Elsevier

The Lancet

Volume 358, Issue 9280, 11 August 2001, Pages 455-460
The Lancet

Articles
Effect of hydroxychloroquine on progression of dementia in early Alzheimer's disease: an 18-month randomised, double-blind, placebo-controlled study

https://doi.org/10.1016/S0140-6736(01)05623-9Get rights and content

Summary

Background

Results of epidemiological studies, neuropathological observations, and in-vitro experiments all suggest that inflammatory mechanisms contribute to the destructive lesions in Alzheimer's disease. We aimed to establish the effect of the anti-inflammatory drug hydroxychloroquine on the progression of dementia.

Methods

We did a double-blind, parallel-group, multicentre trial in which we randomly assigned 168 patients with early Alzheimer's disease to hydroxychloroquine (200 or 400 mg dependent on bodyweight), or placebo for 18 months. Outcome measures were related to activities of daily living, cognitive function, and behavioural abnormalities. Analysis was by intention to treat.

Results

At 18 months, mean scores for the interview for deterioration in daily life in dementia in patients on hydroxychloroquine (22·6 [SD 11·4]) did not differ from those for patients on placebo (21·3 [10·5]). Also, mean scores on the cognitive subscale of the Alzheimer's disease assessment scale were closely similar in hydroxychloroquine (26·4 [14·9]) and placebo (25·7 [14·3]) treated patients, as were behavioural changes, measured by the revised memory and behavioural problems checklist (36·3 [12·0] and 34·2 [12·4], respectively). Explorative analyses did not suggest any specific subgroup that benefited from hydroxychloroquine. The frequency and nature of serious adverse events and side-effects were much the same in both groups. 155 (92%) patients completed all assessments over the entire study.

Interpretation

Anti-inflammatory treatment with hydroxychloroquine for 18 months does not slow the rate of decline in minimal or mild Alzheimer's disease.

Introduction

Three independent lines of evidence suggest that endogenous inflammatory responses have a role in the pathogenesis of Alzheimer's disease. First, cytokines, acute phase reactants, and complement activation fragments are seen in close association with senile plaques in the neuropathology of Alzheimer's disease.1 Microglial cells, the brain-resident cells of the mononuclear phagocyte system that cluster around plaques, express complement receptors and produce inflammatory proteins.1 Messenger RNA concentrations for complement proteins are strongly upregulated in the brain of patients with Alzheimer's disease.2 Second, results of in-vitro studies show that the major constituent of plaques, the β-amyloid protein, can activate the complement system and potentiate cytokine secretion, which might trigger an inflammatory response in the absence of immune complexes or cellular mediated response.3, 4 Finally, findings of numerous cross-sectional and some longitudinal epidemiological studies have shown that anti-inflammatory drugs might delay or even prevent the onset of Alzheimer's disease.5, 6 Therefore, since the 1990s many scientists believe that the inflammatory process in the brain of patients with Alzheimer's disease is a compelling target for therapeutic intervention, an opinion which can be tested with available drugs.7 Indeed, results of a small, early clinical study suggested a beneficial effect of indometacin after 6 months of treatment.8

Since the 1950s, the antimalarials chloroquine and hydroxychloroquine have also been used to treat inflammatory diseases. In vitro, aminoquinoline compounds are specifically effective against β-amyloid protein induced neurotoxicity.9 Hydroxychloroquine suppresses acute-phase reactants, lymphocyte responsiveness, macrophage function, and cytokine release.10 In rheumatoid arthritis, this drug is a well established, slow-acting, disease-modifying treatment. Hydroxychloroquine is generally well tolerated in elderly people, and the risk of retinopathy among patients receiving appropriate doses of the drug is low.11 Because of its broad scope of anti-inflammatory activity, its safety profile, and its ability to cross the blood-brain barrier,10 we chose to test whether hydroxychloroquine could slow the rate of decline in patients with early Alzheimer's disease.

Section snippets

Patients

We recruited patients through four memory clinics in Amsterdam between December, 1996, and October, 1998. Individuals were eligible if they fulfilled criteria for a diagnosis of probable Alzheimer's disease, as outlined by the National Institute of Neurological and Communicative Disorders and Alzheimer's Disease and Related Disorders.12 The severity of dementia had to be minimal or mild according to the guidelines for the gradation of dementia in the Cambridge Examination for Mental Disorders

Results

Figure 1 shows the trial profile, and table 1 shows baseline demographic and clinical characteristics of patients. The IDDD and ADAS-cog scores at baseline show that we were successful in recruitment of patients with early Alzheimer's disease. The ADAS-cog scores in our study are substantially lower than in other clinical trial reports in Alzheimer's disease. The mean IDDD score of about 11 suggests that the typical participant of this trial required (three IDDD points) assistance with taking

Discussion

In our study, hydroxychloroquine did not slow the progression of dementia over 18 months. Furthermore, we did not identify any subgroups, defined by sex, age, genotype, education, or baseline degree of deterioration, which had benefited from treatment. Hydroxychloroquine was well tolerated and did not cause clinically important ophthalmological problems at the cumulative dose used. Our findings suggest that long-term studies with a low drop-out rate are feasible in the early stages of

References (32)

  • H Jiang et al.

    Betaamyloid activates complement by binding to a specific region of the collagen-like domain of the C1q A chain

    J Immunol

    (1994)
  • PL McGeer et al.

    Arthritis and anti-inflammatory agents as possible protective factors for Alzheimer's disease: a review of 17 epidemiologic studies

    Neurology

    (1996)
  • JC Anthony et al.

    Reduced prevalence of AD in users of NSAIDs and H2 receptor antagonists: the Cache County study

    Neurology

    (2000)
  • PD Coleman

    Possible pharmacological approaches to slowing down Alzheimer's disease progression

    Neurobiol Aging

    (1987)
  • J Rogers et al.

    Clinical trial of indomethacin in Alzheimer's disease

    Neurology

    (1993)
  • PS Aisen et al.

    Inflammatory mechanisms in Alzheimer's disease: implications for therapy

    Am J Psychiatry

    (1994)
  • Cited by (211)

    • Immune dysregulation and neurodegenerative diseases

      2023, Translational Neuroimmunology: Neuroinflammation: Volume 7
    • Clinical trials of promising apoptosis modulating drugs

      2021, Clinical Perspectives and Targeted Therapies in Apoptosis: Drug Discovery, Drug Delivery, and Disease Prevention
    View all citing articles on Scopus
    View full text