Project: Natural History of Amyloid Deposition in Adults with Down Syndrome

P.I.: Benjamin Handen, M.D.

Adults with Down Syndrome (DS), an inherited genetic condition, are uniformly affected by Alzheimer’s disease pathology and have a >70% chance of clinical dementia in their 60’s. In nearly all cases DS is associated with an extra copy of chromosome 21, which encodes the Amyloid-β precursor protein and leads to a 1.5-fold increase in Aβ. Nowhere is it clearer that Aβ alone is not sufficient to cause dementia, as DS subjects harbor this pathology for over a decade before cognitive decline is apparent. As such, DS can be seen as a setting of amplified sensitivity to risk and protective factors that moderate the relationship between Aβ, neurodegeneration, and clinical dementia. Understanding the factors that moderate this relationship in DS and biomarkers for those factors is critically important in the design of therapeutic trials for AD in DS and in general. This multi-site consortium, called the Neurodegeneration in Aging Down Syndrome (NIAD) study, is led by the University of Pittsburgh and includes collaborators at the University of Wisconsin, Madison, Cambridge University in the United Kingdom, and the Banner Alzheimer’s Institute. This five-year longitudinal study will examine the progression of AD related biomarkers (Aβ, tau, and FDG PET, structural and functional MRI, cerebrospinal fluid Aβ and tau, plasma Aβ and proteomics, genetics, neuropathology) and cognitive/functional measures in 180 adults with DS and 40 controls. Subjects are re-evaluated every 15 months to assess changes in cognition/adaptive functioning and every 30 months to detect biomarker changes.

Selected Recent Publications

Zammit MD, Laymon CM, Betthauser TJ, Cody KA, Tudorascu DL, Minhas DS, Sabbagh MN, Johnson SC, Zaman SH, Mathis CA, Klunk WE, Handen BL, Cohen AD, Christian BT (2020). Amyloid accumulation in Down syndrome measured with amyloid load. Alzheimer’s & Dement. (Amst) Apr 16:12(1)e:12020. doi:10.1002/dad2.12020. eCollection 2020.

Tudorascu DL, Anderson SJ, Minhas DS, Yu Z, Comer D, Lao P, Hartley S, Laymon CM, Snitz BE, Lopresti BJ, Johnson S, Price JC, Mathis CA, Aizenstein HJ, Klunk WE, Handen BL, Christian BT, Cohen AD (2019). Comparison of longitudinal Aβ in nondemented elderly and Down syndrome. Neurobiol. Aging 73:171-176.

Cohen AD, McDade E, Christian B, Price J, Mathis C, Klunk W, Handen BL (2018). Early striatial amyloid deposition distinguishes Down Syndrome and autosomal dominant Alzheimer’s disease from late-onset amyloid deposition. Alzheimers Dement. 14:743-750.

Lao PJ, Handen BL, Betthauser TJ, Mihaila I, Hartley SL, Cohen AD, Tudorascu DL, Bulova PD, Lopresti BJ, Tumuluru RV, Murali D, Mathis CA, Barnhart TE, Stone CK, Price JC, Devenny DA, Johnson SC, Klunk WE, Christian BT (2018). Alzheimer-like pattern of hypometabolism emerges with elevated Amyloid-beta burden in Down Syndrome. J. Alzheimer’s Disease 61:631-644.

From Cohen et al, 2018: Voxelwise comparisons of amyloid patterns between autosomal dominant Alzheimer’s disease (ADAD), Down syndrome (DS), and late-onset Alzheimer’s disease (LOAD).