Alzheimer’s disease (AD) is a neurodegenerative disorder characterized by β-amyloid (Aβ)-containing extracellular plaques and tau-containing intracellular neurofibrillary tangles (NFT) [
1,
2]. However, AD is also associated with inflammatory processes both within the brain and in the periphery. The inflammatory processes in the brain are foremost characterized by the activation of glial cells and increased production of pro-inflammatory mediators, which is reflected in the cerebrospinal fluid (CSF) [
3,
4]. Associations between the peripheral inflammation and AD can be found in epidemiological studies demonstrating a decreased risk of AD in individuals using non-steroidal anti-inflammatory drugs [
5] and an increased risk of AD in individuals with, for instance, altered gut microbial composition [
6], long-term exposure to air pollution [
7,
8], and oral infections [
9]. Several studies also show altered levels of cytokines, such as interleukin (IL)-6 and IL-1, and complements in the blood of AD patients; however, other studies do not confirm these results [
10]. To establish the link between AD and peripheral inflammation further, studies have investigated the impact of AD pathology on systemic antibody levels. Antibodies can be found in five different isotypes, from which the most prominent isotypes are immunoglobulin G (IgG), M (IgM), and A (IgA). In the primary immune response, IgM is the first antibody isotype being produced during B cell development [
11], whereas in the secondary immune response, mainly IgG is produced and in smaller amounts also IgA. IgG is one of the most abundant proteins in human serum (70 to 160 g/l in serum), being produced in a delayed response to an infection [
12,
13]. IgA, on the other hand, is not as abundant (7 to 40 mg/l in serum) and is found in two forms: monomeric in serum and dimeric in the mucosa (i.e. saliva, tears, colostrum, intestinal and genital tract, respiratory secretions) [
12,
14]. Previous studies have analysed IgA antibody levels in the blood of AD patients and healthy age-matched controls, but the results are inconsistent with demonstrating either increased [
15‐
18], unaltered [
19,
20], or decreased [
21] blood IgA levels in AD patients compared to healthy controls. Normally, circulating antibodies are thought to be largely excluded from the immune-privileged central nervous system (CNS) in healthy individuals. However, increased levels of IgA antibodies have been observed in the CSF of many neurological patients, including AD patients [
20,
22‐
26]. Hence, it has been hypothesized that systemically produced antibodies enter the CSF from blood through the breaches in the blood-brain barrier (BBB) that result from pathological processes such as neuroinflammation [
27]. For instance, Goldwaser et al. reported that IgG autoantibodies cross the BBB, bind to neuronal surface molecules, and enhance Aβ42 penetration and deposition into neuronal cells, possibly leading to subsequent neuronal dysfunction and loss of synapses [
28]. Whether other antibody isotypes, such as IgA or IgM, also cross the BBB and bind to brain cells is less clear. An increasing number of studies report that the inflammatory response in the periphery is also associated with apolipoprotein E (
APOE) gene [
29‐
31], the main genetic determinant for late-onset AD. The APOE is produced in several organs (i.e. liver, adrenal gland, brain) and by various cell types (i.e. ovarian and adrenal cells, macrophages, astrocytes, oligodendrocytes, pericytes, choroid plexus cells, neurons) and is associated with lipid transport and cholesterol homeostasis [
32]. There are three alleles of the
APOE gene:
APOEε2,
APOEε3, and
APOEε4, from which the latter increases the risk of AD by 3–4 times in heterozygotes and by 12–15 times in homozygotes compared with
APOEε3 carriers [
33]. The role of APOEε4 in AD is mostly established in the CNS, where it is known to affect Aβ aggregation and clearance, as well as influence neuroinflammation, BBB permeability, synaptic plasticity, and tau hyperphosphorylation [
34]. However, recent findings suggest a direct link between liver-derived APOEε4 and pathological changes in the mouse brain [
35]. Additionally, given its suggested immune-modulatory effect [
29‐
31], it may be that
APOEε4 contributes to AD pathology via its impact on the peripheral immune response. Such impact might explain the inconsistency in plasma IgA levels reported by other groups [
15‐
21] as
APOE polymorphism was not considered in previously published studies. Hence, we found it interesting to investigate the IgA levels in AD patients in general and when the
APOE polymorphism is accounted for. We therefore analysed the plasma IgA levels in two cohorts consisting of AD patients and non-demented controls (NC), where the plasma was collected antemortem (cohort I) and postmortem (cohort II). To further analyse the potential effect of
APOEε4 on IgA levels in relation to AD pathology, we divided the cohorts based on
APOEε4 status and investigated the differences between clinical diagnoses as well as associations between plasma IgA levels and cognition, CRP, and CSF AD biomarkers in cohort I and neuropathology and brain IgA immunoreactivity in cohort II.