UNLABELLED: Digital biomarkers are defined as objective, quantifiable physiological and behavioral data that are collected and measured by means of digital devices. Their use has revolutionized clinical research by enabling high-frequency, longitudinal, and sensitive measurements. In the field of neurodegenerative diseases, an example of a digital biomarker-based technology is instrumental activities of daily living (iADL) digital medical application, a predictive biomarker of conversion from mild cognitive impairment (MCI) due to Alzheimer's disease (AD) to dementia due to AD in individuals aged 55 + . Digital biomarkers show promise to transform clinical practice. Nevertheless, their use may be affected by variables such as demographics, genetics, and phenotype. Among these factors, sex is particularly important in Alzheimer's, where men and women present with different symptoms and progression patterns that impact diagnosis. In this study, we explore sex differences in Altoida's digital medical application in a sample of 568 subjects consisting of a clinical dataset (MCI and dementia due to AD) and a healthy population. We found that a biological sex-classifier, built on digital biomarker features captured using Altoida's application, achieved a 75% ROC-AUC (receiver operating characteristic - area under curve) performance in predicting biological sex in healthy individuals, indicating significant differences in neurocognitive performance signatures between males and females. The performance dropped when we applied this classifier to more advanced stages on the AD continuum, including MCI and dementia, suggesting that sex differences might be disease-stage dependent. Our results indicate that neurocognitive performance signatures built on data from digital biomarker features are different between men and women. These results stress the need to integrate traditional approaches to dementia research with digital biomarker technologies and personalized medicine perspectives to achieve more precise predictive diagnostics, targeted prevention, and customized treatment of cognitive decline. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s13167-022-00284-3.

Altoida Inc Houston TX USA

Barcelona Supercomputing Center Plaça Eusebi Güell 1 3 08034 Barcelona Spain

Bayer NJ USA

Centre for Medical Research Faculty of Medicine Dentistry and Health Science University of Melbourne Melbourne Australia

Chione GmbH 8122 Binz Switzerland

Department of Psychiatry and Behavioral Sciences University of Miami Miller School of Medicine Miami FL 33136 USA

Dipartimento Di Scienze Mediche E Chirurgiche Università Degli Studi Di Foggia Foggia Italy

Global Brain Health Institute Dublin Ireland

ICREA Institució Catalana de Recerca 1 Estudis Avançats Pg Lluís Companys 23 08010 Barcelona Spain

International Clinical Research Center St Anne's University Hospital Brno Brno Czech Republic

Memory Clinic Department of Neurology 2nd Faculty of Medicine Charles University and Motol University Hospital Prague Czech Republic

Women's Brain Project Guntershausen Switzerland

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Alzheimer disease seen through the lens of sex and gender

An update on mobile applications collecting data among subjects with or at risk of Alzheimer's disease