APOE3 Christchurch Heterozygosity and Autosomal Dominant Alzheimer's Disease
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APOE3 Christchurch Heterozygosity and Autosomal Dominant Alzheimer's Disease. / Quiroz, Yakeel T; Aguillon, David; Aguirre-Acevedo, Daniel C; Vasquez, Daniel; Zuluaga, Yesica; Baena, Ana Y; Madrigal, Lucia; Hincapié, Liliana; Sanchez, Justin S; Langella, Stephanie; Posada-Duque, Rafael; Littau, Jessica L; Villalba-Moreno, Nelson D; Vila-Castelar, Clara; Ramirez Gomez, Liliana; Garcia, Gloria; Kaplan, Elizabeth; Rassi Vargas, Sofia; Ossa, J Alejandro; Valderrama-Carmona, Pablo; Perez-Corredor, Paula; Krasemann, Susanne; Glatzel, Markus; Kosik, Kenneth S; Johnson, Keith; Sperling, Reisa A; Reiman, Eric M; Sepulveda-Falla, Diego; Lopera, Francisco; Arboleda-Velasquez, Joseph F.
In: NEW ENGL J MED, Vol. 390, No. 23, 20.06.2024, p. 2156-2164.Research output: SCORING: Contribution to journal › SCORING: Journal article › Research › peer-review
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TY - JOUR
T1 - APOE3 Christchurch Heterozygosity and Autosomal Dominant Alzheimer's Disease
AU - Quiroz, Yakeel T
AU - Aguillon, David
AU - Aguirre-Acevedo, Daniel C
AU - Vasquez, Daniel
AU - Zuluaga, Yesica
AU - Baena, Ana Y
AU - Madrigal, Lucia
AU - Hincapié, Liliana
AU - Sanchez, Justin S
AU - Langella, Stephanie
AU - Posada-Duque, Rafael
AU - Littau, Jessica L
AU - Villalba-Moreno, Nelson D
AU - Vila-Castelar, Clara
AU - Ramirez Gomez, Liliana
AU - Garcia, Gloria
AU - Kaplan, Elizabeth
AU - Rassi Vargas, Sofia
AU - Ossa, J Alejandro
AU - Valderrama-Carmona, Pablo
AU - Perez-Corredor, Paula
AU - Krasemann, Susanne
AU - Glatzel, Markus
AU - Kosik, Kenneth S
AU - Johnson, Keith
AU - Sperling, Reisa A
AU - Reiman, Eric M
AU - Sepulveda-Falla, Diego
AU - Lopera, Francisco
AU - Arboleda-Velasquez, Joseph F
N1 - Copyright © 2024 Massachusetts Medical Society.
PY - 2024/6/20
Y1 - 2024/6/20
N2 - 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 E280A variant who also had two copies of the apolipoprotein E3 Christchurch variant (APOE3 Ch). Heterozygosity for the APOE3 Ch variant may influence the age at which the onset of cognitive impairment occurs. We assessed this hypothesis in a population in which the PSEN1 E280A variant is prevalent.METHODS: We analyzed data from 27 participants with one copy of the APOE3 Ch variant among 1077 carriers of the PSEN1 E280A 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 Ch variant. Two participants underwent brain imaging, and autopsy was performed in four participants.RESULTS: Among carriers of PSEN1 E280A who were heterozygous for the APOE3 Ch 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 E280A carriers without the APOE3 Ch variant, among whom the median age at the onset was 47 years (95% CI, 47 to 49). In two participants with the APOE3 Ch and PSEN1 E280A variants who underwent brain imaging, 18F-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 18F-flortaucipir PET imaging, tau findings were limited as compared with persons with PSEN1 E280A in whom cognitive impairment occurred at the typical age in this kindred. Four studies of autopsy material obtained from persons with the APOE3 Ch and PSEN1 E280A variants showed fewer vascular amyloid pathologic features than were seen in material obtained from persons who had the PSEN1 E280A variant but not the APOE3 Ch variant.CONCLUSIONS: Clinical data supported a delayed onset of cognitive impairment in persons who were heterozygous for the APOE3 Ch variant in a kindred with a high prevalence of autosomal dominant Alzheimer's disease. (Funded by Good Ventures and others.).
AB - 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 E280A variant who also had two copies of the apolipoprotein E3 Christchurch variant (APOE3 Ch). Heterozygosity for the APOE3 Ch variant may influence the age at which the onset of cognitive impairment occurs. We assessed this hypothesis in a population in which the PSEN1 E280A variant is prevalent.METHODS: We analyzed data from 27 participants with one copy of the APOE3 Ch variant among 1077 carriers of the PSEN1 E280A 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 Ch variant. Two participants underwent brain imaging, and autopsy was performed in four participants.RESULTS: Among carriers of PSEN1 E280A who were heterozygous for the APOE3 Ch 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 E280A carriers without the APOE3 Ch variant, among whom the median age at the onset was 47 years (95% CI, 47 to 49). In two participants with the APOE3 Ch and PSEN1 E280A variants who underwent brain imaging, 18F-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 18F-flortaucipir PET imaging, tau findings were limited as compared with persons with PSEN1 E280A in whom cognitive impairment occurred at the typical age in this kindred. Four studies of autopsy material obtained from persons with the APOE3 Ch and PSEN1 E280A variants showed fewer vascular amyloid pathologic features than were seen in material obtained from persons who had the PSEN1 E280A variant but not the APOE3 Ch variant.CONCLUSIONS: Clinical data supported a delayed onset of cognitive impairment in persons who were heterozygous for the APOE3 Ch variant in a kindred with a high prevalence of autosomal dominant Alzheimer's disease. (Funded by Good Ventures and others.).
KW - Humans
KW - Alzheimer Disease/genetics
KW - Heterozygote
KW - Presenilin-1/genetics
KW - Female
KW - Male
KW - Middle Aged
KW - Apolipoprotein E3/genetics
KW - Age of Onset
KW - Positron-Emission Tomography
KW - Aged
KW - Brain/pathology
KW - Adult
KW - Genes, Dominant
KW - Colombia
U2 - 10.1056/NEJMoa2308583
DO - 10.1056/NEJMoa2308583
M3 - SCORING: Journal article
C2 - 38899694
VL - 390
SP - 2156
EP - 2164
JO - NEW ENGL J MED
JF - NEW ENGL J MED
SN - 0028-4793
IS - 23
ER -