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Low-degree trisomy 21 mosaicism promotes early-onset Alzheimer disease.

Neurobiol Aging. 2021 Feb 28:S0197-4580(21)00076-2. doi: 10.1016/j.neurobiolaging.2021.02.021. Epub ahead of print. PMID: 33789815.

Authors/Editors: Nuebling GS, Prix C, Brendel M, Beyer L, Wlasich E, Loosli SV, Barthel H, Sabri O, Bartenstein P, Vöglein J, Danek A, Rominger A, Edbauer D, Haass C, Levin J.
Publication Date: 2021


Trisomy-21 mosaicism (mT21) with subclinical intellectual development disorder or physical phenotype has very rarely been associated with early-onset cognitive decline. Notably, early-onset Alzheimer's disease (EOAD) patients' family histories frequently suggest genetic causes other than autosomal-dominant APP/PSEN-1/2 mutations. We present an EOAD patient in his late fifties newly diagnosed with low-degree mT21 (13%/21% blood lymphocytes/ectodermal cells). We applied fluorescence in-situ hybridization to confirm a diagnosis of mT21. Multimodal positron-emission-tomography applying 18F-fluodesoxyglucose (metabolism), 18F-florbetaben (amyloid-β deposits) and 18F-PI-2620 (tau-deposits) tracers was used to confirm a diagnosis of EOAD according to the ATN-criteria of AD. Initial PET-studies revealed marked cerebral amyloid-β- and tau-pathology and parietotemporal hypometabolism, confirming EOAD according to the ATN-criteria of AD. A marked cognitive decline was accompanied by an increase in tau pathology in follow-up studies. This is the first case demonstrating that a low-degree APP gene-dose increase suffices to cause EOAD with prominent amyloid-β/tau pathology.

Keywords: Alzheimer disease; Amyloid; Neurogenetics; PI-2620; Positron emission tomography; Tau.

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