Postmortem Neocortical 3H-PiB Binding and Levels of Unmodified and Pyroglutamate Aβ in Down Syndrome and Sporadic Alzheimer's Disease

Individuals with Down syndrome (DS) have a genetic predisposition for amyloid-beta (A beta) overproduction and earlier onset of A beta deposits compared to patients with sporadic late-onset Alzheimer's disease (AD). Positron emission tomography (PET) with Pittsburgh Compound-B (PiB) detects fibrillar A beta pathology in living people with DS and AD, but its relationship with heterogeneous A beta forms aggregated within amyloid deposits is not well understood. We performed quantitative in vitro H-3-PiB binding assays and enzyme linked immunosorbent assays of fibrillar (insoluble) unmodified A beta 40 and A beta 42 forms and N-terminus truncated and pyroglutamate-modified A beta NpE3-40 and A beta NpE3-42 forms in postmortem frontal cortex and precuneus samples from 18 DS cases aged 43-63 years and 17 late-onset AD cases aged 62-99 years. Both diagnostic groups had frequent neocortical neuritic plaques, while the DS group had more severe vascular amyloid pathology (cerebral amyloid angiopathy, CAA). Compared to the AD group, the DS group had higher levels of A beta 40 and A beta NpE3-40, while the two groups did not differ by A beta 42 and A beta NpE3-42 levels. This resulted in lower ratios of A beta 42/A beta 40 and A beta NpE3-42/A beta NpE3-40 in the DS group compared to the AD group. Correlations of A beta 42/A beta 40 and A beta NpE3-42/A beta NpE3-40 ratios with CAA severity were strong in DS cases and weak in AD cases. Pyroglutamate-modified A beta levels were lower than unmodified A beta levels in both diagnostic groups, but within group proportions of both pyroglutamate-modified A beta forms relative to both unmodified A beta forms were lower in the DS group but not in the AD group. The two diagnostic groups did not differ by H-3-PiB binding levels. These results demonstrate that compared to late-onset AD cases, adult DS individuals with similar severity of neocortical neuritic plaques and greater CAA pathology have a preponderance of both pyroglutamate-modified A beta NpE3-40 and unmodified A beta 40 forms. Despite the distinct molecular profile of A beta forms and greater vascular amyloidosis in DS cases, cortical H-3-PiB binding does not distinguish between diagnostic groups that are at an advanced level of amyloid plaque pathology. This underscores the need for the development of CAA-selective PET radiopharmaceuticals to detect and track the progression of cerebral vascular amyloid deposits in relation to A beta plaques in individuals with DS.

Automated summary

Individuals with Down syndrome (DS) have a different molecular profile of A beta forms compared to late-onset Alzheimer's disease (AD) cases, with a higher preponderance of pyroglutamate-modified A beta NpE3-40 and unmodified A beta 40 forms. Despite greater vascular amyloidosis in DS cases, cortical H-3-PiB binding does not distinguish between diagnostic groups at an advanced level of amyloid plaque pathology.