Genetically determined low BMI does not increase risk of Alzheimer’s disease
A recent study has found that genetic and lifelong low body mass index (BMI) is not a causal risk factor for Alzheimer’s disease in the general population and that the corresponding observational association is likely due to reverse causation or confounding.
“Combining common genetic variation in five key BMI genes into strong genetic instruments and supplementing these analyses with data on Alzheimer’s disease risk of 32 BMI variants from international consortia, we found that genetic and hence lifelong low BMI is not associated with high risk of Alzheimer’s disease in the general population,” researchers said.
For a 1-kg/m2 genetically determined lower BMI, the causal odds ratio (OR) was 0.98 (95 percent CI, 0.77 to 1.23) for a weighted allele score in the Copenhagen General Population Study (CGPS). [J Clin Endocrinol Metab 2017;102:2310–2320]
Using 32 BMI-decreasing variants from the Genetic Investigation of Anthropometric Traits (GIANT) and the International Genomics of Alzheimer’s Project (IGAP), the causal OR was 1.02 (0.86 to 1.22) for Alzheimer’s disease for a 1-standard deviation (SD) lower genetically determined BMI.
For a 1-kg/m2 and for a 1-SD lower BMI, the corresponding observational hazard ratios from CGPS were 1.07 (1.05 to 1.09) and 1.32 (1.20 to 1.46).
“The principal finding of this study is that lifelong low BMI due to genetic variation in BMI-related genes is not associated with increased risk of Alzheimer’s disease, in contrast to the observational association,” researchers said.
“The discordance between the observational and genetic estimates suggests that low BMI per se is not a causal risk factor for Alzheimer’s disease, and that the observational association may be due to reverse causation or confounding,” they added.
In previous studies and a meta-analysis, researchers found that midlife obesity elevated the risk of dementia, whereas obesity at older ages correlated with lower risk of Alzheimer’s disease. [Arch Neurol 2009;66:336–342; Arch Neurol 2005;62):1556–1560; Neurology 2008;71:1057–1064; Obesity (Silver Spring) 2013;21:E51–E55; J Am Geriatr Soc 2008;56:2261–2266]
Another study involving large-scale population from the United Kingdom reported that low BMI in all age groups correlated with an increased risk of Alzheimer’s disease. [Lancet Diabetes Endocrinol 2015;3:431–436]
“These conflicting results reflect well-known problems in observational epidemiology, where associations are prone to confounding and reverse causation—the latter of special concern when estimating effects of BMI and Alzheimer’s disease,” researchers noted.
There are a few biological explanations for the observational association between BMI and Alzheimer’s disease. With regard to Alzheimer’s disease and midlife obesity, a possible reason could be obesity-related vascular disease such as stroke and hypertension, and alterations in brain structure, white matter changes and blood-brain barrier disturbances. [J Intern Med 2007;262:643–650; Neuroimage 2006;31:1419–1425; Neurology 2004;63:1876–1881]
“Furthermore, adipokines—defined as hormones, cytokines and peptides secreted by adipose tissue—have been suggested to have widespread influence and functionality in the brain,” said researchers, adding that leptin, adiponectin and interleukin-6 may be involved in synaptic plasticity, amyloid-β processing and neuroprotection. [Eur Neuropsychopharmacol 2014;24:1982–1999]
In the current study, researchers used a Mendelian randomization approach to analyse 95,578 individuals from the CGPS with up to 36 years of follow-up and consortia data on 303,958 individuals from the GIANT and the IGAP.
“Understanding the association between body mass index (BMI) and dementia is becoming a public health priority due to increasing prevalence of dementia and obesity worldwide,” researchers said. [Lancet 2011;377:557–567; Int J Obes 2008;32:1431–1437]