*Article* **Sex-Dependent End-of-Life Mental and Vascular Scenarios for Compensatory Mechanisms in Mice with Normal and AD-Neurodegenerative Aging**

**Aida Muntsant 1,2,†, Francesc Jiménez-Altayó 2,3,\*,†, Lidia Puertas-Umbert 3, Elena Jiménez-Xarrie 4, Elisabet Vila <sup>3</sup> and Lydia Giménez-Llort 1,2,\***

	- <sup>4</sup> Stroke Unit, Department of Neurology, Institut d'Investigació Biomèdica (IIB)-Sant Pau, 08041 Barcelona, Spain; ejimenezx@santpau.cat

**Abstract:** Life expectancy decreases with aging, with cardiovascular, mental health, and neurodegenerative disorders strongly contributing to the total disability-adjusted life years. Interestingly, the morbidity/mortality paradox points to females having a worse healthy life expectancy. Since bidirectional interactions between cardiovascular and Alzheimer's diseases (AD) have been reported, the study of this emerging field is promising. In the present work, we further explored the cardiovascular–brain interactions in mice survivors of two cohorts of non-transgenic and 3xTg-AD mice, including both sexes, to investigate the frailty/survival through their life span. Survival, monitored from birth, showed exceptionally worse mortality rates in females than males, independently of the genotype. This mortality selection provided a "survivors" cohort that could unveil brain–cardiovascular interaction mechanisms relevant for normal and neurodegenerative aging processes restricted to long-lived animals. The results show sex-dependent distinct physical (worse in 3xTg-AD males), neuropsychiatric-like and cognitive phenotypes (worse in 3xTg-AD females), and hypothalamic–pituitary–adrenal (HPA) axis activation (higher in females), with higher cerebral blood flow and improved cardiovascular phenotype in 3xTg-AD female mice survivors. The present study provides an experimental scenario to study the suggested potential compensatory hemodynamic mechanisms in end-of-life dementia, which is sex-dependent and can be a target for pharmacological and non-pharmacological interventions.

**Keywords:** healthy life expectancy (HALE); morbidity/mortality paradox; anxiety; cognition; systolic blood pressure; cerebral blood flow; arterial properties; angiogenesis; gender medicine; neurodegenerative disorders
