Pravastatin at 10 mg/day does not decrease plasma levels of either amyloid-b (Ab) 40 or Ab 42 in humans Kazuhiro Ishii a, * , Takahiko Tokuda b , Teruhiko Matsushima c , Fuyuki Miya a , Shin’ichi Shoji a , Shu-ichi Ikeda b , Akira Tamaoka a a Department of Neurology, Institute of Clinical Medicine, University of Tsukuba, Ten’noudai 1-1-1, Tsukuba, Ibaraki 305-8575, Japan b Third Department of Internal Medicine, Shinshu University School of Medicine, Matsumoto 390-8621, Japan c Tsukuba Memorial Hospital, Kaname 1187-299, Tsukuba, Ibaraki 300-2622, Japan Received 24 May 2003; received in revised form 18 July 2003; accepted 22 July 2003 Abstract It has been assumed that statins work as a preventative drug for Alzheimer’s disease (AD). Although some epidemiological observations raise doubts to the effectiveness of statins for AD, many in vitro and clinical studies insist on the effectiveness of statins decreasing amyloid-b (Ab) levels in medium or blood. To explore the effect of pravastatin on Ab production, we followed the longitudinal plasma levels of both Ab 40 and Ab 42 during the allocation of pravastatin in 46 patients with hyperlipidemia. We found no correlation between plasma cholesterol levels or the decreasing values of total cholesterol and those of Ab 40 or Ab 42. Patients having Apolipoprotein E4 (ApoE4) had higher low-density lipoprotein levels and lower Ab 40 levels in plasma, suggesting ApoE4 seems to influence plasma Ab levels via cholesterol metabolism. q 2003 Elsevier Ireland Ltd. All rights reserved. Keywords: Cholesterol; Pravastatin; Amyloid-b (Ab) 40; Ab 42; Alzheimer’s disease Amyloid-b (Ab), which is mainly 40- – 42-residue proteins, is the major constituent of senile plaques, one of the distinctive features of Alzheimer’s disease (AD). The longer form, Ab 42 is the Ab species initially deposited in the brain, and particularly tends to aggregate in vitro. Therefore, this longer form is believed to be the main culprit in AD pathogenesis. On the other hand, cerebral Ab 40 levels have been found to be statistically linked with levels of apolipoprotein (Apo) epsilon 4 allele [4,6], a risk factor in late-onset familial AD and sporadic AD [1]. ApoE is a cholesterol transporter protein, and ApoE4, the phenotype of Apo epsilon 4, increases the blood cholesterol level more compared with other subtypes of ApoE. However the exact function of ApoE4 in AD pathogenesis has not been elucidated [7]. There is a lot of evidence that cholesterol metabolism influences the incidence of AD and/or the production of Ab protein. Some papers prove that statins reduce blood cholesterol levels by inhibiting the bottleneck enzyme of cholesterol synthesis, 3-hydroxy-3-methylglutaryl coen- zyme A (HMG CoA) reductase, decreasing cerebral Ab production in cultured cells or in animal models [2]. Furthermore, there has been one human study showing that taking lovastatin significantly decreases total serum Ab levels [3], but this study did not measure different Ab species that have different roles in Alzheimer pathophysiol- ogy separately. On the basis of previous studies, we examined the longitudinal Ab species (Ab 40 and Ab 42) plasma levels during pravastatin intake and revealed the correlation between the decreasing values of Ab species and values of total cholesterol or other lipid parameters in plasma. The Japanese subjects, 46 patients (27 females, average age of 63.9 years (36 – 83) and 19 males, average age of 55.1 years (33–75)) with no administration history of any HMG CoA reductase inhibitor before starting this trial, were enrolled in this study. Those subjects were clinically free from neurological symptoms including dementia according to the Mini-Mental State Examination (over 25 points), and were completely absent of any other disease apart from hypertension and/or diabetes mellitus (DM). Concomitant 0304-3940/03/$ - see front matter q 2003 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/S0304-3940(03)00895-4 Neuroscience Letters 350 (2003) 161–164 www.elsevier.com/locate/neulet * Corresponding author. Tel.: þ 81-298-533-223; fax: þ81-298-533-224. E-mail address: kazishii@md.tsukuba.ac.jp (K. Ishii).