Familial Early-Onset Alzheimer's Caused by Novel Genetic Variant and APP Duplication

Introduction: Alzheimer's disease usually occurs sporadically, with onset age ≥65 years. Early-onset Alzheimer's disease (EOAD) manifests before age 65 in a minority of patients. Autosomal dominant (AD) EOAD is linked either to point mutations or indels within three genes, presenilin 1, presenilin 2, and amyloid beta precursor protein (APP) or to APP locus duplication (APP-dup), associated with EOAD and with cerebral amyloid angiopathy. Methods: We present a seven-generation pedigree with familial cognitive and functional decline and intra-cerebral hemorrhages starting at age 40 years. Sixty-eight individuals were recruited to the study. Participants underwent neurological examination, 1½ hours of neuropsychological assessment, and psychological screening. Genetic analysis included chromosomal microarray, Karyotype, florescence in situ hybridization, and whole genome sequencing. Results: Ten affected individuals presenting with dementia (six females) and intra cerebral hemorrhage (four males), were ascertained, and found to carry dup21q21.23 including the APP gene. In five patients dup5p14.1 co-segregated with the dupChr21. Both duplications are co-localized to chromosome 18q21.1, and segregated in AD manner in 25 pre-symptomatic carriers. Neuropsychological results provided evidence for impaired performance on episodic memory tasks when participants are in their mid-thirties. WGS determined the break points of the complexed chromosomal rearrangement. Interpretations: We report a large pedigree with EOAD and special clinical manifestations due to a novel chromosomal copy number variation, whose origin is puzzling. The determination of the genetic variant shared by all affected individuals might shed light on the mechanism underlying EOAD and how it might be modified. This family provides a unique opportunity to study young pre-symptomatic carriers for potential biomarkers in the transformation from pre-symptomatic to symptomatic EOAD. Detecting subtle alterations among genetically at-risk population for developing EOAD, in pre-symptomatic stages, might open a time window for intervention and prevention. Funding Statement: This study was supported by a research grant from TEVA pharmaceutical industries Ltd. and by the Lowell R. Lamb Research Fund for Alzheimer's Diseases (ATS 11393). Declaration of Interests: None. Ethics Approval Statement: The IRB committees of Rambam Health Care Campus, Galilee Medical Center and the Israeli Ministry of Health approved this study. Study participants or their guardians signed informed consent forms.