Effects of medications on plasma amyloid beta (Aβ) 42: Longitudinal data from the VITA cohort

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Abstract

In the course of cognitive deterioration leading to Alzheimer’s disease (AD) the increase of amyloid beta (Aβ42) in cerebrospinal fluid or plasma might be an initial event. We previously reported about the associations between concomitant medication and plasma Aβ42 levels in the non-demented population cohort of the Vienna transdanube aging study at baseline. In the present study, the longitudinal influence of insulin, gingko biloba, non-steroidal anti-inflammatory drugs (NSAIDs), oral anti-diabetics (sulfonylurea and biguanides), estrogens, fibrates, and statins on plasma Aβ42 are presented. Associated with medial temporal lobe atrophy (MTA), users of insulin showed significantly increased levels of Aβ42. Long-term users of gingko biloba, independent of their MTA, had significantly decreased plasma Aβ42 and the age-dependent increase of plasma Aβ42 was significantly smaller in long-term gingko biloba treated subjects. The use of fibrates also decreased plasma Aβ42 levels. In multiple testing considering interactions between medications, gender, APOE-ε4 presence and creatinine, insulin long-term users again showed significantly increased levels; fibrate and gingko biloba users showed a trend to rather decreased plasma Aβ42 levels compared to the non-users (p = 0.05–0.08). Neither statins nor NSAIDs showed a significant effect on plasma Aβ42 in this model. Measuring the effect on cognition, no single medication studied was a significant predictor of conversion to AD or mild cognitive impairment (MCI). Whether the use of gingko biloba might prevent the conversion to MCI or AD needs to be proven in prospective, clinical trials.

Introduction

A number of therapies targeting decrease of Aβ-peptides for treatment of Alzheimer’s disease (AD) approach the clinical phase of studies. In these studies plasma and cerebrospinal fluid (CSF) levels of Aβ42 are considered a surrogate marker for evaluation of efficacy of anti-Aβ42 therapy. Age-dependent increase of plasma Aβ42 was described in persons remaining cognitively healthy over a period of years. Studies demonstrated that, in contrast to cross-sectional measurement, rather longitudinal measurements of Aβ42 might distinguish persons who will convert to MCI or AD (Mayeux et al., 2003, Blasko et al., 2006). The disturbed clearance of Aβ42 peptides is estimated as crucial for the development of sporadic AD. The question whether brain-produced Aβ42 peptides are mainly degraded in brain parenchyma or are also destined for peripheral clearance in liver or kidney is still unresolved (Ghiso et al., 2004). Transportation of newly synthesized Aβ42 peptides from the human brain to CSF undergoes very rapid clearance (Bateman et al., 2006), suggesting that the control of Aβ42 degradation undergoes strict regulation.

Recent study demonstrated that soluble low-density lipoprotein related protein-1 (sLRP) normally controls 70–90% of circulating plasma Aβ through peripheral binding. This mechanism was suggested to provide key endogenous peripheral ‘sink’ activity for Aβ in humans (Sagare et al., 2007). Assuming that significant amount of Aβ42 peptides is delivered throughout the blood brain barrier to plasma circulation, measurement of these changes might be of importance (Shibata et al., 2000). We hypothesize that plasma Aβ42, at least to a certain extent, mirrors the brain load of Aβ42. The peripheral Aβ42 production ascribed to platelets is in this hypothesis of lesser significance (Olsson et al., 2003).

In any model, factors influencing plasma Aβ42 content are of considerable interest. Medications taken for several internal, neurological or psychiatric disorders with high frequency in the elderly population are of particular interest in this context. In the baseline cohort of VITA-population 90% of 75-years old persons took a certain medication. Such medication, by influencing the clearance and production of Aβ42, might influence the balance between peripheral and central pools of Aβ42.

In the non-demented cohort from the Vienna transdanube aging (VITA) study at baseline users of insulin have enhanced and users of ginkgo biloba have decreased levels of Aβ42 (Blasko et al., 2005). Here we present observational data on plasma Aβ42 and its changes induced by medication expected to influence amyloid beta precursor protein (AβPP) processing and Aβ42 production. This study intended to investigate the influence of continuous medication treatment on plasma Aβ42 and cognitive changes at 2.5 years follow up. The question whether the use of concomitant medication taken up to the baseline will influence the conversion to AD at the 2.5 years follow up investigation is the topic of a subsequent study from the VITA cohort.

Section snippets

Study population

The Vienna transdanube aging study (VITA) is a prospective community-based cohort-study of inhabitants aged 75 years from the 21st and 22nd districts of the city of Vienna, Austria (see Fischer et al., 2002, Jungwirth et al., 2004). Recruitment for baseline assessment took place between May 2000 and October 2002 and 30 months follow up measurements between November 2003 and May 2005; these procedures are described in detail elsewhere (Jungwirth et al., 2005, Grunblatt et al., 2006a, Grunblatt

The use of NSAIDs, statins, per-oral anti-diabetics or estrogens did not influence plasma Aβ42 level

Plasma Aβ42 levels at follow up did not distinguish between cognitively healthy persons or persons with MCI or patients with AD in the VITA cohort (Blasko et al., 2006). Therefore plasma Aβ42 levels of all probands, regardless of their cognition, were used for calculation of the possible effect of medication on plasma Aβ42 level. Aβ42 lowering and non-lowering NSAIDs or NSAIDs as whole group, statins, estrogens, per-oral anti-diabetics such as sulfonylurea or biguanides were considered only in

Discussion

In accordance with baseline observations from VITA cohort we could corroborate that long term insulin treatment increased the plasma levels of Aβ42 (Blasko et al., 2005). The possible reason for an association with higher Aβ42 plasma levels only by the insulin users for more then 2.5 years might be due to low proband number in these subgroups. The rational for dividing drug users into three groups (2.5 years cut-off) is in alignment to previous studies. The protective effect of NSAIDs against

Role of the Founding Source

We acknowledge the funding and organization of the Vienna transdanube aging VITA study by the Ludwig Boltzmann Society, Ludwig Boltzmann Institute of Aging Research (head: Prof. Karl-Heinz Tragl).

Conflict of interest

All authors disclose:

  • (a)

    No potential conflict of interest including any financial, personal or other relationships with other people or organizations within three years of beginning the work submitted that could inappropriately bias this work.

  • (b)

    No author’s institution has contracts relating to this research through which it or any other organization may stand to gain financially now or in the future.

  • (c)

    No any other agreements of author’s institutions that could be seen as involving a financial interest

Acknowledgements

We thank Mr P. Bauer for statistical advice in planning of the VITA study, Mr W. Kirchmeyr and Mr S. Torma for medical exploration of subjects and Mr J. Marksteiner for critical reading of manuscript.

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