Taipei, Taiwan — Add leptin, a hormone related to the regulation of appetite and energy balance, to the growing list of biomarker predictors of Alzheimer's disease (AD).
In a presentation here at the Alzheimer's Disease International (ADI) 28th International Conference, researchers led by Leung-Wing Chu, MD, honorary clinical professor of medicine at Queen Mary Hospital of the University of Hong Kong, report that a lower serum leptin level predicted progression of amnestic mild cognitive impairment (aMCI) to AD among older Chinese adults.
Dr. Chu said these findings are consistent with previous data from cross-sectional studies showing lower serum leptin levels in patients with AD vs controls, as well as a positive correlation of leptin levels with greater gray matter volumes in the right hippocampus. Prospective cohort studies have previously shown less cognitive decline with higher serum leptin levels in community-living, dementia-free adults during 4 years of follow-up, as well as a correlation between higher leptin levels and greater total brain and hippocampal volumes with 7.7 years of follow-up.
Animal studies indicate that leptin replacement may hold some therapeutic potential, so Dr. Chu said randomized controlled trials in patients with aMCI should be considered to see whether there is an effect on progression to AD.
Receptors Widely Expressed in Brain
Leptin is secreted mainly by adipocytes, and its receptors are widely expressed in the brain, including the hippocampus, where it enhances function of N-methyl-D-aspartate receptors and modulates plasticity. Dr. Chu said previous studies have shown that higher serum leptin levels are associated with less cognitive decline and with a lower incidence of AD in older adults without dementia. But prospective follow-up data have been lacking on leptin levels and the risk for later development of AD in older adults with aMCI.
In a 1-year cohort study, Dr. Chu enlisted ambulatory Chinese adults aged 55 to 93 years (n = 232) with aMCI (memory symptoms and impaired memory function on tests) but intact activities of daily living and no dementia at baseline between 2004 and 2010.
At 1 year, he determined dementia by criteria in the fourth edition of the Diagnostic and Statistical Manual of Mental Disorders. A probable AD diagnosis was established by using criteria of the National Institute of Neurological and Communicative Disorders and Stroke and the Alzheimer's Disease and Related Disorders Association.
Study patients had a mean age of 76 years at baseline, and 71% were women. The mean education level was 2.7 years; this level is low because many participants grew up during World War II.
Among baseline variables of sex, age, education level, presence of the apolipoprotein E ε4 (APOE ε4) risk allele, and serum leptin level, the only significant predictors of progression from aMCI to AD vs stable aMCI were the presence of APOE ε4 (34.3% vs 15.6%, respectively; P = .018) and serum leptin level (6.95 ± 6.38 ng/mL vs 10.52 ± 8.72 ng/mL, respectively; P = .027).
In a logistic regression analysis adjusting for age, sex, and education, the presence of APOE ε4 was associated with a 2.76-fold increased risk for progression (95% confidence interval [CI], 1.19 - 6.40; P = .018), and a higher serum leptin level was associated with a 7% reduced risk for progression (relative risk, 0.933 per ng/mL; 95% CI, 0.874 - 0.997; P = .04).
Several cognitive and neuropsychological tests, including the Mini-Mental State Examination and the Alzheimer's Disease Assessment Scale-Cognitive subscale, showed a significant association with progression from aMCI to AD (all P ≤ .004). Comorbid diseases of hypertension, diabetes, coronary heart disease, hyperlipidemia, history of stroke, and parkinsonism were not associated with progression to AD.
Cause or Effect?
Session co-chair Brian Draper, MD, from the School of Psychiatry at the University of New South Wales in Sydney, Australia, and chair of the Australian government's Psychogeriatric Care Expert Reference Group, who did not participate in this study, commented to Medscape Medical News that the findings raise the question of cause or effect.
"Is it just simply that you've got a group of individuals who are worried about developing Alzheimer's disease and you're capturing them a bit further on the course in a 1-year period and that these leptin levels are changing in a course with the illness — [whether] it's an epiphenomenon rather than a causal phenomenon?"
He said much bigger studies involving healthy controls and people with AD or MCI and much longer prospective follow-up would be needed to tell the difference.
Referring to the development of biomarkers of AD in general, Dr. Draper said the key will be to find ones that "are truly signs of very, very early disease change that indicate a window of opportunity to make a difference" if preventive therapies are developed.
Dr. Chu and Dr. Draper have disclosed no relevant financial relationships.
Alzheimer's Disease International (ADI) 28th International Conference. Abstract OC077. Presented April 20, 2013.
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Cite this: Leptin Levels Predict Progression to Alzheimer's Disease - Medscape - Apr 23, 2013.