New evidence refers to a high degree of heterogeneity in normal but also Alzheimer’s disease (AD) clinical and temporal patterns, increased mortality, and the need to find specific end-of-life prognosticators. This heterogeneity is scarcely explored in very old male AD mice models due to their reduced survival. In the present work, using 915 (432 APP23 and 483 C57BL/6 littermates) mice, we confirmed the better survival curves in male than female APP23 mice and respective wildtypes, providing the chance to characterize behavioral signatures in middle-aged, old, and long-lived male animals. The sensitivity of a battery of seven paradigms for comprehensive screening of motor (activity and gait analysis), neuropsychiatric and cognitive symptoms was analyzed using a cohort of 56 animals, composed of 12-, 18- and 24-month-old male APP23 mice and wildtype littermates. Most variables analyzed detected age-related differences. However, variables related to coping with stress, thigmotaxis, frailty, gait, and poor cognition better discriminated the behavioral phenotype of male APP23 mice through the three old ages compared with controls. Most importantly, non-linear age- and genotype-dependent behavioral signatures were found in long-lived animals, suggesting crosstalk between chronological and biological/behavioral ages useful to study underlying mechanisms and distinct compensations through physiological and AD-associated aging.

The temporal course and the severity of the involution of sensory systems through aging can be critical since they ensure the ability to perceive and recognize the world. In older people, sensory impairments significantly increase their risk of biological, psychological, and social impoverishment. Besides this, olfactory loss is considered an early biomarker in Alzheimer’s disease (AD) neurodegenerative process. Here we studied olfactory ethograms in middle-aged male and female gold-standard C57BL/6 mice and 3xTg-AD mice, a genetic model of AD that presents cognitive dysfunction and a conspicuous neuropsychiatric-like phenotype. A paradigm involving 1-day food deprivation was used to investigate the ethological patterns shown in the olfactory inspection of a new cage and the sniffing, finding, and eating of hidden food pellets. The sniffing–find–eat temporal patterns were independent of the loss of weight and unveiled (fast) olfactory signatures in Alzheimer’s disease, differing from those (slow progressive) in normal aging. Male 3xTg-AD mice exhibited an early signature than female mice, opposite to animals with normal aging. The sequence of actions was correlated in male and female 3xTg-AD mice in contrast to control mice. Social isolation, naturally occurring in male 3xTg-AD due to the death of cage mates, emphasized their olfactory patterns and disrupted the behavioral correlates. The paradigm provided distinct contextual, sex, and genotype olfactory ethogram signatures useful to investigate olfactory function in normal and AD-pathological aging. Isolation had an impact on enhancing the changes in the olfactory signature here described, for the first time, in the 3xTg-AD model of Alzheimer’s disease.

Sensory systems ensure the ability to perceive and recognize the world. Therefore, the temporal course and the severity of their involution through the aging process can be critical. In the elderly, sensory impairments significantly increase their risk of biological, psychological and social impoverishment. Olfactory loss, known to happen in bacterial and viral infections and considered an early biomarker in Alzheimer’s and Parkinson’s diseases neurodegenerative processes, has been reported also as an early indicator of current infection by SARS-CoV-2. At the translational level, in the present work, we have studied olfactory ethograms in normal and advanced AD-related pathological aging using wildtype and the 3xTg-AD mice, a genetic model of Alzheimer’s disease that presents AD-cognitive dysfunction but also a conspicuous BPSD-like phenotype. An olfactory paradigm, involving the equivalent to one day food deprivation, was used to investigate in middle-aged males and females with normal and AD-pathological aging the ethological patterns shown in the olfactory inspection of a new cage with beddings and the posterior detection, finding and consumption of food pellets hidden in this new anxiogenic environment. Males with normal and pathological aging were equally delayed in their first contact with food pellets, while in female sex this latency was dependent on the genotype (longer in 3xTg-AD mice, shorter in those with normal aging). Once the animals had inspected the arena, the latencies to smell, find and eat the food pellets were found progressively increased in males with normal aging, but consecutively developed in 3xTg-AD mice. In contrast, both groups of females exhibited longer delays as compared to males, and the temporal pattern of their ethogram to smell-find-eat the food was faster. In 3xTg-AD males, social isolation (naturally occurring due to death of counterparts) emphasized these olfactory patterns, which were independent of the punctual loss of weight of this paradigm. The results show that this paradigm provides distinct contextual, sex and genotype olfactory ethogram signatures useful to investigate olfactory function in normal and AD-pathological aging. Also, that isolation has an impact enhancing the changes in the olfactory signature here described, for the first time, in the 3xTg-AD mice model of Alzheimer’s disease.

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