The age of onset and evolution of Braak tangle stage and Thal amyloid pathology of Alzheimer's disease in individuals with Down syndrome

Abstract

While post mortem studies have identified the major cell types and functional systems affected in Alzheimer's disease (AD) the initial sites and molecular characteristics of pathology are still unclear. Because individuals with Down syndrome (DS) (trisomy 21) develop the full pathological changes of AD in a predictable way by the time they reach middle to late age, a study of the brains of such persons at different ages makes an ideal 'model system' in which the sites of earliest onset of pathology can be detected and the subsequent progression of changes be monitored. In the present study we have examined the brains of 56 individuals with DS ranging from new-born to 76 years for the presence of amyloid and tau pathology in key cortical and subcortical regions. Amyloid pathology was found to commence in the late teens to twenties as a deposition of diffuse plaques initially within the temporal neocortex, quickly involving other neocortical regions but only reaching subcortical regions and cerebellum by the late forties. Cerebral amyloid angiopathy did not regularly commence until after 45-50 years of age. Tau pathology usually commenced after 35 years of age, initially involving not only entorhinal areas and hippocampus but also subcortical regions such as locus caeruleus (LC) and dorsal raphe nucleus (DRN). Later, tau pathology spread throughout the neocortex reaching occipital lobes in most instances by mid-50 years of age. Such a pattern of spread is consistent with that seen in typical AD. We found no evidence that tau pathology might commence within the brain in DS before amyloid deposition had occurred, but there was limited data that suggests tau pathology in LC or DRN might predate that in entorhinal areas and hippocampus or at least be coincident.

Keywords: Alzheimer’s disease; Amyloid; Down syndrome; Tau.

Fig. 1

Pathological changes in Down syndrome. In case #8, aged 13 years, amyloid deposits are present in the temporal cortex as diffuse plaques in the absence of any tau pathology (a). A few tau positive neurites are present in locus caeruleus in case #14 (b) and a single tau positive neurofibrillary tangle is seen, again in locus caeruleus, in case #20 (c), in the absence of any tau pathology elsewhere in the brain. A few α-synuclein positive Lewy bodies (d) and Lewy neurites (e) are present in the substantia nigra in case #45, aged 62 years, but these are more densely present in entorhinal cortex (f) and temporal neocortex (g) of the same case. Sparse TDP-43 neuronal cytoplasmic inclusions (arrowed) are seen in dentate gyrus granule cells in case #43, aged 61 years (h). Immunoperoxidase-haematoxylin; × 250 microscope magnification (a) × 400 microscope magnification (b–h)

Fig. 2

‘Heat map’ illustrating the onset and progression of amyloid plaque, CAA and tau pathology across the different brain regions for the 56 cases of Down syndrome. Box colours indicate increasing severity of pathological change from blue through to red. Numbers in boxes are derived from scoring systems described in the text. Tcx = temporal cortex, Fcx = frontal cortex, Ocx = occipital cortex, Ecx = entorhinal cortex, h = molecular layer of hippocampus, CA1 = CA1 region of hippocampus, DG = dentate gyrus of hippocampus, CS = corpus striatum, LC = locus coeruleus, DRN = dorsal raphe nucleus, SN = substantia nigra, CBM = cerebellum, Ab = amyloid deposits (plaques), CAA = cerebral amyloid angiopathy, tau = tau tangles