Distinct Molecular Signatures of Amyloid-Beta and Tau in Alzheimer’s Disease Associated with Down Syndrome

Limited comparative data exist on the molecular spectrum of amyloid-beta (Aβ) and tau deposition in individuals with Down syndrome (DS) and sporadic Alzheimer’s disease (sAD). We assessed Aβ and tau deposition severity in the temporal lobe and cerebellum of ten DS and ten sAD cases. Immunohistochemistry was performed using antibodies against eight different Aβ epitopes (6F/3D, Aβ(38), Aβ(39), Aβ(40), Aβ(42), Aβ(43), pyroglutamate Aβ at third glutamic acid (Aβ(Np3E)), phosphorylated- (p-)Aβ at 8th serine (Aβ(pSer8))), and six different pathological tau epitopes (p-Ser202/Thr205, p-Thr231, p-Ser396, Alz50, MC1, GT38). Findings were evaluated semi-quantitatively and quantitatively using digital pathology. DS cases had significantly higher neocortical parenchymal deposition (Aβ(38), Aβ(42), and Aβ(pSer8)), and cerebellar parenchymal deposition (Aβ(40), Aβ(42), Aβ(Np3E), and Aβ(pSer8)) than sAD cases. Furthermore, DS cases had a significantly larger mean plaque size (6F/3D, Aβ(42), Aβ(Np3E)) in the temporal lobe, and significantly greater deposition of cerebral and cerebellar Aβ(42) than sAD cases in the quantitative analysis. Western blotting corroborated these findings. Regarding tau pathology, DS cases had significantly more severe cerebral tau deposition than sAD cases, especially in the white matter (p-Ser202/Thr205, p-Thr231, Alz50, and MC1). Greater total tau deposition in the white matter (p-Ser202/Thr205, p-Thr231, and Alz50) of DS cases was confirmed by quantitative analysis. Our data suggest that the Aβ and tau molecular signatures in DS are distinct from those in sAD.