In our moderate-sized sample from the general population, higher leptin levels at baseline were prospectively associated with a lower risk for incident AD and dementia. The association of high leptin levels with a reduced risk for all-cause dementia and AD remained significant after adjustment for traditional vascular risk factors, and for WHR. Although this association was statistically not significant in participants with higher WHR, the overall findings are consistent with an emerging, if speculative, hypothesis that one reason for the observed association of midlife central obesity with subsequent risk of AD may be an acquired resistance to effects of leptin, including its neuroprotective effects.30
In addition, in a smaller sub-sample of survivors, higher leptin levels were associated with subclinical MRI measures of healthy aging and lower AD risk, i.e. with a higher TCBV and a lower THV although the associations with THV failed to reach statistical significance.
A growing body of evidence indicates that leptin has beneficial effects on brain development and function.31,32
Leptin-deficient mice have a lower brain weight, an immature expression pattern of synaptic and glial proteins,33
and disrupted projection pathways within the hypothalamus34
indicating that leptin is necessary for normal brain development. Further, leptin appears to mediate structural and functional changes in the hippocampus and to improved memory function.6
Leptin receptors are present in the CA1 region of the hippocampus and leptin-deficient or insensitive rats show reduced synaptic plasticity and poorer performance in spatial memory tasks. Leptin facilitates NMDA receptor mediated conversion of short-term potentiation to long-term potentiation in the hippocampus35
and also improves neuronal survival.36
Leptin has also been shown to increase ApoE dependent β-amyloid uptake into the cell and reduce brain extracellular concentrations of β-amyloid, the major component of the neuritic plaques that are a histopathological hallmark of AD.37
Leptin and insulin act in a dose-dependent and synergistic manner to decrease hyperphosphorylation of tau, the primary component of the neurofibrillary tangle, the second major histopathological hallmark of AD.38
Most interesting is a recent observation that chronic leptin treatment improved memory performance in transgenic animal models of AD.39
Our epidemiological observations of an inverse association of baseline leptin concentrations with incident dementia in general and with AD in particular are consistent with these experimental results, as are our observations of a positive relation of leptin with TCBV and (in age-and sex-adjusted models) with THV. A recent small study of brain MRI in 34 elderly volunteers found that higher leptin levels were associated with larger hippocampal and parahippocampal gray matter volumes, but did not observe any association of leptin with total brain volumes; it is likely that the study was underpowered to detect an effect of the magnitude we observed.40
Together, these data support the concept that leptin exerts multiple functions in the brain, beyond those involved in food consumption and energy expenditure. Interestingly, the association of leptin with AD and all-cause dementia is independent of classic neurodegenerative and vascular risk factors suggesting that leptin might act along a new pathway relevant to cognitive function in humans. Although our study was observational, the biological plausibility of the findings, the temporal relations (leptin measurements antedated dementia), the dose-response noted, and the consistency of results in multiple analyses (including an association with subclinical structural indices that have been correlated with cognitive function) suggest that the association may be a causal one, a premise that merits further investigation. The protective effect of leptin seems particularly strong in non-obese individuals and did not reach statistical significance in obese individuals. However, this finding has to be interpreted with caution, since the number of participants and events are substantially smaller in the obese as compared to the non-obese group, limiting our statistical power to detect modest associations. The literature indicates that leptin measurements are relatively stable over time within a given individual. Intra-class correlation coefficients of repeated samples, drawn over a time period of up to 3 years, ranged around 0.80.41–43
The availability of prospective data on hard clinical endpoints (incident dementia and AD) as well as measures of subclinical disease (TCBV, THV), the comprehensive assessment of covariates and the community-based sample strengthen our study. One potential explanation for the stronger association signal with TCBV might be that TCBV is a more robust and reliable measure, with a lower inherent variability when compared to THV.18
One limitation is the restriction of our sample to older European Americans. It is unclear whether our findings are applicable to other ethnicities or age groups. Furthermore, we did not measure leptin in the cerebrospinal fluid or the brain parenchyma. However, the correlation between plasma and cerebrospinal fluid leptin is high.44
Given our sample size, we had only modest power to exclude multivariable-adjusted associations of leptin with THV and we cannot rule out that the results relating leptin to MRI measures of brain aging (which were obtained almost 8 years after leptin was assayed) were biased through selective/conditional survival. In addition, no measures of physical activity, a potential confounder of the observed associations,45
were available at the baseline examination. Leptin levels were determined only once in each participant. This might have led to some random misclassification, likely biasing our results toward the null hypothesis, although the possibility of differential misclassification cannot be excluded. Leptin levels were not measured in our participants while they were middle-aged, so we are unable to address the relationship between mid-life leptin and cognitive outcomes. Further whereas there is published data to suggest that leptin levels remain stable over time, the temporal stability of levels in obese individuals has not been specifically addressed.
Thus, in our community-based sample, higher baseline concentrations of leptin were associated with a reduced risk of incident dementia and AD, even after adjustment for WHR. Further, higher leptin levels were associated with larger brain parenchymal and smaller ventricular volumes. These findings are consistent with recent experimental data indicating that leptin improves memory function in animals through direct effects on the hippocampus and strengthen the evidence that leptin is a hormone with a broad set of actions in the central nervous system. Due to the exploratory character of the present analyses, we did not adjust for multiple comparisons and acknowledge that our findings require confirmation in independent samples. If our findings are confirmed by others, leptin levels in older adults may serve as one of several possible biomarkers for healthy brain aging and more importantly, may open new pathways for possible preventive and therapeutic intervention.39
Further exploration of the molecular and cellular basis for the observed association may expand our understanding of the pathophysiology underlying brain aging and the development of AD.