• Yakeel T Quiroz, David Aguillon, Daniel C Aguirre-Acevedo, Daniel Vasquez, Yesica Zuluaga, Ana Y Baena, Lucia Madrigal, Liliana Hincapié, Justin S Sanchez, Stephanie Langella, Rafael Posada-Duque, Jessica L Littau, Nelson D Villalba-Moreno, Clara Vila-Castelar, Liliana Ramirez Gomez, Gloria Garcia, Elizabeth Kaplan, Sofia Rassi Vargas, J Alejandro Ossa, Pablo Valderrama-Carmona, Paula Perez-Corredor, Susanne Krasemann, Markus Glatzel, Kenneth S Kosik, Keith Johnson, Reisa A Sperling, Eric M Reiman, Diego Sepulveda-Falla, Francisco Lopera, and Joseph F Arboleda-Velasquez.
• From Massachusetts General Hospital (Y.T.Q., J.S.S., S.L., C.V.-C., L.R.G., E.K., K.J., R.A.S.), the Departments of Neurology (Y.T.Q., J.S.S., L.R.G., K.J., R.A.S.), Psychiatry (Y.T.Q., S.L., C.V.-C., E.K.), and Ophthalmology (P.P.-C., J.F.A.-V.), Harvard Medical School, Brigham and Women's Hospital (K.J., R.A.S.), and Schepens Eye Research Institute, Mass Eye and Ear (P.P.-C., J.F.A.-V.) - all in Boston; Grupo de Neurociencias de Antioquia, Facultad de Medicina, Universidad de Antioquia, Medellín, Colombia (Y.T.Q., D.A., D.C.A-A., D.V., Y.Z., A.Y.B., L.M., L.H., R.P.-D., G.G., S.R.V., J.A.O., P.V.-C., F.L.); the Institute of Neuropathology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany (J.L.L., N.D.V.-M., S.K., M.G., D.S-F.); the Neuroscience Research Institute, Department of Molecular Cellular Developmental Biology, University of California, Santa Barbara, Santa Barbara (K.S.K.); and the Banner Alzheimer's Institute, Phoenix, the University of Arizona, Tucson, and Arizona State University, Tempe - all in Arizona (E.M.R.).
• N. Engl. J. Med. 2024 Jun 20; 390 (23): 215621642156-2164.

BackgroundVariants 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.MethodsWe 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.ResultsAmong 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.ConclusionsClinical 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.).Copyright © 2024 Massachusetts Medical Society.

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