Antibodies against β-Amyloid Slow Cognitive Decline in Alzheimer's Disease

Abstract

To test whether antibodies against beta-amyloid are effective in slowing progression of Alzheimer's disease, we assessed cognitive functions in 30 patients who received a prime and a booster immunization of aggregated Abeta(42) over a 1 year period in a placebo-controlled, randomized trial. Twenty patients generated antibodies against beta-amyloid, as determined by tissue amyloid plaque immunoreactivity assay. Patients who generated such antibodies showed significantly slower rates of decline of cognitive functions and activities of daily living, as indicated by the Mini Mental State Examination, the Disability Assessment for Dementia, and the Visual Paired Associates Test of delayed recall from the Wechsler Memory Scale, as compared to patients without such antibodies. These beneficial clinical effects were also present in two of three patients who had experienced transient episodes of immunization-related aseptic meningoencephalitis. Our results establish that antibodies against beta-amyloid plaques can slow cognitive decline in patients with Alzheimer's disease.

A multimeric immunogen for the induction of immune memory to beta‐amyloid

“…A single injection also induces immunological memory that can be rapidly mobilized by a single booster injection, leading to very high serum concentration of anti-beta-amyloid antibodies. Two injections of Alternative beta-amyloid immunogens F Mantile et al E2 (1)(2)(3)(4)(5)(6)(7)(8)(9)(10)(11) are sufficient to obtain a persistent, high titer anti-betaamyloid response, which is dominated by the presence of the IgG1 isotype relative to the IgG2a isotype, implying that a Th2-type response has been induced. Cells from mice immunized with (1-11)E2 produce IL-4 in response to (1-11)E2 and E2 particles, but not in response to the synthetic peptide 1-11, indicating that the Th2-like response to the (1-11)E2 vaccine is directed to a T-cell epitope internal to E2.…”

“…In mouse models of AD, induction of a high titer of anti-beta-amyloid antibodies correlated with the therapeutic efficacy of vaccination [4][5][6] A clinical trial of immunization of AD patients with whole preaggregated beta-amyloid peptide has shown that immunization has the potential to reduce amyloid plaques in the brains of AD patients and delay disease progression. 7,8 However, the trial was interrupted when 6% of patients developed an adverse inflammatory reaction involving infiltration of T cells into the brain; moreover, only 59 of 300 individuals who received the vaccine mounted a humoral anti-beta-amyloid response with a titer higher than 1:2200. 9 Individuals with the highest titers of anti-beta-amyloid antibodies demonstrated the most pronounced depletion of plaques.…”

Prototype Alzheimer's disease epitope vaccine induced strong Th2-type anti-Aβ antibody response with Alum to Quil A adjuvant switch

“…Despite the adverse events (meningoencephalitis) in the AN-1792 clinical trial, follow up studies demonstrated that strong anti-Aβ antibody responses, rather than autoimmune T cell responses generated in AD patients, were capable of reducing AD pathology and diminishing the progressive cognitive decline associated with the disease [24,[28][29][30][31][32][33]. More specifically, published data from AN-1792 clinical trials suggest that the aseptic meningoencephalitis may have been caused by a T cell-mediated autoimmune response, whereas production of high titers of anti-Aβ antibodies may have been therapeutic to the AD patients.…”

“…The first human AD vaccine consisted of fibrillar Aβ 42 formulated in QS21 adjuvant (AN-1792 trial) that induced strong Th1-type anti-Aβ immune responses [19], even in Th2-prone BALB/c mice [20]. This AN-1792 clinical trial was halted due to the development of meningoencephalitis in a small proportion of the subjects [21][22][23][24][25][26], but follow up studies have demonstrated that strong anti-Aβ antibody responses specific to the linear Aβ [1][2][3][4][5][6][7][8] peptide [27] in some patients reduced AD pathology and diminished the cognitive decline associated with the disease [24,[27][28][29][30][31][32][33]. These data along with preclinical studies demonstrated that anti-Aβ antibodies directed to N-terminal region of Aβ 42 are effective in clearance of amyloid plaques [16,34,35].…”

Biometals and Their Therapeutic Implications in Alzheimer's Disease

“…In PDAPP mice (overexpressing a disease-related mutant APP), immunization prevented and rescued the AD behavioral and pathological phenotypes [13]. The multinational phase 2a trial in people with mild-to-moderate AD was suspended when 6 % of patients had a side effect, including 4 with aseptic meningoencephalitis [14]. In a follow-up analysis of the phase 1 clinical trial, the treatment group had less plaque burden at autopsy (some even had complete plaque removal) but dementia presentation was not different between the treatment and placebo group [15].…”