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

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.