In the last years, many clinical studies highlighted sex-specific differences in the pathophysiology of Alzheimer’s disease (AD). The recent paper published in the Journal of Alzheimer’s Disease shows the influence of sex on amyloid-β plaque deposition, behavior, and dopaminergic signaling in the 5xFAD mouse model of AD, with worse alterations in female mice. This commentary focuses on the importance of recognizing sex as a key variable to consider for a more precise clinical practice, with the challenge to develop sex-specific therapeutic interventions in neurodegenerative diseases such as AD.
FerrettiMT, IulitaMF, CavedoE, ChiesaPA, Schumacher DimechA, Santuccione Chadha A, BaracchiF, GirouardH, MisochS, GiacobiniE, DepypereH, HampelH, Women’s Brain Project and the Alzheimer Precision Medicine Initiative (2018) Sex differences in Alzheimer disease - the gateway to precision medicine. Nat Rev Neurol14, 457–469.
2.
SpallettaG, MusiccoM, PadovaniA, RozziniL, PerriR, FaddaL, CanonicoV, TrequattriniA, PettenatiC, CaltagironeC, PalmerK (2010) Neuropsychiatric symptoms and syndromes in a large cohort of newly diagnosed, untreated patients with Alzheimer disease. Am J Geriatr Psychiatry18, 1026–1035.
3.
ArdekaniBA, ConvitA, BachmanAH (2016) Analysis of the MIRIAD data shows sex differences in hippocampal atrophy progression. J Alzheimers Dis50, 847–857.
LansdellTA, XuH, GalliganJJ, DorranceAM (2023) Effects of striatal amyloidosis on the dopaminergic system and behavior: A comparative study in male and female 5XFAD mice. J Alzheimers Dis94, 1361–1375.
6.
HuY-T, ChenX-L, ZhangY-N, McGurranH, StormmesandJ, BreeuwsmaN, SluiterA, ZhaoJ, SwaabD, BaoA-M (2023) Sex differences in hippocampal β-amyloid accumulation in the triple-transgenic mouse model of Alzheimer’s disease and the potential role of local estrogens. Front Neurosci17, 1117584.
7.
VorobyovV, BakharevB, MedvinskayaN, NesterovaI, SamokhinA, DeevA, TatarnikovaO, UstyugovAA, SengpielF, BobkovaN (2019) Loss of midbrain dopamine neurons and altered apomorphine EEG effects in the 5xFAD mouse model of Alzheimer’s disease. J Alzheimers Dis70, 241–256.
8.
GloriaY, Ceyzeriat K, TsartsalisS, MilletP, TournierBB (2021) Dopaminergic dysfunction in the 3xTg-AD mice model of Alzheimer’s disease. Sci Rep11, 19412.
9.
La BarberaL, NobiliA, CauzziE, PaolettiI, FedericiM, SabaL, GiacometC, MarinoR, KrashiaP, MeloneM, KellerF, MercuriNB, ViscomiMT, ContiF, D’AmelioM (2022) Upregulation of Ca2+-binding proteins contributes to VTA dopamine neuron survival in the early phases of Alzheimer’s disease in Tg2576 mice. Mol Neurodegener17, 76.
10.
La BarberaL, VedeleF, NobiliA, KrashiaP, SpoletiE, LatagliataEC, CutuliD, CauzziE, MarinoR, ViscomiMT, PetrosiniL, Puglisi-AllegraS, MeloneM, KellerF, MercuriNB, ContiF, D’AmelioM (2021) Nilotinib restores memory function by preventing dopaminergic neuron degeneration in a mouse model of Alzheimer’s Disease. Prog Neurobiol202, 102031.
11.
NobiliA, LatagliataEC, ViscomiMT, CavallucciV, CutuliD, GiacovazzoG, KrashiaP, RizzoFR, MarinoR, FedericiM, De BartoloP, AversaD, Dell’AcquaMC, CordellaA, SancandiM, KellerF, PetrosiniL, Puglisi-AllegraS, MercuriNB, CoccurelloR, BerrettaN, D’AmelioM (2017) Dopamine neuronal loss contributes to memory and reward dysfunction in a model of Alzheimer’s disease. Nat Commun8, 14727.
12.
SpoletiE, KrashiaP, La BarberaL, NobiliA, LupascuCA, GiacaloneE, KellerF, MiglioreM, RenziM, D’AmelioM (2021) Early derailment of firing properties in CA1 pyramidal cells of the ventral hippocampus in an Alzheimer’s disease mouse model. Exp Neurol350, 113969.
13.
De MarcoM, VenneriA (2018) Volume and connectivity of the ventral tegmental area are linked to neurocognitive signatures of Alzheimer’s disease in humans. J Alzheimers Dis63, 167–180.
14.
IaccarinoL, SalaA, CaminitiSP, PresottoL, PeraniD, Alzheimer’sDisease Neuroimaging Initiative (2020) In vivo MRI structural and PET metabolic connectivity study of dopamine pathways in Alzheimer’s disease. J Alzheimers Dis75, 1003–1016.
15.
SerraL, D’AmelioM, Di DomenicoC, DipasqualeO, MarraC, MercuriNB, CaltagironeC, CercignaniM, BozzaliM (2018) In vivo mapping of brainstem nuclei functional connectivity disruption in Alzheimer’s disease. Neurobiol Aging72, 72–82.
16.
McArthurS, McHaleE, GilliesGE (2007) The size and distribution of midbrain dopaminergic populations are permanently altered by perinatal glucocorticoid exposure in a sex-region- and time-specific manner. Neuropsychopharmacology32, 1462–1476.
17.
DewingP, ChiangCWK, SinchakK, SimH, FernagutP-O, KellyS, ChesseletM-F, MicevychPE, AlbrechtKH, HarleyVR, VilainE (2006) Direct regulation of adult brain function by the male-specific factor SRY. Curr Biol16, 415–420.
18.
GilliesG, McArthurS, McHaleE (2006) Sex dimorphisms in the 3D cytoarchitecture of the adult VTA and permanent alterations by glucocorticoid exposure in late gestation. Front Neuroendocrinol27, 95–96.
19.
MunroCA, McCaulME, WongDF, OswaldLM, ZhouY, BrasicJ, KuwabaraH, KumarA, AlexanderM, YeW, WandGS (2006) Sex differences in striatal dopamine release in healthy adults. Biol Psychiatry59, 966–974.
20.
LaaksoA, VilkmanH, BergmanJ, HaaparantaM, SolinO, SyvälahtiE, SalokangasRKR, HietalaJ (2002) Sex differences in striatal presynaptic dopamine synthesis capacity in healthy subjects. Biol Psychiatry52, 759–763.
21.
YoestKE, QuigleyJA, BeckerJB (2018) Rapid effects of ovarian hormones in dorsal striatum and nucleus accumbens. Horm Behav104, 119–129.
22.
CreutzLM, KritzerMF (2002) Estrogen receptor-beta immunoreactivity in the midbrain of adult rats: Regional, subregional, and cellular localization in the A10, A9, and A8 dopamine cell groups. J Comp Neurol446, 288–300.
23.
AlmeyA, MilnerTA, BrakeWG (2015) Estrogen receptors in the central nervous system and their implication for dopamine-dependent cognition in females. Horm Behav74, 125–138.
24.
DyeRV, MillerKJ, SingerEJ, LevineAJ (2012) Hormone replacement therapy and risk for neurodegenerative diseases. Int J Alzheimers Dis2012, 258454.
25.
ChangD, KwanJ, TimirasPS (1997) Estrogens influence growth, maturation, and amyloid beta-peptide production in neuroblastoma cells and in a beta-APP transfected kidney 293 cell line. Adv Exp Med Biol429, 261–271.
TschiffelyAE, SchuhRA, Prokai-TatraiK, ProkaiL, OttingerMA (2016) A comparative evaluation of treatments with 17β-estradiol and its brain-selective prodrug in a double-transgenic mouse model of Alzheimer’s disease. Horm Behav83, 39–44.
