Weight, Weight, Don’t Tell Me—Leptin Lowers AD Risk?

Leptin, the satiety hormone that signals when to say when at big holiday feasts, also seems to guard against Alzheimer disease, a report in this week’s JAMA suggests. In a prospective study of 785 dementia-free seniors, those with blood leptin levels in the top quartile were four times less likely to develop AD in the next dozen years, compared to same-sex participants with leptin in the lowest quartile. Higher concentrations of leptin, a chemical made by fat cells, also correlated with greater total cerebral brain volume measured by magnetic resonance imaging.

Led by Sudha Seshadri of Boston University, the new research solidifies animal data suggesting that leptin regulates Aβ pathology (Fewlass et al., 2004 and ARF related news story), and supports a recent prospective study linking leptin with cognition in well-functioning older people. In the latter study, Kristine Yaffe and colleagues at the University of California, San Francisco, found that higher serum leptin slowed preclinical cognitive decline measured by the Modified Mini-Mental State Exam (Holden et al., 2009). “Both studies really suggest there's something going on in terms of leptin and cognition in people, not just in animals,” Yaffe told ARF, “and it looks like higher leptin is protective.” Prior to Yaffe’s report, which was published online last year and appeared in print in the September issue of the Neurobiology of Aging, other data suggesting a leptin-AD connection in people came primarily from small case-control studies. For example, UK researchers had found low leptin levels in AD patients relative to healthy people or those with vascular dementia (Power et al., 2001).

Seshadri, first author Wolfgang Lieb, and colleagues set out to address whether shifts in leptin actually precede dementia onset. Seeing such changes before disease begins would suggest the association could be causal, Seshadri said. Her team analyzed data from community elderly enrolled in the original cohort of the Framingham Heart Study, a huge prospective study launched in 1948 to identify risk factors for heart disease. These seniors (mean age 79) had undergone decades of detailed medical exams, volumetric MRI brain imaging, and follow-up for incident dementia and AD. Mining this wealth of data, Seshadri and colleagues followed participants with plasma leptin measurements from the early 1990s, and determined who went on to develop dementia.

Based on plasma leptin levels at baseline, the researchers divided male and female participants into four groups—low, low-middle, middle, and high. The group with low leptin levels had a 25 percent chance of developing AD after 12 years’ follow-up, whereas people with high concentrations of leptin had a 6 percent chance. “That's essentially a fourfold difference in risk. The leptin level itself seems to be about as determinate as having one ApoE4 allele. So this is a huge thing,” said Wes Ashford of Stanford University and the Veterans Affairs Palo Alto Health Care System in California. “If you have something that makes a fourfold difference, that means if you were to take people with low leptin levels and convert them to a high leptin level, you could delay AD by 10 years.”

The risk associated with low leptin levels appeared over and above effects due to age, Seshadri said. Entering the golden years remains the biggest risk factor for AD. In the new study, leptin’s protection existed independent of ApoE genotype and other potential confounders including blood pressure and plasma homocysteine. However, the association between high leptin and lower dementia risk did not seem to hold for the heaviest individuals—that is, those with a body mass index (BMI) of 30 or above, or with waist-to-hip ratios in the top quartile.

This could be due to limited sample size in these subsets, Seshadri suggested. It could also reflect complications from abnormally high leptin levels in obese people, many of whom develop leptin resistance. Some scientists believe this phenomenon may have tanked earlier clinical trials of leptin as a treatment for obesity. In those studies, participants who took the hormone lost weight initially but did not keep the pounds off.

Figuring out how to increase leptin levels while maintaining leptin sensitivity will also be key if the hormone is to be tested in AD patients. Neurotez, Inc., a biotech company in North Brunswick, New Jersey, has received a $2.7 million grant from the National Institutes of Health to begin clinical development of leptin as an AD therapy. Thus far, making the compound has been a setback, said CEO and president Nikolaos Tezapsidis. “Manufacturing biologics is challenging compared to manufacturing a small compound,” he said. Nonetheless, Tezapsidis told ARF he is “hopeful that we’ll have an IND (Investigational New Drug) package submitted to the FDA by end of second quarter or beginning of third quarter next year.” The company plans to do a 12-week Phase 2a study looking at how leptin affects spinal fluid measures of Aβ and tau in mild AD patients, he said.

In the meantime, scientists note, it is important to learn more about how leptin levels are regulated physiologically and about mechanisms underlying leptin’s effects on neurons. “It looks like there's an association between leptin and cognition,” Yaffe said. “But is it truly leptin per se, or is leptin a marker for some other dysregulation that’s causing the cognitive impairment?”

Already, the new data may suggest that leptin could be used with other factors to help predict who is at high risk for AD. In an editorial accompanying the new study, Thomas Montine of the University of Washington, and Eric Larson of Group Health Research Institute, both in Seattle, write that “if confirmed, these results would provide a rationale for pursuing questions focusing on peripheral and central nervous system leptin biology in the earliest stages of neurodegeneration.”—Esther Landhuis

Comments

  1. In a paper in the Journal of Alzheimer's Disease, we demonstrate that the oxysterol 27-hydroxycholesterol reduces leptin levels and increases levels of both Aβ and phosphorylated tau in organotypic slices from adult rabbit hippocampus. Interestingly, we show that treatment with leptin reversed the 27-OHC-induced increase in Aβ and phosphorylated tau by decreasing the levels of BACE-1 and GSK-3β, respectively. Our results suggest that cholesterol metabolites induce AD-like pathology by altering leptin signaling.

    References:

    Marwarha G, Dasari B, Prasanthi JR, Schommer J, Ghribi O. Leptin is Involved in Accumulation of Amyloid-beta and Tau Phosphorylation Induced by 27-Hydroxycholesterol in Organotypic Slices from Adult Rabbit Hippocampus. J Alzheimers Dis. 2009 Dec 7; PubMed.

    View all comments by Othman Ghribi

  2. Comment by Mark A. Smith, Steven Greco, Jane M. Johnston, J. Wesson Ashford, George Perry, Gemma Casadesus, Nikolaos Tezapsidis

    Leptin—A Key Pathogenic Modulator in Alzheimer Disease
    The finding that high levels of leptin are associated with a reduced incidence of Alzheimer disease (Lieb et al., 2009) is consistent with data from our laboratories showing that: 1) leptin lowers amyloid-β protein in vitro and in vivo (Fewlass et al., 2004); 2) leptin-mediated reductions of amyloid-β in transgenic animals are associated with improved cognition (Greco et al., 2010); and 3) leptin reduces tau phosphorylation (Greco et al., 2008) through AMPK (Greco et al., 2009b) and GSK3β (Greco et al., 2009a). These findings led us (Fewlass et al., 2004; Tezapsidis et al., 2009) and others (Erol, 2008; Lieb et al., 2009) to suggest that leptin offers significant promise as a novel therapeutic strategy for Alzheimer disease (see Business Wire article).

    References:

    Erol A. An integrated and unifying hypothesis for the metabolic basis of sporadic Alzheimer's disease. J Alzheimers Dis. 2008 Apr;13(3):241-53. PubMed.

    Fewlass DC, Noboa K, Pi-Sunyer FX, Johnston JM, Yan SD, Tezapsidis N. Obesity-related leptin regulates Alzheimer's Abeta. FASEB J. 2004 Dec;18(15):1870-8. PubMed.

    Greco SJ, Bryan KJ, Sarkar S, Zhu X, Smith MA, Ashford JW, Johnston JM, Tezapsidis N, Casadesus G. Chronic Leptin Supplementation Ameliorates Pathology and Improves Cognitive Performance in a Transgenic Mouse Model of Alzheimer's Disease. J Alzheimers Dis. 2009 Dec 14; PubMed.

    Greco SJ, Sarkar S, Casadesus G, Zhu X, Smith MA, Ashford JW, Johnston JM, Tezapsidis N. Leptin inhibits glycogen synthase kinase-3beta to prevent tau phosphorylation in neuronal cells. Neurosci Lett. 2009 May 22;455(3):191-4. PubMed.

    Greco SJ, Sarkar S, Johnston JM, Tezapsidis N. Leptin regulates tau phosphorylation and amyloid through AMPK in neuronal cells. Biochem Biophys Res Commun. 2009 Feb 27;380(1):98-104. PubMed.

    Greco SJ, Sarkar S, Johnston JM, Zhu X, Su B, Casadesus G, Ashford JW, Smith MA, Tezapsidis N. Leptin reduces Alzheimer's disease-related tau phosphorylation in neuronal cells. Biochem Biophys Res Commun. 2008 Nov 21;376(3):536-41. PubMed.

    Lieb W, Beiser AS, Vasan RS, Tan ZS, Au R, Harris TB, Roubenoff R, Auerbach S, Decarli C, Wolf PA, Seshadri S. Association of plasma leptin levels with incident Alzheimer disease and MRI measures of brain aging. JAMA. 2009 Dec 16;302(23):2565-72. PubMed.

    Tezapsidis N, Johnston JM, Smith MA, Ashford JW, Casadesus G, Robakis NK, Wolozin B, Perry G, Zhu X, Greco SJ, Sarkar S. Leptin: a novel therapeutic strategy for Alzheimer's disease. J Alzheimers Dis. 2009;16(4):731-40. PubMed.

    View all comments by Jane Johnston

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References

News Citations

  1. Linking Leptin to AD

Paper Citations

  1. Fewlass DC, Noboa K, Pi-Sunyer FX, Johnston JM, Yan SD, Tezapsidis N. Obesity-related leptin regulates Alzheimer's Abeta. FASEB J. 2004 Dec;18(15):1870-8. PubMed.
  2. Holden KF, Lindquist K, Tylavsky FA, Rosano C, Harris TB, Yaffe K, . Serum leptin level and cognition in the elderly: Findings from the Health ABC Study. Neurobiol Aging. 2009 Sep;30(9):1483-9. PubMed.

Further Reading

Papers

  1. Tezapsidis N, Johnston JM, Smith MA, Ashford JW, Casadesus G, Robakis NK, Wolozin B, Perry G, Zhu X, Greco SJ, Sarkar S. Leptin: a novel therapeutic strategy for Alzheimer's disease. J Alzheimers Dis. 2009;16(4):731-40. PubMed.
  2. Fewlass DC, Noboa K, Pi-Sunyer FX, Johnston JM, Yan SD, Tezapsidis N. Obesity-related leptin regulates Alzheimer's Abeta. FASEB J. 2004 Dec;18(15):1870-8. PubMed.
  3. Tang BL. Leptin as a neuroprotective agent. Biochem Biophys Res Commun. 2008 Apr 4;368(2):181-5. PubMed.
  4. Harvey J, Shanley LJ, O'Malley D, Irving AJ. Leptin: a potential cognitive enhancer?. Biochem Soc Trans. 2005 Nov;33(Pt 5):1029-32. PubMed.
  5. Narita K, Kosaka H, Okazawa H, Murata T, Wada Y. Relationship between plasma leptin level and brain structure in elderly: a voxel-based morphometric study. Biol Psychiatry. 2009 Jun 1;65(11):992-4. PubMed.

News

  1. Linking Leptin to AD

Primary Papers

  1. Lieb W, Beiser AS, Vasan RS, Tan ZS, Au R, Harris TB, Roubenoff R, Auerbach S, Decarli C, Wolf PA, Seshadri S. Association of plasma leptin levels with incident Alzheimer disease and MRI measures of brain aging. JAMA. 2009 Dec 16;302(23):2565-72. PubMed.
  2. Montine TJ, Larson EB. Late-life dementias: does this unyielding global challenge require a broader view?. JAMA. 2009 Dec 16;302(23):2593-4. PubMed.

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