Impact of learning APOE genotype on cognitively unimpaired adults: a pre-screening cohort study of the Alzheimer's Prevention Initiative Generation Study 1

Jessica B Langbaum¹, Angela R Bradbury², Brian L Egleston³, Elisabeth McCarty Wood⁴, Carolyn M Langlois⁵, Emily A Largent⁶, Kristin Harkins⁷, Claire M Erickson⁸, Shana D Stites⁹, Emma Oyen¹⁰, Marie-Emmanuelle Riviere¹¹, Fonda Liu¹², Ana Graf¹¹, Scott Y H Kim¹³, Joshua D Grill¹⁴, Eric M Reiman⁵, Pierre N Tariot⁵, J Scott Roberts¹⁵, Jason Karlawish⁶

Affiliations

¹ Banner Alzheimer's Institute, Phoenix, AZ, USA. Electronic address: jessica.langbaum@bannerhealth.com.
² Department of Medicine, Division of Hematology-Oncology, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA; Department of Medical Ethics and Health Policy, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA.
³ Fox Chase Cancer Center, Temple University, Philadelphia, PA, USA.
⁴ Department of Medicine, Division of Hematology-Oncology, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA.
⁵ Banner Alzheimer's Institute, Phoenix, AZ, USA.
⁶ Department of Medical Ethics and Health Policy, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA.
⁷ Department of Medicine, Division of Geriatrics, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA.
⁸ Banner Alzheimer's Institute, Phoenix, AZ, USA; Department of Medical Ethics and Health Policy, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA.
⁹ Department of Psychiatry, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA.
¹⁰ Banner Alzheimer's Institute, Phoenix, AZ, USA; Department of Psychology, University of Southern California Dornsife College of Letters, Arts, and Sciences, Los Angeles, CA, USA.
¹¹ Clinical Development, Neuroscience, Novartis Pharma, Basel, Switzerland.
¹² Clinical Development, Neuroscience, Novartis Pharmaceuticals, East Hanover, NJ, USA.
¹³ Department of Bioethics, National Institutes of Health (NIH) Clinical Center, Bethesda, MD, USA.
¹⁴ Institute for Memory Impairments and Neurological Disorders, Departments of Psychiatry and Human Behavior and Neurobiology and Behavior, University of California, Irvine, Irvine, CA, USA.
¹⁵ Department of Health Behavior and Health Equity, University of Michigan School of Public Health, Ann Arbor, MI, USA.

PMID: 41319675
DOI: 10.1016/j.lanhl.2025.100778

Free article

Multicenter Study

Impact of learning APOE genotype on cognitively unimpaired adults: a pre-screening cohort study of the Alzheimer's Prevention Initiative Generation Study 1

Jessica B Langbaum et al. Lancet Healthy Longev. 2025 Nov.

Free article

. 2025 Nov;6(11):100778.

doi: 10.1016/j.lanhl.2025.100778. Epub 2025 Nov 27.

Authors

Affiliations

¹ Banner Alzheimer's Institute, Phoenix, AZ, USA. Electronic address: jessica.langbaum@bannerhealth.com.
² Department of Medicine, Division of Hematology-Oncology, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA; Department of Medical Ethics and Health Policy, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA.
³ Fox Chase Cancer Center, Temple University, Philadelphia, PA, USA.
⁴ Department of Medicine, Division of Hematology-Oncology, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA.
⁵ Banner Alzheimer's Institute, Phoenix, AZ, USA.
⁶ Department of Medical Ethics and Health Policy, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA.
⁷ Department of Medicine, Division of Geriatrics, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA.
⁸ Banner Alzheimer's Institute, Phoenix, AZ, USA; Department of Medical Ethics and Health Policy, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA.
⁹ Department of Psychiatry, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA.
¹⁰ Banner Alzheimer's Institute, Phoenix, AZ, USA; Department of Psychology, University of Southern California Dornsife College of Letters, Arts, and Sciences, Los Angeles, CA, USA.
¹¹ Clinical Development, Neuroscience, Novartis Pharma, Basel, Switzerland.
¹² Clinical Development, Neuroscience, Novartis Pharmaceuticals, East Hanover, NJ, USA.
¹³ Department of Bioethics, National Institutes of Health (NIH) Clinical Center, Bethesda, MD, USA.
¹⁴ Institute for Memory Impairments and Neurological Disorders, Departments of Psychiatry and Human Behavior and Neurobiology and Behavior, University of California, Irvine, Irvine, CA, USA.
¹⁵ Department of Health Behavior and Health Equity, University of Michigan School of Public Health, Ann Arbor, MI, USA.

PMID: 41319675
DOI: 10.1016/j.lanhl.2025.100778

Abstract

Background: The apolipoprotein E (APOE) gene is the best established genetic risk factor for Alzheimer's disease in later life, with the ε4 allele conferring higher risk. APOE disclosure is becoming increasingly common in the clinical care of people with Alzheimer's disease and in cognitively unimpaired adults. In this study, we aimed to describe changes in measures of genetic disease knowledge and psychiatric symptoms following APOE disclosure to cognitively unimpaired adults.

Methods: Data were collected as part of the screening phase of the global, multicentre, Alzheimer's Prevention Initiative Generation Study 1 (NCT02565511). Eligible individuals were cognitively unimpaired (Mini-Mental State Exam total score ≥24), aged 60-75 years, and psychologically pre-screened for readiness (by measures of depressive symptoms and anxiety) to receive their APOE genotype from a health-care provider. Participants were assessed before disclosure, and 2-7 days, 6 weeks, 6 months, and 12 months after disclosure. Multivariable linear and ordinal logistic regressions were used to compare changes in genetic disease knowledge, anxiety, depression, and distress by APOE4 genotype status, adjusting for key covariates, with a focus on 2-7 days after disclosure. Multiple imputation by chained equations methods was used to account for missing outcome data.

Findings: The trial took place between Nov 30, 2015, and Sept 23, 2019. In total, 9496 participants (including 790 APOE4 homozygotes, 4869 heterozygotes, and 3837 non-carriers) learned their APOE genotype from a health-care provider as part of Generation Study 1 screening. 4038 (42·5%) participants were in the 65-69-year age group, 5790 (61·0%) were female, 3706 (39·0%) were male, and 8862 (93·3%) self-identified as White. Increase in genetic disease knowledge 2-7 days after disclosure was greater in APOE4 homozygotes (mean 1·19 [SD 3·95]) than in heterozygotes (0·78 [3·95], p=0·042) and non-carriers (0·29 [3·96], p=0·0002). Disease-specific distress 2-7 days after disclosure increased more in homozygotes (2·25 [6·42]) than in heterozygotes (0·53 [5·08], p<0·0001) and non-carriers (0·79 [4·95], p<0·0001). Levels of anxiety 2-7 days after disclosure increased in homozygotes (0·17 [2·95]) but decreased in heterozygotes (-0·67 [2·68], p<0·0001) and non-carriers (-0·66 [2·67], p<0·0001). There were no significant changes in depressive symptoms following disclosure for any APOE4 group. Notably, for all APOE4 groups, increases in distress and anxiety were small and did not reach predefined levels of clinical concern.

Interpretation: In cognitively unimpaired, psychologically pre-screened adults, APOE disclosure by a trained health-care provider was generally safe and well tolerated, consistent with results from previous studies. To our knowledge, this is the largest study experience of APOE disclosure to date, especially for homozygotes, and is notable for the older age of participants compared with previous research. These results are timely and important given anticipated increases in APOE disclosure to guide clinical decision making once an Alzheimer's disease prevention treatment is approved for cognitively unimpaired adults or if patients' family members are interested in genetic testing. Scalable approaches for returning Alzheimer's disease risk information are critical to meeting anticipated demand. Results from this study may be useful to bolster clinical translatability of disclosure programmes.

Funding: The National Institute on Aging, Alzheimer's Association, Banner Alzheimer's Foundation, GHR Foundation, F-Prime Biomedical Research Initiative (FBRI), and Novartis Pharma.

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Conflict of interest statement

Declaration of interests JBL, CML, CME, EMR, and PNT are full-time employees of Banner Health. Banner Health received financial support from the National Institutes of Health (NIH), Novartis Pharma, and Amgen, and philanthropic support from the Alzheimer’s Association, FBRI, the GHR Foundation, and the Banner Alzheimer’s Foundation for the conduct of the API Generation Program, from Eli Lilly for the conduct of another Alzheimer’s prevention trial, and from Roche for another Alzheimer’s prevention trial. JBL reports research funding from NIH; and received consulting fees from Alector, Biogen, and Denovo Biopharma. ARB reports research funding from the NIH; her institution received partial research funding for another trial from Astrazeneca and Merck. BLE, EMcCW, KH, CME, SDS, and JSR report research funding from the NIH. EAL reports research funding from the NIH; and she received an honoraria from Eli Lilly, consulting fees from Novartis Pharma, and payment for participation on Data Safety Monitoring Boards. M-ER and AG are employees and shareholders of Novartis Pharma, Basel, Switzerland. FL is an employee and shareholder of Novartis Pharmaceuticals, East Hanover, NJ, USA. SYHK is a US federal employee; the opinions expressed here are his and do not represent the views of the NIH, the US Department of Health and Human Services, or the Federal government. JDG reports research funding from NIH, Alzheimer’s Association, BrightFocus Foundation, Eli Lilly, Genentech, Biogen, and Eisai; he received personal compensation for editorial service to Alzheimer’s & Dementia; he has received travel support from the Alzheimer’s Association. EMR reports research funding from NIH; he is a compensated scientific advisor for Alzheon, Cognition Therapeutics, Denali Therapeutics, Enigma, Jocanta, Retromer Therapeutics, and Vaxxinity; he is a co-founder, advisor, and shareholder in ALZPath. PNT reports research funding from NIH; consulting fees from AbbVie, AC Immune, Acadia Pharmaceuticals, Athira Pharma, Axsome Therapeutics, Bristol Myers Squibb, Cognition Therapeutics, Cognito, Corium, CuraSen Therapeutics, Eisai, Genentech, Immunobrain, Janssen, Lundbeck, MapLight, Merck, Novartis, Novo Nordisk, Ono Pharma, Otsuka/Astek Pharmaceuticals, Roche, T3D Therapeutics; honoraria from Novo Nordisk; travel support from Lundbeck, Axsome, Novo Nordisk, MapLight, and Acadia; and payment for participation on Data Safety Monitoring Boards. JK reports research funding from NIH and works for the University of Pennsylvania; the University of Pennsylvania received financial support from Novartis Pharma and Amgen for the conduct of the API Generation Program, from Eli Lilly for the conduct of another Alzheimer’s prevention trial, from Esai for another Alzheimer’s prevention trial, and from Biogen for an Alzheimer’s treatment trial; he provided paid consultation to Biogen and Darmiyan. He reports payment for participation on Data Safety Monitoring Boards. EO reports no competing interests.

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Impact of learning APOE genotype on cognitively unimpaired adults: a pre-screening cohort study of the Alzheimer's Prevention Initiative Generation Study 1

Affiliations

Impact of learning APOE genotype on cognitively unimpaired adults: a pre-screening cohort study of the Alzheimer's Prevention Initiative Generation Study 1

Authors

Affiliations

Abstract

Conflict of interest statement

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