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More Clues in the Alzheimer Conundrum

Two studies alter our thinking about the cause(s) and treatment(s) for Alzheimer disease.

Two new reports add insights into possible mechanisms of Alzheimer disease (AD).

Tarenflurbil is a nonsteroidal anti-inflammatory drug that modifies -secretase function, thereby decreasing the accumulation of amyloid-beta_1-42 (Aβ[42]) in experimental transgenic animals. In one large clinical trial, researchers attempted to delay functional decline by randomizing more than 1000 patients with mild AD who were seen at 133 centers to receive placebo or tarenflurbil for 18 months. Tarenflurbil did not confer a benefit in any outcome measures, including the coprimary endpoints — rate of cognitive decline or change in activities of daily living — or any secondary outcome measure. The authors comment, "Our results are . . . a reminder that interventions affecting amyloid have not yet been shown to alter the course of AD."

In the other study, researchers prospectively examined the association of baseline plasma leptin levels with AD incidence and cerebral brain volume in 785 Framingham study participants without dementia at baseline. During a median follow-up of 8.3 years, participants with leptin levels in the highest quartile had larger total cerebral brain volume on magnetic resonance imaging and about one fourth of the risk for incident AD compared with those with leptin levels in the lowest quartile (AD risk, 6% vs. 25%, respectively, after 12 years of follow-up). Leptin levels had a similar association with all-cause dementia. The authors suggest that the association of high leptin levels with decreased dementia and AD is related to its "beneficial effects on brain development and function."

Comment: The etiology of AD remains uncertain, despite the prominence of the amyloid hypothesis, which suggests that overproduction of Aβ(42) is the primary cause. The presumption that this gain of function causes AD has led to several pharmacologic and immunologic trials of therapies aimed at reducing Aβ(42), including Aβ vaccination, administration of bapineuzumab (an anti-amyloid antibody), and now tarenflurbil. So far, all have failed to improve the manifestations of AD. These repeated therapeutic failures raise questions about the etiologic role of amyloid in AD and fail to provide a proof of concept, even though amyloid-containing neuritic plaques are the hallmark neuropathology in AD.

By far the most powerful risk factor for AD is advancing age; the risk doubles every 5 years after age 65. Other factors may contribute, including hypertension, diabetes, dyslipidemias, midlife obesity, high homocysteine level, an apolipoprotein E 4 gene — and, possibly, a low leptin level. The authors cite experimental evidence that high plasma leptin levels protect memory processes and that in an animal model of AD, leptin administration reduced Aβ levels. Alternative mechanisms may involve the effect of leptin on endothelial function via increased production of endothelial nitric oxide synthase (Endocrinology 2009; 150:3584), which would support vascular involvement in AD.

Precisely which age-related changes result in the neurodegeneration that leads to AD remains uncertain. With each new risk factor, it seems more likely that multiple converging loss-of-function changes erode brain integrity and less likely that a unique, age-related disorder of Aβ production causes AD. As we await better understanding, the few strategies that may help prevent AD are largely related to reducing vascular risk, including control of blood pressure during middle age, use of statins and angiotensin-receptor blockers, consistent exercise and weight control, and perhaps drinking moderate amounts of red wine.

— David A. Drachman, MD

Dr. Drachman is Professor, Department of Neurology, University of Massachusetts Medical School, Worcester.

Published in Journal Watch Neurology March 9, 2010

Citation(s):

Green RC et al. Effect of tarenflurbil on cognitive decline and activities of daily living in patients with mild Alzheimer disease: A randomized controlled trial. JAMA 2009 Dec 16; 302:2557.

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• Medline abstract (Free)

Lieb W et al. Association of plasma leptin levels with incident Alzheimer disease and MRI measures of brain aging. JAMA 2009 Dec 16; 302:2565.

• Original article (Subscription may be required)
• Medline abstract (Free)

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