Background: The immune system plays a crucial role in the pathogenesis of neurodegenerative diseases. Here, we explored whether blood immune cell profiles are already altered in healthy individuals with a genetic predisposition to amyotrophic lateral sclerosis (ALS) or Alzheimer's disease (AD). Methods: Using multicolor flow cytometry, we analyzed 92 immune cell phenotypes in the blood of 448 healthy participants from the Berlin Aging Study II. We calculated polygenic risk scores (PGS) using genome-wide significant SNPs from recent large genome-wide association studies on ALS and AD. Linear regression analyses were then performed of the immune cell types on the PGS in both the overall sample and a subgroup of older participants (>60 years). Results: While we did not find any significant associations between immune cell subtypes and ALS and AD PGS when controlling for the false discovery rate (FDR=0.05), we observed several nominally significant results (p<0.05) with consistent effect directions across strata. The strongest association was observed with CD57+ CD8+ early-memory T cells and ALS risk (p=0.006). Other immune cell subtypes associated with ALS risk included PD-1+ CD8+ and CD57+ CD4+ early-memory T cells, non-classical monocytes, and myeloid dendritic cells. For AD, naive CD57+ CD8+ T cells, and mature NKG2A+ natural killer cells showed nominally significant associations. Conclusion: We did not observe immune cell changes in individuals with high genetic risk for ALS or AD, suggesting immune alterations may arise later in disease progression. Additional studies are required to validate our nominally significant findings.

The authors have declared no competing interest.

The BASE-II research project (co-PIs: Lars Bertram, Ilja Demuth, Denis Gerstorf, Ulman Lindenberger, Graham Pawelec, Elisabeth Steinhagen-Thiessen, and Gert G. Wagner) has been supported by the German Federal Ministry of Education and Research (Bundesministerium fuer Bildung und Forschung, BMBF) under grant numbers #16SV5536K, #16SV5537, #16SV5538, #16SV5837, #01UW0808,01GL1716A, and 01GL1716B, and by the Max Planck Institute for Human Development, Berlin, Germany. Additional contributions (e.g., equipment, logistics, personnel) were made from each of the other participating sites. The responsibility for the contents of this publication lies with its authors. C.M.L. was supported by the Heisenberg program of the German Research Foundation (DFG; LI 2654/4-1) by the Cure Alzheimer's Fund, and by the CReATe Consortium. CReATe (U54 NS092091) is part of the Rare Diseases Clinical Research Network (RDCRN), an initiative of the Office of Rare Diseases Research (ORDR), NCATS and funded through collaborations between NCATS, NINDS and the ALS Association.

I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained.

Yes

The details of the IRB/oversight body that provided approval or exemption for the research described are given below:

All BASE-II participants provided written informed consent before participation and the study was conducted in accordance with the Declaration of Helsinki and approved by the Ethics Committee of the Charite Universitaetsmedizin Berlin - approval number EA2/029/09.

I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals.

Yes

I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance).

Yes

I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable.

Yes

All summary statistics have been made available in the supplementary material of this manuscript. Raw and source data are available upon reasonable request. Interested researchers may contact the scientific BASE-II coordinator, Ludmila Mueller, lmueller@mpib-berlin.mpg.de. Additional information is available on the BASE-II website: https://www.base2.mpg.de/7549/data-documentation.