Synaptic proteins in pre-symptomatic Alzheimer's disease: biomarkers for early detection of Cognitive Decline

Abstract

Background: Synaptic proteins in the cerebrospinal fluid (CSF) may reveal changes in the pre-symptomatic stages of Alzheimer’s disease (AD), thus may be candidate biomarkers for early detection of the disease.
Method: The PREVENT-AD cohort includes symptom-free (upon enrolment) elderly participants who are at risk of developing AD from their family history. We used enzyme-linked immunosorbent assay kits to assess CSF samples from 129 such participants for the “classical” AD biomarkers total tau, phosphorylated (181) tau and Aβ42. We also used neuroimaging data (MRI, PET) and neuropsychological assessments (MMSE, RBANS) as potential indicators disease progression. We then used Olink Proximity Extension Assay technology in the CSF samples to measure the soluble synaptic biomarkers ADAM 22 (post-synaptic), ADAM23 (pre-synaptic). Immunoprecipitated SYT1 (pre-synaptic) from CSF were analyzed using high-resolution selected ion monitoring analyses on a quadrupole–orbitrap mass spectrometer Q Exactive. Statistical analysis of the association of these markers with evidence of disease in analyses were done included sex and APOE 4 status as covariates.
Result: Among participants who remained cognitively unimpaired, we observed significant correlations between baseline CSF ADAM 22 levels and t-tau (R2 = 0.22, p < 0.0001), p-tau (R2 = 0.22, p < 0.0001), and Aβ42 (R2 = 0.06, p = 0.01488). We also found similarly suggestive correlations also between CSF ADAM 23, CSF SYT1 and the same disease markers. Covariate analyses suggested little or no variation in the associations between these synaptic proteins with t-tau and p-tau by sex, APOE 4 status, negative PET amyloid positivity (standardized uptake value ratio ≤ 1.37) and negative CSF total tau positivity (≤ 335pg/ul). PET amyloid positivity was significantly associated with ADAM22 and p-tau interactions whereas SYT1 was significantly associated with t-tau and p-tau in CSF tau-positive participants. In linear regression analyses, baseline CSF SYT1 levels correlated with the language cognitive performance trajectory slopes estimated over the course of 6 to 8 years on the RBANS (R2 = 0.03, p = 0.03425). We found no significant interaction between other CSF synaptic protein levels and other subscales of the RBANS.
Conclusion: CSF synaptic protein levels show promising correlation with landmark AD proteins and emerging cognitive deficits.

Full text

Synaptic proteins in pre-symptomatic Alzheimer's disease:
biomarkers for early detection of Cognitive Decline
Jiarui Ao, A. Labonté, A. Brinkmalm, K. Blennow, H.Zetterberg, J.Breitner, S. Villeneuve, J.Poirier, for the PREVENT-AD
Research Group.
P2-231
Synaptic proteins as biomarkers that can predict early cognitive decline in patients in the pre-symptomatic phase of Alzheimer’s disease
•Background: Synaptic dysfunctions is
now a common characteristic of AD1.
Those synaptic anomalies happen in
the early stages of the disease before
cognitive symptoms emerge and are
strongly correlated with cognitive
decline2.
•Hypothesis: We hypothesize that
selected synaptic proteins (ADAM22,
ADAM23, SYT1, SNAP25) measured in
the CSF can detect early cognitive
decline in pre-symptomatic AD patients
and predict their conversion to MCI.
•An increase of CSF selected
synaptic proteins strongly suggests
a rise of CSF AD hallmarks, as
expected from literatures.3
•Interestingly, while baseline
selected CSF synaptic protein
correlates with AD hallmarks
longitudinally, the pair of synaptic
protein are especially sensitive at
detecting change of tau.
•Selected CSF synaptic proteins
correlates with RBANS subscales
cross-sectionally (baseline) with a
positive relationship, and
longitudinally with relationships of
both directions.
•An inverse relationship is observed
between CSF synaptic protein
levels and RBANS subscales score
at cross-sectional level, which is of
consistent with our synaptic
hypothesis.4
1. Peng, L., I. Bestard-Lorigados, and W. Song, The
synapse as a treatment avenue for Alzheimer’s
Disease. Molecular Psychiatry, 2022. 27(7): p.
2940-2949.
2. Colom-Cadena, M., et al., The clinical promise of
biomarkers of synapse damage or loss in
Alzheimer’s disease. Alzheimer's Research &
Therapy, 2020. 12(1): p. 21.
3. Öhrfelt, Annika et al. The pre-synaptic vesicle
protein synaptotagmin is a novel biomarker for
Alzheimer's disease. Alzheimer's research &
therapy vol. 8,1 41. 3 Oct. 2016,
doi:10.1186/s13195-016-0208- 8
4. Brinkmalm, Ann et al. SNAP-25 is a promising novel
cerebrospinal fluid biomarker for synapse
degeneration in Alzheimer's disease. Molecular
neurodegeneration vol. 9 53. 23 Nov. 2014,
doi:10.1186/1750-1326-9-53
Introduction
Methods
Results Discussions References
Contact
Contacts:
jiarui.ao@mail.mcgill.ca
We wish to thank the FRQS,
CIHR, J.L. Levesque
Foundation, McGill University
and Douglas Hospital
Research Centre for funding.
•PREVENT-AD cohort: Symptom-free (upon
enrolment) elderly participants with a
family history of sporadic AD
•Neuroimaging (MRI, PET), cognitive
assessments (MMSE, RBANS)
•Olink Proximity Extension Assay and IP-
LC/MS/MS assays for CSF biomarkers
•Statistical analysis: R, Plink
Fig 1: CSF level of selected synaptic proteins are strongly
correlated with CSF AD hallmarks, with a positive relationship.
(NADAM22/23 = 99, NSYT1 = 131, NSNAP25 = 137)
a) Synaptic protein correlation with Aβ
b) Synaptic protein correlation with phospho-Ta u 18 1
c) Synaptic protein correlation with total Tau
abc
Figure 3: at baseline, the CSF selected synaptic proteins are correlates
at trend level with several RBANS subscales with a negative
relationship. (NADAM22/23 = 81, NSYT1 = 78, NSNAP25 = 80)
a) Baseline CSF SYT1 correlation with baseline RBANS immediate memory score
b) Baseline CSF SNAP25 correlation with baseline RBANS language score
c) Baseline CSF ADAM23 correlation with baseline RBANS attention score
abc
Fig 4: rate of change in CSF level of selected synaptic proteins correlates
with rate of change for several RBANS subscales.
(NADAM22/23 = 25, NSYT1 = 79, NSNAP25 = 82)
a) Rate of change of CSF synaptic proteins correlation with rate of change of RBANS attention
score
b) Rate of change of CSF synaptic protein correlation with rate of change of RBANS delayed
memory score
c) Rate of change of CSF synaptic protein correlation with rate of change of RBANS total score
a b c
Fig 2: CSF level of selected synaptic proteins are strongly
correlated with change of CSF AD hallmarks across years.
(NADAM22/23 = 78, NSYT1 = 76, NSNAP25 = 77)
a) Baseline synaptic protein correlation with Aβacross years
b) Baseline synaptic protein correlation with phospho-Ta u 18 1 a cro ss ye ars
c) Baseline synaptic protein correlation with total Tau across years
bca
pg/ml
pg/(ml*yr)
NPX (ADAM22/23), peak area ratio (SYT1, SNAP25)
NPX/yr (ADAM22.23), peak area ratio/yr (SYT1, SNAP25)