TY  - JOUR
AU  - Kommaddi, Reddy Peera
AU  - Verma, Aditi
AU  - Muniz-Terrera, Graciela
AU  - Tiwari, Vivek
AU  - Chithanathan, Keerthana
AU  - Diwakar, Latha
AU  - Gowaikar, Ruturaj
AU  - Karunakaran, Smitha
AU  - Malo, Palash Kumar
AU  - Graff-Radford, Neill R
AU  - Day, Gregory S
AU  - Laske, Christoph
AU  - Vöglein, Jonathan
AU  - Nübling, Georg
AU  - Ikeuchi, Takeshi
AU  - Kasuga, Kensaku
AU  - Ravindranath, Vijayalakshmi
TI  - Sex difference in evolution of cognitive decline: studies on mouse model and the Dominantly Inherited Alzheimer Network cohort.
JO  - Translational Psychiatry
VL  - 13
IS  - 1
SN  - 2158-3188
CY  - London
PB  - Nature Publishing Group
M1  - DZNE-2023-00455
SP  - 123
PY  - 2023
AB  - Women carry a higher burden of Alzheimer's disease (AD) compared to men, which is not accounted entirely by differences in lifespan. To identify the mechanisms underlying this effect, we investigated sex-specific differences in the progression of familial AD in humans and in APPswe/PS1ΔE9 mice. Activity dependent protein translation and associative learning and memory deficits were examined in APPswe/PS1ΔE9 mice and wild-type mice. As a human comparator group, progression of cognitive dysfunction was assessed in mutation carriers and non-carriers from DIAN (Dominantly Inherited Alzheimer Network) cohort. Female APPswe/PS1ΔE9 mice did not show recall deficits after contextual fear conditioning until 8 months of age. Further, activity dependent protein translation and Akt1-mTOR signaling at the synapse were impaired in male but not in female mice until 8 months of age. Ovariectomized APPswe/PS1ΔE9 mice displayed recall deficits at 4 months of age and these were sustained until 8 months of age. Moreover, activity dependent protein translation was also impaired in 4 months old ovariectomized APPswe/PS1ΔE9 mice compared with sham female APPswe/PS1ΔE9 mice. Progression of memory impairment differed between men and women in the DIAN cohort as analyzed using linear mixed effects model, wherein men showed steeper cognitive decline irrespective of the age of entry in the study, while women showed significantly greater performance and slower decline in immediate recall (LOGIMEM) and delayed recall (MEMUNITS) than men. However, when the performance of men and women in several cognitive tasks (such as Wechsler's logical memory) are compared with the estimated year from expected symptom onset (EYO) we found no significant differences between men and women. We conclude that in familial AD patients and mouse models, females are protected, and the onset of disease is delayed as long as estrogen levels are intact.
KW  - Humans
KW  - Female
KW  - Male
KW  - Mice
KW  - Animals
KW  - Infant
KW  - Alzheimer Disease: metabolism
KW  - Mice, Transgenic
KW  - Sex Characteristics
KW  - Cognitive Dysfunction: genetics
KW  - Fear
KW  - Memory Disorders
KW  - Disease Models, Animal
KW  - Amyloid beta-Protein Precursor: genetics
KW  - Amyloid beta-Peptides: metabolism
KW  - Amyloid beta-Protein Precursor (NLM Chemicals)
KW  - Amyloid beta-Peptides (NLM Chemicals)
LB  - PUB:(DE-HGF)16
C2  - pmc:PMC10097702
C6  - pmid:37045867
DO  - DOI:10.1038/s41398-023-02411-8
UR  - https://pub.dzne.de/record/257575
ER  -