Vlaams Instituut voor Biotechnologie - Flanders Institute

While immune function is known to play a mechanistic role in Alzheimer’s disease (AD), whether immune proteins in peripheral circulation influence the rate of amyloid‐b (Aβ) progression remains unknown.

Using the Baltimore Longitudinal Study of Aging (BLSA; n = 196; mean follow‐up: 5 years/4 scans), we identified immune‐related proteins in plasma (candidate proteins) related to rates of change in cortical Aβ levels, as measured by 11C‐PiB PET. Along with identifying genetic variants that contributed to candidate protein associations, characterizing their relationships with tau‐PET and changes in ADRD biomarkers (Aβ42/40, NfL, GFAP, pTau‐181), and assessing their expression patterns in human microglia, we leveraged data from the Atherosclerosis Risk in Communities (ARIC) study to determine if changes in candidate protein levels precede Ab = β onset (n = 272), and whether they predict 20‐year dementia risk during mid‐life (n = 11,596) and 8‐year dementia risk during late‐life (n = 4,288).

32 immunological proteins in plasma (out of 942) were associated with cortical Ab = β accumulation (Figure 1A). Longitudinal changes in a subset of candidate proteins also predicted cortical Aβ accumulation (Figure 1B), and the mid‐ to late‐life trajectory of one protein, CAT, was associated with late‐life Aβ‐positive status in ARIC (Figure 1C). Genetic variants associated with the plasma abundance of CAT and two additional candidate proteins (CD36 and KRT19) predicted rates of Aβ accumulation (Figure 2A‐F). In addition to associations with other AD‐related phenotypes (tau‐PET, plasma AD biomarker changes) (Figure 2G‐H), we showed that 31% of candidate proteins were related to mid‐life (20‐year) or late‐life (8‐year) dementia risk in ARIC (Figure 2I). Single‐cell RNA‐seq showed a prominent dysregulation of candidate protein expression in homeostatic, interferon‐response and disease‐associated human microglia subtypes (Figure 3A). Candidate proteins were enriched for biological processes implicated in AD (Figure 3B), susceptible to regulation by key pro‐inflammatory cytokines (Figure 3C), displayed robust protein‐interaction networks, showed differential expression in AD brains (especially neurovascular cell types), were externally validated, and are targets of existing therapeutics (Figure 3D).

Findings provide insights into how immune proteins in peripheral circulation influence the rate of Aβ accumulation, and identify specific peripheral immune mediators that may contribute to the progression of AD pathophysiology.

Microglia are central players in Alzheimer’s Disease (AD) pathology, but analyzing microglia states in human brain samples is challenging due to genetic diversity, postmortem delay and admixture of pathologies.

To circumvent these issues, here we collected 138,577 single cell expression profiles of human stem cell derived‐microglia from a xenotransplantation model of AD.

Xenografted human microglia adopt a disease‐associated (DAM) profile similar to that seen in mouse microglia, but display a more pronounced HLA state, likely related to antigen presentation in response to amyloid plaques. The human microglial response also involves a pro‐inflammatory cytokine/chemokine CRM response to oligomeric Aβo. Expression of AD risk genes is distributed over this multi‐pronged response to amyloid pathology. Genetic deletion of TREM2 or APOE, as well as APOE polymorphisms and TREM2R47H expression in the transplanted microglia modulate these responses differentially.

We have identified multiple transcriptomic cell states adopted by microglia in response to AD‐related pathology, which should be taken into account in translational studies.

While social and medical debate about the efficacy and safety of anti‐Aβ immunotherapy is ongoing, one thing that emerged is that we have little understanding of the working mechanisms of these antibodies and this lack of knowledge complicates the interpretation of the clinical results. Here, we aimed to establish if microglia are required for the efficacy of Lecanemab, one of the most promising FDA‐approved disease‐modifying therapy for AD (Van Dyck et al. N Engl J Med 2023).

To do so, we crossed AppNL‐G‐F mice with Csf1rΔFIRE/ΔFIRE mice (Rojo et al. Nat Commun 2019) to generate mice that show key features of Aβ pathology but genetically lack mouse microglia. We then assessed the effect of Lecanemab treatment on Aβ load and neuritic dystrophy.

We demonstrate that Lecanemab lacks efficacy in the absence of microglia. On the other hand, when we xenotransplant human microglia into the brain of these mice (as described in Mancuso et al. Nat Neurosci 2019), we show that Lecanemab treatment significantly ameliorates both Aβ load and neuritic dystrophy. Furthermore, by employing scRNAseq on sorted human microglia, we demonstrate that Lecanemab treatment affects the transcriptome of the microglia by inducing a number of genes related phagocytosis, interferon response and immune activation. Functionally, we also established that Lecanemab‐treated human microglia ingest more amyloid‐β in vivo.

Overall, we provide the first evidence that microglia are crucial for the efficacy of anti‐Aβ immunotherapy and provide real insight into the working mechanisms of this first disease‐modifying therapy for AD.