Sir,

We read with much interest the article “Association of plasma leptin levels with incident Alzheimer disease and MRI measures of brain aging” by Lieb et al.¹ published recently in JAMA. Lieb et al.¹ have demonstrated that circulating leptin levels were associated with a reduced incidence of dementia and Alzheimer disease and with cerebral brain volume in asymptomatic older adults. Nevertheless, in the general population, overweight and obesity, conditions characterized by high circulating levels of leptin, are associated with poorer cognitive function and an increased risk of incident dementia.^2,3 These intriguing results have led to the emerging, if speculative, hypothesis that one reason for the observed association of midlife central obesity with subsequent risk of Alzheimer disease may be acquired resistance to the effects of leptin including neuroprotective effects.

Indeed, it has been suggested that in obese patients a state of relative leptin resistance may occur.^4,5 This issue has been recently reviewed by Munzberg and Myers.⁶ Leptin stimulates the production of anorectic neuropeptides and inhibits the action of orexigenic peptides in the arcuate nucleus through complex mechanisms.⁶ When leptin binds to its receptor (LRb) it activates the LRb-associated Jak2 tyrosine kinase, leading to the autophosphorylation of tyrosine residues on Jak2 and the phosphorylation of Tyr985 and Tyr1138 on the intracellular tail of LRb. Phosphorylation of Tyr1138 mediates the activation of the transcription factor STAT3. STAT3 also induces the transcription of SOCS3. SOCS3 binding to the LRb–Jak2 complex attenuates LRb-mediated signalling.⁶ Munzberg and Myers⁶ postulate that when leptin levels are low and thus baseline STAT3 activation is modest, SOCS3 expression is low, and incremental changes in leptin would be almost fully translated into increased LRb signalling. When circulating leptin levels are high (as in obesity), the increased baseline STAT3 activation would lead to an increased expression of SOCS3, mitigating much of the effect of increased leptin binding to LRb6.⁶

Recently, we conducted a study in end-stage renal disease patients receiving chronic hemodialysis to ascertain if hyperleptinemia is causally implicated in the pathogenesis of anorexia in such patients.⁷ Our study has confirmed that hemodialysis patients (HDPs), both males and females, have higher levels of serum leptin than healthy subjects as well as a higher leptin/body mass index ratio. We also demonstrated that serum leptin levels and the serum leptin/body mass index ratio were not different in anorexic and in nonanorexic HDPs. Moreover, no statistically significant differences in terms of serum leptin levels and leptin/body mass index ratio were observed between patients with dietary energy intake of <30 kcal/kg/day and those with dietary intake of ≥30 kcal/kg/day and between those with a protein intake of <1.2 g/kg/day and those with a protein intake of ≥1.2 g/kg/day. The findings of our study would indicate that leptin would not play a major pathogenic role in anorexia of HDPs. To explain such results, we successively suggested that a state of relative leptin resistance may occur also in patients with end-stage renal disease receiving hemodialysis in which circulating leptin levels are significantly higher than in healthy subjects.⁸

Now, this hypothesis is further supported by the results of a recent study of our group that aimed at evaluating if changes of mini-mental state examination (MMSE) over time in HDPs and elderly patients (EPs) differ significantly and determining the variables associated with such possible changes.⁹ In 80 HDPs and 160 EPs, the MMSE was assessed at baseline and after 1 year. Patients were stratified at baseline and at 1 year in three groups according to the MMSE: normal cognitive function >23; mild–moderate cognitive dysfunction 18–23; severe cognitive dysfunction <18. One-year median reduction of MMSE was greater in HDPs (from 24 to 21) than in EPs (from 26 to 25) (p < 0.0001). A higher percentage of HDPs than EPs switched from normal to mild–moderate or severe MMSE group (p < 0.0001). At baseline, MMSE was negatively correlated with hypertension (p = 0.013), angina (p = 0.007), and BDI (p = 0.041) and positively correlated with education (p = 0.017) and male gender (p = 0.015). No factors were found to be significantly associated with change of MMSE between baseline and month 12 in HDPs.

Taking into account the results obtained by Lieb et al.¹ as well as their speculative hypothesis, it is possible that the greater MMSE reduction observed in HDP, who are per definition characterized by hyperleptinemia, is due at least in part to the mechanism of leptin resistance outlined above with consequent loss of neuroprotective effects of leptin. If further studies in the next future will confirm these hypotheses, the hyperleptinemia of HDPs would be considered detrimental for cognition and subject of treatment.

Declaration of interest: The authors report no conflicts of interest. The authors alone are responsible for the content and writing of the paper.