Antigen–antibody dissociation in Alzheimer disease: a novel approach to diagnosis

Abstract

With the ever‐increasing population of aged individuals at risk of developing Alzheimer’s disease (AD), there is an urgent need for a sensitive, specific, non‐invasive, and diagnostic standard. The majority of efforts have focused on auto‐antibodies against amyloid‐β (Aβ) protein, both as a potential treatment, and a reliable biomarker of AD pathology. Naturally occurring antibodies against Aβ are found in the CSF and plasma of patients with AD as well as healthy control subjects. To date, differences between diseased and control subjects have been highly variable. However, some of the antibody will be in preformed antigen–antibody complexes and the extent and nature of such complexes may provide a potential explanation for the variable results reported in human studies. Thus, measuring total amounts of antigen or antibody following unmasking is critical. Here, using a technique for dissociating antibody–antigen complexes, we found significant differences in serum antibodies to Aβ between AD and aged‐matched control subjects. While the current study demonstrates the relevance of measuring total antibody, bound and unbound, against Aβ in AD, this technique may be applicable to diseases such as acquired immune deficiency syndrome and hepatitis B where determination of antigen and antibody levels are important for disease diagnosis and assessing disease progression.

Neuroprotective natural antibodies to assemblies of amyloidogenic peptides decrease with normal aging and advancing Alzheimer's disease

“…2D) compared with untreated samples. This finding is similar to reports in human serum and IvIg preparations (25,26). The percentage of free antibodies out of the total pool recognizing A␤1-42 oligomers ranged from 13% to 50% but was not associated with age or AD (Fig.…”

“…Cerebral A␤ appears to be in equilibrium with plasma A␤ (44) and it was proposed that CNS A␤ levels could be reduced by trapping the peptide in a ''peripheral sink'' (12,45). Once A␤ is in the periphery, it is possible that A␤-specific IgGs form immune complexes more readily in plasma of certain AD patients compared with NDC (26). This could be because of higher levels of A␤ available for binding to antibodies or because of increased complement-mediated clearance of immune complexes (46,47).…”

“…Studies in mice (22,38,41) and humans (20)(21)(22)(24)(25)(26) described natural antibodies against A␤1-40 or A␤1-42 before, without assessing their fine specificity or preference for specific assembly states in detail. Because the typical overnight coating of ELISA plates with A␤ resuspended in PBS is similar to the protocol for generating oligomeric A␤ species (42) it is likely that some of (39).…”

“…In patients with mild to moderate AD active immunization appears to reduce plaque load (15), and in some patients production of A␤ antibodies correlated with attenuated cognitive decline (16). It has also been suggested that antibodies recognizing different domains (12,13,17) or conformations (18, 19) of A␤ may have different efficacy in humans.Interestingly, antibodies against A␤ occur naturally in blood and cerebrospinal fluid (CSF) in free form or in complex with A␤, both in AD patients and healthy individuals (20)(21)(22)(23)(24)(25)(26). The titers of these antibodies are low, and their origin and physiological or pathological role is unknown.…”

“…Interestingly, antibodies against A␤ occur naturally in blood and cerebrospinal fluid (CSF) in free form or in complex with A␤, both in AD patients and healthy individuals (20)(21)(22)(23)(24)(25)(26). The titers of these antibodies are low, and their origin and physiological or pathological role is unknown.…”