Distinct Patterns of Antiamyloid-β Antibodies in Typical and Atypical Alzheimer Disease

Abstract

Subjects: Thirteen patients with AD, 8 patients with posterior cortical atrophy with evidence of AD (PCA-AD) pathophysiological process by both cerebrospinal fluid (CSF) biomarkers and amyloid imaging, and 12 agematched control individuals. Interventions:The class and subclass levels of serum anti-A␤ antibodies were measured using an oligomerbased enzyme-linked immunosorbent assay. This method allowed measuring both free antibodies and, after acidic treatment, the total fraction that includes all antibodies complexed with circulating A␤ 40/42 and any cross-reacting antigen.Results: Anti-A␤ IgG were restricted to the IgG1 and IgG3 subclasses. Their total levels were strikingly lower and more homogeneous in patients with PCA compared with both typical AD and controls, while biomarkers of amyloid deposition (CSF A␤ 42 and positron emission tomography amyloid imaging) were similar in patients with AD and patients with PCA.Conclusions: Serum anti-A␤ IgG1 and IgG3 antibodies differ between distinct forms of AD. Its significance is discussed for possible implications as immune effectors in the specific pathophysiology of AD variants.

Autoimmune Manifestations in the 3xTg-AD Model of Alzheimer's Disease

“…In addition, serum levels of anti-Aβ and anti-RAGE autoantibodies are several times higher in AD patients, showing positive correlation with cognitive dysfunction [82]. Consistent with these findings, anti-Aβ antibodies were documented in AD patients [83] and aged Aβ PP mice with AD-like neuropathology [84]. Moreover, serum from these mice potentiated the neurotoxicity of Aβ, prompting the authors to suggest that humoral immune responses may promote neuronal degeneration [84].…”

Autoimmune Manifestations in the 3xTg-AD Model of Alzheimer's Disease

“…In addition, serum levels of anti-Aβ and anti-RAGE autoantibodies are several times higher in AD patients, showing positive correlation with cognitive dysfunction [82]. Consistent with these findings, anti-Aβ antibodies were documented in AD patients [83] and aged Aβ PP mice with AD-like neuropathology [84]. Moreover, serum from these mice potentiated the neurotoxicity of Aβ, prompting the authors to suggest that humoral immune responses may promote neuronal degeneration [84].…”

TDP-43–specific Autoantibody Decline in Patients With Amyotrophic Lateral Sclerosis

“…Alterations in NAbs toward specific pathogenic proteins such as α-synuclein, amyloid β, and tau have previously been reported in relation to 2 of the most common neurodegenerative disorders, namely Parkinson disease and Alzheimer disease. [25][26][27][28] We have recently shown a reduction in apparent high-affinity/avidity anti-α-synuclein NAbs in Parkinson disease and multiple system atrophy, 24 both disorders characterized by abnormal aggregation of this protein in neurons and glial cells, respectively.…”

Positive Florbetapir PET Amyloid Imaging in a Subject with Frequent Cortical Neuritic Plaques and Frontotemporal Lobar Degeneration with TDP43-Positive Inclusions

“…Amyloid imaging promises to become a remarkable tool for the clinical evaluation of AD [7, 8, 17-19] and offers a new opportunity to identify asymptomatic, amyloid-positive subjects for testing anti-amyloid therapeutic agents. However, because neuritic amyloid plaques may be seen at autopsy in clinically normal individuals and concurrent with other dementing diseases, a positive amyloid scan should be interpreted with caution, since this does not exclude a concurrent cause of dementia.…”

Autoimmune Manifestations in the 3xTg-AD Model of Alzheimer's Disease

“…In addition, serum levels of anti-Aβ and anti-RAGE autoantibodies are several times higher in AD patients, showing positive correlation with cognitive dysfunction [82]. Consistent with these findings, anti-Aβ antibodies were documented in AD patients [83] and aged Aβ PP mice with AD-like neuropathology [84]. Moreover, serum from these mice potentiated the neurotoxicity of Aβ, prompting the authors to suggest that humoral immune responses may promote neuronal degeneration [84].…”

TDP-43–specific Autoantibody Decline in Patients With Amyotrophic Lateral Sclerosis

“…Alterations in NAbs toward specific pathogenic proteins such as α-synuclein, amyloid β, and tau have previously been reported in relation to 2 of the most common neurodegenerative disorders, namely Parkinson disease and Alzheimer disease. [25][26][27][28] We have recently shown a reduction in apparent high-affinity/avidity anti-α-synuclein NAbs in Parkinson disease and multiple system atrophy, 24 both disorders characterized by abnormal aggregation of this protein in neurons and glial cells, respectively.…”

Positive Florbetapir PET Amyloid Imaging in a Subject with Frequent Cortical Neuritic Plaques and Frontotemporal Lobar Degeneration with TDP43-Positive Inclusions

“…Amyloid imaging promises to become a remarkable tool for the clinical evaluation of AD [7, 8, 17-19] and offers a new opportunity to identify asymptomatic, amyloid-positive subjects for testing anti-amyloid therapeutic agents. However, because neuritic amyloid plaques may be seen at autopsy in clinically normal individuals and concurrent with other dementing diseases, a positive amyloid scan should be interpreted with caution, since this does not exclude a concurrent cause of dementia.…”

Autoimmune Manifestations in the 3xTg-AD Model of Alzheimer's Disease

“…In addition, serum levels of anti-Aβ and anti-RAGE autoantibodies are several times higher in AD patients, showing positive correlation with cognitive dysfunction [82]. Consistent with these findings, anti-Aβ antibodies were documented in AD patients [83] and aged Aβ PP mice with AD-like neuropathology [84]. Moreover, serum from these mice potentiated the neurotoxicity of Aβ, prompting the authors to suggest that humoral immune responses may promote neuronal degeneration [84].…”

TDP-43–specific Autoantibody Decline in Patients With Amyotrophic Lateral Sclerosis

“…Alterations in NAbs toward specific pathogenic proteins such as α-synuclein, amyloid β, and tau have previously been reported in relation to 2 of the most common neurodegenerative disorders, namely Parkinson disease and Alzheimer disease. [25][26][27][28] We have recently shown a reduction in apparent high-affinity/avidity anti-α-synuclein NAbs in Parkinson disease and multiple system atrophy, 24 both disorders characterized by abnormal aggregation of this protein in neurons and glial cells, respectively.…”

Positive Florbetapir PET Amyloid Imaging in a Subject with Frequent Cortical Neuritic Plaques and Frontotemporal Lobar Degeneration with TDP43-Positive Inclusions

“…Amyloid imaging promises to become a remarkable tool for the clinical evaluation of AD [7, 8, 17-19] and offers a new opportunity to identify asymptomatic, amyloid-positive subjects for testing anti-amyloid therapeutic agents. However, because neuritic amyloid plaques may be seen at autopsy in clinically normal individuals and concurrent with other dementing diseases, a positive amyloid scan should be interpreted with caution, since this does not exclude a concurrent cause of dementia.…”