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APOE3 Christchurch Heterozygosity and Autosomal Dominant Alzheimer's Disease.

APOE3 Christchurch Heterozygosity and Autosomal Dominant Alzheimer's Disease.

Authors :
Quiroz YT
Aguillon D
Aguirre-Acevedo DC
Vasquez D
Zuluaga Y
Baena AY
Madrigal L
HincapiƩ L
Sanchez JS
Langella S
Posada-Duque R
Littau JL
Villalba-Moreno ND
Vila-Castelar C
Ramirez Gomez L
Garcia G
Kaplan E
Rassi Vargas S
Ossa JA
Valderrama-Carmona P
Perez-Corredor P
Krasemann S
Glatzel M
Kosik KS
Johnson K
Sperling RA
Reiman EM
Sepulveda-Falla D
Lopera F
Arboleda-Velasquez JF
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.)

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