Alzheimer's disease (AD) disproportionately affects women, yet most preclinical research studies are male-centric. We performed lifespan analyses of male and female AD mouse models (APP/PS1 and APPNL-F/NL-F) and their shared genetic background control (C57BL/6). Survival curves support significant sex differences between genotypes. Minimal longevity revealed increased age in male APP/PS1, and decreased age in male APPNL-F/NL-F mice. Maximal longevity revealed an increased average age in males. Furthermore, median lifespan differed between sex and genotype. This study supports dimorphic survival in two mouse models of AD, emphasizing the need to examine mechanisms and treatments in both sexes.
ZhaoLMaoZWoodySK,et al.Sex differences in metabolic aging of the brain: insights into female susceptibility to Alzheimer’s disease. Neurobiol Aging2016; 42: 69–79.
3.
BlenckCLHarveyPAReckelhoffJF, et al.The importance of biological sex and estrogen in rodent models of cardiovascular health and disease. Circ Res2016; 118: 1294–1312.
4.
Torres-ListaVDe La FuenteMGiménez-LlortL. Survival curves and behavioral profiles of female 3xTg-AD mice surviving to 18-months of age as compared to mice with normal aging. J Alzheimers Dis Rep2017; 1: 47–57.
5.
KaneAEShinSWongAA, et al.Sex differences in healthspan predict lifespan in the 3xTg-AD mouse model of Alzheimer’s disease. Front Aging Neurosci2018; 10: 172.
6.
BritzJOjoEHaqueN, et al.Sex-dependent effects of chronic circadian disruption in AβPP/PS1 mice. J Alzheimers Dis2024; 97: 855–870.
7.
FindleyCAMcFaddenSAHillT, et al.Sexual dimorphism, altered hippocampal glutamatergic neurotransmission, and cognitive impairment in APP knock-in mice. J Alzheimers Dis2024; 102: 491–505.
8.
McFaddenSSimeLNCoxMKF, et al.Chronic, mild hypothermic environmental temperature does not ameliorate cognitive deficits in an Alzheimer’s disease mouse. J Gerontol A Biol Sci Med Sci2023; 78: 911–919.
9.
BritzJOjoEDhukhwaA, et al.Assessing sex-specific circadian, metabolic, and cognitive phenotypes in the AβPP/PS1 and APPNL-F/NL-F models of Alzheimer’s disease. J Alzheimers Dis2022; 85: 1077–1093.
10.
FangYPeckMRQuinnK, et al.Senolytic intervention improves cognition, metabolism, and adiposity in female APPNL−F/NL−F mice. Geroscience. 2024. DOI: https://doi.org/10.1007/s11357-024-01308-8
11.
McFaddenSAPeckMRSimeLN, et al.Thermotherapy has sexually dimorphic responses in APP/PS1 mice. Aging (Albany NY)2024; 16: 13237–13251.
12.
FangYMedinaDStockwellR, et al.Sexual dimorphic metabolic and cognitive responses of C57BL/6 mice to Fisetin or Dasatinib and quercetin cocktail oral treatment. Geroscience2023; 45: 2835–2850.
13.
CoxMKFHascupERBartkeA, et al.Friend or foe? Defining the role of glutamate in aging and Alzheimer’s disease. Front Aging2022; 3: 929474.
14.
FindleyCAMcFaddenSACoxMKF, et al.Prodromal glutamatergic modulation with riluzole impacts glucose homeostasis and spatial cognition in Alzheimer’s disease mice. J Alzheimers Dis2023; 94: 371–392.
15.
SasaguriHNilssonPHashimotoS, et al.APP Mouse models for Alzheimer’s disease preclinical studies. EMBO J2017; 36: e201797397.
16.
GulyaevaNV. Hippocampal hyperglutamatergic signaling matters: early targeting glutamate neurotransmission as a preventive strategy in Alzheimer’s disease: an Editorial Highlight for “Riluzole attenuates glutamatergic tone and cognitive decline in AβPP/PS1 mice” on page 513. J Neurochem2021; 156: 399–402.
17.
FindleyCABartkeAHascupKN, et al.Amyloid beta-related alterations to glutamate signaling dynamics during Alzheimer’s disease progression. ASN Neuro2019; 11: 1759091419855541.
18.
HascupKNFindleyCASimeLN, et al.Hippocampal alterations in glutamatergic signaling during amyloid progression in AβPP/PS1 mice. Sci Rep2020; 10: 14503.
19.
JankowskyJLZhengH. Practical considerations for choosing a mouse model of Alzheimer’s disease. Mol Neurodegener2017; 12: 89.
20.
MasudaAKobayashiYKogoN, et al.Cognitive deficits in single App knock-in mouse models. Neurobiol Learn Mem2016; 135: 73–82.
21.
BaumannCWKwakDThompsonLV. Sex-specific components of frailty in C57BL/6 mice. Aging2019; 11: 5206–5214.
22.
KunstyrILeuenbergerHGW. Gerontological data of C57BL/6J mice. I. Sex differences in survival curves. J Gerontol1975; 30: 157–162.
23.
InglisCCampbellERAucielloSL, et al. Effects of enrichment devices on stress-related problems in mouse breeding. 2004.
24.
WangJTanilaHPuoliväliJ, et al.Gender differences in the amount and deposition of amyloidbeta in APPswe and PS1 double transgenic mice. Neurobiol Dis2003; 14: 318–327.
25.
GallagherJJMinogueAMLynchMA. Impaired performance of female APP/PS1 mice in the Morris water maze is coupled with increased Aβ accumulation and microglial activation. Neurodegener Dis2013; 11: 33–41.
26.
RahmaniRRambarackNSinghJ, et al.Age-dependent sex differences in perineuronal nets in an APP mouse model of Alzheimer’s disease are brain region-specific. Int J Mol Sci2023; 24: 14917.
27.
Sala FrigerioCWolfsLFattorelliN, et al.The major risk factors for Alzheimer’s disease: age, sex, and genes modulate the microglia response to Aβ plaques. Cell Rep2019; 27: 1293–1306.e6.
28.
LiRSinghM. Sex differences in cognitive impairment and Alzheimer’s disease. Front Neuroendocrinol2014; 35: 385–403.
29.
BenitezDPJiangSWoodJ, et al.Knock-in models related to Alzheimer’s disease: synaptic transmission, plaques and the role of microglia. Mol Neurodegener2021; 16: 47.
30.
ViñaJLloretA. Why women have more Alzheimer’s disease than men: gender and mitochondrial toxicity of amyloid-beta peptide. J Alzheimers Dis2010; 20: S527–S533.
31.
MengQChaoYZhangS, et al.Attenuation of estrogen and its receptors in the post-menopausal stage exacerbates dyslipidemia and leads to cognitive impairment. Mol Brain2023; 16: 80.
32.
SyedFAMödderUIlRoforthM, et al.Effects of chronic estrogen treatment on modulating age-related bone loss in female mice. J Bone Miner Res2010; 25: 2438–2446.
33.
CarterAEMerriamS. Menopause. Med Clin North Am2023; 107: 199–212.
