Plasma and serum markers of Alzheimer’s Disease and endothelial dysfunction

Plasma and serum markers of Alzheimer’s Disease and endothelial dysfunction

LASA filenames: LASAC868, LASAG868, LASAG878

Contact: Almar Kok

Background
Alzheimer’s disease (AD) dementia has a long preclinical phase of up to 20 years (Vermunt et al., 2019),  which is characterized by accumulation of cerebral amyloid-β (Aβ) plaques, aggregates of phosphorylated tau (pTau) and neurodegeneration (Masters et al., 2015). Furthermore, it has been suggested that microscopic damage to blood vessel walls can be indicative of the development of AD. The extent to which such microscopic damages are present is referred to as “endothelial dysfunction”. The current methods used for detecting the early onset of Alzheimer’s disease (AD) involve either the extraction of cerebrospinal fluid (CSF) or the use of positron emission tomography (PET) scans. While those methods have proven to be accurate for the detection of Alzheimer’s disease pathophysiology, they have a high cost, are invasive, and burdensome to obtain in large cohort studies, such as LASA. Blood-based biomarkers for Alzheimer’s disease and endothelial function could be a solution.

In the context of its participation in the Netherlands Consortium for Dementia Cohorts (NCDC), LASA has obtained blood plasma markers of amyloid pathology and P-tau 181 as well as a range of plasma markers for endothelial dysfunction (Karikari et al., 2020; Verberk et al., 2020). These are available for a subgroup of n=370 participants and based on blood obtained during the G-wave (2008).


Measurement instruments in LASA


Measurement equipment for SAP (wave C)
SAP was measured using an ELISA (Enzyme-Linked ImmunoSorbent Assay), validated by the department of Clinical Chemistry, VU University Medical Center.


Measurement equipment for plasma AD markers (wave G)
These markers were assessed using Single Molecular Array (Simoa; Quanterix) assays.

For pTAU181 (wave G):
Quanterix Simoa™ pTau-181 Advantage V2 Kit:

Kit Cat. Nr.          103714
Kit Lot#:               502691
Cal. Lot #             101201

https://www.quanterix.com/simoa-assay-kits/p-tau181-v2-new/

For Aβ-40, Aβ-42, GFAP, NFL:
Quanterix Neuro 4-Plex advantage kit

Kit Cat. Nr.          103670
Kit Lot#:               Pilot Simoa Neuro 4-plex E
Cal. Lot #             Pilot Simoa Neuro 4-plex E

Subgroup selection for AD and endothelial markers at wave G

The criteria for selection of this subgroup of participants were as follows (see also Figure 1):

  • 60 years or older
  • Has provided blood at the G-wave (2008/09)
  • MMSE score available at the G-wave and H-wave (2011/12)
  • MMSE score at G-wave 27 or higher
  • ApoE-status available
  • GWAS available

Subsequently we used a nested case-control design by selecting 50% participants who were Apoe-4 positive and 50% who were Apoe-4 negative. However, in the ApoE-4 negative group there were <50% of participants who fulfilled all criteria (n=140 out of the desired n=185). Therefore, we randomly sampled an additional n=45 from those who fulfilled all criteria but had no GWAS data available.

Moreover, in the lab it appeared that for n=36 insufficient plasma was available to determine the markers. Therefore, these were taken from the spare list of participants. The final distribution of ApoE-4 positive/negative was therefore not equal to 50/50%, but n=209 ApoE negative (56.5%) and n=161 ApoE positive (43.5%). The complete flowchart is displayed in Figure 1.

Outside the context of NCDC, Serum Amyloid component (SAP) is available in the LASA C-wave in n=1244 participants.

Figure 1. Flowchart for inclusion of n=370 participants in the LASA G-wave


Variable information

LASAC868, LASAG868, LASAG878


Availability of information per wave ¹

BCDE
2B*		FGH

3B*		MB*IJK
Serum Amyloid component (SAP)X
Alzheimer’s disease plasma markers
(Aβ-40, Aβ-42, GFAP, NfL, pTau-181)**		X
Plasma markers of endothelial dysfunction
(sVCAM-1, sE-selectin, sICAM-1)**		X

¹ More information about the LASA data collection waves is available here
* 2B=baseline second cohort;
**In selection of n=370 participants
3B=baseline third cohort;
MB=migrants: baseline first cohort


Previous use in LASA

  • Twait, E.L., Kamarioti, M., (…), van der Flier, W.M., & Geerlings, M.I. (2024). Depressive symptoms and plasma markers of Alzheimer’s disease and neurodegeneration: a coordinated meta-analysis of 8 cohort studies. The American Journal of Geriatric Psychiatry. https://doi.org/10.1016/j.jagp.2024.03.004


References

  1. Karikari, T. K., Pascoal, T. A., Ashton, N. J., Janelidze, S., Benedet, A. L., Rodriguez, J. L., … & Blennow, K. (2020). Blood phosphorylated tau 181 as a biomarker for Alzheimer’s disease: a diagnostic performance and prediction modelling study using data from four prospective cohorts. The Lancet Neurology, 19, 422-433.
  2. Masters CL, Bateman R, Blennow K, Rowe CC, Sperling RA, Cummings JL. Alzheimer’s disease. Nature Reviews Disease Primers 2015; 1.
  3. Verberk, I. M., Thijssen, E., Koelewijn, J., Mauroo, K., Vanbrabant, J., De Wilde, & Teunissen, C. E. (2020). Combination of plasma amyloid beta (1-42/1-40) and glial fibrillary acidic protein strongly associates with cerebral amyloid pathology. Alzheimer’s research & therapy, 12, 1-14.
  4. Vermunt L, Sikkes SAM, van den Hout A, et al. Duration of preclinical, prodromal, and dementia stages of Alzheimer’s disease in relation to age, sex, and APOE genotype. Alzheimer’s & dementia : the journal of the Alzheimer’s Association 2019; 15(7): 888-98.


Date of last update: May 28, 2024