Exome analysis of 22,319 individuals links extremely rare copy-number variants and 22q11.21 dosage to Alzheimer risk.

Rare coding CNVs and 22q11.21 dosage variations are linked to Alzheimer disease risk, with deletions increasing and duplications decreasing risk in affected individuals.

• Why it matters: Understanding the role of CNVs in non-monogenic Alzheimer disease can reveal genetic factors influencing disease susceptibility and potential protective mechanisms.
• What they did: Analyzing 22,319 exomes from affected and unaffected individuals, the study identified rare CNVs, performed burden and dosage analyses, and validated findings in a large replication cohort.
• The result: Deletions in genes like ABCA1, ABCA7, and 22q11.21 are associated with increased AD risk, while 22q11.21 duplications are linked to decreased risk, with overexpression of SCARF2 reducing amyloid-β uptake.