*4.1. Sex- and Genotype-Dependent Mortality/Morbidity Paradox*

People with AD show worse survival than the general old population, and deranged neuro-immuno-endocrine system in males could explain their worse survival than females despite their less bad neuropathological status [4,6]. At the translational level, we have consistently reported increased vulnerability of 3xTg-AD mice concurrent with impairment of the neuro-immuno-endocrine system and in agreement with this sex-dependent profile [11,12,38]. However, we found cohorts that offered a distinct survival scenario, with pairwise comparisons in the survival curves confirming an effect of sex factor with worse survival of females, independently of the genotype. 3xTg-AD mice females had a shorter lifespan than males, and sex differences were less pronounced in NTg mice. The retrospective analysis of survival indicated that both groups of females exhibited an early mortality window, starting as soon as 2–3 months of age. While the male sex has worse cardiovascular mortality rates than females, the burden of cardiovascular disease in the female sex is widely reported [39]. Less is known in this regard in Alzheimer's disease. Therefore, the present cohorts offer an interesting experimental setting to study the morbidity/mortality paradox in surviving females. In this scenario, we were interested in studying the relationship between frailty, mental health, and cardiovascular phenotype.

Heterogeneity is found in the aging process, and prognostic tools to identify end-of-life dementia stages are difficult [7]. In NTg and 3xTg-AD mice, we described heterogeneity as part of the complexity of age-related scenarios [8,40,41]. The frailty index, a common tool to measure health status that seems to be sensitive to predict mortality [5], is a valuable tool in longevity and aging studies in mice [31]. In the general population, women usually present higher frailty scores and a reduced risk of mortality than men [42]. In contrast, higher frailty scores are recorded in men with AD [43]. In agreement, the Mouse Clinical Frailty Index, a translational adaptation of the frailty index data in humans [31], was increased in male 3xTg-AD mice compared to NTg counterparts, while females exhibited similar frailty scores. A worse sensorimotor function was also previously reported [8,10,12]. Using the same frailty index, other researchers also noticed that 3xTg-AD males show higher scores, with sex differences in health span predicting lifespan in the 3xTg-AD mouse model of AD [44].
