Dense-core senile plaques in the Flemish variant of Alzheimer's disease are vasocentric

Alzheimer's disease (AD) is characterized by deposition of β-amyloid (Aβ) in diffuse and senile plaques, and variably in vessels. Mutations in the Aβ-encoding region of the amyloid precursor protein (APP) gene are frequently associated with very severe forms of vascular Aβ deposition, sometimes also accompanied by AD pathology. We earlier described a Flemish APP (A692G) mutation causing a form of early-onset AD with a prominent cerebral amyloid angiopathy and unusually large senile plaque cores. The pathogenic basis of Flemish AD is unknown. By image and mass spectrometric Aβ analyses, we demonstrated that in contrast to other familial AD cases with predominant brain Aβ42, Flemish AD patients predominantly deposit Aβ40. On serial histological section analysis we further showed that the neuritic senile plaques in APP692 brains were centered on vessels. Of a total of 2400 senile plaque cores studied from various brain regions from three patients, 68% enclosed a vessel, whereas the remainder were associated with vascular walls. These observations were confirmed by electron microscopy coupled with examination of serial semithin plastic sections, as well as three-dimensional observations by confocal microscopy. Diffuse plaques did not associate with vessels, or with neuritic or inflammatory pathology. Together with earlier in vitro data on APP692, our analyses suggest that the altered biological properties of the Flemish APP and Aβ facilitate progressive Aβ deposition in vascular walls that in addition to causing strokes, initiates formation of dense-core senile plaques in the Flemish variant of AD.