Abrogation of autoimmune disease in Lyn-deficient mice by the mutation of the Btk gene

Alzheimer's disease (AD) is associated with a reduction in cholinergic activity as a result of specific neuronal loss. Current potential treatments for the disease include both cholinomimetic drugs and anticholinesterase inhibitors. One of the drugs approved by the FDA is tacrine (9-amine-1,2,3,4 tetrahydroacridine; THA), a strong acetylcholinesterase (AChE) inhibitor. We have studied the effects of tacrine on glial and neuronal cells in culture assessing cell survival and viability and morphology. Lactate dehydrogenase (LDH) activity and methylthiazol-diphenyl-tetrazolium (MTT) reduction were used as toxicity indicators. We found that tacrine toxicity on rat B12 glial cells and mouse Neuro 2A cells was strongly dependent on its concentration (up to 500 microM) and time of exposure. The toxic effect was not prevented by serum factors nor by bovine serum albumin. Fluorescein-conjugated phalloidin was used to examine the arrangement of actin filaments at substrate adhesion regions and cell-cell contacts. Primary events following exposure to tacrine included changes in cell morphology, disappearance of actin filament bundles, and disruption of focal adhesion contacts. At concentrations between 10 and 50 microM, tacrine induced neurite outgrowth in Neuro 2A cells, an effect that was not observed in B12 cells, suggesting that certain tacrine effects could be specific for neuronal cells. Although similar trends of response were observed for both cell types, some differences between undifferentiated and differentiated cells were apparent.     

Central cardiovascular effects of tacrine in the conscious dog: a role for catecholamines and vasopressin release

Centrally acting cholinergic agents are currently reported to increase blood pressure in various species through the stimulation of muscarinic cholinoceptors. Moreover, several cardiovascular adverse effects have been reported from clinical studies. The aim of this study was to investigate the effects of tacrine, an acetylcholinesterase inhibitor which has been reported to have therapeutic potential in Alzheimer's disease, on blood pressure and two vasopressor systems (sympathetic and vasopressinergic) in Beagle dogs. Intravenous (i.v.) tacrine (2 mg kg(-1)) induced, in conscious and anesthetized dogs, an increase in systolic and diastolic blood pressure, accompanied by bradycardia. This increase was dose-dependent with a peak effect at 1.5 min following administration. Tacrine also induced an increase in noradrenaline, adrenaline and vasopressin plasma levels. Pretreatment with the muscarinic receptor antagonist, atropine (2 mg kg(-1), i.v.), abolished the pressor response to i.v. injection of tacrine while pretreatment with the peripheral muscarinic receptor antagonist, methylscopolamine (0.2 mg kg(-1), i.v.), did not alter the increase in blood pressure. Similarly, noradrenaline and adrenaline changes in plasma levels were not modified by methylscopolamine but were abolished by atropine pretreatment. A similar tendency although not significant was observed for vasopressin plasma levels. The present results demonstrate that in dogs, tacrine (2 mg kg(-1), i.v.) stimulates central muscarinic cholinoceptors to increase blood pressure through activation of the two components of the sympathetic nervous system (i.e., neuroneuronal noradrenergic and the neurohormonal adrenergic pathways) as well as through increasing noradrenaline, adrenaline and vasopressin plasma levels.     

Cholinesterase inhibitors in the treatment of Alzheimer's disease: a comparison of tolerability and pharmacology

Cholinesterase inhibitors are currently the most established treatment strategy in Alzheimer's disease. The treatment effect appears mainly to be symptomatic. Effects on progression of the disease following long term treatment, and possible neuroprotective effects, have been investigated. Delay until nursing home placement has been reported. Three cholinesterase inhibitors, tacrine, donepezil and rivastigmine, are in clinical use. Other cholinesterase inhibitors, such as galantamine (galanthamine), metrifonate, physostigmine, eptastigmine, are currently under clinical evaluation. So far the efficacy appears to be comparable between the various cholinesterase inhibitors; treatment for up to 6 months has produced an improvement in Alzheimer's Disease Assessment Scale -- Cognitive Subscale score (ADAS-cog) of between 1.8 and 4.9 in patients with Alzheimer's disease. Tacrine, donepezil, galantamine and physostigmine are reversible inhibitors of acetylcholinesterase and butyrylcholinesterase, while metrifonate is considered to be an irreversible inhibitor and rivastigmine a pseudoirreversible inhibitor. Tacrine and physostigmine have lower bioavailability, 17 to 37% and 3 to 8%, respectively, than the other cholinesterase inhibitors such as rivastigmine, galantamine and donepezil (40 to 100%). The elimination half-life is considerably longer for donepezil (70 to 80h) in comparison to most of the other cholinesterase inhibitors (0.3 to 12h). Donepezil is therefore administered once daily in comparison to rivastigmine which is administered twice daily and tacrine which is administered 4 times daily. Simultaneous food intake lowers the plasma concentration of tacrine and reduces the adverse effects of rivastigmine. Drugs like theophylline and cimetidine have been reported to change the pharmacokinetics of tacrine and donepezil. In contrast, concomitant medication with various drugs with rivastigmine does not seem to cause any drug interactions in patients with Alzheimer's disease. Tacrine, donepezil and galantamine are metabolised via the cytochrome P450 (CYP) liver enzymes. Active metabolites are known for tacrine and galantamine. Rivastigmine is not metabolised via CYP enzymes, but via esterases and is excreted in the urine. Tacrine is associated with hepatotoxicity while other cholinesterase inhibitors seem devoid this adverse effect. Increased liver enzyme values have been observed in 49% of patients with Alzheimer's disease treated with tacrine. Rechallenge with tacrine reduces the incidence of elevated liver enzyme levels. Peripheral cholinergic adverse effects are common for the cholinesterase inhibitors, with an incidence ranging between 7 to 30%. For some cholinesterase inhibitors, such as rivastigmine, the cholinergic adverse effects such as nausea, vomiting, dizziness, diarrhoea and abdominal pain can be reduced by slowing the rate of dose titration.     

Characterization of perforant path lesions in rodent models of memory and attention

Early stage Alzheimer's disease (AD) pathology is associated with neurodegeneration of systems within the temporal cortex, e.g. the entorhinal cortex, perforant pathway and hippocampus. The perforant pathway provides the major neuronal input to the hippocampus from the entorhinal cortex and thus relays multimodal sensory information derived from cortical zones into the hippocampus. The earliest symptoms of AD include cognitive impairments, e.g. deficits in short-term memory and attention. Consequently, we have investigated the effect of bilateral knife cut lesions to the perforant path on cognition in rats using models measuring primarily short-term memory (operant delayed match to position task), attention (serial five-choice reaction time task) and spatial learning (Morris water maze). Rats receiving bilateral perforant path lesions showed normal neurological function and a mild hyperactivity. The lesion produced little effect on attention assessed using the five-choice task. In contrast, animals with equivalent lesions showed a robust delay-dependent deficit in the delayed match to position task. Spatial learning in the water maze task was also severely impaired. The delay-dependent deficit in the match to position task was not reversed by tacrine (3 mg/kg) pretreatment. The present data support a selective impairment of cognitive function following perforant path lesions that was confined to mnemonic rather than attentional processing. These findings complement primate and human studies identifying a critical role of the perforant pathway and associated temporal lobe structures in declarative memory. Degeneration of the perforant pathway is likely to contribute to the mnemonic deficits characteristic of early AD. The failure of tacrine to ameliorate these deficits may be relevant to an emerging clinical literature suggesting that cholinomimetic therapies improve attentional rather than mnemonic function in AD.     

Nerve growth factor: structure, function and therapeutic implications for Alzheimer's disease

Over the past decade, neurotrophic factors have generated much excitement for their potential as therapy for neurological disorders. In this regard, nerve growth factor (NGF), the founding member of the neurotrophin family, has generated great interest as a potential target for the treatment of Alzheimer's disease (AD). This interest is based on the observation that cholinergic basal forebrain (CBF) neurons which provide the major source of cholinergic innervation to the cerebral cortex and hippocampus undergo selective and severe degeneration in advanced AD and that these neurons are dependent upon NGF and its receptors for their survival. In fact, NGF transduces its effects by binding two classes of cell surface receptors, TrkA and p75(NTR), both of which are produced by CBF neurons. This review focuses on NGF/receptor binding, signal transduction, regulation of specific cellular endpoints, and the potential use of NGF in AD. Alterations in NGF ligand and receptor expression at different stages of AD are summarized. Recent results suggest that cognitive deficits in early AD and mild cognitive impairment (MCI) are not associated with a cholinergic deficit. Thus, the earliest cognitive deficits in AD may involve brain changes other than simply cholinergic system dysfunction. Recent findings indicate an early defect in NGF receptor expression in CBF neurons; therefore treatments aimed at facilitating NGF actions may prove highly beneficial in counteracting the cholinergic dysfunction found in end-stage AD and attenuating the rate of degeneration of these cholinergic neurons.     

Pharmacological treatment of Alzheimer's disease: present situation and perspectives

Alzheimer's disease (AD) is the commonest cause of dementia. Although its ethology is unknown, there is increasing evidence in support of the view that an abnormal degradation of the amyloid precursor protein (APP), perhaps influenced by a number of genetic, tisular or environmental factors, may be the primary cause of the many biochemical and morphological disorders that exist in the associative areas of the brain of these patients. Histopathologically it can be shown by the presence of extracellular senile plaques, intraneuronal fibrilar tangles and neuronal loss. There is no specific pharmacological treatment at present to prevent the disease or its development, in spite of the numerous and diverse drugs studied. Many of these studies are methodologically inadequate. The attempt of activating the cholinergic system has deserved special attention. A reversible inhibitor of acetylcholinesterase, tacrine, has been approved in the United States and other countries for the symptomatic treatment of mild to moderate AD, but its use still arises many questions. Different drug and non drug related interventions may be of great value in the care of these patients, and may influence the specific pharmacological treatments. The complexity and heterogeneity of AD and the multiple factors which may take part in its evolution make it necessary to place special attention on the methodological aspects of the clinical trials with new drugs for the treatment of this disease.     

M1 muscarinic agonist treatment reverses cognitive and cholinergic impairments of apolipoprotein E-deficient mice

Recent studies suggest that apolipoprotein E (apoE) plays a specific role in brain cholinergic function and that the E4 allele of apoE (apoE4), a major risk factor for Alzheimer's disease (AD), may predict the extent of cholinergic dysfunction and the efficacy of cholinergic therapy in this disease. Animal model studies relevant to this hypothesis revealed that apoE-deficient (knockout) mice have working memory impairments that are associated with distinct dysfunction of basal forebrain cholinergic neurons. Cholinergic replacement therapy utilizing M1-selective muscarinic agonists has been proposed as effective treatment for AD patients. In the present study, we examined whether the memory deficits and brain cholinergic deficiency of apoE-deficient mice can be ameliorated by the M1-selective agonist 1-methylpiperidine-4-spiro-(2'-methylthiazoline), [AF150(S)]. Treatment of apoE-deficient mice with AF150(S) for 3 weeks completely abolished their working memory impairments. Furthermore, this reversal of cognitive deficit was associated with a parallel increase of histochemically determined brain choline acetyltransferase and acetylcholinesterase levels and with the recovery of these cholinergic markers back to control levels. These findings show that apoE deficiency-related cognitive and cholinergic deficits can be ameliorated by M1-selective muscarinic treatment. They also provide a novel model system for development and evaluation of therapeutic strategies directed specifically at the AD patients whose condition is attributed to the apoE genotype.     

A new method for evaluation of motor deficits in 3-acetylpyridine-treated rats

BACKGROUND: approximately one-third of patients with Alzheimer's disease (AD) respond favourably to the anticholinesterase tacrine, but the drug's usefulness is marred by a high incidence of side-effects. OBJECTIVE: to discover if AD patients with white matter low attenuation (WMLA) represents a subgroup that responds differently to tacrine from those with no WMLA. DESIGN: the results come from a combination of double-blind and open studies. Seventy-two AD patients prescribed tacrine in our centre were divided into two groups according to the presence or absence of WMLA on brain CT scans. We compared the rate of response to and withdrawal from tacrine between the groups. Response was defined as an improvement in the Mini-Mental State Examination score of three or more points at 3 months. RESULTS: 18 of the 72 patients were found to have WMLA. There was no significant difference in the proportion of patients responding to tacrine in each group (28.5% in those with WMLA and 31% in those without), but the rate of withdrawal from tacrine did differ: 11 patients with WMLA (61%) had to be withdrawn prematurely, compared with 14 patients (26%) in the group without evidence of WMLA (P = 0.015). CONCLUSION: AD patients with WMLA can still respond to tacrine, although the rate of withdrawal from treatment is much higher in such patients.     

Treating Alzheimer's disease. Pharmacologic options now and in the near future

Treatment of Alzheimer's disease has in the past been limited to empirical trials of psychotropics for relief of behavioral complications. At present, tacrine and doneprezil are the only FDA-approved antidementia agents available. In the very near future, however, other cholinesterases inhibitors (e.g., ENA 713, metrifonate, long-acting physostigmine) are expected to be approved for clinical use. The evidence at this point suggests that they have modest but meaningful clinical effects and possible long-term benefits. Clinical use of the newer agents is likely to be influenced by their side-effect profiles, which consist largely of cholinergic effects, although without the hepatotoxic effects associated with tacrine. To what extent these agents are accepted by patients and physicians remains to be seen. On the one hand, benefits are modest; on the other, these medications are increasingly safe. Continuing research is clarifying the role of cholinergic therapy in relieving behavioral symptoms, as well as the possible side effects on rates of illness progression, institutionalizaton, and even mortality. In the not-too-distant future, physicians can expect to see a variety of medications, now in early stages of development, that are intended to affect cholinergic systems in other ways. Further down the road, a host of mechanism-based therapeutic strategies, which hope to deal with the first cause of this devastating illness, will have been assessed in clinical trials.     

Amyloid beta-protein reduces acetylcholine synthesis in a cell line derived from cholinergic neurons of the basal forebrain

The characteristic features of a brain with Alzheimer disease (AD) include the presence of neuritic plaques composed of amyloid beta-protein (Abeta) and reductions in the levels of cholinergic markers. Neurotoxic responses to Abeta have been reported in vivo and in vitro, suggesting that the cholinergic deficit in AD brain may be secondary to the degeneration of cholinergic neurons caused by Abeta. However, it remains to be determined if Abeta contributes to the cholinergic deficit in AD brain by nontoxic effects. We examined the effects of synthetic Abeta peptides on the cholinergic properties of a mouse cell line, SN56, derived from basal forebrain cholinergic neurons. Abeta 1-42 and Abeta 1-28 reduced the acetylcholine (AcCho) content of the cells in a concentration-dependent fashion, whereas Abeta 1-16 was inactive. Maximal reductions of 43% and 33% were observed after a 48-h treatment with 100 nM of Abeta 1-42 and 50 pM of Abeta 1-28, respectively. Neither Abeta 1-28 nor Abeta 1-42 at a concentration of 100 nM and a treatment period of 2 weeks was toxic to the cells. Treatment of the cells with Abeta 25-28 (48 h; 100 nM) significantly decreased AcCho levels, suggesting that the sequence GSNK (aa 25-28) is responsible for the AcCho-reducing effect of Abeta. The reductions in AcCho levels caused by Abeta 1-42 and Abeta 1-28 were accompanied by proportional decreases in choline acetyltransferase activity. In contrast, acetylcholinesterase activity was unaltered, indicating that Abeta specifically reduces the synthesis of AcCho in SN56 cells. The reductions in AcCho content caused by Abeta 1-42 could be prevented by a cotreatment with all-trans-retinoic acid (10 nM), a compound previously shown to increase choline acetyltransferase mRNA expression in SN56 cells. These results demonstrate a nontoxic, suppressive effect of Abeta on AcCho synthesis, an action that may contribute to the cholinergic deficit in AD brain.     

Tacrine efficacy in Lewy body dementia

BACKGROUND: Response to tacrine varies among patients with Alzheimer's disease (AD). Lewy body dementia (LBD) could be a high responder subtype of AD. The aim of the study was to compare the effects of tacrine in LBD and AD. METHODS: Seventy-five consecutive outpatients with mild or moderate AD were screened. Tacrine was given at a dose of 40 mg/day during 6 weeks. During the next 6 weeks, the patients were treated with 80 mg/day and afterwards with 120 mg/day. Patients were assessed at baseline and treated with a dose of 120 mg/day tacrine for 2 weeks. RESULTS: Analysis was performed on 39 patients (AD, N = 20; LBD, N = 19). Eight patients were lost to follow-up, eight patients manifested with side-effects, six suffered from an intercurrent somatic disease during the study and 14 patients had poor compliance or were treated with incompatible drugs. Twenty-two patients (11 AD/11 LBD) increased their cognitive performances with tacrine. Among the 22 patients, the improvement differed between the AD and the LBD groups. In AD, conceptualization improved; in LBD, the improvements occurred in verbal initiation and digit span. CONCLUSION: This study emphasizes the importance of using appropriate tests to determine the positive effects of pharmacological treatments.     

Age-related deficits in context discrimination learning in Ts65Dn mice that model Down syndrome and Alzheimer's disease.

All individuals with Down syndrome (DS) eventually develop the neuropathology of Alzheimer's disease (AD), which is characterized by a premature loss of basal forebrain cholinergic neurons. Similarly, between 4 and 6 months of age, Ts65Dn mice, which model DS, lose cholinergic markers in their medial septal neurons. It is not known whether Ts65Dn mice have age-related learning deficits as well. Control and Ts65Dn mice were tested at several ages in context discrimination. Controls at all ages showed no deficits in learning this task. Ts65Dn mice younger than 3 months demonstrated impaired learning, suggesting a possible developmental delay in Ts65Dn mice. Four-month-old Ts65Dn mice showed no deficits, whereas Ts65Dn mice older than 5 months were impaired in learning the task. Therefore, Ts65Dn mice have an age-related learning impairment that coincides with their age-related neuroanatomical abnormalities and, consequently, may be a useful model of AD. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Patients with Alzheimer's disease who cannot perform some motor skills show normal learning of other motor skills.

Previous researchers have claimed that patients with Alzheimer's disease (AD) learn new motor skills normally, although many AD patients cannot perform the tasks and must be eliminated from the analysis. Excluding them assumes that they have a deficit of motor performance (competence to perform the task), but not of motor learning (ability to improve performance). The present study administered 4 motor tasks to 20 AD patients and 20 controls. The results showed that the ability to complete 1 task (performance) did not predict the rate of improvement (learning) on another task, which indicates that AD patients do indeed have a performance deficit and not a general deficit of motor skill learning. Dementia ratings predicted the ability to perform tasks but not the ability to learn them. It is concluded that it is defensible to claim that AD patients learn a motor skill normally, even if some of the patients are unable to perform the task. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Training to criterion in eyeblink classical conditioning in Alzheimer's disease, Down's syndrome with Alzheimer's disease, and healthy elderly.

The cholinergic antagonist scopolamine delays acquisition of eyeblink classical conditioning (EBCC) in rabbits and humans, but scopolamine-treated organisms eventually acquire conditioned responses (CRs). Patients with probable Alzheimer's disease (AD) and older adults with Down's syndrome (DS/AD) have disrupted cholinergic systems and perform EBCC very poorly. It was hypothesized that patients with probable AD and DS/AD, like scopolamine-injected organisms, would acquire CRs if given sufficient training. Twelve probable AD patients, 12 DS/AD patients, and 6 healthy elderly control individuals participated in 5 daily 90-trial sessions of EBCC. Fifty-eight percent of the probable AD, 92% of the DS-AD, and 100% of the control participants achieved learning criterion. Probable AD, DS/AD, and control participants had statistically significant increases in the percentage of CRs produced over 5 EBCC sessions. The neural substrate for EBCC was not eliminated in probable AD or DS/AD patients, although the learning mechanism was disrupted. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Metrifonate improves associative learning and retention in aging rabbits.

The cholinergic system is known to show deterioration during aging and Alzheimer's disease (AD). In response, a therapeutic approach to AD has been to attempt to compensate for the decrease in central cholinergic function by potentiating the activity of the remaining intact cholinergic cells with cholinesterase (ChE) inhibitors. In this study treatment with the long-lasting ChE inhibitor metrifonate facilitated acquisition and retention of eyeblink conditioning in aging rabbits. Metrifonate treatment resulted in steady-state, dose-dependent acetylcholinesterase (AChE) inhibition in red blood cells. Maximal behavioral efficacy was achieved with AChE inhibition of approximately 40%, with no further improvements resulting from increased levels of inhibition. Metrifonate was behaviorally effective in the absence of the severe side effects that can plague ChE inhibitors, supporting metrifonate as a possible treatment for the cognitive deficits resulting from normal aging and AD. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

The management of cryptococcal meningitis in Papua New Guinea

The efficacy of tacrine for treatment of Alzheimer's has been demonstrated in several clinical trials but has not been assessed in cases complicated by medical and psychiatric comorbidities. Additionally, the benefit-risk ratio of tacrine is small, so it is best administered with carefully developed guidelines that specify this ratio for patients and families. On the basis of guidelines developed for the Johns Hopkins Dementia Research Clinic, tacrine treatment was offered to 162 patients with probable Alzheimer's. Only 35 accepted, and only 22 continued on tacrine beyond 3 months. The latter group declined by 1.36 points over 1 year on the Mini-Mental State Examination, significantly less than expected. The authors conclude that, if used in the context of clinical guidelines, tacrine is an effective treatment for Alzheimer's.     

Learning and retention in preclinical and early Alzheimer's disease.

Accelerated forgetting has been proposed as the first sign in preclinical and early Alzheimer's disease (AD). The authors investigated learning and retention in participants who later developed AD with free and cued selective reminding (FCSR; H. Buschke, 1984; E. Grober & H. Buschke, 1987), a test that maximizes learning by inducing deep semantic processing and by controlling study and test conditions. AD patients in the preclinical stage recalled significantly fewer words than did matched control participants, indicating an impairment of learning; nonetheless, patients' retention was identical to that of control participants. A retention deficit was documented 3 years later for AD patients but not for control participants, whose retention was still perfect. Thus, a retention deficit is not present in preclinical AD when hallmark learning deficits can be documented. Detection of preclinical and very early AD may be best accomplished by using robust learning tests that control cognitive processing. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

The cardinal features of cognitive and noncognitive dysfunction and the differential efficacy of tacrine in Alzheimer's disease patients

The Alzheimer's Disease Assessment Scale (ADAS), frequently used in clinical trials to assess overall pathology of Alzheimer's disease (AD), comprises two subscales. The cognitive subscale (ADAS-COG) consists of 11 items, and the noncognitive subscale consists of 9 items. Factor analyses were carried out on ADAS-COG and ADAS-NONCOG item scores from the most recent and largest (n = 663) placebo-controlled, multicenter, 30-week study (970-61) of tacrine in patients with AD conducted by the clinical research group at Parke-Davis Pharmaceutical Research. Through factor analyses the primary dimensions of variation in the ADAS-COG and ADAS-NONCOG were defined. Obliquely rotated three principal factors of ADAS-COG and three principal factors of ADAS-NONCOG have been interpreted as three cardinal features of cognitive function corresponding to memory, language, and praxis, and three cardinal features of noncognitive function corresponding to agitation, depression, and lack of concentration. Reliably defined factors of ADAS-COG enabled comparisons of longitudinal changes in cognitive dysfunction. Factor scores at week 30, adjusted to baseline factor scores, were used to compare the effects of tacrine with those of placebo on cognitive cardinal features. Additionally, the effect of concurrent depression on cardinal features of cognitive dysfunction was evaluated by gender.     

Correlation of nicotinic binding with neurochemical markers in Alzheimer's disease

The loss of neocortical synapses that occurs in Alzheimer's disease (AD) has been shown to correlate with cognitive decline. In addition, marked losses in the cholinergic system in AD, specifically choline acetyltransferase (ChAT) activity and high affinity presynaptic neuronal nicotinic cholinergic receptors (nAChRs), have also been described. We hypothesized that in AD, the loss of [3H]-ligand binding to nAChRs, which are largely presynaptic, would correlate with changes in two other presynaptic markers: synaptophysin (Syn), a measure of synaptic density, and ChAT activity. The midfrontal (MF) cortex of 36 autopsy confirmed (NIA and CERAD criteria) AD patients (mean death age +/- SD 80.1 +/- 8.4 years) who met NINDS-ADRDA criteria for a clinical diagnosis of probable or possible AD, and 11 nondemented controls (mean death age +/- SD 77.9 +/- 8.0) were examined. Synapse counts were quantified by a dotimmunobinding assay for Syn. ChAT activity was assessed by standard biochemical assays. Nicotinic cholinergic receptor binding was assayed using the high affinity nicotinic agonist [3H]-(+/-)-epibatidine ([3H]-EPI). The mean +/- SD Syn in AD (83.4 +/- 31.9 arbitrary units (AU)/mg protein) was significantly lower than controls (126.1 +/- 19.9, p = 0.0003; t-test). The mean ChAT activity in AD (139.0 +/- 75.6 nmol ACh/hr/100 mg protein) was significantly lower than controls (219.6 +/- 70.8, p = 0.004). The mean [3H]-EPI total binding in AD (6.2 +/- 2.8 fmol/mg protein) was significantly lower than controls (14.8 +/- 3.2; p < 0.0001). Syn correlated with [3H]-EPI binding in AD (r = 0.48, p = 0.006; Pearson) but ChAT did not (r = -0.20, p = 0.34). We conclude that loss of high affinity nAChR binding correlates with loss of synapses in AD. The lack of correlation between [3H]-EPI binding and ChAT activity suggests that the targeted receptor populations may not be located exclusively on cholinergic neurons.