The New England Journal of MedicineAPOE3 Christchurch Heterozygosity and Autosomal Dominant Alzheimer’s Disease

APOE3 Christchurch Variant Linked to Delayed Cognitive Impairment in Autosomal Dominant Alzheimer’s Disease

This study investigates the impact of heterozygosity for the APOE3 Christchurch (APOE3Ch) variant on the onset of cognitive impairment in individuals with autosomal dominant Alzheimer’s disease caused by the PSEN1E280A variant. The research focused on a Colombian population with a high prevalence of the PSEN1E280A variant, aiming to determine if the APOE3Ch variant delays cognitive decline.

Study Design:

• Population: 27 participants with one copy of the APOE3Ch variant among 1077 carriers of the PSEN1E280A variant in a kindred from Antioquia, Colombia.
• Comparison Groups: Participants with APOE3Ch variant vs. those without.
• Age at Onset: Analysis of the age at cognitive impairment onset.
• Brain Imaging: Two participants underwent 18F-fluorodeoxyglucose PET and 18F-flortaucipir PET imaging.
• Autopsy: Conducted on four participants.

Key Findings:

• Onset of Cognitive Impairment: Median age at onset for APOE3Ch heterozygotes was 52 years (95% CI, 51 to 58) compared to 47 years (95% CI, 47 to 49) in those without the variant.
• Brain Metabolic Activity: PET imaging showed relatively preserved metabolic activity in typical Alzheimer’s-affected brain areas in APOE3Ch heterozygotes.
• Tau Imaging: Limited tau pathology in APOE3Ch heterozygotes compared to typical PSEN1E280A carriers.
• Autopsy Results: Fewer vascular amyloid pathologic features in APOE3Ch heterozygotes compared to non-APOE3Ch carriers.

HCN Medical Memo
For clinicians managing patients with autosomal dominant Alzheimer’s disease, the presence of the APOE3 Christchurch variant may indicate a delayed onset of cognitive impairment. This finding highlights the importance of genetic screening and personalized approaches in the prognosis and management of Alzheimer’s disease.

More on Genetics