Sequence of Deposition of Heterogeneous Amyloid β-Peptides and APO E in Down Syndrome: Implications for Initial Events in Amyloid Plaque Formation

Patients with trisomy 21 [Down syndrome (DS)] progressively develop amyloid β-protein (Aβ) deposits and then other features of Alzheimer's disease (AD), apparently due to increased gene dosage and thus expression of the β-amyloid precursor protein. Because the neuropathological phenotype in older DS subjects closely resembles that of AD, the examination of DS brains of increasing age provides a unique model of the progression of AD. Here, we characterized the deposition of several Aβ peptides and apolipoprotein E in formalin-fixed brain sections from 29 DS subjects between 3 and 73 years old. Amyloid plaque number and the percentage of cortical area they occupied were quantified by computerized image analysis. Aβ ending at amino acid 42 (Aβ42) was the earliest form of Aβ deposited in DS cortex. It was observed in 7 of 16 young (3–30 years) subjects, with the earliest deposition occurring at age 12. Aβ ending at residue 40 (Aβ40) was not detected until ≈age 30, a time when degenerating neurites around Aβ immunoreactive (IR) plaques were first observed, and the frequency of Aβ40IR plaques then rose with age. Even in old (51–73 years) DS subjects, Aβ42IR plaques were always more abundant than Aβ40IR plaques. Aβ peptides starting at aspartate 1 or pyroglutamate 3 were detected in small subsets of compacted, neuritic plaques beginning around age 30 and rose with age, the latter species always exceeding the former. Thus, the N-termini of the Aβ42peptides abundantly deposited in very young DS subjects remain unknown. Apo E was detectable in a small subset of Aβ42IR plaques beginning at age 12 and rose steadily with age; it clearly followed the deposition of Aβ. Our analysis of very young DS brains suggests that amyloid plaque formation begins with Aβ42-ending peptides, and the number and percentage of cortical area of Aβ42plaques increase very little with advancing age, while other heterogeneous Aβ species and Apo E progressively accrue onto plaques containing Aβ42.