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Abstract
Amyloid-beta peptide (Abeta) has a key role in the pathogenesis of Alzheimer disease
(AD). Immunization with Abeta in a transgenic mouse model of AD reduces both age-related
accumulation of Abeta in the brain and associated cognitive impairment. Here we present
the first analysis of human neuropathology after immunization with Abeta (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 Abeta plaques; (ii) those areas of
cortex that were devoid of Abeta 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, Abeta-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 Abeta
immunotherapy in mouse models of AD and suggest that the immune response generated
against the peptide elicited clearance of Abeta 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).