Serum immunoglobulins and biomarkers of dementia: a population-based study

Dementia is a multifactorial neurodegenerative syndrome marked by a progressive decline in cognitive ability and loss of independent functioning, with Alzheimer’s disease as the most common form [1]. At a cellular level, pathologic features of Alzheimer’s disease include loss of synaptic function, extracellular deposits of amyloid-β (Aβ plaques) and intracellular aggregates of hyperphosphorylated tau (tangles) [2], which can be present years prior to clinical manifestation of disease. Interestingly, a growing body of literature suggests that dysregulation of the immune system, triggered by inflammatory processes on a peripheral or central level, may contribute to the pathogenesis of dementia [3]. In the context of neuroinflammation, most scientific interest has been garnered towards the innate immune system, a non-specific first line response to a variety of stimuli [4]. For instance, pattern recognition receptors on astrocytes and microglia have been shown to activate an inflammatory cascade in response to Aβ and tau formation, which in turn cyclically increases their production [3, 4]. Meanwhile, relatively little is known about how immunoglobulins, that constantly evolve with exposure to antigens, may be associated with early biomarkers of dementia.

Immunoglobulins, including IgA, IgG, and IgM, are produced by B-lymphocytes in response to different stimuli [5]. The role of these immunoglobulins in the pathophysiology of dementia remains uncertain, as studies thus far have reported conflicting results [6‐8]. In our previous work, we did not find an association between serum immunoglobulins and prevalent or incident dementia, but noted that individuals with poor cognition exhibited higher levels of serum IgG [9]. Consistent with the latter observation, several studies have reported high levels of immunoglobulins targeting proteins in nerve cells, such as the N-Methyl-D-Asparate receptor (NMDAR) [10‐12], which suggest that immunoglobulins may have detrimental effects on synaptic transmission and plasticity. However, certain immunoglobulins have also been attributed protective effects, as they are inherently produced in response to Aβ and tau formation [7, 13]. For instance, cognitively healthy older adults are known to exhibit higher levels of IgM targeting Aβ compared to individuals with Alzheimer’s disease [8]. Such observations prompted numerous therapeutic trials to explore the use of intravenous immunoglobulins (IVIG) for Alzheimer’s disease [14], but with moderate success. While research on antigen-specific immunoglobulins is advancing, studies using general inflammation markers have provided additional insights. In a prior population-based study, a higher lymphocyte count was suggested to be neuroprotective, while elevated granulocyte and platelet levels were associated with an increased risk of dementia [15]. In the current study, we raised the hypothesis that immunoglobulin levels are associated with early markers of dementia, including neurofilament light chain (NfL), t-tau, and Aβ, as well as structural markers on neuroimaging. This hypothesis is based on the premise that inflammatory processes can disrupt neuronal integrity [16]. To date, prior studies were underpowered or only focused on specific antigens while examining such associations [6, 11, 17].

To advance insight in pathways underlying inflammation and dementia, we determined cross-sectional associations between whole serum immunoglobulin (IgA, IgG and IgM) levels and plasma biomarkers of dementia, including Aβ, t-tau and NfL, in a large population-based cohort. These plasma biomarkers have recently been introduced as non-invasive indicators of neuroaxonal damage (NfL, t-tau) and the accumulation of amyloid beta (Aβ-40, Aβ-42) [18]. Likewise, by studying associations between immunoglobulins and structural neuroimaging markers, such as brain atrophy and white matter disintegrity, we attempt to identify neuropathological correlates of an inflammatory state.

From 8,768 participants who gave informed consent and had serum immunoglobulins available, 3,455 had assessments of plasma biomarkers of dementia and 3,139 visited the centre for a brain MRI within five years after blood sampling (median time-interval in years 0.07, interquartile range (IQR) [0.04 – 0.15]). Characteristics of the study population are presented in Table 1. The median age of participants with plasma biomarkers was 65.8 years [IQR 61.5 – 72.0], and 57.2% were female. The median age of participants with neuroimaging data was 57.4 years [IQR 52.7 – 60.7], and 54.4% were female. Only 285 participants were overlapping between the two study samples and the number of participants with prevalent dementia was limited (n = 3). Throughout the results section, we present the results of model II, which includes the main potential confounders. Similar results were obtained for model I (the basic model: adjusted for age, sex, cohort and time difference) and model III (adjusted for covariates that may act as confounders or mediators), details of which can be found in the Supplementary files.

The absence of consistent associations between serum immunoglobulins and biomarkers of dementia aligns with our previous research that investigated the link between serum immunoglobulins, cognition, and dementia [9]. Dementia is a complex syndrome with diverse underlying mechanisms, wherein serum immunoglobulins may perhaps not directly impact the specific biomarkers examined. Genetic variations in immune response [32], interactions with environmental exposures [29], or comorbidities not accounted for in this analysis, could also have contributed to the lack of strong associations. In addition, while neuroinflammation and neurodegeneration are both complex processes with widespread effects, their manifestation may only be partially captured by peripheral blood measures of immunoglobulins (in serum) and biomarkers of dementia (in plasma).

Overall, this study illustrates the intricate relationship between immunoglobulins and early biomarkers of dementia. IgA, an immunoglobulin abundant in mucous membranes, was previously shown to be elevated in saliva of patients with mild Alzheimer’s disease, but not in those with moderate to severe Alzheimer’s disease [17]. This phenomenon may be best explained by hyperactivity of the immune response in early stages of Alzheimer’s disease, possibly resulting in an enhanced clearance of Aβ in plasma, which may later transition to lower but chronic activation of the adaptive immune system as neurodegeneration ensues [33]. In both the overall and reference population, we observed that higher serum IgA levels concurred with lower plasma levels of Aβ, which could either indicate appropriate clearance mechanisms at an early stage, or more sequestration of Aβ in the brain. What supports the latter view is that in neuroimaging associations, higher levels of IgA were seen with a smaller total brain volume, particularly gray matter, and a higher volume of white matter hyperintensities. However, it is also worth noting that serum IgA interacts with many other serum components, such as albumin, a1-antitrypsin, the HC-protein and fibronectin, and is influenced by the mucosa [34]. Therefore, the values of IgA may be relatively low in serum and not comparable to for instance, saliva.

Given the abundance of IgG in serum and its involvement in the secondary immune response, we postulated that it would be elevated during chronic neuroinflammatory processes. Within this context, high IgG levels could signify a disruption of the blood–brain-barrier [35]. Several studies have previously shown that high levels of IgG are found in serum, cerebrospinal fluids and brains of post-mortem patients with Alzheimer’s disease [36, 37]. Although we could not establish this association within our overall study population, we did observe a suggestive association amongst individuals with immunoglobulin levels within the reference range and those who were not using immunomodulating drugs (sensitivity analysis). In this particular subgroup, higher IgG levels concurred with higher NfL, suggesting greater neuroaxonal damage, but this relationship did not extend to neuroimaging markers. Notably, our study cohort primarily consisted of individuals with subtle signs of neurodegeneration in plasma and brain MRI, but without clinical dementia, which could also account for the lack of associations.

IgM is the first immunoglobulin to be produced during B-cell ontogeny, followed by class-switching to IgG or formation of T-cell memory cells. Due to their pentameric structure, IgM antibodies have a high avidity for binding to antigens, such as Aβ or tau [38], which can facilitate their clearance. In our study, this did not apply to the entire study population, but only to participants with immunoglobulin levels in the reference range and not using immunomodulating drugs. This subset of participants exhibited higher serum IgM levels and lower plasma levels of t-tau, Aβ-40 and Aβ-42, and diminished white matter microstructural integrity. In keeping with our observations, a previous study reported significantly higher levels of plasma IgM targeted against Aβ-42 in healthy aged subjects, compared to young controls [8]. Conversely, in AD subjects compared to age-matched controls, they observed a decline of IgM targeted against Aβ-42. Taken together, these findings imply that immunocompetence for IgM could be important in early pathological stages of Alzheimer’s disease [6], but that this effectiveness appears to wane as neurodegeneration advances or when dementia manifests.

Consistent with associations described for innate immunity in previous literature [4, 15, 31], carriership of the APOE-ε4 allele may play an important role in the association between serum immunoglobulins and plasma biomarkers of dementia. In the brain, APOE is predominantly expressed by astrocytes and microglia. Carriership of the APOE-ε4 allele has been shown to disrupt homeostasis of these glial cells [39], prompting an enhanced inflammatory cascade in response to antigens (such as Aβ-40 and Aβ-42), which could have implications for immunoglobulins. Indeed, with elevated IgA levels, our stratified analyses suggest lower plasma Aβ in non-carriers of the APOE-ε4 allele, while APOE-ε4 carriers show more signs of neuronal compromise, including higher t-tau levels, increased gray matter atrophy, and more white matter hyperintensities.

Sex-differences have long been acknowledged for inflammatory neurodegenerative disorders, such as multiple sclerosis [40]. Previous research has shown that in post-mortem brains of patients with Alzheimer’s disease, women tend to have a higher Aβ burden compared to men [41]. Such differential patterns were also observed in our sex-stratified analyses. Among women with elevated IgA and IgM levels, we found lower plasma Aβ levels. However, in women with higher IgA levels, we also noted increased gray matter atrophy, more white matter hyperintensities, and compromised white matter integrity. In contrast, men with higher IgA levels showed no associations with biomarkers in plasma, but predominantly had total brain and hippocampal atrophy.