Common types of dementia occurring in old age are associated with the loss of cholinergic activity from basal forebrain neurons projecting to the cerebral cortex. In Alzheimer's disease this loss correlates with cognitive decline, and in dementia with Lewy bodies with neuropsychiatric features such a hallucinations. New therapies aimed at restoring the levels of acetylcholine, such as the cholinesterase inhibitors tacrine or donepezil, provide some symptomatic benefit and may also be protective. Similar symptomatic and protective effects of oestrogen may operate through stimulation of the affected cholinergic neurons. These neurons have oestrogen receptors and, in animal models, oestrogen elevates cortical cholinergic activity. Cholinergic control of vasodilation is also affected by oestrogen. Declining oestrogen in postmenopausal women is thus likely to contribute to age-related cognitive decline and increased risk of Alzheimer's via cholinergic mechanisms. In addition to accumulating evidence of the protective effect of oestrogen in Alzheimer's, there is already a report that oestrogen replacement therapy enhances the response of female patients to cholinergic medication (eg, tacrine).
. RobbinsTWMcAlonanGMuirJLEverittBJ. Cognitive enhancers in theory and practice: studies of the cholinergic hypothesis of cognitive deficits in Alzheimer's disease. Behavioural Brain Research1997; 83: 15–23.
2.
. BollerEOrgogozaJM. Tacrine, Alzheimer's disease and the cholinergic theory. A critical review and results of a new therapy. Neurologica1995; 10: 194–195.
3.
. ShintaniEYUchidaKM. Donepezil: an anticholinesterase inhibitor for Alzheimer's disease. Am J Health Syst Pharmacology1997; 54: 2805–2810.
. BuckwalterJGSobelEDunnMEDizMMHendersonVW. Gender differences on a brief measure of cognitive functioning in Alzheimer's disease. Arch Neurol1993; 50: 757–760.
6.
. HendersonVWBuckwalterJG. Cognitive deficits of men and women with Alzheimer's disease. Neurology1994; 44: 90–98.
7.
. CohenDEisdorferCGorelickPLuchinsDFreelsSSemlaTPavezaGShawHAshfordJM. Sex differences in the psychiatric manifestations of Alzheimer's disease. Jl Ame Geriatric Soc1993; 41: 229–230.
8.
. HendersonVW. Estrogen, cognition and a women's risk of Alzheimer's disease. Am J Med1997; 103: 115–185.
9.
. BeckmannCR. Alzheimer's disease: an estrogen link. Current opinion in obstetrics and gynecology1997; 9: 295–299.
10.
. HonjoHIwasaKUrabeM.Clinical studies of oestrogen therapy for dementia. J British Menopause Society1998; 4: 12–30.
11.
. MesulamHM. The cholinergic contribution to neuromodulation in the cerebral cortex. The Neurosciences1995; 7: 297–307.
12.
. MesulamMM. The systems-level organisation of cholinergic innervation in the human cerebral cortex and its alterations in Alzheimer's disease. Prog Brain Res1996; 109: 285–297.
13.
. BuzsakiGBickfordTGPonamareffGThalLJMandelRJGageFH. Nucleus basalis and thalamic control of neocortical activity in the freely moving rat. J Neurosci1988; 26: 735–744.
14.
. BloklandA.Acetylcholine: A neurotransmitter for learning and memory?Brain Research Reviews1995; 21: 285–300.
15.
. EverittBJRobbinsTW. Central cholinergic systems and cognition. Annual Reviews Psychology1997; 48: 649–684.
16.
. WenkGL. The nucleus basalis magnocellularis cholinergic system: one hundred years of progress. Neurobiology of learning and memory1997; 67: 85–95.
17.
. SarterMBrunoJP. Cognitive functions of acetylcholine: towards a unifying hypothesis. Brain Research Reviews1997; 23: 28–46.
18.
. BlinJIvanoiuACopperSADe VolderALabarDMichelCLaterreEC. Cholinergic neurotransmission has different effects on cerebral glucose consumption and blood flow in young normals, aged normals and Alzheimer's disease patients. Neuroimage1997; 6: 335–343.
19.
. PerryEK. The cholinergic hypothesis - ten years on. Br Med Bull1986; 42: 63–69.
20.
. McKeithIGGalaskoDKosakaMDDicksonDWHansenLA. Dementia with Lewy bodies: diagnostic criteria and pathological guidelines: report of the Consortium on Dementia with Lewy bodies. Neurology1996; 47: 1113–1124.
21.
. PerryEKMarshallEKerwinJSmithCJJabeenSChengAVPerryRH. Evidence of a monoaminergic cholinergic imbalance related to visual hallucinations in Lewy body dementia. J Neurochem1990; 55: 1454–1456.
22.
. RodriguezMMGrossbergGT. Estrogen as a psychotherapeutic agent. Clinics in Geriatric Medicine1998; 14: 177–189.
23.
. PerryEKCourtJGoodchileR. Clinical neurochemistry: new opportunities for research into brain aging and dementia. J Neural Transmission1998; in press.
24.
. HobsonJA. Sleep and dreaming: induction and mediation of REM sleep by cholinergic mechanisms. Current Opinion in Neurobiology1992; 2: 759–763.
25.
. TariotPNPatelSVCoxCHendersonRE. Age-related decline in central cholinergic function demonstrated with scopolamine. Psychopharmacol1996; 125: 50–56.
26.
. CourtJMPerryEKGriffithsMLloydSJohnsonMPiggottMIncePPerryRH. Cholinergic nicotinic and muscarinic receptor binding in the developing and aging human hippocampus. Devel Brain Res1997; 101: 93–105.
27.
. PerryEKPerryRH. Acetylcholine and hallucinations, disease-related compared to drug induced alterations in human consciousness. Brain and Cognition1995; 28: 240–258.
28.
. PerryEK. Cholinergic phytochemicals from magic to medicine. Aging and Mental Health1997; 1: 23–32.
29.
. BrizerDAManningDW. Delirium induced by poisoning with anticholinergic agents. Am J Psych1982; 139: 1342–1344.
30.
. LindstromJ.Nicotinic acetylcholine receptors in health and disease. Mol Neurobiol1997; 15: 193–221.
31.
. PerryRHIrvingDBlessedGFairbairnAFPerryEK. Senile dementia of Lewy body type: a clinically and pathologically distinct form of Lewy body dementia in the elderly. J Neurol Sciences1990; 95: 119–139.
32.
. CummingsJT. Changes in neuropsychiatric symptoms as outcome measures in clinical trials with cholinergic therapies foe Alzheimer's disease. Alzheimer's disease and associated disorders1997; 11, suppl 4: 51–59.
33.
. LiHYBlausteinJDDe VriesGLWadeGN. Estrogen-receptor immunoreactivity in hamster brain: Preoptic area, hypothalamus and amygdala. Brain Research1993; 631: 304–312.
34.
. LehmanMNEblingFJMoenterSMKarschFJ. Distribution of estrogen receptor-immunoreactive cells in the sheep brain. Endocrinology1993; 133: 876–886.
35.
. Toran-AllerandCDMirandaRCBenthamWDSohrabjFBrownTJHochbergRBMacLuskeyNJ. Estrogen receptors colocalize with low-affinity nerve growth factor receptors in cholinergic neurons of the basal forebrain. Proceedings National Academy of Sciences, USA1992; 89: 4668–4672.
36.
. LuineVNParkVNJohTReisDMcEwanBS. Immunochemical demonstration of increased choline acetyltransferase concentration in rat proptic area after estradiol administration. Brain Research1980; 191: 273–277.
37.
. LuineVN. Estradiol increases choline acetyltransferase activity in specific basal forebrain nuclei and projection areas of female rats. Experimental Neurology1985; 89: 484–490.
38.
. GibbsRBPfaffDW. Effects of estrogen and fimbria/fornix transection on p75(NGFR) and ChAT expression in the medial septum and diagonal band of Broca. Experimental Neurology1992; 116: 23–39.
39.
. MorleyBJRodriguez-SierraJFCloughRW. Increase in hypothalamic nicotinic acetylcholine receptors in prepubertal female rats administered estrogen. Brain Resaerch1983; 453: 389–392.
40.
. HonjoHTamuraTMatsumoto. Estrogen as a growth factor to central nervous cells. Estrogen treatment promotes development of acetylcholinesterase positive basal forebrain neurons transplanted in the anterior eye chamber. Journal of Steroid Biochemistry and Molecular Biology1992; 41: 633–635.
41.
. GibbsRBHashashAJohnsonDA. Effects of estrogen on potassium-stimulated acetylcholine release in the hippocampus and overlying cortex of adult rats. Brain Research1997; 749: 143–146.
42.
. PintoSVirdisAGhiadoniLBerniniGLombardoMPetragliaFGenazziniARTaddeiSSalvettiA.Endogenous estrogen and acetylcholine induced vasodilation in normotensive women. Hypertension1997; 29: 268–273.
43.
. TaddeiSVirdisAGhiadoniLMatteiPSudanoIBerniniGPintoSSalvettiA.Menopause is associated with endothelial dysfunction in women. Hypertension1996; 28: 576–582.
44.
. GilliganDMBadarDMPanzaJAQuyyamiAACannonRO. Effects of estrogen replacement therapy on peripheral vasomotor function in postmenopausal women. A Medical Journal of Cardiology1995; 75: 264–268.
. BehlCWidmannMTrappTHolsboerF.17-beta estradiol protects neurons from oxidative stress - induced cell death in vitro. Biochem Biophysical Research Communications1995; 216: 473–482.
47.
. PrasherVPKrishnanVHR. Age of onset and duration of dementia in people with Down syndrome: Integration of 98 reported cases in the literature. Int J Geriatric Psych1993; 8: 915–922.
48.
. MaziereM.Cholinergic neurotransmission studied in vivo using positron emission tomography or single photon emission computerized tomography. Pharmacology Therapeutics1995; 66: 83–101.
49.
. SchneiderLSFarlowM.Combined tacrine and estrogen replacement therapy in patients with Alzheimer's disease. Annals New York Academy of Sciences1997; 836: 317–322.
50.
. GhuraHSFrancisRWeddellAPerryRPerryEFairbairnA.Oestrogen and sex hormone binding globulin concentrations in Alzheimer's disease. Alzheimer's Research1997; 3: 191–194.
