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APOE3 Christchurch Heterozygosity and Autosomal Dominant Alzheimer's Disease.
APOE3 Christchurch Heterozygosity and Autosomal Dominant Alzheimer's Disease.
- Source :
-
The New England journal of medicine [N Engl J Med] 2024 Jun 20; Vol. 390 (23), pp. 2156-2164. - Publication Year :
- 2024
-
Abstract
- Background: Variants in APOE and PSEN1 (encoding apolipoprotein E and presenilin 1, respectively) alter the risk of Alzheimer's disease. We previously reported a delay of cognitive impairment in a person with autosomal dominant Alzheimer's disease caused by the PSEN1 <superscript>E280A</superscript> variant who also had two copies of the apolipoprotein E3 Christchurch variant ( APOE3 <superscript>Ch</superscript> ). Heterozygosity for the APOE3 <superscript>Ch</superscript> variant may influence the age at which the onset of cognitive impairment occurs. We assessed this hypothesis in a population in which the PSEN1 <superscript>E280A</superscript> variant is prevalent.<br />Methods: We analyzed data from 27 participants with one copy of the APOE3 <superscript>Ch</superscript> variant among 1077 carriers of the PSEN1 <superscript>E280A</superscript> variant in a kindred from Antioquia, Colombia, to estimate the age at the onset of cognitive impairment and dementia in this group as compared with persons without the APOE3 <superscript>Ch</superscript> variant. Two participants underwent brain imaging, and autopsy was performed in four participants.<br />Results: Among carriers of PSEN1 <superscript>E280A</superscript> who were heterozygous for the APOE3 <superscript>Ch</superscript> variant, the median age at the onset of cognitive impairment was 52 years (95% confidence interval [CI], 51 to 58), in contrast to a matched group of PSEN1 <superscript>E280A</superscript> carriers without the APOE3 <superscript>Ch</superscript> variant, among whom the median age at the onset was 47 years (95% CI, 47 to 49). In two participants with the APOE3 <superscript>Ch</superscript> and PSEN1 <superscript>E280A</superscript> variants who underwent brain imaging, <superscript>18</superscript> F-fluorodeoxyglucose positron-emission tomographic (PET) imaging showed relatively preserved metabolic activity in areas typically involved in Alzheimer's disease. In one of these participants, who underwent <superscript>18</superscript> F-flortaucipir PET imaging, tau findings were limited as compared with persons with PSEN1 <superscript>E280A</superscript> in whom cognitive impairment occurred at the typical age in this kindred. Four studies of autopsy material obtained from persons with the APOE3 <superscript>Ch</superscript> and PSEN1 <superscript>E280A</superscript> variants showed fewer vascular amyloid pathologic features than were seen in material obtained from persons who had the PSEN1 <superscript>E280A</superscript> variant but not the APOE3 <superscript>Ch</superscript> variant.<br />Conclusions: Clinical data supported a delayed onset of cognitive impairment in persons who were heterozygous for the APOE3 <superscript>Ch</superscript> variant in a kindred with a high prevalence of autosomal dominant Alzheimer's disease. (Funded by Good Ventures and others.).<br /> (Copyright © 2024 Massachusetts Medical Society.)
- Subjects :
- Adult
Aged
Female
Humans
Male
Middle Aged
Age of Onset
Brain pathology
Brain diagnostic imaging
Colombia
Family
Genes, Dominant
Heterozygote
Positron-Emission Tomography
Retrospective Studies
Alzheimer Disease diagnosis
Alzheimer Disease diagnostic imaging
Alzheimer Disease genetics
Alzheimer Disease pathology
Apolipoprotein E3 genetics
Presenilin-1 genetics
Subjects
Details
- Language :
- English
- ISSN :
- 1533-4406
- Volume :
- 390
- Issue :
- 23
- Database :
- MEDLINE
- Journal :
- The New England journal of medicine
- Publication Type :
- Academic Journal
- Accession number :
- 38899694
- Full Text :
- https://doi.org/10.1056/NEJMoa2308583