Patterns of Antiamyloid-β Antibodies in Typical and Atypical Alzheimer Disease
A major feature of Alzheimer disease (AD) is the deposition of brain amyloid-β (Aβ) peptide. IgG antibodies directed to Aβ naturally occur in the elderly, and their serum and cerebrospinal fluid levels may be significantly altered in the course of AD. Anti-Aβ antibodies have been shown to possibly control the development of amyloid plaques, but the clinical significance of their serum levels is unclear. The investigators, from a group of French physicians, had recently shown that posterior cortical atrophy (PCA) may be defined as an atypical focal form of AD (PCA-AD). AD and PCA-AD show clearly distinct clinical presentations and are similar for certain biomarkers of amyloid deposition, such as CSF Aβ42 levels and Pittsburgh Compound B (PiB) binding patterns.
The objective of this study [Arch Neurol. doi:10.1001/archneurol.2012.604], from preliminary observations compiled by the French group, was to compare serum Aβ antibodies in typical and atypical AD. The investigators analyzed 13 patients with AD, 8 patients with PCA-AD, and 12 age-matched controls.
The PCA-AD patients were enrolled according to the following diagnostic criteria: gradual progression of cognitive impairment beginning with visual complaints; presentation with visuospatial deficits with intact primary visual function; features suggestive of Balint syndrome associated or not with Gerstmann syndrome; proportionally less episodic memory impairment; relatively preserved insight; no signs of parkinsonism; glucose hypometabolism on fluorodeoxyglucose F18-positron emission tomographic (PET) examination; cortical atrophy on magnetic resonance imaging with a predominance in the posterior cortical region; an AD profile of CSF biomarkers; and a global cortical index of radiolabeled carbon11 (11C)-PiB uptake on PiB-PET >1.6.
The typical AD patients (Clinical Dementia Rating [CDR] ≥0.5) matched to patients with PCA-AD for age, disease duration, and Mini-Mental State Examination (MMSE) score were selected according to the New Research Criteria. The 12 healthy elderly controls were recruited according to the following criteria: MMSE score ≥27/30 and CDR=0; no history of neurological or psychiatric disorders; and no memory complaint or cognitive deficit.
The class and subclass levels of serum anti-Aβ antibodies (total Tau [T-Tau], T181-phosphorylated Tau [P-Tau)], and Aβ42) were measured by enzyme-linked immunosorbent assay (ELISA) in CSF samples from all the patients except 3 with AD.
There was no statistical difference between the AD and PCA-AD groups in terms of Aβ42, T-Tau, P-Tau levels, and Aβ:Tau ratios. Mean PiB indices were identical in the PCA-AD and AD groups in all the analyzed regions of interest. Total serum anti-Aβ antibodies essentially belonged to the IgM class and IgG1 and IgG3 subclasses. While IgM antibody levels were similar in the 3 groups, patients with PCA-AD displayed significantly lower and more homogeneous concentrations of IgG antibodies than patients with AD and healthy controls. This was most evident for IgG1.
Overall serum IgG, IgM, and IgG subclass levels were similar in the PCA-AD and AD groups, which ruled out possible immunoglobulin deficiencies. Comparisons of ratios between anti-Aβ antibodies and corresponding total immunoglobulin levels for each class and subclass confirmed that anti-Aβ IgG1 and IgG3 were strongly and specifically lower in patients with PCA-AD than in patients with AD (P<.001 for both IgG1 and IgG3). No significant correlation was found between antibody levels and any of the tested clinical data (age, MMSE, disease duration), levels of CSF biomarkers, and PiB global index.
