NAFLD and risk of dementia

It is nowadays well established that nonalcoholic fatty liver disease (NAFLD) shares many risk factors with cardiovascular diseases (eg diabetes mellitus, hypertension, dyslipidemia) [1]. It is therefore not difficult to imagine that there may also be a link between NAFLD and dementia. However, it is at present time not clear whether NAFLD and dementia only share common risk factors or if NAFLD has an actual role in the development of dementia.

The majority of studies examining the association between NAFLD and dementia is currently related to patients with mild cognitive impairment [2]. Among the few studies related to patient with diagnosed dementia, the results are not always in agreement, with a recent study reporting a higher risk of all-cause dementia in patients with both liver fibrosis due to NAFLD and frailty [3], and other studies that did not find any direct correlation between NAFLD and dementia [4-5]. Many mechanisms that are common in patients with NAFLD could be responsible for the development of dementia, such as insulin resistance (that increases inflammation and cytokines secretion), hyperammonemia (which is known to worsen cognitive function even in patients without liver disease), vascular dysfunction and disruption of the gut microbiota.

Many uncertainties lay also in the relationship between NAFLD and the different subtypes of dementia. Vascular dementia is probably the subtype that is more commonly linked to NAFLD, since they share similar risk factors. A recent study by Shang Y et al [6] tried to investigate the impact of NAFLD on the risk of dementia and dementia subtypes (i.e. vascular dementia vs Alzheimer Disease [AD]). They followed prospectively 2898 patients older than 65 years old with a diagnosis of NAFLD and confronted them with 28357 subjects selected from the general population matched for age, sex and municipality with no diagnosis of NAFLD. The 5-year cumulative incidence of all-cause dementia was 3.6% for patients with NAFLD and 2.0% for the matched population, with an hazard ratio for dementia in patients with NAFLD of 1.86 (95% CI 1.55–2.25), and an association with vascular dementia that however did not reach statistical significance (aHR 1.44, 95% CI 0.96–2.23, p=0.07), while there was no significant association with AD (aHR 1.15, 95% CI 0.78–1.70).

However, many other studies suggested a positive correlation also between NAFLD and AD. For example, in NAFLD mice, there is an increase of AD signs due to a decreased brain expression of low-density lipoprotein receptor-related protein-1 (LRP-1) which is involved in β-amyloid clearance [7] and an altered clearance of amyloid- β peptide both in human and animal models [8].

Whether the causes and the subtypes involved in the process, it’s therefore very important to consider cognitive impairment in the evaluation and follow up of patients with NAFLD. Considering the increasing prevalence of this etiology of liver disease and the burden that dementia represents for health of the general population in terms of mortality, management costs, hospitalization and disability, further studies are therefore needed and certainly welcomed in order to assess the actual relationship between these two conditions and to plan a correct diagnostic and prognostic management for these patients.

REFERENCES

1. Dongiovanni P, Paolini E, Corsini A, Sirtori CR, Ruscica M. Nonalcoholic fatty liver disease or metabolic dysfunction-associated fatty liver disease diagnoses and cardiovascular diseases: From epidemiology to drug approaches. Eur J Clin Invest. 2021 Jul;51(7):e13519.
2. Seo SW, Gottesman RF, Clark JM, et al. Nonalcoholic fatty liver disease is associated with cognitive function in adults. Neurology. 2016;86(12):1136-1142.
3. Solfrizzi V, Scafato E, Custodero C, et al; Italian Longitudinal Study on Aging Working Group. Liver fibrosis score, physical frailty, and the risk of dementia in older adults: the Italian Longitudinal Study on Aging. Alzheimers Dement. 2020;6(1):e12065.
4. Shang Y, Nasr P, Ekstedt M, et al. Non-alcoholic fatty liver disease does not increase dementia risk although histology data might improve risk prediction. JHEP Rep innovation Hepatol. 2020;3(2):100218.
5. Gerber Y, VanWagner LB, Yaffe K et al. Non-alcoholic fatty liver disease and cognitive function in middle-aged adults: the CARDIA study. BMC Gastroenterol. 2021 Mar 2;21(1):96.
6. Shang Y, Widman L, Hagström H. Nonalcoholic Fatty Liver Disease and Risk of Dementia: A Population-Based Cohort Study. Neurology. 2022 Jul 13:10.1212/WNL.0000000000200853.
7. Kim DG, Krenz A, Toussaint LE et al. Non-alcoholic fatty liver disease induces signs of Alzheimer’s disease (AD) in wild-type mice and accelerates pathological signs of AD in an AD model. J Neuroinflammation. 2016 Jan 5;13:1.
8. Estrada LD, Ahumada P, Cabrera D, Arab JP. Liver Dysfunction as a Novel Player in Alzheimer’s Progression: Looking Outside the Brain. Front Aging Neurosci. 2019 Jul 17;11:174.