Combined Therapy for Alzheimer's Disease: Tacrine and PAMAM Dendrimers Co-Administration Reduces the Side Effects of the Drug without Modifying its Activity.

Alzheimer's disease has become a public health priority, so an investigation of new therapies is required. Tacrine (TAC) was licensed for treatments; however, its oral administration caused hepatotoxicity, so it is essential to reduce the side effects. PAMAM dendrimer generation 4.0 and 4.5 (DG4.0 and DG4.5) can be used as drug delivery systems and as nanodrugs per se. Our work aims to propose a combined therapy based on TAC and PAMAM dendrimer co-administration. TAC and dendrimer interactions were studied by in vitro drug release, drug stability, and FTIR. The toxicity profile of co-administration was evaluated in human red blood cells, in Neuro-2a cell culture, and in zebrafish larvae. Also, the anti-acetylcholinesterase activity was studied in cell culture. It was possible to obtain DG4.0-TAC and DG4.5-TAC suspensions, without reducing the drug solubility and stability. FTIR and in vitro release studies confirmed that interaction between TAC and DG4.5 was of the electrostatic type. No toxicity effects on human red blood cells were observed, whereas the co-administration with DG4.5 reduced cytotoxicity of TAC on the Neuro-2a cell line. Moreover, in vivo co-administration of both DG4.0-TAC and DG4.5-TAC reduced the morphological and hepatotoxic effects of TAC in zebrafish larvae. The reduction of TAC toxicity was not accompanied by a reduction in its activity since the anti-acetylcholinesterase activity remains when it is co-administrated with dendrimers. In conclusion, the co-administration of TAC with both DG4.0 and DG4.5 is a novel therapy since it was less-toxic, was more biocompatible, and has the same effectiveness than the free drug. Graphical abstract.

Large-scale in silico identification of drugs exerting sex-specific effects in the heart.

BACKGROUND: Major differences exist between men and women in both physiology and pathophysiology. Dissecting the underlying processes and contributing mechanisms of sex differences in health and disease represents a crucial step towards precision medicine. Considering the significant differences between men and women in the response to pharmacotherapies, our aim was to develop an in silico model able to predict sex-specific drug responses in a large-scale. METHODS: For this purpose, we focused on cardiovascular effects because of their high morbidity and mortality. Our model predicted several drugs (including acebutolol and tacrine) with significant differences in the heart between men and women. To validate the sex-specific drug responses identified by our model, acebutolol was selected to lower blood pressure in spontaneous hypertensive rats (SHR), tacrine was used to assess cardiac injury in mice and metformin as control for a non-sex-specific response. RESULTS: As our model predicted, acebutolol exhibited a stronger decrease in heart rate and blood pressure in female than male SHRs. Tacrine lowered heart rate in male but not in female mice, induced higher plasma cTNI level and increased cardiac superoxide (DHE staining) generation in female than male mice, indicating stronger cardiac toxicity in female than male mice. To validate our model in humans, we employed two Chinese cohorts, which showed that among patients taking a beta-receptor blocker (metoprolol), women reached significantly lower diastolic blood pressure than men. CONCLUSIONS: We conclude that our in silico model could be translated into clinical practice to predict sex-specific drug responses, thereby contributing towards a more appropriate medical care for both men and women.

Tacrine-propargylamine derivatives with improved acetylcholinesterase inhibitory activity and lower hepatotoxicity as a potential lead compound for the treatment of Alzheimer's disease.

A series of tacrine-propargylamine derivatives were synthesised and evaluated as possible anti-Alzheimer's disease (AD) agents. Among these derivatives, compounds 3a and 3b exhibited superior activities and a favourable balance of AChE and BuChE activities (3a: IC50 values of 51.3 and 77.6 nM; 3b: IC50 values of 11.2 and 83.5 nM). Compounds 3a and 3b also exhibited increased hAChE inhibitory activity compared with tacrine by approximately 5- and 28-fold, respectively, and low neurotoxicity. Importantly, these compounds also had lower hepatotoxicity than tacrine. Based on these results, compounds 3a and 3b could be considered as potential lead compounds for the treatment of AD and other AChE related diseases, such as schizophrenia, glaucoma and myasthenia gravis.

Tacrine and its analogues impair mitochondrial function and bioenergetics: a lipidomic analysis in rat brain.

Tacrine is an acetylcholinesterase (AChE) inhibitor used as a cognitive enhancer in the treatment of Alzheimer's disease (AD). However, its low therapeutic efficiency and a high incidence of side effects have limited its clinical use. In this study, the molecular mechanisms underlying the impact on brain activity of tacrine and two novel tacrine analogues (T1, T2) were approached by focusing on three aspects: (i) their effects on brain cholinesterase activity; (ii) perturbations on electron transport chain enzymes activities of non-synaptic brain mitochondria; and (iii) the role of mitochondrial lipidome changes induced by these compounds on mitochondrial bioenergetics. Brain effects were evaluated 18 h after the administration of a single dose (75.6 µmol/kg) of tacrine or tacrine analogues. The three compounds promoted a significant reduction in brain AChE and butyrylcholinesterase (BuChE) activities. Additionally, tacrine was shown to be more efficient in brain AChE inhibition than T2 tacrine analogue and less active than T1 tacrine analogue, whereas BuChE inhibition followed the order: T1 > T2 > tacrine. The studies using non-synaptic brain mitochondria show that all the compounds studied disturbed brain mitochondrial bioenergetics mainly via the inhibition of complex I activity. Furthermore, the activity of complex IV is also affected by tacrine and T1 treatments while FoF(1) -ATPase is only affected by tacrine. Therefore, the compounds' toxicity as regards brain mitochondria, which follows the order: tacrine >> T1 > T2, does not correlate with their ability to inhibit brain cholinesterase enzymes. Lipidomics approaches show that phosphatidylethanolamine (PE) is the most abundant phospholipids (PL) class in non-synaptic brain mitochondria and cardiolipin (CL) present the greatest diversity of molecular species. Tacrine induced significant perturbations in the mitochondrial PL profile, which were detected by means of changes in the relative abundance of phosphatidylcholine (PC), PE, phosphatidylinositol (PI) and CL and by the presence of oxidized phosphatidylserines. Additionally, in both the T1 and T2 groups, the lipid content and molecular composition of brain mitochondria PL are perturbed to a lesser extent than in the tacrine group. Abnormalities in CL content and the amount of oxidized phosphatidylserines were associated with significant reductions in mitochondrial enzymes activities, mainly complex I. These results indicate that tacrine and its analogues impair mitochondrial function and bioenergetics, thus compromising the activity of brain cells.

Evaluation of anti-amnesic effect of Conyza bonariensis in rats.

OBJECTIVE: Conyza bonariensis is an ornamental medicinal weed. This experiment was planned to explore the outcome of petroleum ether extract of C. bonariensis (PECB) leaves on scopolamine-induced amnesia in rats. MATERIALS AND METHODS: For impairing memory, 0.4 mg/kg (i. p.) of scopolamine was given. Fifty to 200 mg/kg of PECB was fed orally to rats and 3 mg/kg (i. p.) of tacrine was given as a standard drug. Anti-amnesic property was evaluated in Barnes maze using ANY-maze software. Following a behavioral study, acetylcholinesterase (AChE), ß-amyloid1-41, antioxidant enzymes, and cytokine levels were measured. Furthermore, reverse transcription-polymerase chain reaction was done for expression of the marker genes such as AChE, Nrf2, NF-κB, PP2A, and HO-1, whereas BDNF, TrkB, caspase-3, and Bax were measured by Western blotting. RESULTS: PECB and tacrine significantly improved memory dysfunction by decreasing escape latency in Barnes maze. At the highest dose, treatment with PECB altered the scopolamine-induced hyperactivation of AChE and ß-amyloid1-41 activity. PECB elevated the levels of superoxide dismutase, glutathione, and catalase and decreased lipid peroxidation and nitric oxide dose dependently. PECB attenuated scopolamine-induced increase of tumor necrosis factor-α and interleukin (IL)-1ß concentrations in the hippocampus with reversed diminished IL-10 level toward normal in the brain. Nrf2, HO-1, PP2A, BDNF, and TrkB were significantly upregulated with downregulation of AChE, NF-κB, Tau, Bax, and caspase-3. Different components such as beta-amyrin and alpha-amyrin were isolated from leaves of the plant. CONCLUSION: The results indicated that PECB might be a potential curative drug for the treatment of cognitive impairment.

Pharmacokinetic and pharmacodynamic properties of cholinesterase inhibitors donepezil, tacrine, and galantamine in aged and young Lister hooded rats.

Physiological alterations that may change pharmacological response accompany aging. Pharmacokinetic/pharmacodynamic properties of cholinesterase inhibitors (ChEIs) used in the treatment of Alzheimer's disease, donepezil, tacrine, and galantamine, were investigated in an aged Lister hooded rat model. Intravenous and oral 6-h blood sampling profiles in old (30 months old) and young (7 months old) rats revealed pharmacokinetic changes similar to those in humans with an approximately 40% increase in C(max) of galantamine and prolonged t(1/2) (1.4-fold) and mean residence time (1.5-fold) of donepezil. Tacrine disposition was maintained with age, and area under the concentration-time curve and clearance in old rats were similar to those in young rats for all drugs tested as was bioavailability. Old rats showed a trend of increased pharmacodynamic sensitivity (<20%) to ChEIs in cholinesterase activity assays, which was attributed to pharmacokinetic effects because a trend of higher blood and brain concentrations was seen in the old rats although brain/blood ratios remained unaffected. Enhanced cholinergic-mediated behaviors such as tremor, hypothermia, salivation, and lacrimation were also observed in the old rats, which could not be accounted for by a similar magnitude of change in pharmacokinetics. A decrease in expression of muscarinic acetylcholine receptor subtype 2 detected in old rat brains was postulated to play a role. Greater age effects in both pharmacokinetics and pharmacodynamics of donepezil and tacrine were seen in previous studies with Fischer 344 rats, indicating a potential risk in overreliance on this rat strain for aging studies.

Delayed evacuatory function due to specific smooth muscle reactivity in the gastrointestinal tracts of tacrine-treated rats.

Most of the side effects induced by tacrine are associated with the gastrointestinal (GI) tract. The aim of the study was to analyze the nature of radiographically registered, tacrine-induced changes in evacuatory function, as well as to find a possible correlation with the immediate in vitro action of the drug on smooth muscles from the GI tracts of rats. The tacrine dose we used reliably delayed GI passage: contrast matter was not fully evacuated, predominantly from the stomach and cecum. The delay resulted from changes in tone and peristaltic activity, specific for the various regions of the tract. These changes were associated with a superposing of the responses due to the anticholinesterase and noncholinergic action of tacrine.

Evaluation of centrally acting cholinesterase inhibitor exposures in adults.

BACKGROUND: There are 4 centrally acting cholinesterase inhibitors (CA-ChEI) available in the US: tacrine, galantamine, rivastigmine, and donepezil. Documented clinical experience involving exposure to these agents is limited. The lack of information makes decisions involving excessive or unintended CA-ChEI exposure difficult. OBJECTIVE: To assess the effects, demographics, and outcomes of CA-ChEI exposures reported to US poison centers. METHODS: A retrospective review of the Toxic Exposure Surveillance System of the American Association of Poison Control Centers data of acute and acute-onchronic exposures involving only a CA-ChEI in patients 19 years of age or older with documented medical outcomes from 2000-2005 was performed. RESULTS: There were 1026 records that met criteria for this study. Patients aged 70-89 years made up 73% of reports; 69% of the patients were female. Moderate (197) and major outcomes (20) accounted for 21% of exposures. There were no deaths. Clinical effects that occurred in 5% or more of patients included vomiting (34%), nausea (28%), diarrhea (12%), dizziness/vertigo (9.9%), drowsiness/lethargy (7.7%), diaphoresis (7.4%), tremor (5.2%), and bradycardia (5%). Patients were admitted to the hospital in 19% of all exposures. Of those patients, 42% were admitted to a critical care unit. The majority (65%) of exposures were attributed to unintentional therapeutic error. Patients received at least one form of therapy in 47% of exposures, including intravenous fluid (111), antiemetic (48), atropine (17), benzodiazepine (15), oxygen (14), antihypertensive (4), pralidoxime (4), intubation (3), antihistamine (2), antiarrhythmic (1), anticonvulsant (1), and pacemaker (1). CONCLUSIONS: The majority of patients evaluated in this retrospective study experienced no or mild effect; however, significant or life-threatening effects were observed in a small group of patients and an appreciable number of patients were admitted to a healthcare facility.

The role of cytochrome P450 enzymes in hepatic and extrahepatic human drug toxicity.

The human cytochrome P450 enzyme system metabolises a wide array of xenobiotics to pharmacologically inactive metabolites, and occasionally, to toxicologically active metabolites. Impairment of cytochrome P450 activity, which may be either genetic or environmental, may lead to toxicity caused by the parent compound itself. In practise, this usually only applies to drugs that have a narrow therapeutic index and when their clearance is critically dependent upon the fraction normally metabolised by that pathway. P450 enzymes may also convert the drug to a chemically reactive metabolite, which, if not detoxified, may lead to various forms of hepatic and extrahepatic toxicity, including cellular necrosis, hypersensitivity, teratogenicity, and carcinogenicity, depending on the site of formation and the relative stability of the metabolite, and the cellular macromolecule with which it reacts. Variation in the regulation and expression of the drug metabolising enzymes may play a key role in both interindividual variation in sensitivity to drug toxicity and tissue-specific damage. Avoidance of toxicity may be possible in rare instances by prediction of individual susceptibility or by designing new chemical entities that are metabolised by a range of enzymes (both cytochromes P450 and others) and do not undergo bioactivation.

Effectiveness and safety of velnacrine for the treatment of Alzheimer's disease. A double-blind, placebo-controlled study. Mentane Study Group.

BACKGROUND: Alzheimer's disease is characterized by cognitive and behavioral disturbances that are mediated in part by cholinergic brain deficits. OBJECTIVE: To evaluate the long-term effectiveness and safety of an investigational cholinesterase inhibitor, that is, velnacrine maleate, in treating patients with clinically probable Alzheimer's disease (according to the criteria of the National Institute of Neurological Disorders and Stroke [Washington, DC]-Alzheimer Disease and Related Disorders Association [Chicago, Ill]). METHODS: This was a double-blind, placebo-controlled study. After a single-blind washout period, patients were randomized to receive placebo (n = 152), velnacrine maleate, 150 mg/d (n = 149), or velnacrine maleate, 225 mg/d (n = 148) for 24 weeks. Primary end points were cognitive behavior and memory components of the Alzheimer's Disease Assessment Scale and the Clinical Global Impression of Change scale. Secondary end points were caregiver-rated scales. RESULTS: The scores for the cognitive behavior and memory components of the Alzheimer's Disease Assessment Scale deteriorated in the placebo-treated group (P < .05) but not in the velnacrine-treated groups. Between-group comparisons favored velnacrine maleate, 225 mg over 150 mg (P < .05). Findings were similar for the Clinical Global Impression of Change scale and three of the four caregiver-rated scales. Treatment-related adverse clinical events occurred in 36%, 28%, and 30% of patients in the groups that received placebo, velnacrine maleate (150 mg), and velnacrine maleate (225 mg), respectively. The most common adverse clinical event was diarrhea, which rarely interrupted therapy. Treatment was stopped because of reversible abnormal liver function test results (five or more times the upper limits of normal) in 3%, 30%, and 24% of the patients who received placebo, velnacrine maleate (150 mg), and velnacrine maleate (225 mg), respectively. CONCLUSIONS: Velnacrine produces modest but significant benefits in patients with Alzheimer's disease. Velnacrine maleate (225 mg) is more effective than 150 mg of velnacrine. Both dosages have acceptable safety profiles.

Multifunctional tacrine-trolox hybrids for the treatment of Alzheimer's disease with cholinergic, antioxidant, neuroprotective and hepatoprotective properties.

Combining tacrine with trolox in a single molecule, novel multifunctional hybrids have been designed and synthesized. All these hybrids showed ChE inhibitory activity in nanomolar range and strong antioxidant activity close to the parent compound trolox. Among them, compound 6d was the most potent inhibitor against AChE (IC50 value of 9.8 nM for eeAChE and 23.5 nM for hAChE), and it was also a strong inhibitor to BuChE (IC50 value of 22.2 nM for eqBuChE and 20.5 nM for hBuChE). Molecular modeling and kinetic studies suggested that 6d was a mixed-type inhibitor, binding simultaneously to CAS and PAS of AChE. In vivo hepatotoxicity assays indicated that 6d was much less toxic than tacrine. In addition, it showed neuroprotective effect and good ability to penetrate the BBB. Overall, all these results highlighted 6d a promising multifunctional agent for AD treatment.

Use of tacrine hydrochloride (Cognex) in private practice.

Before administering tacrine hydrochloride (Cognex), an examination is conducted that includes a medical history, neurological examination, laboratory studies, EEG, CT or MRI, and sometimes lumbar puncture. Much consideration by physicians patients, and caregivers goes into the decision to prescribe Cognex. Aside from a diagnosis of mild to moderate Alzheimer's disease, the patient must be in good health. Patient and caregivers must accept the need for weekly ALT measurements for at least the first 18 weeks of treatment, and for periodic office evaluations. Many of our patients who have received Cognex show considerable improvement in overall sense of well-being, affect, and the abilities to converse and participate in daily activities. The most common adverse effects in our patients are nausea, vomiting, and gastrointestinal upset. In our experience, administration of Cognex extends the time that patients with AD can function in a home environment. This approach often represents a cost savings to the patient's family.

Evaluation of tacrine hydrochloride (Cognex) in two parallel-group studies.

The efficacy of tacrine hydrochloride (Cognex) for the treatment of Alzheimer's disease (AD) has been confirmed in two randomized, double-blind, placebo-controlled, parallel-group studies. More than 1100 patients with mild to moderate, probable AD were randomized to receive placebo or tacrine for 12 or 30 weeks. Outcome measures included objective assessments of cognitive function, qualitative assessments of treatment response from the caregiver and clinician perspective, and assessments of activities of daily living. Statistically significant treatment effects favoring tacrine were demonstrated in each domain. These results suggest several considerations for clinicians. Because response to treatment is dose related, patients should be titrated to their maximum tolerated dose. Response may be subtle and may range from improvement to stabilization or slowed decline. A minimum treatment period of 6 months is recommended to evaluate a response and treatment should be continued depending on patient tolerability.

Clinical trials with velnacrine: (PROPP) the physician reference of predicted probabilities--a statistical model for the estimation of hepatotoxicity risk with velnacrine maleate.

Safety observations during the clinical development of Mentane (velnacrine maleate) have included the occurrence of generally asymptomatic liver enzyme elevations confined to patients with Alzheimer's disease (AD). The clinical presentation of this reversible hepatocellular injury is analogous to that reported for tetrahydroaminoacridine (THA). Direct liver injury, possibly associated with the production of a toxic metabolite, would be consistent with reports of aberrant xenobiotic metabolism in Alzheimer's disease patients. Since a patient related aberration in drug metabolism was suspected, a biostatistical strategy was developed with the objective of predicting hepatotoxicity in individual patients prior to exposure to velnacrine maleate. The method used logistic regression techniques with variable selection restricted to those items which could be routinely and inexpensively accessed at screen evaluation for potential candidates for treatment. The model was to be predictive (a marker for eventual hepatotoxicity) rather than a causative model, and techniques employed "goodness of fit", percentage correct, and positive and negative predictive values. On the basis of demographic and baseline laboratory data from 942 patients, the PROPP statistic was developed (the Physician Reference Of Predicted Probabilities). Main effect variables included age, gender, and nine hematological and serum chemistry variables. The sensitivity of the current model is approximately 49%, specificity approximately 88%. Using prior probability estimates, however, in which the patient's likelihood of liver toxicity is presumed to be at least 30%, the positive predictive value ranged between 64-77%. Although the clinical utility of this statistic will require refinements and additional prospective confirmation, its potential existence speaks to the possibility of markers for idiosyncratic drug metabolism in patients with Alzheimer's disease.

Side effects of long acting cholinesterase inhibitors.

This paper reviews the side effects of the two long acting cholinesterase inhibitors tacrine and velnacrine. It will focus on tacrine which has been most studied. The two drugs are special as the dosage of them is guided mainly by side effects and not by therapeutic effects in contrast to most drugs used for psychiatric disorders.

Serum concentrations of tacrine hydrochloride predict its adverse effects in Alzheimer's disease.

OBJECTIVE: To assess the value of serum measurements of tacrine hydrochloride and its metabolite in predicting risk of adverse reaction in Alzheimer's disease. METHODS: The study was an outpatient-based controlled clinical trial. Study subjects were 35 female and 31 male patients who were receiving 50 to 150 mg tacrine hydrochloride per day. RESULTS: Serum concentration of tacrine hydrochloride and ratio of tacrine hydrochloride to metabolite were significantly higher in the 45 patients with symptomatic adverse effects (p < 0.001). The tacrine hydrochloride to metabolite ratio was significantly higher (p < 0.05) in the 30 patients in whom abnormal liver function developed, but concentration of tacrine hydrochloride was not significantly higher. Women showed a higher incidence of adverse effects (p < 0.05), and tacrine hydrochloride concentrations were higher (p < 0.05). Tacrine hydrochloride concentration and tacrine hydrochloride to metabolite ratio were higher in both men and women in whom adverse effects developed. CONCLUSION: Tacrine hydrochloride concentration is valuable in predicting the development of adverse effects, and its measurement may improve the use of the drug.

Pharmacokinetics of tacrine hydrochloride in Alzheimer's disease.

The clinical pharmacokinetics of tacrine hydrochloride have been characterized in patients who have Alzheimer's disease. Serum concentrations of the drug and of its probable metabolite were monitored in eight patients after a 25 mg oral dose, in six patients after a 50 mg oral dose, in four patients after repeated administration of 50 mg, and in two patients after a small intravenous dose. Urinary excretion of drug and metabolite for 24 hours was measured in one of the patients who received a small intravenous dose. The serum half-life was 1.59 +/- 0.15 hours (mean +/- SEM) after the 25 mg dose, 2.14 +/- 0.24 hours after the 50 mg dose, and 2.91 +/- 0.39 hours after continuous treatment. After intravenous administration, clearance was above 600 ml/min in both patients, and oral bioavailability was calculated at below 5%. Urine recovery was less than 3% of the dose. The low bioavailability of tacrine hydrochloride is partly explained by presystemic metabolism.

Combined glutathione-S-transferase M1 and T1 genetic polymorphism and tacrine hepatotoxicity.

BACKGROUND: Glutathione conjugation of tacrine reactive metabolites depends in part on the activity of glutathione-S-transferases (GST), of which two isozymes (GST M1 and GST T1) are polymorphically expressed. OBJECTIVE AND METHODS: To determine whether GST M1, GST T1, and the combined GST M1 and GST T1 null genotypes predict individual susceptibility to tacrine hepatotoxicity, 141 patients with mild to moderate Alzheimer's disease treated with tacrine were genotyped. RESULTS: During the treatment period, 52 patients had elevated alanine aminotransferase (ALT) levels at least three times the upper limit of normal, whereas 89 patients had normal ALT values (< or = upper limit of normal). Both groups were comparable in demographic and clinical characteristics. Twenty-eight patients were found to be GST T1-negative (20%; with a 95% confidence interval [95% CI] from 13% to 27%), and 68 patients (48%; 95% CI from 40% to 57%) were GST M1-negative. The combined GST M1-T1 null genotype was observed in 18 patients (13%; 95% CI from 7% to 18%) of whom 13 had an elevated plasma ALT at least three times the upper limit of normal during the study period. Although the cumulative percentage of elevated plasma ALT tended to be higher in the GST M1 null genotype, neither GST M1 nor GST T1 alone could predict individual susceptibility to tacrine hepatotoxicity. Multivariate Cox hazards model showed that the association of the GST M1-T1 null genotype was an independent risk factor of hepatotoxicity. CONCLUSIONS: The presence of combined alleles M1 and T1 deficiencies in glutathione-S-transferase genes increases the susceptibility to tacrine hepatotoxicity.

Prospects for pharmacological intervention in Alzheimer disease.

Alzheimer disease (AD) involves neuronal degeneration with impaired cholinergic transmission in the cerebral cortex and hippocampus in areas of the brain particularly associated with memory and higher intellectual functioning. Other neurotransmitter deficits also occur, but the mechanisms underlying the widespread impairment of synaptic functions remain uncertain. Research on the molecular basis of AD has elucidated a pathogenic pathway from which a range of rational pharmacological interventions has emerged. Although at least 3 cholinesterase inhibitors (tacrine hydrochloride, donepezil, and rivastigmine tartrate) are now available and provide patients with modest relief, the most promising strategy involves approaches to retarding, halting, or preventing the formation or accumulation of beta-amyloid (Abeta) plaques. Estrogen is believed to have antioxidant or other anti-Abeta effects, as hormonal replacement therapy in women with menopause is associated with a reduced risk or delayed onset of AD. The association between nonsteroidal anti-inflammatory drugs and a reduced risk of AD has not yet been confirmed, but these agents may protect the brain from the reactive glial and microglial responses associated with Abeta deposition. Also, recent studies suggested that antioxidants, such as vitamin E taken alone or in combination with selegiline hydrochloride, can delay the progression of AD. Despite these encouraging results, no current therapy has been shown to halt or reverse the underlying disease process. The proof of the principle that anti-Abeta drugs will work in the transgenic models of AD is eagerly awaited with the expectation that they will eventually prove successful in humans.