Regular articleLevel of body fat relates to memory decline and interacts with age in its association with hippocampal and subcortical atrophy
Introduction
Episodic memory function declines with higher age (Ronnlund et al., 2005), a deterioration partially associated with structural brain changes, including in the medial temporal lobe (Fjell et al., 2014, Raz et al., 2004). People do not decline at the same rate, however, with both environmental and genetic factors affecting the age trajectories (Josefsson et al., 2012). General health measures may be important in explaining why some decline more than others in older age (Livingston et al., 2017). Overweight is a growing concern for general health worldwide and represents such a possible factor, with one in 2 adults and almost one in six children being overweight or obese in The Organisation for Economic Co-operation and Development (OECD) member countries (OECD, 2017). The concern is largely due to the many known health consequences of overweight (Bray, 2004, Pi-Sunyer, 2002, Poirier et al., 2006). Cross-sectional studies have repeatedly reported negative relations between increasing levels of adiposity and measures of gray and white matter volume in cognitively healthy adults (Brooks et al., 2013, Debette et al., 2010, Gunstad et al., 2008, Karlsson et al., 2013, Kurth et al., 2013, Raji et al., 2010, Walther et al., 2010, Ward et al., 2005), including hippocampus and brain areas known to be involved in memory and cognitive functioning (Isaac et al., 2011, Jagust et al., 2005, Stranahan and Mattson, 2012). Consistent with neuroanatomical findings, associations have been found between adiposity and dementia (Gustafson, 2006, Jagust, 2007, Luchsinger and Gustafson, 2009, Whitmer et al., 2008), as well as cognitive performance in nondemented middle-aged and older people (Cournot et al., 2006, Elias et al., 2005, Gunstad et al., 2010).
In more recent longitudinal studies, higher levels of BMI have been related to hippocampal atrophy (Cherbuin et al., 2015) and cortical thinning (Walhovd et al., 2014) in samples with normal and overweight to obese participants. Debette et al found that waist-hip-ratio in midlife was associated with longitudinal changes in total brain volume, however, with no relation being found between obesity as measured by BMI (BMI ≥30) and neuroanatomical changes (Debette et al., 2011). This suggests that it is important to study the whole continuum of adiposity, as well as using complementary measures to BMI. Whereas relations between BMI and brain structure in the normal weight range (BMI 18.5–24.9) have not been observed (Cherbuin et al., 2015, Walhovd et al., 2014), and although there is considerable focus on obesity (BMI ≥30) as a health issue, a relationship between cerebral atrophy and adiposity parameters is found even at the level of overweight (BMI ≥25–30) in cognitively normal older adults (Raji et al., 2010, Walhovd et al., 2014).
Different anthropometric measures have been used to estimate levels of adiposity, the most common being BMI. The World Health Organization has used BMI as a defining parameter for overweight and obesity (WHO, 2014), as it is found to be a good indirect measure of adiposity and strongly related to total body fat (Pi-Sunyer, 2002). However, BMI is an imprecise measure, as its relation to both adiposity and health risk seems to be affected by ethnicity and body type (Deurenberg-Yap et al., 2001, Wang et al., 1994), and it does not reflect the pattern of fat distribution. Visceral adipose tissue has been found to have a stronger association to a cluster of cardiovascular risk factors and disease compared with fat in peripheral parts of the body, subcutaneous adipose tissue, or measures of BMI (de Koning et al., 2007, Janssen et al., 2004, Liu et al., 2010, Wajchenberg, 2000). Nonetheless, when examining multiple adiposity measures simultaneously, including BMI, waist circumference, waist-hip-ratio, subcutaneous adipose tissue, and visceral adipose tissue, all measures have been found to have an inverse association with total brain volume (Debette et al., 2010) and cognitive function (Kanaya et al., 2009).
Sex is related to fat distribution. Men have been found to be more prone to abdominal fat distribution than women (Geer and Shen, 2009, Kotani et al., 1994, Wajchenberg, 2000), which has been related to cardiovascular disease, brain atrophy, and cognitive decline (Debette et al., 2010, Isaac et al., 2011, Van Gaal et al., 2006). Furthermore, the relation between adiposity and brain structures and memory has frequently been found to differ between the sexes (Elias et al., 2005, Elias et al., 2003, Kanaya et al., 2009, Kurth et al., 2013). Besides the difference in fat distribution, this effect of sex has been suggested to be related to cardiovascular and metabolic effects of sex steroid hormones (Vitale et al., 2010).
The nature of the relationship between body fat, brain structure, and cognition may further be confounded by other health characteristics of the sample. Both cholesterol levels (Kivipelto et al., 2002, Leritz et al., 2011, Mielke et al., 2005, Reitz et al., 2004, Walhovd et al., 2014) and blood pressure (BP) (den Heijer et al., 2005, Firbank et al., 2007, Jochemsen et al., 2013, Tzourio et al., 2014) have repeatedly been considered in association with cognitive impairment and neuroanatomical features, but results have been conflicting. A number of studies investigating the relation between overweight and brain characteristics have controlled for comorbid conditions such as hypertension and cholesterol (Cherbuin et al., 2015, Debette et al., 2014, Jagust et al., 2005, Janowitz et al., 2015, Walther et al., 2010), suggesting that body fat has an independent effect on brain structure. It is, however, unclear to what degree these aspects play a role in brain atrophy and declining cognition.
Although lowering of adiposity in late life has been associated with lower cognitive function (West et al., 2017), high body fat levels may also be assumed to work with time toward increasing effect with higher age, and obesity has been associated with increased atrophy from midlife (Ronan et al., 2016). As age is an important predictor for both memory and neuroanatomical volumes (Fjell et al., 2014, Nyberg et al., 2012, Walhovd et al., 2005, Walhovd et al., 2011), it is essential to establish whether a possible relation to body fat is dependent on age. To better understand the nature of the effect of overweight on the age-trajectories of neuroanatomy, especially hippocampal atrophy, and memory, longitudinal studies of a healthy population are needed. In this study, we aimed to test if there is an age-dependent predictive value of body fat on volumetric changes in the hippocampus, subcortical gray matter, and episodic memory in a healthy adult life span sample. We hypothesized that higher levels of body fat would induce steeper decline in brain volume and episodic memory with higher age. As distribution and risk profile of body fat have been reported to be sex dependent (Cnop et al., 2003, Larsson et al., 1992, Ley et al., 1992), we tested if relations between body fat and neuroanatomical volumes and memory vary with sex. To test the relevance of other possible related markers on the effect of body fat, we investigated the relations to cholesterol level and used cholesterol level and BP measures as covariates.
Section snippets
Sample
The sample was drawn from the longitudinal database of the ongoing projects at the Center for Life span Changes in Brain and Cognition at the University of Oslo (de Lange et al., 2017, Fjell et al., 2015, Walhovd et al., 2014). All procedures have been approved by the Regional Ethical Committee of Southern Norway. Participants were recruited through newspaper and webpage adverts, and written consent was obtained from all participants. A combined cross-sectional and longitudinal sample was used
Background analyses on sample characteristics
Sample characteristics are presented in Table 1. The mean age was 40.1 years (SD = 16.6) in the full sample. Of the 957 unique examinations, 38 had missing body fat, and 15 of the participants from the longitudinal subsample missed MRI at one tp. Individuals with missing MRI measures had a mean age of 31.7 years (SD = 11.3), and individuals with missing body fat had a mean age of 33.0 years (SD = 13.6), both significantly lower than the age in the rest of the group (p < 0.05). Missing data are
Discussion
In the current combined longitudinal and cross-sectional study on primarily normal weight to overweight healthy adults, we tested the effect of body fat and total cholesterol on the age trajectories of SCV, HCV, and memory function throughout the adult life span. We found a general decline in both memory and neuroanatomical measures, as expected in normal aging (Nyberg et al., 2012, Raz et al., 2004, Walhovd et al., 2005, Walhovd et al., 2011), including a steeper decline for the hippocampus
Conclusion
This study demonstrates that higher levels of body fat in cognitively healthy adults were negatively associated with HCV and SCV over time as a function of age, where steeper declines were seen with higher body fat in higher age. Body fat was also related to longitudinal memory decline. Longitudinal studies with multiple measurements are needed to provide a better understanding of the pathophysiological mechanisms linking level of body fat to the brain and cognition.
Disclosure
The authors have no conflicts of interest to disclose.
Acknowledgements
This work was supported by the Department of Psychology, University of Oslo (to KBW and AMF), the Norwegian Research Council (to KBW and AMF), Extrastiftelsen (to CKN), and the project has received funding from the European Research Council's Starting Grant and Consolidator Grant scheme under grant agreements 283634 and 725025 (to AMF) and 313440 (to KBW).
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