Leptin: the missing link in Alzheimer disease?

In Western societies life expectancy is increasing steadily and as a consequence more individuals are suffering from age-related disorders such as Alzheimer disease (AD). The prevalence of AD is predicted to rise rapidly in the coming decades, which is likely to pose a huge burden on health care services in the future. Although significant advances have been made in this field in recent years, our understanding of the principle cellular changes that occur in the initial stages of this disease and the means to identify these changes clinically are limited. Thus key research priorities are to determine the key cellular events that underlie the development and pathogenesis of AD and to identify possible biomarkers associated with the early stages of AD. Studies in these areas are of paramount importance as they are likely to aid in the detection of the early brain changes in AD and could potentially lead to the development of novel therapies to treat this debilitating neurodegenerative disorder.

Combinations of factors, such as lifestyle and genetic and vascular influences are known to modify the risk of developing AD. Several lines of evidence also support a link between mid-life obesity and an increased risk of AD, but the mechanisms responsible for this association are not entirely clear. Recent studies have identified the endocrine hormone leptin as one possible factor linking obesity and AD. Leptin plays a pivotal role in the regulation of food intake and body weight via its actions on specific nuclei within the hypothalamus. In addition, leptin receptors are expressed in many extra-hypothalamic brain regions, and numerous studies indicate that leptin is a pleiotropic hormone with diverse actions reported throughout the CNS. In particular, limbic structures such as the hippocampus display high levels of leptin receptor expression, and several studies have identified a role for leptin in regulating cognitive processes in this brain region. Specifically, leptin has been shown to markedly influence the cellular events underlying hippocampal-dependent learning and memory (1). Indeed, activation of leptin receptors enhances NMDA receptor function and it facilitates the induction of hippocampal long-term potentiation (LTP; 1). In addition, leptin promotes rapid alterations in hippocampal dendritic morphology and the density of hippocampal synapses, which are likely to contribute to leptin-driven changes in excitatory synaptic strength (2). Studies performed in obese leptin-insensitive rodents (db/db mice; Zucker fa/fa rats) have detected deficits in hippocampal synaptic plasticity and in spatial memory tasks performed in the Morris water maze (3). More recent studies also provide support for a link between impaired and/or altered leptin function and the development of AD. Indeed, the circulating concentrations of leptin are reported to be significantly lower than normal in individuals with AD and are markedly attenuated in murine models of AD. Furthermore, application of leptin improves memory processing in AD models. In neuronal cell lines, leptin has been shown to act in concert with insulin to attenuate the phosphorylation of tau, a protein that is a key component of neurofibrillary tangles, a pathological hallmark of AD. It is not yet known, however if the circulating levels of leptin in healthy individuals show any correlation with the risk of developing AD later in life.

In a new prospective study by Lieb et al (4), the plasma concentrations of leptin were evaluated in 785 individuals from the original Framingham study cohort (5) in order to determine if the baseline plasma concentrations of leptin relate to the incidence of AD. None of the 785 individuals had dementia at the start of the study. All were assessed periodically for impairments in cognitive function and dementia using standard neuropsychological and neurological tests. Moreover a subset of 198 individuals underwent volumetric brain magnetic resonance imaging (MRI) to evaluate two recognized markers of early AD pathology, the temporal horn volume (THV; which is an inverse measure of hippocampal volume) and the total cerebral brain volume (TCBV). The main findings of this prospective study are that higher baseline plasma concentrations of leptin correlated with a significantly lower risk of dementia and AD. Indeed, individuals with leptin concentrations in the lowest quartile had a 25% risk of developing AD after 12 years, whereas those with higher leptin levels (in the top quartile) had only a 6% risk. Moreover, this correlation was independent of traditional vascular and neurodegenerative risk factors as significant correlation between high leptin levels and a lower incidence of AD was evident even after adjustment for vascular risk factors and waist-to-hip ratio. Furthermore, data obtained from MRI studies indicated that the higher leptin concentrations in the plasma were positively correlated with two structural indices of cognitive function (larger cerebral brain and hippocampal volumes), suggesting enhanced cognitive function in individuals with higher leptin levels. Together, these epidemiological findings support the concept that the risk of developing AD is significantly lower in individuals with higher leptin concentrations.

It is well established that the circulating concentrations of leptin are correlated with body fat content and that in obese individuals leptin concentrations are increased and resistance to leptin develops. Because of the small number of obese participants in the new study, however, no significant association between leptin concentrations and AD could be found in obese individuals. Nevertheless, the data obtained from this study are still consistent with leptin being one possible etiologic factor in the development of AD in non-obese individuals.

Although this study provides compelling evidence to support a linkage between leptin and development of AD, there are still numerous questions that remain unanswered. Two related aspects that need to be addressed are (1) the mechanism by which high circulating concentrations of leptin protect individuals from developing AD and (2) the stage of the disease process at which leptin acts. A growing body of evidence supports the notion that in the early stages of AD, changes in synaptic function occur prior to neuronal cell death and plaque formation. Indeed, β-amyloid, which accumulates in AD, detrimentally affects hippocampal excitatory synaptic transmission and synaptic plasticity. Thus it is conceivable that leptin reduces the adverse effects of β-amyloid on synaptic function, but this remains to be determined. Several recent studies also indicate that leptin has the capacity to protect neurons from a number of toxic insults, including TNF-α and 6-hydroxydopamine. Thus another possibility is that leptin protects neurons against β-amyloid-induced toxicity. In support of this, leptin reduces toxic β-amyloid levels in vitro and it increases ApoE-dependent uptake of β-amyloid into cells. Leptin may also influence the amount of β-amyloid in cells by directly altering β-amyloid processing. Indeed, the activity of β-secretase, a protease that cleaves amyloid precursor protein (APP), is reduced by the hormone leptin.

In accordance with previous studies, Lieb et al (4) found that plama leptin was significantly higher in females compared to males. It is well known that differences exist in the susceptibility of males and females to develop certain age-related neurodegenerative diseases. However, the incidence of AD is significantly higher in the female population (~ 68%). Thus it needs to be addressed why the incidence of AD is not significantly lower in the female population given the higher leptin concentrations in females. This disparity between the sexes suggests that distinct risk factors and/or combinations of risk factors contribute to development of AD in males versus females. Further studies are required to determine what, if any, gender-specific factors play a role in contributing to the increased incidence of AD in females.

In conclusion, the study of Lieb et al. provides good, prospective evidence for an association between circulating concentrations of leptin and the incidence of AD, such that a lower incidence of AD is linked with higher leptin in non-obese individuals. Although further research is required to address the precise cellular mechanisms underlying the reduced incidence of AD when leptin concentrations are high, it is possible that leptin may be a good indicator of susceptibility to AD in the elderly population.