The World Health Organization defines dementia as a progressive deterioration of cognitive function at a level which is beyond expected in normal aging. Dementia can reduce quality of life, as it affects memory, thinking, learning capacity, judgement, and language (1). Currently, 50 million people globally are living with dementia, and among them 60% are from low to middle income countries. Worldwide, each year 10 million new cases of dementia are observed; the prevalence of dementia is projected to increase to 152 million by mid-century (1). Although age and genetics are inexorable risk factors for dementia, it is important to identify modifiable risk factors for dementia. Obesity is one such factor, which has been independently shown to increase the risk of dementia (2).
The incidence of obesity is increasing at a disturbing rate. From 1975 to 2016, the prevalence of overweight and obesity increased by four-fold worldwide (3). In 2016, 1.9 billion adults were estimated to be overweight globally, among those 650 million were obese (3). Further, 340 million children and teenagers were found to be overweight. Moreover, every year 4 million people die due to being overweight/ obese (3). In the United States, 42.4% of adults and 18.5% children are suffering from obesity (4,5). Obesity is linked with several heath complications including cardiovascular diseases and diabetes (3), which themselves are risk factors for dementia.
A longitudinal analysis on 6583 individuals in California showed that individuals with the largest sagittal abdominal diameter (SAD), which is a measure of fat in the gut region, have three-fold risk of developing dementia in comparison to individuals with the smallest diameters (6). SAD in individuals was measured from 1964 to 1973 and medical records from those individuals were analyzed to identify patients with dementia from 1994 to 2006 (6). Further, the larger waist-hip ratio has been associated with decreased hippocampal volume, analyzed using magnetic resonance imaging, the region of the brain associated with learning and memory (7). Obesity specifically at midlife has been correlated with incidence of dementia development. A retrospective cohort study showed that obesity between the age of 30 to 39 years significantly increased the risk of dementia; however, this risk steadily decreased as obesity decreased in these subjects as they aged (8). The link between obesity and dementia was based on a dataset, supplied by English National Health and Social Care Information Centre, that has information of all National Health Service (NHS) hospital admission including obesity and dementia levels in patients (8). Moreover, a cohort projection model based on Australian population predicted that risk of dementia can be decreased by 10% if obesity in midlife can be reduced by 20% (9).
The pathological mechanisms by which obesity can exacerbate dementia are not very well studied; however, chronic low-grade inflammation associated with obesity may be one culprit (2). A high-fat diet is the number one cause of obesity, and having chronic high levels of circulating free fatty acids has been projected to cause low-grade inflammation. This can trigger insulin resistance in obese individuals (2). Additionally, patients with metabolic syndrome have shown to have a higher uptake and accumulation of fatty acids in the brain which is linked with neuroinflammation (10). Both insulin resistance and metabolic syndrome, which has shown to be reversed by weight loss, are risk factors for dementia and Alzheimer’s disease (11). The free fatty acids can cause the assembly of amyloid and tau filaments, thereby promoting Alzheimer’s pathogenesis which is the leading cause of dementia (12). The saturated fatty acids can activate toll-like receptor 4 which can itself stimulate cytokines production, small immunomodulatory proteins, in astrocytes (2). In addition, saturated fatty acids can also activate microglia in the brain (2). The presence of activated microglia has been observed at sites of amyloid deposition in the brain of Alzheimer’s mouse model (13). The activation of astrocyte and microglia can cause activation of several proinflammatory cytokines including tumor necrosis factor-alpha (TNF-α), interleukin-1beta (IL-1β) and IL-6. The cytokines can cause oxidative stress, demyelination and apoptosis, ultimately causing neurodegeneration and cognitive decline (13).
The above evidence suggests how obesity can trigger low-grade inflammation, which can ultimately cause neurodegenerative damage. Given there is no cure for dementia and Alzheimer’s currently, it is important to identify modifiable risk factors so that incidence of the disease can be reduced. Obesity is one of the risk factors which can be reversed by making healthy choices including exercise and a balanced diet. Further, it is important to identify these risk groups so that early detection of dementia and AD can be made. Esurgi is developing a multi-modal adjunct diagnostics, Eye AD, to detect early cognitive decline in real-time. Eye AD, a cost-effective tool, can be used to perform a risk assessment in high risk populations and early interventions can be provided to patients for maximum benefit.
2. Pugazhenthi S, Qin L, Reddy PH. Common neurodegenerative pathways in obesity, diabetes, and Alzheimer’s disease. Biochim Biophys Acta Mol Basis Dis. May 2017;1863(5):1037-1045. doi:10.1016/j.bbadis.2016.04.017
6. Whitmer RA, Gustafson DR, Barrett-Connor E, Haan MN, Gunderson EP, Yaffe K. Central obesity and increased risk of dementia more than three decades later. Neurology. Sep 2008;71(14):1057-64. doi:10.1212/01.wnl.0000306313.89165.ef
12. Wilson DM, Binder LI. Free fatty acids stimulate the polymerization of tau and amyloid beta peptides. In vitro evidence for a common effector of pathogenesis in Alzheimer’s disease. Am J Pathol. Jun 1997;150(6):2181-95.