Age and Ageing 2015; 44: 4–6 © The Author 2014. Published by Oxford University Press on behalf of the British Geriatrics Society. doi: 10.1093/ageing/afu179 All rights reserved. For Permissions, please email: [email protected] Published electronically 21 November 2014

Is blood leptin a biomarker for dementia development?


The relationship between leptin and dementia seems to be more complex than their initially reported inverse relationship. This evidence comes from a number of longitudinal studies conducted over 4–32 years period, that confirmed the findings from cross-sectional studies [11– 15], reported the opposite finding [16] or found mid-[17] and late-life [2] leptin levels to be unrelated to dementia risk. The answer for these discrepancies in research outcomes may lie within the methodological limitation of the studies, e.g. using somewhat inadequate cognitive screening tools (e.g. MMSE [12]) or being population biased (e.g. women only [17]). However, the above studies also indicated that the levels of peripherally circulating leptin can be influenced by race and gender [13], and co-morbidities, especially diabetes [16], but not necessarily associated with body mass index [14, 18]. The latest study [2] adds several additional factors influencing serum leptin level, including hypertensive medication (in men only) and inflammation (females only). We cannot, similarly, exclude the potential impact of participants’ high educational level, which brings into the equation the role of larger brain size, masking the contribution of the underlying neuropathology to the dementia syndrome(s). Interestingly, women, despite having higher serum leptin levels at baseline, showed similar level of conversion to AD like their male counterparts, arguing that additional factors may influence the dementia progression. A recent study, using the same ADNI sample as Oania and co-workers [2], reported lower plasma leptin levels than the median values of cognitively intact individuals in up to 70% of MCI subjects, and this appears to be related to having at least one apoEε4 allele [15]. This suggests the peripherally circulating leptin levels need to be interpreted cautiously in relation to dementia, thus making leptin blood levels alone an unlikely biomarker to predict dementia conversion. All the above studies concentrated on analysis of systemic circulating leptin levels. Being a regulator of the inflammatory response, leptin function may be modulated by a number of factors, including local leptin concentration, the ratio between free and bound leptin, the expression of different forms of the receptors, the ratio between signalling and nonsignalling receptors, and the presence of specific inhibitors (reviewed in Fantuzzi and Faggioni [19]). They all have to be accounted for when evaluating the possible role of leptin in dementia conversion.

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At present, there are at least 36 million people living with dementia worldwide, with the prevalence rates estimated to double in the following 20 years [1]. This places a burden on current health and social care systems to diagnose, treat, deliver continuous care and plan future needs of this population. Although our understanding about molecular mechanisms underlying dementia has rapidly increased over the last two decades, in clinical setting there are a number of yet unmet needs, including easy accessible and minimally invasive diagnostic methods that reflect the neuropathological hallmarks characteristic for a specific dementia syndrome. In the current issue, Oania with co-authors [2] address the utility of a potential blood biomarker to early diagnose and predict dementia development, using the example of leptin, an adipose-derived protein hormone that plays a role in regulating hunger and weight, and has an impact on feeding behaviour and energy homeostasis. The authors’ finding of unchanged serum leptin levels in people converting from mild cognitive impairment to dementia adds to the puzzle of the role of this ‘anti-obesity’ hormone in the pathogenesis of dementia and further questions its utility for diagnosing dementia in clinical setting. Central obesity is linked to development of dementia. Decreased blood circulating ( plasma and serum) leptin levels are known to induce overfeeding [3], whereas its increased levels are associated with metabolic syndrome, chronic heart failure and cerebrovascular disease [4], all known risk factors for dementia. Furthermore, at the central nervous system molecular level, leptin influences long-term potentiation and synaptic plasticity in the hippocampus, modulates NMDA receptors and influences tau protein phosphorylation, and amyloid clearance [5–7]. All these properties argue that blood leptin could be a strong candidate for a dementia peripheral biomarker, since it seems to be indirectly involved in the central neuropathological changes associated with neurodegenerative disorders, in particular Alzheimer’s disease (AD). The initial studies documented a strong inverse relationship between the plasma leptin levels and the risk to develop AD [8]. What mechanisms are driving this relationship? Could it be that the loss of appetite and decrease in body fat in AD subjects cause low peripheral leptin levels? Or, is it the low leptin levels per sé enhancing the AD pathology and result in poor cognitive function? Is there a role for leptin to be used as a replacement therapy for dementia prevention or therapeutic intervention in AD [9, 10]?


Key points • Growing scale of dementia burden in society requires development of (bio)markers for early dementia diagnosis. • Leptin, a hormone-regulating feeding behaviour, has multiple functions indirectly related to dementia development. • The relationship between blood leptin levels and dementia diagnosis (AD) or risk for developing dementia remains controversial due to methodological and/or population limitations, and influenced by numerous factors, including co-morbidities. • Future work is needed to address the usefulness of blood leptin levels in combination with other peripheral biomarkers to be used in determining both dementia risk and diagnosis.

Conflicts of interest None declared.

Funding EBM-L was supported by Alzheimer's Society, London, UK. 1

ELIZABETA B. MUKAETOVA-LADINSKA1, IRINA S. BOKSHA2 Campus for Ageing and Vitality, Institute of Neuroscience, Newcastle University, Newcastle upon Tyne NE4 5PL, UK 2 Laboratory of Neurochemistry, Mental Health Research Center of Russian Academy of Sciences, Moscow, Russia Address correspondence to: E. B. Mukaetova-Ladinska. Tel : (+44) 191 282 0045 or (+44) 191 246 8777; Fax: (+44) 191 282 4839. Email: [email protected]

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The currently available evidence, reviewed above, also suggests that the dementia predictive capacity of peripheral leptin levels may be restricted to specific subgroups of older people, e.g. African American men or people with normal or low body mass index. In addition, lower levels of leptin can also be a result of long-term physical activity, diet [20], antiinflammatory treatment or lower limb muscle strength [21]. The evidence from most recent proteomic studies supports the use of multianalyte profiling (e.g. subsets of 4–5 plasma proteins, closely related to the amyloid protein precursor and tau protein [22] and inflammation [23], or lipids associated with cell membrane integrity [24]) for diagnosing and even predicting dementia. This suggests that a combination of several biomarkers may be best suited for developing a blood test for cognitive decline and dementia progression. In this respect, circulating leptin may still have a place in dementia diagnosis.

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proteomics for the identification of Alzheimer disease. Alzheimer Dis Assoc Disord 2013; 27: 337–42. 23. Hu WT, Holtzman DM, Fagan AM et al. Alzheimer’s disease neuroimaging initiative. Plasma multianalyte profiling in mild cognitive impairment and Alzheimer disease. Neurology 2012; 79: 897–905. 24. Mapstone M, Cheema AK, Fiandaca MS et al. Plasma phospholipids identify antecedent memory impairment in older adults. Nat Med 2014; 20: 415–8.

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Is blood leptin a biomarker for dementia development?

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