- Email: [email protected]
O1-05-08
Oral O1-05: Psychosocial/Neuropsychology studies in German-speaking countries. Objective: To demonstrate that an intensive, long-term caregiver education and support program delays patient nursing home admission. Methods: The AENEAS study is a multicenter, randomized, controlled trial. A total of 292 community-dwelling patients at a mean age of 76 years with moderate (CDR 2, MMSE 18 to 8) probable or possible Alzheimer’s Disease (NINCDS-ADRDA) and their primary caregivers were enrolled in 15 centers in Austria, Germany, and Switzerland. Caregivers in the intervention group participated in a multicomponent, highly standardized, education and support program which had been developed by the German Alzheimer’s Association. It was composed of 7 bi-weekly group sessions (6 to 8 participants, 120 minutes duration) followed by 6 bi-monthly refresher meetings. Caregivers in the control group received one session of standard social worker counseling. Caregivers were re-interviewed 12 months after the initial 7 group meetings to ascertain patient nursing home admission. Raters were blinded to participants’ group allocation. Results: For a preliminary analysis follow-up data were available on 259 participants from 13 centers. In each group, 22 patients had been permanently admitted to a nursing home (p ⫽ 0.74). The mean time to nursing home admission was approximately 2 months longer in the intervention than in the control group, but this difference did not reach statistical significance. Conclusions: The multi-component, longterm caregiver intervention was associated with a non-significant delay in patient nursing home admissions. These findings will be discussed in terms of caregiver intervention design and targeting. This work was supported by the German Ministry of Education and Research (Grant 01GL0305). O1-05-06
FREE AND CUED RECALL TEST IN MEMORY CLINICS: A GOOD PREDICTOR OF CONVERSION TO AD OR A MARKER OF PRODROMAL AD ?
Claudine Berr1, Marie Sarazin2, Colette Fabrigoule3, Bernard Michel4, Jocelyne De Rotrou5, Miche`le Puel6, Marc Verny7, Sylvie Legrain8, Jacques Touchon9, Bruno Dubois2, for the French PreAl study group, 1 INSERM E361, Montpellier, France; 2INSERM U610, Paris, France; 3 INSERM U593, Bordeaux, France; 4CHU, Marseille, France; 5Hopital Broca, Paris, France; 6CHU, Toulouse, France; 7Hopital La Salpetrie`re, Paris, France; 8Hopital Bichat, Paris, France; 9Hopital Gui De Chauliac, Montpellier, France. Contact e-mail: [email protected] Objective: To identify the most sensitive tools for distinguishing, prior to dementia, patients at early stage, i.e., with prodromal Alzheimer’s disease (AD), from normal aged subjects consulting at memory clinics. Background: It was recently proposed that the diagnosis of AD could be made at very mild stages of the disease. Design/Methods: In 2001-02, 251 patients were included in the French Pre-AL study if they had an objective memory or attention impairment, asserted by an MMSE score higher than 25 with at least one missing word recall and/or an Isaac set test score ⬍ 28. Dementia cases were excluded. All subjects were tested by a standardized neuropsychological battery including Free and Cued Recall Test (FCRT) for verbal episodic memory; Benton visual retention test for visual memory; and a more complete battery assessing language, working memory, conceptual elaboration and executive functions. Conversion to dementia was assessed at 6-month intervals for up to 3 years. We used ROC curve to determine the most sensitive and specific tests for conversion. Results: 56 individuals converted to dementia, of which 53 had AD and 49 occurred in the first 2 years. The best tool for prediction of conversion to AD was the FCRT and more specifically the free recall and the cued recall scores. Significant threshold for the diagnosis was of 17/48 for free recall (Sensibility⫽.74, Specificity⫽.87); 40/48 for total recall (Se⫽.79, Sp⫽.81); 6/16 for delayed free recall (Se⫽.75, Sp⫽.83). Learning score and memory consolidation, which qualify memory deficits of the hippocampal type, add information to better characterize subjects who converted to dementia. The other tests were less specific.Conclusions/Relevance: Among all the cognitive parameters, FCRT is the best tool for the prediction of conversion to dementia, because it reveals the deficit in storage information, early before
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dementia is clinically detected. The study suggests that, in addition, the FCRT can be considered as a diagnosis marker for early or prodromal AD. O1-05-07
HIGHER EDUCATIONAL AND OCCUPATIONAL ACHIEVEMENT ARE ASSOCIATED WITH MORE RAPID MEMORY DECLINE IN PRECLINICAL ALZHEIMER’S DISEASE: EVIDENCE FOR COGNITIVE RESERVE
Charles B. Hall1, Joe Verghese1, Carol A. Derby1, Mindy J. Katz1, Herman Buschke1, Gail Kuslansky1, Richard B. Lipton2, 1Albert Einstein College of Medicine, Bronx, NY, USA; 2Albert Einstein College of Medicine, Bronx, NY, NY, USA. Contact e-mail: [email protected] Background: High educational acheivment has been shown to be protective against Alzheimer’s Disease (AD). The cognitive reserve hypothesis suggests that this is because it is associated with greater cognitive reserve and thus higher cognitive performance for a given level of disease burden. It thus predicts that greater education and or occupational acheivement is associated with more rapid rates of decline proximal to the time of diagnosis due to increased disease burden. Objective(s): To test the cognitive reserve hypothesis by examining the effect of education and lifetime occupational achievement on memory decline during the preclinical course of dementia. Methods: We estimated rates of memory decline on the free recall score of the Buschke and Grober Free and Cued Selective Reminding Test with Immediate Recall (FCSRT-IR) as a function of education (measured in years) and occupational achievement (9 point scale) in 94 participants in the Einstein Aging Study age 70-97 who had detailed cognitive assessments at entry and at annual follow-up visits, and were diagnosed with incident dementia (70% AD or mixed). Linear mixed models were used to estimate the rate of cognitive decline as a function of time to diagnosis, and education or occupational achievement. Conclusions: Participants scored a mean of 23.5 on the FCSRT-IR (sd 8.2) at baseline and reported a mean of 12.6 years of formal education, with mean occupational achievement of 5.6. Occupational achievement and education were highly correlated (Spearman 0.67). The median follow up time before dementia diagnosis was 1.8 years (max 11.3 years). Participants reporting occupational achievement 4 or less declined 1.44 points per year (95% CI 0.682.20) on the FCSRT compared to 2.34 points per year (95% CI 1.91-2.78) for persons reporting occupational achievement 5 or higher. The difference was statistically significant (p⫽.045). Participants reporting 12 or fewer years of formal education declined 1.72 points per year (1.24, 2.19) and participants reporting more than 12 years declined 2.61 (1.94, 3.29) points per year, a statistically significant difference (p⫽.035). Thus as predicted by the cognitive reserve hypothesis, greater occupational and educational achievement are associated with more rapid cognitive decline in the years prior to dementia diagnosis. O1-05-08
THE WORLDWIDE DIRECTS COSTS AND COSTS OF INFORMAL CARE OF DEMENTIA
Bengt Winblad1, Anders Wimo1, Linus Jo¨nsson2, 1Karolinska Institutet, Stockholm, Sweden; 2European Health Economics, London, United Kingdom. Contact e-mail: [email protected] Background: One consequence of an aging population worldwide is an extensive increase of people suffering from dementia. Dementia disorders are also important cost drivers in the health and social care systems in advanced economies as well as in developing countries. Objective(s): To estimate the worldwide direct costs and costs of informal care of dementia. Methods: In a previously published paper, we have estimated the worldwide direct costs of dementia in 2003 to 156 billion US$ (Wimo A, Jonsson L, Winblad B. An estimate of the worldwide prevalence and direct costs of dementia in 1993. Dement Geriatr Cogn Disord 2006;21:175-181), based on a prevalence of 27.7 million demented worldwide. We have now expanded the cost model to also include costs of informal care. The cost model for informal care is based on a) published papers of the amount of
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Oral O1-06: Therapeutic Strategies 1
informal care in terms of personal (basic) ADL and b) average wage levels in different countries. Results: In the base-case scenario, the worldwide cost of informal care is estimated at 92 billion US$, which together with the estimate of direct cost results in a total worldwide cost of dementia of 248 billion US$. 62% of the demented live in the developing countries which account for 16% of the total costs. In a sensitivity analysis several alternative estimates are presented. Conclusions: All assumptions include both uncertainties and variability. However, this study demonstrates that the worldwide costs of dementia are substantial. Particularly the future increase of people with dementia in the developing countries presents is a great challenge. SUNDAY, JULY 16, 2006 ORAL O1-06 THERAPEUTIC STRATEGIES 1 O1-06-01
IMMUNIZATION WITH A1-6 COUPLED TO THE VIRUS-LIKE PARTICLE Q (CAD106) EFFICIENTLY REMOVES -AMYLOID WITHOUT INDUCING A〉-REACTIVE T-CELLS
Matthias Staufenbiel1, Karl-Heinz Wiederhold1, Alain C. Tissot2, Peter Frey1, Alma Fulurija2, Peter Hiestand1, Gary T. Jennings2, Rainer Lu¨o¨nd1, Peter Mayer3, Rainer Ortmann1, Markus Stoeckli1, Barbara Stumper3, Mauro Zurini1, Anis Mir1, Martin F. Bachmann2, Wiessner Christoph1, 1Novartis Institutes for BioMedical Research, Basel, Switzerland; 2Cytos Biotechnology, Zurich-Schlieren, Switzerland; 3 Novartis Institutes for BioMedical Research, Wien, Austria. Contact e-mail: [email protected] Background: Immunization against A has been shown to reduce amyloid accumulation and associated pathology in APP transgenic mouse models. Clinical trials with a vaccine comprising aggregated A1-42 and the adjuvant QS21 were, however, stopped in phase 2 due to development of aseptic meningoencephalitis in 6% of the treated patients. Autopsy studies of two affected patients demonstrated a T-cell mediated autoimmune response presumably directed against A. Objective: To avoid A-specific T-cell responses we developed CAD106, an immunotherapeutic vaccine comprising the A1-6 peptide covalently coupled to the Q virus-like particle (VLP). This N-terminal A peptide is shorter than T-cell epitopes, is predicted not to induce T-cell responses and was shown to contain B- but not T-cell epitopes. T-cell help is provided by Q. The ordered and repetitive display of A1-6 on the Q VLPs renders the peptide highly immunogenic, even in the absence of added adjuvant. Results and Conclusions: CAD106 generated high A antibody titers in mice, rabbits and monkeys. A 100% responder rate was observed in both young and old animals. CAD106-induced A antibodies recognized the N-terminus of A and selectively stained amyloid deposits in human and APP transgenic mouse brain sections. They also protected against toxicity of oligomeric or fibrillar A in vitro. Immunization with CAD106 reproducibly prevented amyloid plaque accumulation in the brains of two different APP transgenic mouse models (APP24 and APP23) which develop mostly diffuse (CongoRed negative) or mostly compact (Congo-Red positive) amyloid deposits, respectively. Furthermore, immunization of aged mice, showing advanced amyloid pathology already present in the brain, resulted in a reduction of further amyloid plaque accumulation. Neither adverse immune reactions nor increased incidence of microhemorrhages were observed in these studies. Importantly, immunization of different mouse strains with CAD106 did not induce A-responsive T-cells even in the presence of additional adjuvant. The expected strong T-cell response to Q was however found. In contrast, A1-42 immunization gave rise to A-responsive T-cells. They could be re-stimulated in vitro with A1-40/2 and A6-20 but not with A1-6, confirming the lack of a T-cell epitope on this peptide. CAD106 is currently being tested in a phase 1 study in humans.
O1-06-02
THE DESIGN AND SYNTHESIS OF AN EFFICACIOUS BACE INHIBITOR
James R. McCarthy1, Javier Agejas2, David M. Bender1, Howard Broughton2, Ana Bueno2, Robert D. Dally1, Timothy Durham1, Jon A. Erickson1, Juan F. Espinosa2, Rosario Gonzalez2, Patric J. Hahn1, Debra K. Laigle1, Todd J. Kohn1, Patrick C. May1, Juan R. Rodriguez2, Gema Sanz2, Timothy A. Shepherd1, David Timm1, Paloma Vidal2, Hsiu-Chiung Yang1, 1Eli Lilly and Company, Indianapolis, IN, USA; 2Eli Lilly and Company, Alcobendas, Spain. Contact e-mail: [email protected] Background: Inhibition of the aspartyl protease BACE (-APP cleaving enzyme) is of considerable interest as a therapeutic target for the treatment of Alzheimer’s disease. BACE catalyzes the first step of the two-step amyloid prercursor protein (APP) cleavage process resulting in the formation of A40/42 peptides. The accumulation of these peptides in the CNS is directly involved in the onset of Alzheimer’s disease according to the amyloid hypothesis. Objective(s): We wished to design and synthesize a BACE inhibitor that penetrated the BBB and demonstrated efficacy in animal models of Alzheimer’s disease by limiting the formation of A40/42 peptides. Methods: Stereoselective methods were developed to synthesize chiral compounds that are potent BACE inhibitors and penetrate the BBB. Results: The structure of a nanomolar BACE inhibitor, 2434074, that readily penetrates the BBB will be disclosed for the first time. The X-ray structure of this compound co-crystalized with BACE will highlight the importance of stereochemistry on potency. Conclusions: Utilizing rational design a new class of brain penetrating efficacious BACE inhibitors were synthesized by stereoselective synthetic methods. O1-06-03
MEMAPSIN 2 (BETA-SECRETASE, BACE) IMMUNIZATION AS THERAPY FOR ALZHEIMER’S DISEASE
Wan-Pin Chang1, Gerald Koelsch2, Deborah Downs1, Kar-Ming Fung3, Huining Da1, Jordan Tang1, 1Oklahoma Medical Research Foundation, Oklahoma City, OK, USA; 2Zapaq, Inc., Oklahoma City, OK, USA; 3 University of Oklahoma Health Science Center, Oklahoma City, OK, USA. Contact e-mail: [email protected] Memapsin 2 (-secretase, BACE) is the protease that initiates cleavage on amyloid precursor protein (APP) leading to the production of amyloid  (A) and the onset of Alzheimer’s disease (AD). Reduction of A production is a major goal in the development of treatments for AD. Here we show that immunization of transgenic AD mice with memapsin 2 resulted in A reduction. The implicit mechanism for this approach is the ability for anti-memapsin 2 antibody to reach the brain and neutralize memapsin 2 activity. We first demonstrated that this mechanism is operative in transfected cells where affinity-purified memapsin 2 antibodies reduced A production in a dose-dependent manner. We then performed an active immunization with the recombinant memapsin 2 in the AD transgenic mouse Tg2576. The studies were conducted in young (3-month-old) mice as a model of preventive immunization or in old (10-month-old) mice as a therapeutic model. In both studies, memapsin 2 immunization attenuated plasma A levels, temporally correlated with rising anti-memapsin 2 antibody titers. However, the attenuation effect from the therapeutic study was not as dramatic as in the preventative. Quantitative analysis of the A-immunostained brain sections showed a significant reduction on amyloid load resulting from memapsin 2 immunization (in both plaque numbers and percentage occupied area). A similar reduction of CHAPS-soluble and insoluble A40 and A42 amounts in the brain was also seen. The contention that memapsin 2 antibodies actually reach the brain was supported by the observation that the memapsin 2 antibodies were found in cerebrospinal fluid (CSF) 2 hours after an intravenous injection of the antibodies. The immunostained sections revealed that the antibodies crossed the blood-brain barrier (BBB) and localized specifically in cortex (cinguli area) and hippocampus (CA2 area). These results suggest that memapsin 2 immunization in transgenic AD mice was effective in reducing
FREE AND CUED RECALL TEST IN MEMORY CLINICS: A GOOD PREDICTOR OF CONVERSION TO AD OR A MARKER OF PRODROMAL AD ?
Claudine Berr1, Marie Sarazin2, Colette Fabrigoule3, Bernard Michel4, Jocelyne De Rotrou5, Miche`le Puel6, Marc Verny7, Sylvie Legrain8, Jacques Touchon9, Bruno Dubois2, for the French PreAl study group, 1 INSERM E361, Montpellier, France; 2INSERM U610, Paris, France; 3 INSERM U593, Bordeaux, France; 4CHU, Marseille, France; 5Hopital Broca, Paris, France; 6CHU, Toulouse, France; 7Hopital La Salpetrie`re, Paris, France; 8Hopital Bichat, Paris, France; 9Hopital Gui De Chauliac, Montpellier, France. Contact e-mail: [email protected] Objective: To identify the most sensitive tools for distinguishing, prior to dementia, patients at early stage, i.e., with prodromal Alzheimer’s disease (AD), from normal aged subjects consulting at memory clinics. Background: It was recently proposed that the diagnosis of AD could be made at very mild stages of the disease. Design/Methods: In 2001-02, 251 patients were included in the French Pre-AL study if they had an objective memory or attention impairment, asserted by an MMSE score higher than 25 with at least one missing word recall and/or an Isaac set test score ⬍ 28. Dementia cases were excluded. All subjects were tested by a standardized neuropsychological battery including Free and Cued Recall Test (FCRT) for verbal episodic memory; Benton visual retention test for visual memory; and a more complete battery assessing language, working memory, conceptual elaboration and executive functions. Conversion to dementia was assessed at 6-month intervals for up to 3 years. We used ROC curve to determine the most sensitive and specific tests for conversion. Results: 56 individuals converted to dementia, of which 53 had AD and 49 occurred in the first 2 years. The best tool for prediction of conversion to AD was the FCRT and more specifically the free recall and the cued recall scores. Significant threshold for the diagnosis was of 17/48 for free recall (Sensibility⫽.74, Specificity⫽.87); 40/48 for total recall (Se⫽.79, Sp⫽.81); 6/16 for delayed free recall (Se⫽.75, Sp⫽.83). Learning score and memory consolidation, which qualify memory deficits of the hippocampal type, add information to better characterize subjects who converted to dementia. The other tests were less specific.Conclusions/Relevance: Among all the cognitive parameters, FCRT is the best tool for the prediction of conversion to dementia, because it reveals the deficit in storage information, early before
S19
dementia is clinically detected. The study suggests that, in addition, the FCRT can be considered as a diagnosis marker for early or prodromal AD. O1-05-07
HIGHER EDUCATIONAL AND OCCUPATIONAL ACHIEVEMENT ARE ASSOCIATED WITH MORE RAPID MEMORY DECLINE IN PRECLINICAL ALZHEIMER’S DISEASE: EVIDENCE FOR COGNITIVE RESERVE
Charles B. Hall1, Joe Verghese1, Carol A. Derby1, Mindy J. Katz1, Herman Buschke1, Gail Kuslansky1, Richard B. Lipton2, 1Albert Einstein College of Medicine, Bronx, NY, USA; 2Albert Einstein College of Medicine, Bronx, NY, NY, USA. Contact e-mail: [email protected] Background: High educational acheivment has been shown to be protective against Alzheimer’s Disease (AD). The cognitive reserve hypothesis suggests that this is because it is associated with greater cognitive reserve and thus higher cognitive performance for a given level of disease burden. It thus predicts that greater education and or occupational acheivement is associated with more rapid rates of decline proximal to the time of diagnosis due to increased disease burden. Objective(s): To test the cognitive reserve hypothesis by examining the effect of education and lifetime occupational achievement on memory decline during the preclinical course of dementia. Methods: We estimated rates of memory decline on the free recall score of the Buschke and Grober Free and Cued Selective Reminding Test with Immediate Recall (FCSRT-IR) as a function of education (measured in years) and occupational achievement (9 point scale) in 94 participants in the Einstein Aging Study age 70-97 who had detailed cognitive assessments at entry and at annual follow-up visits, and were diagnosed with incident dementia (70% AD or mixed). Linear mixed models were used to estimate the rate of cognitive decline as a function of time to diagnosis, and education or occupational achievement. Conclusions: Participants scored a mean of 23.5 on the FCSRT-IR (sd 8.2) at baseline and reported a mean of 12.6 years of formal education, with mean occupational achievement of 5.6. Occupational achievement and education were highly correlated (Spearman 0.67). The median follow up time before dementia diagnosis was 1.8 years (max 11.3 years). Participants reporting occupational achievement 4 or less declined 1.44 points per year (95% CI 0.682.20) on the FCSRT compared to 2.34 points per year (95% CI 1.91-2.78) for persons reporting occupational achievement 5 or higher. The difference was statistically significant (p⫽.045). Participants reporting 12 or fewer years of formal education declined 1.72 points per year (1.24, 2.19) and participants reporting more than 12 years declined 2.61 (1.94, 3.29) points per year, a statistically significant difference (p⫽.035). Thus as predicted by the cognitive reserve hypothesis, greater occupational and educational achievement are associated with more rapid cognitive decline in the years prior to dementia diagnosis. O1-05-08
THE WORLDWIDE DIRECTS COSTS AND COSTS OF INFORMAL CARE OF DEMENTIA
Bengt Winblad1, Anders Wimo1, Linus Jo¨nsson2, 1Karolinska Institutet, Stockholm, Sweden; 2European Health Economics, London, United Kingdom. Contact e-mail: [email protected] Background: One consequence of an aging population worldwide is an extensive increase of people suffering from dementia. Dementia disorders are also important cost drivers in the health and social care systems in advanced economies as well as in developing countries. Objective(s): To estimate the worldwide direct costs and costs of informal care of dementia. Methods: In a previously published paper, we have estimated the worldwide direct costs of dementia in 2003 to 156 billion US$ (Wimo A, Jonsson L, Winblad B. An estimate of the worldwide prevalence and direct costs of dementia in 1993. Dement Geriatr Cogn Disord 2006;21:175-181), based on a prevalence of 27.7 million demented worldwide. We have now expanded the cost model to also include costs of informal care. The cost model for informal care is based on a) published papers of the amount of
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Oral O1-06: Therapeutic Strategies 1
informal care in terms of personal (basic) ADL and b) average wage levels in different countries. Results: In the base-case scenario, the worldwide cost of informal care is estimated at 92 billion US$, which together with the estimate of direct cost results in a total worldwide cost of dementia of 248 billion US$. 62% of the demented live in the developing countries which account for 16% of the total costs. In a sensitivity analysis several alternative estimates are presented. Conclusions: All assumptions include both uncertainties and variability. However, this study demonstrates that the worldwide costs of dementia are substantial. Particularly the future increase of people with dementia in the developing countries presents is a great challenge. SUNDAY, JULY 16, 2006 ORAL O1-06 THERAPEUTIC STRATEGIES 1 O1-06-01
IMMUNIZATION WITH A1-6 COUPLED TO THE VIRUS-LIKE PARTICLE Q (CAD106) EFFICIENTLY REMOVES -AMYLOID WITHOUT INDUCING A〉-REACTIVE T-CELLS
Matthias Staufenbiel1, Karl-Heinz Wiederhold1, Alain C. Tissot2, Peter Frey1, Alma Fulurija2, Peter Hiestand1, Gary T. Jennings2, Rainer Lu¨o¨nd1, Peter Mayer3, Rainer Ortmann1, Markus Stoeckli1, Barbara Stumper3, Mauro Zurini1, Anis Mir1, Martin F. Bachmann2, Wiessner Christoph1, 1Novartis Institutes for BioMedical Research, Basel, Switzerland; 2Cytos Biotechnology, Zurich-Schlieren, Switzerland; 3 Novartis Institutes for BioMedical Research, Wien, Austria. Contact e-mail: [email protected] Background: Immunization against A has been shown to reduce amyloid accumulation and associated pathology in APP transgenic mouse models. Clinical trials with a vaccine comprising aggregated A1-42 and the adjuvant QS21 were, however, stopped in phase 2 due to development of aseptic meningoencephalitis in 6% of the treated patients. Autopsy studies of two affected patients demonstrated a T-cell mediated autoimmune response presumably directed against A. Objective: To avoid A-specific T-cell responses we developed CAD106, an immunotherapeutic vaccine comprising the A1-6 peptide covalently coupled to the Q virus-like particle (VLP). This N-terminal A peptide is shorter than T-cell epitopes, is predicted not to induce T-cell responses and was shown to contain B- but not T-cell epitopes. T-cell help is provided by Q. The ordered and repetitive display of A1-6 on the Q VLPs renders the peptide highly immunogenic, even in the absence of added adjuvant. Results and Conclusions: CAD106 generated high A antibody titers in mice, rabbits and monkeys. A 100% responder rate was observed in both young and old animals. CAD106-induced A antibodies recognized the N-terminus of A and selectively stained amyloid deposits in human and APP transgenic mouse brain sections. They also protected against toxicity of oligomeric or fibrillar A in vitro. Immunization with CAD106 reproducibly prevented amyloid plaque accumulation in the brains of two different APP transgenic mouse models (APP24 and APP23) which develop mostly diffuse (CongoRed negative) or mostly compact (Congo-Red positive) amyloid deposits, respectively. Furthermore, immunization of aged mice, showing advanced amyloid pathology already present in the brain, resulted in a reduction of further amyloid plaque accumulation. Neither adverse immune reactions nor increased incidence of microhemorrhages were observed in these studies. Importantly, immunization of different mouse strains with CAD106 did not induce A-responsive T-cells even in the presence of additional adjuvant. The expected strong T-cell response to Q was however found. In contrast, A1-42 immunization gave rise to A-responsive T-cells. They could be re-stimulated in vitro with A1-40/2 and A6-20 but not with A1-6, confirming the lack of a T-cell epitope on this peptide. CAD106 is currently being tested in a phase 1 study in humans.
O1-06-02
THE DESIGN AND SYNTHESIS OF AN EFFICACIOUS BACE INHIBITOR
James R. McCarthy1, Javier Agejas2, David M. Bender1, Howard Broughton2, Ana Bueno2, Robert D. Dally1, Timothy Durham1, Jon A. Erickson1, Juan F. Espinosa2, Rosario Gonzalez2, Patric J. Hahn1, Debra K. Laigle1, Todd J. Kohn1, Patrick C. May1, Juan R. Rodriguez2, Gema Sanz2, Timothy A. Shepherd1, David Timm1, Paloma Vidal2, Hsiu-Chiung Yang1, 1Eli Lilly and Company, Indianapolis, IN, USA; 2Eli Lilly and Company, Alcobendas, Spain. Contact e-mail: [email protected] Background: Inhibition of the aspartyl protease BACE (-APP cleaving enzyme) is of considerable interest as a therapeutic target for the treatment of Alzheimer’s disease. BACE catalyzes the first step of the two-step amyloid prercursor protein (APP) cleavage process resulting in the formation of A40/42 peptides. The accumulation of these peptides in the CNS is directly involved in the onset of Alzheimer’s disease according to the amyloid hypothesis. Objective(s): We wished to design and synthesize a BACE inhibitor that penetrated the BBB and demonstrated efficacy in animal models of Alzheimer’s disease by limiting the formation of A40/42 peptides. Methods: Stereoselective methods were developed to synthesize chiral compounds that are potent BACE inhibitors and penetrate the BBB. Results: The structure of a nanomolar BACE inhibitor, 2434074, that readily penetrates the BBB will be disclosed for the first time. The X-ray structure of this compound co-crystalized with BACE will highlight the importance of stereochemistry on potency. Conclusions: Utilizing rational design a new class of brain penetrating efficacious BACE inhibitors were synthesized by stereoselective synthetic methods. O1-06-03
MEMAPSIN 2 (BETA-SECRETASE, BACE) IMMUNIZATION AS THERAPY FOR ALZHEIMER’S DISEASE
Wan-Pin Chang1, Gerald Koelsch2, Deborah Downs1, Kar-Ming Fung3, Huining Da1, Jordan Tang1, 1Oklahoma Medical Research Foundation, Oklahoma City, OK, USA; 2Zapaq, Inc., Oklahoma City, OK, USA; 3 University of Oklahoma Health Science Center, Oklahoma City, OK, USA. Contact e-mail: [email protected] Memapsin 2 (-secretase, BACE) is the protease that initiates cleavage on amyloid precursor protein (APP) leading to the production of amyloid  (A) and the onset of Alzheimer’s disease (AD). Reduction of A production is a major goal in the development of treatments for AD. Here we show that immunization of transgenic AD mice with memapsin 2 resulted in A reduction. The implicit mechanism for this approach is the ability for anti-memapsin 2 antibody to reach the brain and neutralize memapsin 2 activity. We first demonstrated that this mechanism is operative in transfected cells where affinity-purified memapsin 2 antibodies reduced A production in a dose-dependent manner. We then performed an active immunization with the recombinant memapsin 2 in the AD transgenic mouse Tg2576. The studies were conducted in young (3-month-old) mice as a model of preventive immunization or in old (10-month-old) mice as a therapeutic model. In both studies, memapsin 2 immunization attenuated plasma A levels, temporally correlated with rising anti-memapsin 2 antibody titers. However, the attenuation effect from the therapeutic study was not as dramatic as in the preventative. Quantitative analysis of the A-immunostained brain sections showed a significant reduction on amyloid load resulting from memapsin 2 immunization (in both plaque numbers and percentage occupied area). A similar reduction of CHAPS-soluble and insoluble A40 and A42 amounts in the brain was also seen. The contention that memapsin 2 antibodies actually reach the brain was supported by the observation that the memapsin 2 antibodies were found in cerebrospinal fluid (CSF) 2 hours after an intravenous injection of the antibodies. The immunostained sections revealed that the antibodies crossed the blood-brain barrier (BBB) and localized specifically in cortex (cinguli area) and hippocampus (CA2 area). These results suggest that memapsin 2 immunization in transgenic AD mice was effective in reducing