A Reduced Astrocyte Response to β-Amyloid Plaques in the Ageing Brain Associates with Cognitive Impairment

Aims beta-amyloid (A beta) plaques are a key feature of Alzheimer's disease pathology but correlate poorly with dementia. They are associated with astrocytes which may modulate the effect of A beta-deposition on the neuropil. This study characterised the astrocyte response to A beta plaque subtypes, and investigated their association with cognitive impairment. Methods A beta plaque subtypes were identified in the cingulate gyrus using dual labelling immunohistochemistry to A beta and GFAP(+) astrocytes, and quantitated in two cortical areas: the area of densest plaque burden and the deep cortex near the white matter border (layer VI). Three subtypes were defined for both diffuse and compact plaques (also known as classical or core-plaques): A beta plaque with (1) no associated astrocytes, (2) focal astrogliosis or (3) circumferential astrogliosis. Results In the area of densest burden, diffuse plaques with no astrogliosis (beta = -0.05, p = 0.001) and with focal astrogliosis (beta = -0.27, p = 0.009) significantly associated with lower MMSE scores when controlling for sex and age at death. In the deep cortex (layer VI), both diffuse and compact plaques without astrogliosis associated with lower MMSE scores (beta = -0.15, p = 0.017 and beta = -0.81, p = 0.03, respectively). Diffuse plaques with no astrogliosis in layer VI related to dementia status (OR = 1.05, p = 0.025). In the area of densest burden, diffuse plaques with no astrogliosis or with focal astrogliosis associated with increasing Braak stage (beta = 0.01, p< 0.001 and beta = 0.07, p< 0.001, respectively), and ApoE epsilon 4 genotype OR = 1.02, p = 0.001 and OR = 1.10, p = 0.016, respectively). In layer VI all plaque subtypes associated with Braak stage, and compact amyloid plaques with little and no associated astrogliosis associated with ApoE epsilon 4 genotype ( OR = 1.50, p = 0.014 and OR = 0.10, p = 0.003, respectively). Conclusions Reactive astrocytes in close proximity to either diffuse or compact plaques may have a neuroprotective role in the ageing brain, and possession of at least one copy of the ApoEe4 allele impacts the astroglial response to A beta plaques.