as a model for sporadic Alzheimer disease. However, clarifying the genetic effects on the Aβ-levels in different matrices such as cerebrospinal fluid or plasma is crucial for generalizability and utility of data. We aimed to explore plasma Aβ concentrations over the Alzheimer disease continuum in a longitudinal cohort of genetic Alzheimer disease. 92 plasma samples were collected from at-risk individuals (n = 47) in a Swedish cohort of ADAD, including 18 mutation carriers (13 APPswe (p.KM670/671NL) MC), 5 PSEN1 (p.H163Y) MC) and 29 non-carriers (NC) as the reference group. Concentrations of Aβ1-38, Aβ1-40 and Aβ1-42 were analyzed in plasma using immunoprecipitation coupled to tandem liquid chromatography mass spectrometry (IP-LC-MS/MS). Cross-sectional and repeated-measures data analyses were investigated family-wise, applying non-parametric tests as well as mixed-effects models. Cross-sectional analysis at baseline showed more than a 3-fold increase in all plasma Aβ peptides in APPswe MC, regardless of clinical status, compared to controls (p < 0.01). PSEN1 (p.H163Y) presymptomatic MC had a decrease of plasma Aβ1-38 compared to controls (p < 0.05). There was no difference in Aβ1-42/1-40 ratio between APPswe MC (PMC and SMC), PSEN1 MC (PMC) and controls at baseline. Notably, both cross-sectional data and repeated-measures analysis suggested that APPswe MC have a stable Aβ1-42/1-40 ratio with increasing age, in contrast to the decrease seen with aging in both controls and PSEN1 (p.H163Y) MC. These data show very strong mutation-specific effects on Aβ profiles in blood, most likely due to a ubiquitous production outside of the CNS. Hence, analyses in an unselected clinical setting might unintentionally disclose genetic status. Furthermore, our findings suggest that the Aβ ratio might be a poor indicator of brain Aβ pathology in selected genetic cases. The very small sample size is a limitation that needs to be considered but reflects the scarcity of longitudinal in vivo data from genetic cohorts.
Sections du résumé
BACKGROUND
BACKGROUND
Several blood-based biomarkers offer the opportunity of in vivo detection of brain pathology and neurodegeneration in Alzheimer disease with high specificity and sensitivity, but the performance of amyloid-β (Aβ) measurements remains under evaluation. Autosomal dominant Alzheimer disease (ADAD) with mutations in PSEN1, PSEN2 and APP can be studied as a model for sporadic Alzheimer disease. However, clarifying the genetic effects on the Aβ-levels in different matrices such as cerebrospinal fluid or plasma is crucial for generalizability and utility of data. We aimed to explore plasma Aβ concentrations over the Alzheimer disease continuum in a longitudinal cohort of genetic Alzheimer disease.
METHODS
METHODS
92 plasma samples were collected from at-risk individuals (n = 47) in a Swedish cohort of ADAD, including 18 mutation carriers (13 APPswe (p.KM670/671NL) MC), 5 PSEN1 (p.H163Y) MC) and 29 non-carriers (NC) as the reference group. Concentrations of Aβ1-38, Aβ1-40 and Aβ1-42 were analyzed in plasma using immunoprecipitation coupled to tandem liquid chromatography mass spectrometry (IP-LC-MS/MS). Cross-sectional and repeated-measures data analyses were investigated family-wise, applying non-parametric tests as well as mixed-effects models.
RESULTS
RESULTS
Cross-sectional analysis at baseline showed more than a 3-fold increase in all plasma Aβ peptides in APPswe MC, regardless of clinical status, compared to controls (p < 0.01). PSEN1 (p.H163Y) presymptomatic MC had a decrease of plasma Aβ1-38 compared to controls (p < 0.05). There was no difference in Aβ1-42/1-40 ratio between APPswe MC (PMC and SMC), PSEN1 MC (PMC) and controls at baseline. Notably, both cross-sectional data and repeated-measures analysis suggested that APPswe MC have a stable Aβ1-42/1-40 ratio with increasing age, in contrast to the decrease seen with aging in both controls and PSEN1 (p.H163Y) MC.
CONCLUSION
CONCLUSIONS
These data show very strong mutation-specific effects on Aβ profiles in blood, most likely due to a ubiquitous production outside of the CNS. Hence, analyses in an unselected clinical setting might unintentionally disclose genetic status. Furthermore, our findings suggest that the Aβ ratio might be a poor indicator of brain Aβ pathology in selected genetic cases. The very small sample size is a limitation that needs to be considered but reflects the scarcity of longitudinal in vivo data from genetic cohorts.
Identifiants
pubmed: 39322953
doi: 10.1186/s13195-024-01574-w
pii: 10.1186/s13195-024-01574-w
doi:
Substances chimiques
Amyloid beta-Peptides
0
Presenilin-1
0
PSEN1 protein, human
0
Presenilin-2
0
Amyloid beta-Protein Precursor
0
PSEN2 protein, human
0
Biomarkers
0
Peptide Fragments
0
APP protein, human
0
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
207Informations de copyright
© 2024. The Author(s).
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