Neuropathology of human Alzheimer disease after immunization with amyloid-β peptide: a case report

Abstract

ARTICLESAmyloid-β peptide (Aβ) has a key role in the pathogenesis of Alzheimer disease (AD). Immunization with Aβ in a transgenic mouse model of AD reduces both age-related accumulation of Aβ in the brain 1 and associated cognitive impairment 2,3 . Here we present the first analysis of human neuropathology after immunization with Aβ (AN-1792). Comparison with unimmunized cases of AD (n = 7) revealed the following unusual features in the immunized case, despite diagnostic neuropathological features of AD: (i) there were extensive areas of neocortex with very few Aβ plaques; (ii) those areas of cortex that were devoid of Aβ plaques contained densities of tangles, neuropil threads and cerebral amyloid angiopathy (CAA) similar to unimmunized AD, but lacked plaque-associated dystrophic neurites and astrocyte clusters; (iii) in some regions devoid of plaques, Aβ-immunoreactivity was associated with microglia; (iv) T-lymphocyte meningoencephalitis was present; and (v) cerebral white matter showed infiltration by macrophages. Findings (i)-(iii) strongly resemble the changes seen after Aβ immunotherapy in mouse models of AD 1-6 and suggest that the immune response generated against the peptide elicited clearance of Aβ plaques in this patient. The T-lymphocyte meningoencephalitis is likely to correspond to the side effect seen in some other patients who received AN-1792 (refs. 7-9).A 72-year-old woman with a 5-year history of gradually progressive memory impairment presented with worsening confusion and disorientation. Her Mini Mental State Examination (MMSE) score (23/30) represented a three-point deterioration in two years. She had global cognitive impairment and satisfied the National Institute of Neurological and Communicative Disorders and Stroke-Alzheimer's Disease and Related Disorders Association's criteria for probable AD, with no cardiovascular risk factors and a modified Haschinski score <4. Therapy with rivastigmine tartrate, a cholinesterase inhibitor, resulted in improvements in the Alzheimer's Disease Assessment Scale cognitive section (ADAS cog), MMSE, clock drawing and verbal fluency, but ten months later she had returned to baseline levels on all these parameters. The patient was then enrolled in a randomized, double-blind, multiple-dose immunogenicity study of Aβ42 (AN-1792; Elan Pharmaceuticals). She received her first injection, containing 50 µg of AN-1792, in July 2000. This was repeated 4, 12 and 24 weeks later with no apparent adverse effects. A fifth injection with a reformulated preparation containing polysorbate-80, subsequently used in a multinational phase 2a trial, was given 36 weeks after the first injection. Four weeks after her last injection, her cognitive test results were unchanged (MMSE 23), but at six weeks she suddenly became unwell with dizzy spells, drowsiness, an unstable gait and fever. Two weeks after that, she deteriorated such that an MMSE could not be performed. Neuroimaging (Fig. 1a) showed extensive bilateral alterations in the cerebral white matter and enhancement on the b...

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

“…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]. On the contrary, the strong autoreactive Th1-type response specific to Aβ is thought to underlie the development of meningoencephalitis observed in the AN-1792 trial [30,31,33]. It is known that Th1-type pro-inflammatory immune responses that are important for the generation of protection against viral infections and cancer are also implicated in autoimmune disorders, whereas Th2-type anti-inflammatory responses have generally been shown to inhibit autoimmune disease.…”

“…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].…”

“…It is known that Th1-type pro-inflammatory immune responses that are important for the generation of protection against viral infections and cancer are also implicated in autoimmune disorders, whereas Th2-type anti-inflammatory responses have generally been shown to inhibit autoimmune disease. It is important, therefore, that future AD immunotherapy results in the clearing of Aβ peptides by specific anti-Aβ antibodies while limiting the Th1-type immune response [28][29][30][31][32][33]. To reduce the risk of an adverse T cell-mediated immune response to Aβ-immunotherapy, we developed an epitope vaccine, PADRE-Aβ 1-15 -MAP, and demonstrated that immunizations with this vaccine induced high titers of anti-Aβ antibodies, but not anti-PADRE antibodies.…”

Comparison of Efficacy of Preventive and Therapeutic Vaccines Targeting the N Terminus of β-Amyloid in an Animal Model of Alzheimer’s Disease

“…[24][25][26][27][28][29][30][31] Data from active vaccine trials indicate that, to be effective, anti-Ab therapeutic should induce high titers of anti-Ab antibodies without activation of autoreactive T cells. [31][32][33][34] On the other hand, published results from both active and passive Ab-immunotherapy suggest that it should be initiated early in the disease, probably before toxic forms of this peptide accumulate in the brain. 30,35,36 In fact, we recently pointed out that active Ab-vaccines tested in clinical trials so far have produced ambivalent 31 To support our position and suggest an effective future clinical trials protocol, we decided for the first time to test the efficacy of our proteinbased epitope vaccine (EV) composed of three copies of immunogenic N-terminal epitope of Ab 37-41 and two Th epitopes from tetanus toxoid (TT) in preventive and therapeutic settings in parallel.…”

The genetics of the amyloidoses: interactions with immunity and inflammation

“…Nonetheless pathologic examination of the brains of some of the individuals suggested reductions in plaques. 102 Subsequent studies have shown that passive immunization with antibodies directed toward particular Ab epitopes could be carried out in the transgenic mice, and trials with humanized antibodies of relatively refined specificities are now ongoing. 103,104 The success of this approach has led to similar animal studies in models of AL and the transthyretin amyloidoses with some success.…”