A Clinical Study of Lupron Depot in the Treatment of Women with Alzheimer's Disease: Preservation of Cognitive Function in Patients Taking an Acetylcholinesterase Inhibitor and Treated with High Dose Lupron Over 48 Weeks

Article type: Research Article

Authors: Bowen, Richard L.^{a; *} | Perry, George^{b; c} | Xiong, Chengjie^d | Smith, Mark A.^{c; †} | Atwood, Craig S.^{e; f; g; *}

Affiliations: [a] OTB Research, Charleston, SC, USA | [b] UTSA Neurosciences Institute and Department of Biology, University of Texas at San Antonio, San Antonio, TX, USA | [c] Department of Pathology, School of Medicine, Case Western Reserve University, Cleveland, OH, USA | [d] Department of Biostatistics, Washington University School of Medicine, St. Louis, MO, USA | [e] Department of Medicine, University of Wisconsin-Madison School of Medicine and Public Health, Madison, WI, USA | [f] Geriatric Research, Education and Clinical Center, Veterans Administration Hospital, Madison, WI, USA | [g] School of Exercise, Biomedical and Health Sciences, Edith Cowan University, Joondalup, WA, Australia

Correspondence: [*] Correspondence to: Richard L. Bowen, MD, OTB Research, 217 Calhoun St, Unit 1, Charleston, SC 29401, USA. Tel.: +1 843 480 2273; Fax: +1 843 501 7698; E-mail: [email protected] and Craig S. Atwood, PhD, University of Wisconsin-Madison School of Medicine and Public Health, William S. Middleton Memorial VA (GRECC 11 G), 2500 Overlook Terrace, Madison, WI 53705, USA. Tel.: +1 608 256 1901/Ext. 11664; Fax: +1 608 280 7291; E-mail: [email protected].

Note: [†] Deceased.

Abstract: To test the efficacy and safety of leuprolide acetate (Lupron Depot®) in the treatment of Alzheimer's disease (AD), we conducted a 48-week, double-blind, placebo-controlled, dose-ranging study in women aged 65 years or older with mild to moderate AD. A total of 109 women with mild to moderate AD and a Mini-Mental State Examination score between 12 and 24 inclusive were randomized to low dose Lupron Depot® (11.25 mg leuprolide acetate), high dose Lupron Depot® (22.5 mg leuprolide acetate), or placebo injections every 12 weeks. There were no statistically significant differences in primary efficacy parameters (ADAS-Cog and ADCS-CGIC), although there was a non-statistically significant trend in favor of the high dose Lupron group on the ADAS-Cog. There were no statistically significant differences in secondary efficacy parameters (NPI, ADCS-ADL, BI, and ADCS-Severity Rating). However, in the a priori designated subgroup analysis of patients taking an acetylcholinesterase inhibitor (AChEI), there was a statistically significant benefit in the high dose group compared to both the low dose and placebo groups as determined by ADAS-Cog (mean decline: 0.18, 4.21, and 3.30), ADCS-CGIC (% subjects experiencing decline: 38, 82, and 63), and ADCS-ADL (mean decline: −0.54, −8.00, and −6.85), respectively. No differences between treatment groups were seen on the NPI, ADCS-CGI Severity Rating, or the BI in the subgroup analysis. These data indicate that cognitive function is preserved in patients treated with high dose Lupron who were already using AChEIs. The positive interaction between Lupron and AChEIs warrants further investigation for the treatment of AD.

Keywords: 17β-estradiol, acetylcholinesterase inhibitor, Alzheimer's disease, apolipoprotein E, clinical trial, cognitive testing, gonadotropin-releasing hormone, Lupron, luteinizing hormone, women

DOI: 10.3233/JAD-141626

Journal: Journal of Alzheimer's Disease, vol. 44, no. 2, pp. 549-560, 2015