Exome analysis of 22,319 individuals links extremely rare CNVs and 22q11.21 dosage to Alzheimer’s risk

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Abstract Copy number variants (CNVs), defined as deletions or duplications of genomic segments >100 bp, are major contributors to human disease, yet their role in non-monogenic Alzheimer disease (AD) remains poorly characterized. We analyzed rare CNVs from 22,319 exomes, including 4,150 early-onset AD (EOAD), 8,519 late-onset AD and 9,650 unaffected controls. EOAD cases showed increased burdens of rare CNVs, particularly rare deletions within AD-related genes. Loss-of-function analyses implicated deletions in ABCA1 and ABCA7 and identified CTSB as a candidate locus . Exome-wide gene-level dosage analysis highlighted 18 genes across five loci , including chr22q11.21, where deletions were restricted to EOAD and duplications enriched in controls. Replication in 33,992 cases and 362,305 controls confirmed AD-risk reduction in 22q11.21 duplication carriers (mega-analysis dosage OR(SCARF2)=0.34, p=5.52×10 -7 ). SCARF2 overexpression increased amyloid-β uptake in vitro , supporting a functional link. These findings highlight CNVs as contributors to AD risk and identify 22q11.21 dosage as a strong genetic determinant.

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