Alzheimer Disease: Forlenza OV

Engelhardt E, Brucki SM, Cavalcanti JL, Forlenza OV, Laks J, Vale FA, Anonymous00032. · Setor de Neurologia Cognitiva e do Comportamento, Instituto de Neurologia Deolindo Couto, Universidade Federal do Rio de Janeiro, RJ, Brasil. · Arq Neuropsiquiatr. · Pubmed #16400437 links to  free full text

Abstract: The present recommendations and suggestions on "Treatment of Alzheimer's Disease" were elaborated by a work group constituted by participants of the IV Meeting of Researchers on Alzheimer's Disease and Related Disorders, sponsored by the Scientific Department of Cognitive Neurology and Aging of the Brazilian Academy of Neurology. They comprise topics on pharmacological and non-pharmacological treatment of cognitive impairment and functional decline, as well as of behavioral and psychological symptoms of this dementing disease. Several levels of evidence and of recommendations and suggestions are used for the various proposed drugs, as well as for non-pharmacological treatment, underpinned by a wide national and international bibliographical review.

Forlenza OV, Chiu E. · No affiliation provided · Curr Opin Psychiatry. · Pubmed #18852557 No free full text.

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Diniz BS, Pinto Júnior JA, Forlenza OV. · Laboratory of Neuroscience-LIM 27, Department and Institute of Psychiatry, Faculty of Medicine, University of Sao Paulo, Sao Paulo, Brazil. · World J Biol Psychiatry. · Pubmed #17886169 No free full text.

Abstract: The search for biomarkers as a diagnostic aid to the identification of patients in pre-dementia stages is a fast growing research area. In view of the low specificity attained with the clinically based diagnostic criteria, including those for mild cognitive impairment (MCI), biomarker information will add precision to the incipient dementia diagnostic work-up, particularly Alzheimer's disease (AD). We present a systematic review of the literature and meta-analysis of the most relevant publications about the role of CSF biomarkers in the identification of patients with probable Alzheimer's disease at pre-dementia stages. A total of 16 studies were included in the systematic review, five of which were suitable for meta-analysis. We compared the standard mean differences (SMD) of beta-amyloid 42 (Abeta42), total tau (T-tau) and phosphorylated tau (P-tau) for 130, 169 and 123 patients with MCI who converted to AD (MCI-AD) and 142, 157 and 130 controls, respectively. We conclude that when a clinical diagnosis of MCI is made at baseline assessment, low CSF levels of Abeta42 (SMD: -1.57, CI 95% [-2.30 to -0.84], P < 0.001), along with high T-tau (SMD: 1.52, CI 95% [1.25 to 1.79], P < 0.001), and high P-tau (SMD: 1.75, CI 95% [0.99 to 2.51], P < 0.001), help to predict the conversion to Alzheimer's disease as compared to controls subjects.

Forlenza OV, Schaeffer EL, Gattaz WF. · Laboratory of Neuroscience, Department & Institute of Psychiatry, Faculty of Medicine, University of São Paulo, São Paulo, Brazil. · J Neural Transm. · Pubmed #17131232 No free full text.

Abstract: Phospholipase A(2) (PLA(2)) is a key enzyme in cerebral phospholipid metabolism. Preliminary post-mortem studies have shown that PLA(2) activity is decreased in frontal and parietal areas of the AD brain, which is in accordance with recent (31)P-Magnetic Resonance Spectroscopy evidence of reduced phospholipid turnover in the pre-frontal cortex of moderately demented AD patients. Such abnormality may also be observed in peripheral cells, and reduced PLA(2) activity in platelet membranes of AD patients, and correlates with the severity of dementia. In rat hippocampal slices, PLA(2) has been implicated in mechanisms of synaptic plasticity. In adult rats, the stereotaxic injection of PLA(2) inhibitors in the CA1 area of hippocampus impaired, in a dose-dependent manner, the formation of short- and long-term memory. Additionally, such inhibition resulted in a reduction of the fluidity of hippocampal membranes. In primary cultures of cortical and hippocampal neurons, the inhibition of PLA(2) precluded neurite outgrowth, and the sustained inhibition of the enzyme in mature cultures lead to loss of viability. Taken together, these findings reinforce the involvement of PLA(2) enzymes in neurodevelopment and neurodegeneration processes, and further suggest that reduced PLA(2) activity, probably reducing membrane phospholipids breakdown, may contribute to the memory impairment in AD.

Diniz BS, Pinto JA, Gonzaga ML, Guimarães FM, Gattaz WF, Forlenza OV. · Laboratory of Neuroscience (LIM 27), Institute and Department of Psychiatry, Faculty of Medicine, University of Sao Paulo, Rua Ovidio Pires de Campos, 785, 3th floor, Sao Paulo, SP, CEP: 05403-010, Brazil. · Eur Arch Psychiatry Clin Neurosci. · Pubmed #19224111 No free full text.

Abstract: BACKGROUND: Individual randomized clinical trials (RCTs) with cholinesterase inhibitors (ChEIs) aiming to delay the progression from mild cognitive impairment (MCI) to Alzheimer's disease (AD) have not found significant benefit of their use for this purpose. The objective of this study is to meta-analyze the RCTs conducted with ChEIs in order to assess whether pooled analysis could show the benefit of these drugs in delaying the progression from MCI to AD. METHODS: We searched for references of published and unpublished studies on electronic databases (Medline, Embase, Web of Science, and Clinical Trial Database Registry, particularly the Clinicaltrials.gov--http://www.clinicaltrials.gov ). We retrieved 173 references, which yielded three references for data extraction. A total of 3.574 subjects from four RCTs were included in the meta-analysis. Among 1,784 subjects allocated in the ChEI-treatment group, 275 (15.4%) progressed to AD/dementia, as opposed to 366 (20.4%) out of 1,790 subjects in the placebo group. The relative risk (RR) for progression to AD/dementia in the ChEI-treated group was 0.75 [CI(95%) 0.66-0.87], z = -3.89, P < 0.001. The patients on the ChEI group had a significantly higher all-cause dropout risk than the patients on the placebo group (RR = 1.36 CI(95%) [1.24-1.49]; z = 6.59, P < 0.001). The RR for serious adverse events (SAE) in the ChEI-treated group showed no significantly statistical difference from the placebo group (RR = 0.95 [CI(95%) 0.83-1.09], z = -0.72, P = 0.47). The subjects in the ChEI-treated group had a marginally, non-significant, higher risk of death due to any cause than those in the placebo-treated group (RR = 1.04, CI(95%) 0.63-1.70, z = 0.16, P = 0.86). CONCLUSION: The long-term use of ChEIs in subjects with MCI may attenuate the risk of progression to AD/dementia. This finding may have a significant impact on public health and pharmaco-economic policies.

Diniz BS, Nunes PV, Yassuda MS, Pereira FS, Flaks MK, Viola LF, Radanovic M, Abreu ID, Borelli DT, Gattaz WF, Forlenza OV. · Psychogeriatric Clinic and Laboratory of Neuroscience (LIM 27), Department and Institute of Psychiatry, School of Medicine, Universidade de São Paulo, São Paulo, SP, Brazil. · Rev Bras Psiquiatr. · Pubmed #19142405 links to  free full text

Abstract: OBJECTIVE: To describe the neuropsychological profile of mild cognitive impairment subtypes (amnestic, non-amnestic and multiple-domain) of a clinical sample. We further address the diagnostic properties of the Mini-Mental State Examination and the Cambridge Cognitive Examination for the identification of the different mild cognitive impairment subtypes in clinical practice. METHOD: Cross-sectional clinical and neuropsychological evaluation of 249 elderly patients attending a memory clinic at a university hospital in Sao Paulo, Brazil. RESULTS: The performance of patients with mild cognitive impairment was heterogeneous across the different subtests of the neuropsychological battery, with a trend towards an overall worse performance for amnestic (particularly multiple domain) mild cognitive impairment as compared to non-amnestic subtypes. Screening tests for dementia (Mini-Mental State Examination and Cambridge Cognitive Examination) adequately discriminated cases of mild Alzheimer's disease from controls, but they were not accurate to discriminate patients with mild cognitive impairment (all subtypes) from control subjects. CONCLUSIONS: The discrimination of mild cognitive impairment subtypes was possible only with the aid of a comprehensive neuropsychological assessment. It is necessary to develop new strategies for mild cognitive impairment screening in clinical practice.

Apel C, Forlenza OV, de Paula VJ, Talib LL, Denecke B, Eduardo CP, Gattaz WF. · Department and Institute of Psychiatry, University of São Paulo, São Paulo, Brazil. · J Neural Transm. · Pubmed #18972063 No free full text.

Abstract: Aim of the present study was to investigate the neuroprotective effect of dental pulp cells (DPCs) in in vitro models of Alzheimer and Parkinson disease. Primary cultures of hippocampal and ventral mesencephalic neurons were treated for 24 h with amyloid beta (Abeta(1-42)) peptide 1-42 and 6-OHDA, respectively. DPCs isolated from adult rat incisors were previously cultured in tissue culture inserts and added to the neuron cultures 2 days prior to neurotoxin treatment. Cell viability was assessed by the MTT assay. The co-culture with DPCs significantly attenuated 6-OHDA and Abeta(1-42)-induced toxicity in primary cultures of mesencephalic and hippocampal neurons, and lead to an increase in neuronal viability in untreated cultures, suggesting a neurotrophic effect in both models. Furthermore, human dental pulp cells expressed a neuronal phenotype and produced the neurotrophic factors NGF, GDNF, BDNF, and BMP2 shown by microarray screening and antibody staining for the representative proteins. DPCs protected primary neurons in in vitro models of Alzheimer's and Parkinson's disease and can be viewed as possible candidates for studies on cell-based therapy.

Mendes CT, Mury FB, de Sá Moreira E, Alberto FL, Forlenza OV, Dias-Neto E, Gattaz WF. · Laboratory of Neurosciences-LIM27, Department & Institute of Psychiatry, Faculty of Medicine, University of Sao Paulo, Sao Paulo, Brazil. · Eur Arch Psychiatry Clin Neurosci. · Pubmed #18932008 No free full text.

Abstract: BACKGROUND: There is evidence of increased systemic expression of active GSK3B in Alzheimer's disease patients, which apparently is associated with the formation of senile plaques and neurofibrillary tangles. Due to its central role in the pathogenesis of AD, GSK3B is currently a promising target of the pharmaceutical industry. Whilst trials with specific GSK inhibitors in AD are under way, major attention has been focused on the neuroprotective effects of lithium. Whereas the direct and indirect inhibitory effects of lithium over GSK3 activity have been documented by several groups, its effects over Gsk3 transcription have not yet been addressed. METHODS: We used quantitative PCR to evaluate the transcriptional regulation of Gsk3a and Gsk3b in lithium-treated primary cultures of rat cortical and hippocampal neurons. RESULTS: We found a significant and dose-dependent reduction in the expression of Gsk3b, which was specific to hippocampal cells. This same effect was further confirmed in vivo by measuring Gsk3 expression in different brain regions and in peripheral leukocytes of adult rats treated with lithium. CONCLUSION: Our studies show that LiCl can modulate Gsk3b transcription in vitro and in vivo. This observation suggest new regulatory effects of lithium over Gsk3b, contributing to the better understanding of its mechanisms of action, offering a new and complementary explanation for Gsk3b modulation and reinforcing its potential for the inhibition of key pathological pathways in Alzheimer's disease.

Schaeffer EL, Forlenza OV, Gattaz WF. · Laboratory of Neuroscience (LIM-27), Department and Institute of Psychiatry, Faculty of Medicine, University of São Paulo, Rua Dr. Ovídio Pires de Campos 785, 05403-010 São Paulo, SP, Brazil. · Psychopharmacology (Berl). · Pubmed #18853146 No free full text.

Abstract: RATIONALE: Alzheimer disease (AD) is the leading cause of dementia in the elderly and has no known cure. Evidence suggests that reduced activity of specific subtypes of intracellular phospholipases A2 (cPLA2 and iPLA2) is an early event in AD and may contribute to memory impairment and neuropathology in the disease. OBJECTIVE: The objective of this study was to review the literature focusing on the therapeutic role of PLA2 stimulation by cognitive training and positive modulators, or of supplementation with arachidonic acid (PLA2 product) in facilitating memory function and synaptic transmission and plasticity in either research animals or human subjects. METHODS: MEDLINE database was searched (no date restrictions) for published articles using the keywords Alzheimer disease (mild, moderate, severe), mild cognitive impairment, healthy elderly, rats, mice, phospholipase A(2), phospholipid metabolism, phosphatidylcholine, arachidonic acid, cognitive training, learning, memory, long-term potentiation, protein kinases, dietary lipid compounds, cell proliferation, neurogenesis, and neuritogenesis. Reference lists of the identified articles were checked to select additional studies of interest. RESULTS: Overall, the data suggest that PLA2 activation is induced in the healthy brain during learning and memory. Furthermore, learning seems to regulate endogenous neurogenesis, which has been observed in AD brains. Finally, PLA2 appears to be implicated in homeostatic processes related to neurite outgrowth and differentiation in both neurodevelopmental processes and response to neuronal injury. CONCLUSION: The use of positive modulators of PLA2 (especially of cPLA2 and iPLA2) or supplementation with dietary lipid compounds (e.g., arachidonic acid) in combination with cognitive training could be a valuable therapeutic strategy for cognitive enhancement in early-stage AD.

Pereira FS, Yassuda MS, Oliveira AM, Forlenza OV. · Department and Institute of Psychiatry, Faculty of Medicine, University of São Paulo, Brazil. · Int Psychogeriatr. · Pubmed #18752698 No free full text.

Abstract: BACKGROUND: Previous studies have reported an association between executive dysfunction and the ability to perform activities of daily living (ADL)s among older adults. This study aims to examine the association between executive functions and functional status in a cross-section of older adults with varying degrees of cognitive impairment. METHODS: 89 individuals (mean age 73.8 years) were recruited at a memory clinic in São Paulo, Brazil. Subjects underwent evaluation, and were allocated into three diagnostic groups according to cognitive status: normal controls (NC, n = 32), mild cognitive impairment (MCI, n = 31) and mild Alzheimer's disease (AD, n = 26). Executive functions were assessed with the 25-item Executive Interview (EXIT25), and functional status was measured with the Direct Assessment of Functional Status test (DAFS-R). RESULTS: Significantly different total DAFS-R scores were observed across the three diagnostic groups. Patients with AD performed significantly worse in EXIT25 compared with subjects without dementia, and no significant differences were detected between NC and MCI patients. We found a robust negative correlation between the DAFS-R and the EXIT25 scores (r =-0.872, p < 0.001). Linear regression analyses suggested a significant influence of the EXIT-25 and the CAMCOG on the DAFS-R scores. CONCLUSION: Executive dysfunction and decline in general measures of cognitive functioning are associated with a lower ability to undertake instrumental ADLs. MCI patients showed worse functional status than NC subjects. MCI patients may show subtle changes in functional status that may only be captured by objective measures of ADLs.

Nunes PV, Forlenza OV, Gattaz WF. · Department and Institute of Psychiatry,Faculty of Medicine, University of Sao Paulo, Sao Paulo, Brazil. · Br J Psychiatry. · Pubmed #17401045 links to  free full text

Abstract: Bipolar disorder is associated with increased risk for dementia. We compared the prevalence of Alzheimer's disease between 66 elderly euthymic patients with bipolar disorder who were on chronic lithium therapy and 48 similar patients without recent lithium therapy. The prevalence of dementia in the whole sample was 19% v. 7% in an age-comparable population. Alzheimer's disease was diagnosed in 3 patients (5%) on lithium and in 16 patients (33%) who were not on lithium (P<0.001). Our case-control data suggest that lithium treatment reduced the prevalence of Alzheimer's disease in patients with bipolar disorder to levels in the general elderly population. This is in accordance with reports that lithium inhibits crucial processes in the pathogenesis of Alzheimer's disease.

Zainaghi IA, Forlenza OV, Gattaz WF. · Laboratory of Neuroscience LIM 27, Department and Institute of Psychiatry, Faculty of Medicine, University of São Paulo, São Paulo, Brazil. · Psychopharmacology (Berl). · Pubmed #17356877 No free full text.

Abstract: RATIONALE: Previous studies have implicated platelet amyloid precursor protein (APP) as a candidate biomarker for Alzheimer's disease (AD). Platelets contain more than 95% of the circulating APP and enclose the enzymatic machinery for the APP metabolism yielding both soluble APP and amyloid-beta peptides. OBJECTIVES: The objective of this study is to compare the ratio of 130- to 110-kDa fragments of APP in platelets from patients with AD, mild cognitive impairment (MCI), and elderly controls. MATERIALS AND METHODS: After subjects were grouped according to diagnosis, APP ratio in platelets was evaluated by means of Western blot analysis. RESULTS: The APP ratio was significantly lower in AD patients (1.01 +/- 0.21) as compared to controls (1.24 +/- 0.21, p = 0.001) and MCI patients (1.18 +/- 0.21, p = 0.027), but no significant differences were found between MCI and controls (p = 0.904). In addition, we found positive correlations between the APP ratio and 1,6-diphenyl-1,3,5-hexatriene anisotropy (r = 0.3, p = 0.01), as well as with certain parameters of cognitive decline, namely, the mini-mental state examination score (r = 0.33, p = 0.003), the total Cambridge cognitive test (CAMCOG) score (r = 0.37, p = 0.001), and the score on the memory subscale of the CAMCOG (r = 0.38, p = 0.001). CONCLUSIONS: The pattern of platelet APP fragments was altered in patients with AD but not in patients with MCI. The alteration of APP fragments was correlated with membrane fluidity and the cognitive decline.

Wacker P, Nunes PV, Cabrita H, Forlenza OV. · Laboratory of Neuroscience (LIM-27), Department and Institute of Psychiatry, University of Sao Paulo, Brazil. · Dement Geriatr Cogn Disord. · Pubmed #16428883 No free full text.

Abstract: The objective of the present study is to evaluate the association between the occurrence of delirium and the cognitive outcome in elderly subjects. Hospital files of 572 patients who underwent hip or knee replacement between 1998 and 2004 were examined. A sample of 90 elderly subjects (31 with evidence of post-operative delirium), non-demented at baseline, was screened for cognitive decline and dementia. Diagnosis of dementia was highly associated with the occurrence of delirium. The relative risk for the diagnosis of dementia among subjects with previous history of delirium, according to the IQcode screening, was 10.5 (95% CI: 3.3-33.2). Such patients had a significantly higher mean IQcode score (3.75) as compared to controls (3.1; p < 0.001). Cognitive functions most affected in these patients were memory, orientation and abstract thinking. We conclude that the occurrence of post-operative delirium in cognitively unimpaired elderly subjects is associated with a worse cognitive outcome and an increased risk of dementia.

Flaks MK, Yassuda MS, Regina AC, Cid CG, Camargo CH, Gattaz WF, Forlenza OV. · Laboratory of Neuroscience, Institute of Psychiatry, Faculty of Medicine, University of São Paulo, Brazil. · Int Psychogeriatr. · Pubmed #16255841 No free full text.

Abstract: BACKGROUND: Most instruments designed to detect dementia can lack appropriate sensitivity in the early stages of Alzheimer's disease (AD), and are subject to educational bias. The Short Cognitive Performance Test (Syndrom-Kurztest, SKT) is considered a suitable instrument to measure cognitive decline as it assesses memory, attention, and related cognitive functions, taking into account the speed of information processing. OBJECTIVES: The aim of this study was to examine the psychometric characteristics of the SKT as a dementia screening instrument in a Brazilian population sample, as compared to the Mini-mental State Examination (MMSE) and the Clock-Drawing Test (CDT). The effect of educational level on performance in the three screening tests was also verified. METHODS: Fifty-one elderly subjects were assessed. Consensus diagnoses were established by an expert multidisciplinary team, considering clinical, neuropsychological and neuroimaging data. Subjects were further classified into those with (1) mild and moderate AD, (2) non-Alzheimer's dementia, (3) mild cognitive impairment, and (4) controls, according to National Institute for Communicative Disorders and Stroke--Alzheimer's Disease and Related Disorders Association (NINCDS-ADRDA) criteria. RESULTS: Statistical analyses revealed high internal consistency for the SKT (Cronbach's alpha = 0.80) and significant correlations between the total score and the SKT subscores separately (p < 0.01). Comparison of the three tests revealed strong correlations between the SKT and the MMSE (r = -0.66, p < 0.0001) and between the SKT and the CDT (r = -0.57, p < 0.0001). The SKT, MMSE and CDT scores were correlated with education. CONCLUSIONS: The Brazilian version of the SKT maintains its original psychometric properties and displays significant correlation with previously validated screening tools for dementia. Like other dementia screening tests, the SKT is subject to educational bias.

Forlenza OV, Wacker P, Nunes PV, Yacubian J, Castro CC, Otaduy MC, Gattaz WF. · Laboratory of Neuroscience (LIM-27) Department and Institute of Psychiatry, Faculty of Medicine, University of São Paulo, Rua Doutor Ovídio Pires de Campos 785, 05403-010, São Paulo, SP, Brazil. · Psychopharmacology (Berl). · Pubmed #15700180 No free full text.

Abstract: BACKGROUND: Abnormalities of membrane phospholipid metabolism have been described in Alzheimer's disease (AD). We investigated, with the aid of (31)P magnetic resonance spectroscopy, the in vivo intracerebral availability of phosphomonoesters (PME) and phosphodiesters (PDE) in patients with AD. METHODS: Eighteen outpatients with mild or moderate probable AD and 16 nondemented elderly volunteers were assessed with the Cambridge Examination for Mental Disorders of the Elderly (CAMDEX) and its cognitive subscale of the CAMDEX schedule (CAMCOG). Scans were performed on a 1.5 T magnetic resonance imager addressing a 40-cm(3) voxel in the left prefrontal cortex. Main outcome measures were mean relative peak areas of PME and PDE, which provide an estimate of membrane phospholipid metabolism. RESULTS: PME resonance and the PME/PDE ratio were increased in AD patients as compared to controls (p<0.05). PME was negatively correlated with global cognitive performance as shown by the Mini-Mental State Examination (r(s)=-0.36, p=0.05) and CAMCOG scores (r(s)=-0.49, p=0.007), as well as with discrete neuropsychological functions, namely, memory (r(s)=-0.53, p=0.004), visual perception (r(s)=-0.54, p=0.003), orientation (r(s)=-0.36, p=0.05), and abstract thinking (r(s)=-0.48, p=0.01). CONCLUSIONS: We provide evidence of reduced membrane phospholipid breakdown in the prefrontal cortex of mild and moderately demented AD patients. These abnormalities correlate with neuropsychological deficits that are characteristic of AD.

Gattaz WF, Forlenza OV, Talib LL, Barbosa NR, Bottino CM. · Laboratory of Neuroscience, University of São Paulo, Brazil. · J Neural Transm. · Pubmed #15088152 No free full text.

Abstract: Phospholipase A(2) (PLA(2)) controls the metabolism of phospholipids in cell membranes. In the brain, PLA(2) influences the processing of the amyloid precursor protein (APP) and thus the production of the amyloid-beta peptides (Abeta), which are the major components of the senile plaques in Alzheimer's disease (AD). Reduced PLA(2) activity has been reported in brain and in platelets of AD patients. In the present study we investigated PLA(2) activity in platelets from 21 AD patients as compared to 17 healthy elderly controls and 11 individuals with mild cognitive impairment (MCI). Subjects were cognitively assessed by the Mini-Mental State Examination (MMSE) and the CAMDEX schedule. Platelet PLA(2) activity was determined by radio-enzymatic assay, which mainly detected a calcium-independent form of the enzyme present also in the brain (iPLA(2)). PLA(2) activity was significantly lower in AD than in controls (p < 0.001). Mean PLA(2) activity in MCI individuals was between the values of AD patients and controls, with a subgroup showing PLA as low as the lowest AD patients, but the differences from MCI were not significant from AD and control groups. Lower PLA(2) activity was significantly correlated with a worse cognitive performance both at the MMSE (p = 0.001) and the cognitive sub-scale of the CAMDEX inventory (p = 0.002). Our data replicate previous findings of reduced platelet PLA(2) activity in AD. Both reduced PLA(2) activity and the correlation with impaired cognition were also reported in brain tissue of AD patients, suggesting thus that the present determinations in platelets may be related to a reduction in the brain. In the brain the inhibition of PLA(2) inhibits the physiological secretion of the APP, a mechanism that increases Abeta formation. Further longitudinal studies should investigate whether those MCI individuals with the lowest PLA(2) values in platelets would be at a higher risk to develop AD during a longitudinal follow up.

Forlenza OV, Spink JM, Dayanandan R, Anderton BH, Olesen OF, Lovestone S. · Institute of Psychiatry, Faculty of Medicine, University of São Paulo, Brazil. · J Neural Transm. · Pubmed #11129110 No free full text.

Abstract: Muscarinic agonists alter the metabolism of amyloid precursor protein, leading to an increase in alpha-secretase cleavage and a decreased production of amyloidogenic peptides; suggesting that these compounds might modify the Alzheimer's disease process. A second therapeutic target in AD is the accumulation of stably phosphorylated tau into neurofibrillary tangles; an early event correlating with cognitive impairment. Glycogen synthase kinase-3 (GSK-3beta) phosphorylates tau and is inhibited via protein kinase C (PKC). As certain muscarinic receptors are linked to PKC, we examined the effect of a range of agonists on GSK-3beta phosphorylation of tau. In neurons a nonspecific muscarinic agonist, carbachol, reduced tau phosphorylation. In nonneuronal cells expressing the ml receptor a range of ml agonists reduced transiently-expressed tau phosphorylation and altered its microtubulebinding properties. These findings link the two pathological process of AD-APP metabolism and tau phosphorylation - and suggest that muscarinic and other cholinergic compounds might have disease-modifying properties.