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, Aβ₃₈, Aβ₃₉, Aβ₄₀, Aβ₄₂, Aβ₄₃, 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 (Aβ₃₈, Aβ₄₂, and Aβ_pSer8), and cerebellar parenchymal deposition (Aβ₄₀, Aβ₄₂, Aβ_Np3E, and Aβ_pSer8) than sAD cases. Furthermore, DS cases had a significantly larger mean plaque size (6F/3D, Aβ₄₂, Aβ_Np3E) in the temporal lobe, and significantly greater deposition of cerebral and cerebellar Aβ₄₂ 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.