Age-related hormone changes play important roles in cognitive decline in older men, and apolipoprotein E ɛ4 (APOEɛ4) is a risk factor for Alzheimer’s disease (AD).
Objective:
This study aimed to investigate the interactive role of androgen decline and APOEɛ4 genotype in the pathogenesis of amnestic mild cognitive impairment (aMCI) and AD.
Methods:
In total, 576 elderly men over 65 years old from communities in Shijiazhuang were enrolled in this study, including 243 with normal cognition (NC), 271 with aMCI, and 62 with probable AD. Cognitive function was evaluated with a battery of neuropsychological tests. The serum levels of androgen and gonadotropin were detected by ELISA and chemiluminescence immunoassay.
Results:
The levels of free testosterone (FT) and dihydrotestosterone (DHT) were lower in the aMCI group (p < 0.05), and even lower in the AD group (p < 0.001), but the levels of follicle stimulating hormone (FSH) and luteinizing hormone (LH)
were higher in AD group (p < 0.01), comparing with that in NC or aMCI group. The interaction of lower FT or DHT levels with APOEɛ4 had a risk role in global cognitive impairment (p < 0.05). The area under the curve (AUC) of the ROC curve for predicting aMCI by serum FT levels was 0.745.
Conclusion:
These results indicated that the interaction of androgen decline and APOEɛ4 genotype play a role in aMCI and AD. Serum FT levels have a predictive value for aMCI and might be a potential biomarker for prodromal AD.
JackCRJr, AlbertMS, KnopmanDS, McKhannGM, SperlingRA, CarrilloMC, ThiesB, PhelpsCH (2011) Introduction to the recommendations from the National Institute on Aging-Alzheimer’s Association workgroups on diagnostic guidelines for Alzheimer’s disease. Alzheimers Dement7, 257–262.
2.
PetersenRC, DoodyR, KurzA, MohsRC, MorrisJC, RabinsPV, RitchieK, RossorM, ThalL, WinbladB (2001) Current concepts in mild cognitive impairment. Arch Neurol58, 1985–1992.
3.
AmoreM, InnamoratiM, CostiS, SherL, GirardiP, PompiliM (2012) Partial androgen deficiency, depression, and testosterone supplementation in aging men. Int J Endocrinol2012, 280724.
4.
MoffatSD, ZondermanAB, MetterEJ, BlackmanMR, HarmanSM, ResnickSM (2002) Longitudinal assessment of serum free testosterone concentration predicts memory performance and cognitive status in elderly men. J Clin Endocrinol Metab87, 5001–5007.
5.
WuFC, TajarA, PyeSR, SilmanAJ, FinnJD, O’NeillTW, BartfaiG, CasanuevaF, FortiG, GiwercmanA, HuhtaniemiIT, KulaK, PunabM, BoonenS, VanderschuerenD, EuropeanMASG (2008) Hypothalamic-pituitary-testicular axis disruptions in older men are differentially linked to age and modifiable risk factors: The European Male Aging Study. J Clin Endocrinol Metab93, 2737–2745.
6.
VerdileG, LawsSM, HenleyD, AmesD, BushAI, EllisKA, FauxNG, GuptaVB, LiQX, MastersCL, PikeKE, RoweCC, SzoekeC, TaddeiK, VillemagneVL, MartinsRN, AIBLRG (2014) Associations between gonadotropins, testosterone and β amyloid in men at risk of Alzheimer’s disease. Mol Psychiatry19, 69–75.
7.
MoffatSD, ZondermanAB, MetterEJ, KawasC, BlackmanMR, HarmanSM, ResnickSM (2004) Free testosterone and risk for Alzheimer disease in older men. Neurology62, 188–193.
8.
SeidlJN, MassmanPJ (2015) Relationships between testosterone levels and cognition in patients with Alzheimer disease and nondemented elderly men. J Geriatr Psychiatry Neurol28, 27–39.
9.
LvW, DuN, LiuY, FanX, WangY, JiaX, HouX, WangB (2016) Low testosterone level and risk of Alzheimer’s disease in the elderly men: A systematic review and meta-analysis. Mol Neurobiol53, 2679–2684.
10.
Jiménez-RubioG, Herrera-PérezJJ, Hernández-HernándezOT, Martínez-MotaL (2017) Relationship between androgen deficiency and memory impairment in aging and Alzheimer’s disease. Actas Esp Psiquiatr45, 227–247.
11.
UchoaMF, MoserVA, PikeCJ (2016) Interactions between inflammation, sex steroids, and Alzheimer’s disease risk factors. Front Neuroendocrinol43, 60–82.
12.
CherrierMM, AndersonK, ShoferJ, MillardS, MatsumotoAM (2015) Testosterone treatment of men with mild cognitive impairment and low testosterone levels. Am J Alzheimers Dis Other Demen30, 421–430.
13.
MohamadNV, Ima-NirwanaS, ChinKY (2018) A review on the effects of testosterone supplementation in hypogonadal men with cognitive impairment. Curr Drug Targets19, 898–906.
14.
BowenRL, IsleyJP, AtkinsonRL (2000) An association of elevated serum gonadotropin concentrations and Alzheimer disease?J Neuroendocrinol12, 351–354.
BowenRL, VerdileG, LiuT, ParlowAF, PerryG, SmithMA, MartinsRN, AtwoodCS (2004) Luteinizing hormone, a reproductive regulator that modulates the processing of amyloid-beta precursor protein and amyloid-beta deposition. J Biol Chem279, 20539–20545.
17.
LeeJH, ByunMS, YiD, ChoeYM, ChoiHJ, BaekH, SohnBK, LeeJY, KimHJ, KimJW, LeeY, KimYK, SohnCH, WooJI, LeeDY, KBASEResearch Group (2017) Sex-specific association of sex hormones and gonadotropins, with brain amyloid and hippocampal neurodegeneration. Neurobiol Aging58, 34–40.
18.
MarxCE, TrostWT, ShampineLJ, StevensRD, HuletteCM, SteffensDC, ErvinJF, ButterfieldMI, BlazerDG, MassingMW, LiebermanJA (2006) The neurosteroid allopregnanolone is reduced in prefrontal cortex in Alzheimer’s disease. Biol Psychiatry60, 1287–1294.
19.
WangS, GuanL, LuoD, LiuJ, LinH, LiX, LiuX (2017) Gene-gene interaction between PPARG and APOE gene on late-onset Alzheimer’s disease: A case-control study in Chinese Han population. J Nutr Health Aging21, 397–403.
20.
XuWL, CaraccioloB, WangHX, SantoniG, WinbladB, FratiglioniL (2013) Accelerated progression from mild cognitive impairment to dementia among APOE ɛ4ɛ4 carriers. J Alzheimers Dis33, 507–515.
21.
SamaranchL, CervantesS, BarabashA, AlonsoA, CabranesJA, LametI, AncínI, LorenzoE, Martínez-LageP, MarcosA, ClarimónJ, AlcoleaD, LleóA, BlesaR, Gómez-IslaT, PastorP (2010) The effect of MAPT H1 and APOE ɛ4 on transition from mild cognitive impairment to dementia. J Alzheimers Dis22, 1065–1071.
22.
BurkhardtMS, FosterJK, ClarnetteRM, ChubbSA, BruceDG, DrummondPD, MartinsRN, YeapBB (2006) Interaction between testosterone and apolipoprotein E epsilon4 status on cognition in healthy older men. J Clin Endocrinol Metab91, 1168–1172.
23.
PanizzonMS, HaugerR, XianH, VuoksimaaE, SpoonKM, MendozaSP, JacobsonKC, VasilopoulosT, RanaBK, McKenzieR, McCafferyJM, LyonsMJ, KremenWS, FranzCE (2014) Interaction of APOE genotype and testosterone on episodic memory in middle-aged men. Neurobiol Aging35, 1771–1778.
LuJ, LiD, LiF, ZhouA, WangF, ZuoX, JiaXF, SongH, JiaJ (2011) Montreal cognitive assessment in detecting cognitive impairment in Chinese elderly individuals: A population-based study. J Geriatr Psychiatry Neurol24, 184–190.
26.
LiX, JiaS, ZhouZ, JinY, ZhangX, HouC, ZhengW, RongP, JiaoJ (2018) The role of the Montreal Cognitive Assessment (MoCA) and its memory tasks for detecting mild cognitive impairment. Neurol Sci39, 1029–1034.
27.
TuQ, JinH, DingB, YangX, LeiZ, BaiS, TangX (2012) The study on reliability, validity of Montreal Cognitive Assessment (Changsha Version) and preliminary exploration of its optimal cutoff score for detecting vascular cognitive impairment. Chin J Nerv Ment Dis38, 339–345.
28.
PetersenRC (2004) Mild cognitive impairment as a diagnostic entity. J Intern Med256, 183–194.
29.
AlbertMS, DeKoskyST, DicksonD, DuboisB, FeldmanHH, FoxNC, GamstA, HoltzmanDM, JagustWJ, PetersenRC, SnyderPJ, CarrilloMC, ThiesB, PhelpsCH (2011) The diagnosis of mild cognitive impairment due to Alzheimer’s disease: Recommendations from the National Institute on Aging-Alzheimer’s Association workgroups on diagnostic guidelines for Alzheimer’s disease. Alzheimers Dement7, 270–279.
30.
ZhangJ, YangC, WeiD, LiH, LeungEL, DengQ, LiuZ, FanXX, ZhangZ (2019) Long-term efficacy of Chinese medicine Bushen Capsule on cognition and brain activity in patients with amnestic mild cognitive impairment. Pharmacol Res146, 104319.
31.
LiuS, PanJ, TangK, LeiQ, HeL, CaiX, LiZ (2019) Alpha 1-antichymotrypsin may be a biomarker for the progression of amnestic mild cognitive impairment. Acta Neurol Belg–10.1007/s13760-019-01206-3.
32.
SunZ, WangZ, XuL, LvX, LiQ, WangH, YuX (2019) Characteristics of cognitive deficit in amnestic mild cognitive impairment with subthreshold depression. J Geriatr Psychiatry Neurol32, 344–353.
33.
McKhannG, DrachmanD, FolsteinM, KatzmanR, PriceD, StadlanEM (1984) Clinical diagnosis of Alzheimer’s disease: Report of the NINCDS-ADRDA Work Group under the auspices of Department of Health and Human Services Task Force on Alzheimer’s Disease. Neurology34, 939–944.
34.
McKhannGM, KnopmanDS, ChertkowH, HymanBT, JackCR, KawasCH, KlunkWE, KoroshetzWJ, ManlyJJ, MayeuxR, MohsRC, MorrisJC, RossorMN, ScheltensP, CarrilloMC, ThiesB, WeintraubS, PhelpsCH (2011) The diagnosis of dementia due to Alzheimer’s disease: Recommendations from the National Institute on Aging-Alzheimer’s Association workgroups on diagnostic guidelines for Alzheimer’s disease. Alzheimers Dement7, 263–269.
35.
LyLP, SartoriusG, HullL, LeungA, SwerdloffRS, WangC, HandelsmanDJ (2010) Accuracy of calculated free testosterone formulae in men. Clin Endocrinol (Oxf)73, 382–388.
36.
SartoriusG, LyLP, SikarisK, McLachlanR, HandelsmanDJ (2009) Predictive accuracy and sources of variability in calculated free testosterone estimates. Ann Clin Biochem46, 137–143.
37.
FordAH, YeapBB, FlickerL, HankeyGJ, ChubbS, GolledgeJ, AlmeidaOP (2018) Sex hormones and incident dementia in older men: The health in men study. Psychoneuroendocrinology98, 139–147.
38.
VerdileG, YeapBB, ClarnetteRM, DhaliwalS, BurkhardtMS, ChubbSA, DeRuyck K, RodriguesM, MehtaPD, FosterJK, BruceDG, MartinsRN (2008) Luteinizing hormone levels are positively correlated with plasma amyloid-beta protein levels in elderly men. J Alzheimers Dis14, 201–208.
39.
HogervorstE, BandelowS, CombrinckM, SmithAD (2004) Low free testosterone is an independent risk factor for Alzheimer’s disease. Exp Gerontol39, 1633–1639.
40.
AtwiS, McMahonD, ScharfmanH, MacLuskyNJ (2016) Androgen modulation of hippocampal structure and function. Neuroscientist22, 46–60.
41.
GrimmA, BiliourisEE, LangUE, GötzJ, Mensah-NyaganAG, EckertA (2016) Sex hormone-related neurosteroids differentially rescue bioenergetic deficits induced by amyloid-β or hyperphosphorylated tau protein. Cell Mol Life Sci73, 201–215.
42.
PanW, HanS, KangL, LiS, DuJ, CuiH (2016) Effects of dihydrotestosterone on synaptic plasticity of the hippocampus in mild cognitive impairment male SAMP8 mice. Exp Ther Med12, 1455–1463.
43.
KangL, LiS, XingZ, LiJ, SuY, FanP, WangL, CuiH (2014) Dihydrotestosterone treatment delays the conversion from mild cognitive impairment to Alzheimer’s disease in SAMP8 mice. Horm Behav65, 505–515.
44.
ChuLW, TamS, WongRL, YikPY, SongY, CheungBM, MorleyJE, LamKS (2010) Bioavailable testosterone predicts a lower risk of Alzheimer’s disease in older men. J Alzheimers Dis21, 1335–1345.
45.
ChuLW, TamS, LeePW, WongRL, YikPY, TsuiW, SongY, CheungBM, MorleyJE, LamKS (2008) Bioavailable testosterone is associated with a reduced risk of amnestic mild cognitive impairment in older men. Clin Endocrinol (Oxf)68, 589–598.
46.
MoraM, SánchezL, Serra-PratM, PalomeraE, BlancoJ, ArandaG, FalcónI, CadenasI, BoquetX, OriolaJ, Puig-DomingoM, MataróASG (2012) Hormonal determinants and effect of ER22/23EK glucocorticoid receptor gene polymorphism on health status deterioration in the participants of the Mataró Ageing Study. Age (Dordr)34, 553–561.
47.
ResnickSM, MatsumotoAM, Stephens-ShieldsAJ, EllenbergSS, GillTM, ShumakerSA, PleasantsDD, Barrett-ConnorE, BhasinS, CauleyJA, CellaD, CrandallJP, CunninghamGR, EnsrudKE, FarrarJT, LewisCE, MolitchME, PahorM, SwerdloffRS, CifelliD, AntonS, BasariaS, DiemSJ, WangC, HouX, SnyderPJ (2017) Testosterone treatment and cognitive function in older men with low testosterone and age-associated memory impairment. JAMA317, 717–727.
48.
HirschC (2017) In older men with low testosterone levels and age-associated memory impairment, testosterone did not improve memory. Ann Intern Med166, JC56.
49.
SeoEH, KimSH, ParkSH, KangSH, ChooIH, Alzheimer’sDNI (2016) Independent and interactive influences of the APOE genotype and beta-amyloid burden on cognitive function in mild cognitive impairment. J Korean Med Sci31, 286–295.
50.
YoonB, ShimYS, CheongHK, KimYD, LeeKO, HongYJ, OhYS, NaHR, KimBC, ChoiSH, YangDW (2013) Interaction of white matter hyperintensities (WMHs) and apolipoprotein E (APOE) genotypes on cognition in patients with amnestic mild cognitive impairment (aMCI). Arch Gerontol Geriatr57, 292–297.
51.
LópezME, TurreroA, DelgadoML, Rodríguez-RojoIC, ArrazolaJ, BarabashA, MaestúF, FernándezA (2017) APOE ɛ4 genotype and cognitive reserve effects on the cognitive functioning of healthy elders. Dement Geriatr Cogn Disord44, 328–342.
52.
HogervorstE, LehmannDJ, WardenDR, McBroomJ, SmithAD (2002) Apolipoprotein E epsilon4 and testosterone interact in the risk of Alzheimer’s disease in men. Int J Geriatr Psychiatry17, 938–940.
RaberJ (2008) AR, apoE, and cognitive function. Horm Behav53, 706–715.
55.
BrownCM, XuQ, OkhuboN, VitekMP, ColtonCA (2007) Androgen-mediated immune function is altered by the apolipoprotein E gene. Endocrinology148, 3383–3390.
56.
ZhenJ, HuangX, VanHalm-Lutterodt N, DongS, MaW, XiaoR, YuanL (2017) ApoE rs429358 and rs7412 polymorphism and gender differences of serum lipid profile and cognition in aging Chinese population. Front Aging Neurosci9, 248.
57.
ReinvangI, WinjevollIL, RootweltH, EspesethT (2010) Working memory deficits in healthy APOE epsilon 4 carriers. Neuropsychologia48, 566–573.
58.
PanizzonMS, HaugerR, DaleAM, EavesLJ, EylerLT, FischlB, Fennema-NotestineC, FranzCE, GrantMD, JakAJ, JacobsonKC, LyonsMJ, MendozaSP, NealeMC, Prom-WormleyEC, SeidmanLJ, TsuangMT, XianH, KremenWS (2010) Testosterone modifies the effect of APOE genotype on hippocampal volume in middle-aged men. Neurology75, 874–880.
59.
RosarioER, PikeCJ (2008) Androgen regulation of beta-amyloid protein and the risk of Alzheimer’s disease. Brain Res Rev57, 444–453.
60.
YaoM, NguyenTV, RosarioER, RamsdenM, PikeCJ (2008) Androgens regulate neprilysin expression: Role in reducing beta-amyloid levels. J Neurochem105, 2477–2488.
61.
MantheyD, HeckS, EngertS, BehlC (2001) Estrogen induces a rapid secretion of amyloid beta precursor protein via the mitogen-activated protein kinase pathway. Eur J Biochem268, 4285–4291.
62.
GoodenoughS, EngertS, BehlC (2000) Testosterone stimulates rapid secretory amyloid precursor protein release from rat hypothalamic cells via the activation of the mitogen-activated protein kinase pathway. Neurosci Lett296, 49–52.
63.
GourasGK, XuH, GrossRS, GreenfieldJP, HaiB, WangR, GreengardP (2000) Testosterone reduces neuronal secretion of Alzheimer’s beta-amyloid peptides. Proc Natl Acad Sci U S A97, 1202–1205.
64.
YaffeK, HaanM, ByersA, TangenC, KullerL (2000) Estrogen use, APOE, and cognitive decline: Evidence of gene-environment interaction. Neurology54, 1949–1954.
65.
XuJ, XiaLL, SongN, ChenSD, WangG (2016) Testosterone, estradiol, and sex hormone-binding globulin in Alzheimer’s disease: A meta-analysis. Curr Alzheimer Res13, 215–222.
66.
LinSY, LinKJ, LinPC, HuangCC, ChangCC, LeeYC, HsiaoIT, YenTC, HuangWS, YangBH, WangPN (2019) Plasma amyloid assay as a pre-screening tool for amyloid positron emission tomography imaging in early stage Alzheimer’s disease. Alzheimers Res Ther11, 111.
