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    Insights into NAFLD & Cognitive Function

    IiStock-1129860760n a recent review published in Cell & Bioscience, many of the common pathologies characteristic of non-alcoholic fatty liver disease (NAFLD) are discussed, as well as how they overlap and contribute to the onset and progression of dementia. To help understand the scope of this problem, it’s worth noting that although the precise prevalence of NAFLD is not clear, it is almost certainly widespread. A cross-sectional study using data from the 11-14 NHANES (National Health and Nutrition Examination Survey) pins the prevalence at 21.9% among US adults over 20, including over 12 million with F2 fibrosis and 5 million with at least F3 fibrosis. It’s also important to note that this estimate used a very strict definition of NAFLD, requiring the presence of both metabolic syndrome and elevated ALT levels; definitions that did not include these requirements have estimated a prevalence of NAFLD nearly twice as high, affecting as many as 100 million adults, in the U.S. alone.

    This growing problem is not limited to adults. 17-20 NHANES data found as many as 40% of adolescents and young adults (age 15-39) without excess alcohol consumption are estimated to have NAFLD, while 56% of those with excessive alcohol consumption have alcohol-associated fatty liver disease (AFLD). When the prevalence of these conditions was reported in 2008, they were substantially lower (40% vs. 11% NAFLD and 56% vs. 4% AFLD), due in part to increased sensitivity in screening, but also to significant increases in obesity and alcohol use, respectively. Obesity was certainly a risk factor in the 11-14 NHANES data, with nearly a 3-fold greater risk with a BMI >= 30 kg/m2 vs. a BMI <30 kg/m2. The prevalence among NHANES participants with diabetes was 55% vs. 15% without, and 41% among those with hypertension, vs. 11% without. NAFLD is a risk factor for cardiovascular disease (CVD), and the presence of CVD increases the likelihood of NAFLD. In fact, it increases the risk for CVD independently of other well-established risk factors, and indicates a multi-system disease that likely plays a role in the pathogenesis of CVD and other chronic conditions.

    Only in the last few years has NAFLD emerged as a risk factor for cognitive impairment and dementia. For example, in 2018 a report in JAMA Neurology detailed a significant association between NAFLD and smaller total cerebral brain volume in a study population of nearly 800 adults participating in the Framingham offspring study. This decrease in brain volume corresponded with 4.2 years of brain aging in the general sample, and 7.3 years in participants under 60.

    In the Cell & Bioscience review, 5 pathologies are reviewed which contribute to NAFLD and potentially to cognitive impairment and dementia: insulin resistance, hyperammonemia, vascular dysfunction, gut dysbiosis/intestinal hyperpermeability, and inflammation. For example, insulin resistance is a hallmark of NAFLD, and brain insulin defects and hyperinsulinemia contribute to both memory loss and dementia. The triglyceride glucose index, a surrogate marker for insulin resistance, was found to be independently associated with dementia, with a 14% adjusted increase in risk in the highest vs. lowest quartiles in a large cohort study. Over 80% of people with Alzheimer’s disease (AD) have been reported to either have diabetes or impaired glucose metabolism, with nearly double the risk of AD with a diagnosis of diabetes. This is one mechanism by which insulin-sensitizing agents like berberine may have an impact.

    Hyperammonemia is also found in both NAFLD and dementia, accelerating the progression of the former, with neurotoxic effects that increases neuronal damage, brain edema, and cognitive dysfunction. Ammonia is thought to have several pathogenic mechanisms of action, including the disruption of mitochondrial function and induction of inflammatory cytokines. Animal models suggest that mitochondrial dysfunction may also underlie the pathology in NAFLD, and that deficits in the expression of the carbamoyl phosphate synthetase-1 (CPS1) gene could be restored with dietary changes. Omega-3 supplementation also appears to improve the mitochondrial function and endoplasmic reticulum stress that drives NAFLD progression.

    Gut dysbiosis is clearly linked both to NAFLD and cognitive impairment. Decreased microbial diversity and specific gut microbes have been correlated to both fibrosis and steatosis. In a recently published pilot study, two “leaky gut” biomarkers (LPS and sCD14) were found to be associated with cognitive decline, lending support to the role of intestinal hyperpermeability and dysbiosis in cognitive impairment. Indeed, a recent review published in Cells suggests that many of the protective effects of natural dietary compounds (e.g., polyphenols, polyunsaturated fats, probiotics, etc.) may be mediated by their action on the gut microbiota (or modification by the microbiota is necessary for benefit). Probiotics have been shown to reduce both intrahepatic fat fraction and body weight among NAFLD participants, and have potential to target specific pathologies in AD as well.

    The review in Cell & Bioscience points to many possible therapeutic targets in patients with NAFLD that may also be relevant to the prevention of cognitive decline. For example, B12 and folate as interventions to help reduce homocysteine may be important to both NAFLD and dementia pathophysiology. Given the complexity of each, it is likely that multiple and individualized approaches are more clinically effective than single therapies alone.

    Related Biotics Research Products:

    B12/Folate Plus

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