We hypothesized that nonalcoholic fatty liver disease (NAFLD) is independently associated with cognitive impairment in a representative sample of the general US population regardless of the presence of cardiovascular disease (CVD) or its risk factors.This was a cross-sectional study of 4,472 adults aged 20-59 years who participated in the Third National Health and Nutritional Examination Survey. The participants underwent assessment of liver enzyme activity and hepatic steatosis by ultrasound, and underwent cognitive evaluation using the following computer-administered tests: the Simple Reaction Time Test (SRTT), the Symbol-Digit Substitution Test (SDST), and the Serial Digit Learning Test (SDLT). We defined NAFLD as moderate/severe steatosis as determined by ultrasound in the absence of hepatitis B or C or excessive alcohol consumption. We used multiple linear regression models to examine the association between NAFLD and cognitive function while controlling for potential confounders.Participants with NAFLD showed lower overall performance on the SDLT (β = 0.726, 95% confidence interval [CI] 0.105-1.347), while associations with SRTT and SDST did not reach significance. Increased activity of the liver enzymes alanine aminotransferase (β = 0.018, 95% CI 0.006-0.030) and aspartate aminotransferase (β = 0.021, 95% CI 0.005-0.037) correlated with lower performance on the SDLT, while increased alanine aminotransferase was also correlated with lower performance in the SDST (β = 0.002, 95% CI 0.0001-0.004).NAFLD was independently associated with lower cognitive performance independent of CVD and its risk factors. Given the scarcity of risk factors associated with age-related cognitive decline, these findings may have significant implications.© 2016 American Academy of Neurology.

& Objectives: Non-alcoholic fatty liver disease (NAFLD) might affect brain health, via the so-called liver-brain axis. Whether this results in increased risk for dementia remains unclear. Therefore, we investigated the association of NAFLD and fibrosis with incident dementia and cognition among the elderly.We performed longitudinal and cross-sectional analyses within The Rotterdam Study, an ongoing prospective cohort. Participants visiting between 1997 and 2002 with available fatty liver index (FLI) (set 1)) or participants visiting between 2009 and 2014 with abdominal ultrasound (set 2) and liver stiffness (set 3) were included. Exclusion criteria were secondary causes for steatosis, prevalent dementia and missing alcohol data. NAFLD was defined as FLI≥60 or steatosis on ultrasound and fibrosis as liver stiffness ≥8.0kPa. Dementia was defined according to the DSM-III-R. Associations between NAFLD, fibrosis or liver stiffness and incident dementia were quantified using Cox regression. Last, the association between NAFLD and cognitive function was assessed cross-sectionally.Set 1 included 3.975 participants (age 70 years, follow-up 15.5 years), set 2 4.577 participants (age 69.9 years, follow-up 5.7 years) and set 3 3.300 participants (age 67.6 years, follow-up 5.6 years). NAFLD and fibrosis were consistently not associated with increased risk for dementia (NAFLD based on ultrasound, HR:0.84, 95%CI:0.61-1.16; NAFLD based on FLI, HR:0.92, 95%CI:0.69-1.22; fibrosis, HR:1.07, 95%CI:0.58-1.99) in fully adjusted models. Interestingly, NAFLD was associated with a significantly decreased risk for incident dementia until five years after FLI-assessment (HR:0.48; 95%CI:0.24-0.94). Moreover, NAFLD was not associated with worse cognitive function, covering several domains.NAFLD and fibrosis were not associated with increased risk for incident dementia, nor was NAFLD associated with impaired cognitive function. In contrast, NAFLD was even protective in the first five years of follow up, hinting towards NAFLD regression before dementia onset. number: NTR6831.Copyright © 2022 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.

Non-alcoholic fatty liver disease (NAFLD) and dementia share common risk factors including metabolic disorders. However, whether NAFLD is associated with dementia risk is unclear. We investigated the association between NAFLD and dementia risk as well as the role of cardiovascular complications including heart disease and stroke.In this population-based matched cohort study, we identified all Swedish patients aged ≥65 years with NAFLD identified from the National Patient Register (NPR) between 1987 and 2016. These were matched with up to ten reference individuals from the general population on age, sex, and municipality at the year of diagnosis. Incident dementia diagnosis was derived from the NPR or the Cause of Death Register until 2016. Adjusted hazard ratios (aHR) and 95% confidence intervals (CI) were estimated with Cox regression models.A total of 2898 patients with NAFLD and 28357 matched controls were identified (median age at entry, interquartile range [IQR], 70 [8]; 55.1% female). During a median follow-up of 5.5 years (IQR: 8.5 years), 145 (5.0%) patients with NAFLD and 1291 (4.6%) reference individuals were diagnosed with dementia. Compared to the reference individuals, patients with NAFLD had higher rates of dementia (aHR 1.38, 95% CI 1.10-1.72) and vascular dementia (aHR 1.44, 95% CI 0.96-2.23, p=0.07). Comorbid NAFLD and either heart disease (aHR 1.50 95% 1.08-2.05) or stroke (aHR 2.60 95% CI 1.95-3.47) conferred a greater risk of dementia.NAFLD had a modest association with increased rates of dementia. This was stronger among patients with NAFLD diagnosed with cardiovascular comorbidities.This study provides Class II evidence that non-alcoholic fatty liver disease is associated with the development of vascular and non-vascular dementia.Copyright © 2022 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.

The association between liver and brain health has gained attention as biomarkers of liver function have been revealed to predict neurodegeneration. The liver is a central regulator in metabolic homeostasis. However, in nonalcoholic fatty liver disease (NAFLD), homeostasis is disrupted which can result in extrahepatic organ pathologies. Emerging literature provides insight into the mechanisms behind the liver-brain health axis. These include the increased production of liver-derived factors that promote insulin resistance and loss of neuroprotective factors under conditions of NAFLD that increase insulin resistance in the central nervous system. In addition, elevated proinflammatory cytokines linked to NAFLD negatively impact the blood-brain barrier and increase neuroinflammation. Furthermore, exacerbated dyslipidemia associated with NAFLD and hepatic dysfunction can promote altered brain bioenergetics and oxidative stress. In this review, we summarize the current knowledge of the crosstalk between liver and brain as it relates to the pathophysiology between NAFLD and neurodegeneration, with an emphasis on Alzheimer's disease. We also highlight knowledge gaps and future areas for investigation to strengthen the potential link between NAFLD and neurodegeneration.Thieme. All rights reserved.

Hepatitis C virus (HCV) infection may cause cognitive impairment, but no studies have focused specifically on cognitive impairment stemming from HCV. The purpose of this study was to investigate the potential increased risk for dementia in HCV-infected patients.A population-based cohort study based on the Taiwan National Health Insurance Research Database was conducted. From all potential participants aged 50 years or more, a total of 58,570 matched (1:1) pairs of HCV-infected patients and non-HCV-infected patients were included. Each subject was individually tracked from 1997 to 2009 to identify incident cases of dementia (onset in 1999 or later). Cox proportional hazards regressions were employed to calculate the hazard ratios (HRs) and 95% confidence intervals (CIs) for the association between HCV infection and dementia.There were 2989 dementia cases from the HCV-infected cohort during the follow-up period of 533,861.1 person-years; the overall incidence rates of dementia differed from the non-HCV cohort (56.0 vs. 47.7 cases per 10,000 person-years, P < 0.05). The adjusted HR for dementia was 1.36 (95% CI 1.27-1.42) for HCV-infected patients after adjusting for alcohol-related disease, liver cirrhosis, hepatic encephalopathy and hepatocellular carcinoma.HCV infection may increase the risk for dementia. Further mechanistic research is needed.© 2013 The Author(s) European Journal of Neurology © 2013 EAN.

There is growing recognition that chronic liver conditions influence brain health. The impact of liver fibrosis on dementia risk was unclear. We evaluated the association between liver fibrosis and incident dementia in a cohort study.We performed a cohort analysis using data from the UK Biobank study, which prospectively enrolled adults starting in 2007, and continues to follow them. People with a Fibrosis-4 (FIB-4) liver fibrosis score >2.67 were categorized as at high risk of advanced fibrosis. The primary outcome was incident dementia, ascertained using a validated approach. We excluded participants with prevalent dementia at baseline. We used Cox proportional hazards models to evaluate the association between liver fibrosis and dementia while adjusting for potential confounders.Among 455,226 participants included in this analysis, the mean age was 56.5 years and 54% were women. Approximately 2.17% (95% confidence interval [CI] 2.13%-2.22%) had liver fibrosis. The rate of dementia per 1000 person-years was 1.76 (95% CI 1.50-2.07) in participants with liver fibrosis and 0.52 (95% CI 0.50-0.54) in those without. After adjusting for demographics, socioeconomic deprivation, educational attainment, metabolic syndrome, hypertension, diabetes, dyslipidemia, and tobacco and alcohol use, liver fibrosis was associated with an increased risk of dementia (hazard ratio 1.52, 95% CI 1.22-1.90). Results were robust to sensitivity analyses. Effect modification by sex, metabolic syndrome, and apolipoprotein E4 carrier status was not observed.Liver fibrosis in middle age was associated with an increased risk of incident dementia, independent of shared risk factors. Liver fibrosis may be an underrecognized risk factor for dementia.© 2022 European Academy of Neurology.

Alzheimer's disease (AD) is regarded as a metabolic disorder, and more attention has been paid to brain metabolism. However, AD may also affect metabolism in the peripheral organs beyond the brain. In this study, therefore, we investigated metabolic changes in the liver, kidney, and heart of amyloid precursor protein/presenilin 1 (APP/PS1) mice at 1, 5, and 10 months of age by using H NMR-based metabolomics and chemometrics. Metabolomic results reveal that the liver was the earliest affected organ in APP/PS1 mice during amyloid pathology progression, followed by the kidney and heart. Moreover, a hypometabolic state was found in the liver of APP/PS1 mice at 5 months of age, and the disturbed metabolites were mainly involved in energy metabolism, amino acid metabolism, nucleic acid metabolism, as well as ketone and fatty acid metabolism. In conclusion, our results suggest that AD is a systemic metabolic dysfunction, and hepatic metabolic abnormality may reflect amyloid pathology progression.

目的: 探索血浆中高水平A&#x003b2;₄₂对阿尔茨海默病（Alzheimer's disease,AD）小鼠模型肝脏的影响及肝脏在AD发病机制中的作用。 方法: 采用11月龄野生雌性C57小鼠（Wt鼠）、APP/PS-1双转基因小鼠(Tg鼠）,以及3月龄Wt鼠与Wt鼠、Wt鼠与Tg鼠分别建立paWt (Wt-Wt)和paWt (Wt-Tg)循环并联模型（n = 6）,循环并联持续8个月至11月龄;11月龄时用ELISA试剂盒测定各组中血浆A&#x003b2;₄₂水平、测量各组小鼠肝脏重量并进行肝脏HE染色。结果: 11月龄Wt鼠、Tg鼠、paWt (Wt-Wt) 鼠、paWt (Wt-Tg) 鼠和paTg (Wt-Tg）鼠血浆中A&#x003b2;₄₂水平分别为（7.47 &#x000b1;1.83）pg/ml、（368.59&#x000b1;55.14）pg/ml、（7.20&#x000b1;2.06）pg/ml、（264.04&#x000b1;13.28）pg/ml和（330.25&#x000b1;12.97）pg/ml,Tg鼠、paWt (Wt-Tg)鼠和paTg (Wt-Tg)鼠血浆A&#x003b2;₄₂水平均显著升高（p &lt; 0.002）;11月龄时Wt鼠、Tg鼠、paWt (Wt-Wt)鼠、paWt (Wt-Tg)鼠和paTg (Wt-Tg）鼠肝脏重量分别为（1.60&#x000b1;0.19）g、（0.83&#x000b1;0.2）g、（1.34&#x000b1;0.18）g、（1.53&#x000b1;0.14）g和（1.51&#x000b1;0.33）g,Tg鼠肝脏重量显著减轻（p &lt; 0.005）,Tg鼠与Wt鼠并联后肝脏重量恢复正常,HE染色显示Tg鼠肝脏肝细胞坏死和淋巴细胞浸润显著增加,Tg鼠与Wt鼠并联后肝脏细胞坏死和淋巴浸润显著减轻。结论: 血浆中高水平A&#x003b2;₄₂可以导致肝细胞坏死和淋巴浸润显著增加,肝脏可能参与了阿尔茨海默病的发病机制,值得进一步研究。

In 2011, the National Institute on Aging and Alzheimer's Association created separate diagnostic recommendations for the preclinical, mild cognitive impairment, and dementia stages of Alzheimer's disease. Scientific progress in the interim led to an initiative by the National Institute on Aging and Alzheimer's Association to update and unify the 2011 guidelines. This unifying update is labeled a "research framework" because its intended use is for observational and interventional research, not routine clinical care. In the National Institute on Aging and Alzheimer's Association Research Framework, Alzheimer's disease (AD) is defined by its underlying pathologic processes that can be documented by postmortem examination or in vivo by biomarkers. The diagnosis is not based on the clinical consequences of the disease (i.e., symptoms/signs) in this research framework, which shifts the definition of AD in living people from a syndromal to a biological construct. The research framework focuses on the diagnosis of AD with biomarkers in living persons. Biomarkers are grouped into those of β amyloid deposition, pathologic tau, and neurodegeneration [AT(N)]. This ATN classification system groups different biomarkers (imaging and biofluids) by the pathologic process each measures. The AT(N) system is flexible in that new biomarkers can be added to the three existing AT(N) groups, and new biomarker groups beyond AT(N) can be added when they become available. We focus on AD as a continuum, and cognitive staging may be accomplished using continuous measures. However, we also outline two different categorical cognitive schemes for staging the severity of cognitive impairment: a scheme using three traditional syndromal categories and a six-stage numeric scheme. It is important to stress that this framework seeks to create a common language with which investigators can generate and test hypotheses about the interactions among different pathologic processes (denoted by biomarkers) and cognitive symptoms. We appreciate the concern that this biomarker-based research framework has the potential to be misused. Therefore, we emphasize, first, it is premature and inappropriate to use this research framework in general medical practice. Second, this research framework should not be used to restrict alternative approaches to hypothesis testing that do not use biomarkers. There will be situations where biomarkers are not available or requiring them would be counterproductive to the specific research goals (discussed in more detail later in the document). Thus, biomarker-based research should not be considered a template for all research into age-related cognitive impairment and dementia; rather, it should be applied when it is fit for the purpose of the specific research goals of a study. Importantly, this framework should be examined in diverse populations. Although it is possible that β-amyloid plaques and neurofibrillary tau deposits are not causal in AD pathogenesis, it is these abnormal protein deposits that define AD as a unique neurodegenerative disease among different disorders that can lead to dementia. We envision that defining AD as a biological construct will enable a more accurate characterization and understanding of the sequence of events that lead to cognitive impairment that is associated with AD, as well as the multifactorial etiology of dementia. This approach also will enable a more precise approach to interventional trials where specific pathways can be targeted in the disease process and in the appropriate people.Copyright © 2018 The Authors. Published by Elsevier Inc. All rights reserved.

Amyloid-beta (Aβ) plays a pivotal role in the pathogenesis of Alzheimer's disease (AD). The physiological capacity of peripheral tissues and organs in clearing brain-derived Aβ and its therapeutic potential for AD remains largely unknown. Here, we measured blood Aβ levels in different locations of the circulation in humans and mice, and used a parabiosis model to investigate the effect of peripheral Aβ catabolism on AD pathogenesis. We found that blood Aβ levels in the inferior/posterior vena cava were lower than that in the superior vena cava in both humans and mice. In addition, injected (125)I labeled Aβ40 was located mostly in the liver, kidney, gastrointestinal tract, and skin but very little in the brain; suggesting that Aβ derived from the brain can be cleared in the periphery. Parabiosis before and after Aβ deposition in the brain significantly reduced brain Aβ burden without alterations in the expression of amyloid precursor protein, Aβ generating and degrading enzymes, Aβ transport receptors, and AD-type pathologies including hyperphosphorylated tau, neuroinflammation, as well as neuronal degeneration and loss in the brains of parabiotic AD mice. Our study revealed that the peripheral system is potent in clearing brain Aβ and preventing AD pathogenesis. The present work suggests that peripheral Aβ clearance is a valid therapeutic approach for AD, and implies that deficits in the Aβ clearance in the periphery might also contribute to AD pathogenesis.

Polymorphism in the apolipoprotein E (APOE) gene is a major genetic risk determinant of late-onset Alzheimer disease (AD), with the APOE*ε4 allele conferring an increased risk and the APOE*ε2 allele conferring a decreased risk relative to the common APOE*ε3 allele. Strong evidence from clinical and basic research suggests that a major pathway by which APOE4 increases the risk of AD is by driving earlier and more abundant amyloid pathology in the brains of APOE*ε4 carriers. The number of amyloid-β (Aβ)-dependent and Aβ-independent pathways that are known to be differentially modulated by APOE isoforms is increasing. For example, evidence is accumulating that APOE influences tau pathology, tau-mediated neurodegeneration and microglial responses to AD-related pathologies. In addition, APOE4 is either pathogenic or shows reduced efficiency in multiple brain homeostatic pathways, including lipid transport, synaptic integrity and plasticity, glucose metabolism and cerebrovascular function. Here, we review the recent progress in clinical and basic research into the role of APOE in AD pathogenesis. We also discuss how APOE can be targeted for AD therapy using a precision medicine approach.

Alzheimer's disease (AD) is the most common type of dementia, and no disease-modifying treatments are available to halt or slow its progression. Amyloid-beta (Aβ) is suggested to play a pivotal role in the pathogenesis of AD, and clearance of Aβ from the brain becomes a main therapeutic strategy for AD. Recent studies found that Aβ clearance in the periphery contributes substantially to reducing Aβ accumulation in the brain. Therefore, understanding the mechanism of how Aβ is cleared in the periphery is important for the development of effective therapies for AD. In this review, we summarized recent findings on the mechanisms of Aβ efflux from the brain to the periphery and discuss where and how the brain-derived Aβ is cleared in the periphery. Based on these findings, we propose future strategies to enhance peripheral Aβ clearance for the prevention and treatment of AD. This review provides a novel perspective to understand the pathogenesis of AD and develop interventions for this disease from a systemic approach.

Chronic stress induces anxiety disorders via both neural pathways and circulating factors. Although many studies have elucidated the neural circuits involved in stress-coping behaviors, the origin and regulatory mechanism of peripheral cytokines in behavioural regulation under stress conditions are not fully understood. Here, we identified a serum cytokine, lipocalin 2 (LCN2), that was upregulated in participants with anxiety disorders. Using a mouse model of chronic restraint stress (CRS), circulating LCN2 was found to be related to stress-induced anxiety-like behaviour via modulation of neural activity in the medial prefrontal cortex (mPFC). These results suggest that stress increases hepatic LCN2 via a neural pathway, leading to disrupted cortical functions and behaviour.© 2024. The Author(s).

Alzheimer's disease (AD) is caused by a complex interaction between genetic and environmental factors. However, how the role of peripheral organ changes in response to environmental stimuli during aging in AD pathogenesis remains unknown. Hepatic soluble epoxide hydrolase (sEH) activity increases with age. Hepatic sEH manipulation bidirectionally attenuates brain amyloid-β (Aβ) burden, tauopathy, and cognitive deficits in AD mouse models. Moreover, hepatic sEH manipulation bidirectionally regulates the plasma level of 14,15-epoxyeicosatrienoic acid (-EET), which rapidly crosses the blood-brain barrier and modulates brain Aβ metabolism through multiple pathways. A balance between the brain levels of 14,15-EET and Aβ is essential for preventing Aβ deposition. In AD models, 14,15-EET infusion mimicked the neuroprotective effects of hepatic sEH ablation at biological and behavioral levels. These results highlight the liver's key role in AD pathology, and targeting the liver-brain axis in response to environmental stimuli may constitute a promising therapeutic approach for AD prevention.Copyright © 2023 Elsevier Inc. All rights reserved.

Fibroblast Growth Factor 21 (FGF21), Growth Differentiation Factor 15 (GDF15), and Humanin (HN) are mitochondrial stress-related mitokines, whose role in health and disease is still debated. In this study, we confirmed that their plasma levels are positively correlated with age in healthy subjects. However, when looking at patients with type 2 diabetes (T2D) or Alzheimer's disease (AD), two age-related diseases sharing a mitochondrial impairment, we found that GDF15 is elevated in T2D but not in AD and represents a risk factor for T2D complications, while FGF21 and HN are lower in AD but not in T2D. Moreover, FGF21 reaches the highest levels in centenarian' offspring, a model of successful aging. As a whole, these data indicate that (i) the adaptive mitokine response observed in healthy aging is lost in age-related diseases, (ii) a common expression pattern of mitokines does not emerge in T2D and AD, suggesting an unpredicted complexity and disease-specificity, and (iii) FGF21 emerges as a candidate marker of healthy aging.

: Till now, the effect of serum lipid levels on cognitive function is still controversial. The apolipoprotein E (APOE) ε4 allele is the most critical genetic risk factor for Alzheimer's disease (AD) and cognitive impairment. Additionally, ε4 allele has a major impact on lipid metabolism. The aim of this study was to investigate the genotype-dependent relationship between peripheral serum lipid levels and cognitive impairment. : A total of 1,273 subjects aged 40-86 years participated in this cross-sectional study. Serum lipid levels and the genotype were detected. Mini-Mental State Examination was used to diagnose the cognitive impairment or not. Univariate and multivariate analyses were used to analyze the relationships between genotype, serum lipid levels, and cognition function. : After controlling for all possible covariates, a significant interaction between low serum high-density lipoprotein and the ε4 allele on cognitive impairment (Wald's χ = 4.269, = 1, OR = 20.094, = 0.039) was found in the total participants. In ε4 carriers, low serum high-density lipoprotein was positively associated with cognitive impairment (Wald's χ = 8.200, = 1, OR = 60.335, = 0.004) and serum high-density lipoprotein levels were positively correlated with Mini-Mental State Examination score ( = 0.217, = 176, = 0.004). There was no significant correlation between serum total cholesterol (TC), low-density lipoprotein, triglycerides (TG) levels, and cognitive impairment in either the total participants or ε4 carriers/non-carriers. : ε4 carriers, but not non-carriers, with lower serum high-density lipoprotein had a higher prevalence of cognitive impairment and a lower Mini-Mental State Examination score. These results suggest that the ε4 allele may affect the relationship between serum lipid levels and cognitive impairment. However, the specific mechanism needs to be further elucidated.Copyright © 2020 Wei, Gao, Jiang, Shang, Chen, Dang, Wang, Huo, Wang and Qu.

Increasing evidence suggests a role for the gut microbiome in central nervous system disorders and a specific role for the gut-brain axis in neurodegeneration. Bile acids (BAs), products of cholesterol metabolism and clearance, are produced in the liver and are further metabolized by gut bacteria. They have major regulatory and signaling functions and seem dysregulated in Alzheimer's disease (AD).Serum levels of 15 primary and secondary BAs and their conjugated forms were measured in 1464 subjects including 370 cognitively normal older adults, 284 with early mild cognitive impairment, 505 with late mild cognitive impairment, and 305 AD cases enrolled in the AD Neuroimaging Initiative. We assessed associations of BA profiles including selected ratios with diagnosis, cognition, and AD-related genetic variants, adjusting for confounders and multiple testing.In AD compared to cognitively normal older adults, we observed significantly lower serum concentrations of a primary BA (cholic acid [CA]) and increased levels of the bacterially produced, secondary BA, deoxycholic acid, and its glycine and taurine conjugated forms. An increased ratio of deoxycholic acid:CA, which reflects 7α-dehydroxylation of CA by gut bacteria, strongly associated with cognitive decline, a finding replicated in serum and brain samples in the Rush Religious Orders and Memory and Aging Project. Several genetic variants in immune response-related genes implicated in AD showed associations with BA profiles.We report for the first time an association between altered BA profile, genetic variants implicated in AD, and cognitive changes in disease using a large multicenter study. These findings warrant further investigation of gut dysbiosis and possible role of gut-liver-brain axis in the pathogenesis of AD.Copyright © 2018 The Authors. Published by Elsevier Inc. All rights reserved.

Low levels of alanine aminotransferase (ALT) and aspartate aminotransferase (AST) in the low physiologic range, surrogate markers for reduced liver metabolic function, are associated with cerebral hypometabolism, impairment in neurotransmitter production and synaptic maintenance, and a higher prevalence of dementia. It is unknown whether a prospective association exists between low liver enzyme levels and incident dementia.To determine whether low levels of ALT and AST are associated with higher risk of incident dementia.Plasma ALT and AST were measured on 10,100 study participants (mean age 63.2 years, 55% female, 22% black) in 1996-1998. Dementia was ascertained from comprehensive neuropsychological assessments, annual contact, and medical record surveillance. Cox proportional hazards regression was used to estimate the association.During a median follow-up of 18.3 years (maximum 21.9 years), 1,857 individuals developed dementia. Adjusted for demographic factors, incidence rates of dementia were higher at the lower levels of ALT and AST. Compared to the second quintile, ALT values <10th percentile were associated with a higher risk of dementia (hazard ratio [HR] 1.34, 95% CI 1.08-1.65). The corresponding HR was 1.22 (0.99-1.51) for AST.Plasma aminotransferases <10th percentile of the physiologic range at mid-life, particularly ALT, were associated with greater long-term risk of dementia, advocating for attention to the putative role of hepatic function in the pathogenesis of dementia.

ABSTRACTBackground:A recently published study suggests that Gamma-Glutamyltransferase (GGT) in midlife is related to an increased risk of dementia. In the present longitudinal study, we explore the effects of serum GGT on cognitive decline and dementia also in more advanced ages.We analyzed GGT in a sample of 452 individuals, aged 80 years and older at baseline, with the purpose to explore subsequent effects on cognitive performance. We specifically modeled GGT to cognitive change, time to death, and dementia.Our main finding is that a higher level of GGT is associated with cognitive decline prior to death and vascular dementia in late life. These findings were evident across cognitive domains.This is the first longitudinal study to report on significant associations in late life between GGT, cognitive performance and dementia. Further research is needed to examine the underlying mechanisms of GGT as a marker of age-related cognitive decline.

Impaired liver function affects brain health and therefore understanding potential mechanisms for subclinical liver disease is essential. We assessed the liver-brain associations using liver measures with brain imaging markers, and cognitive measures in the general population.Within the population-based Rotterdam Study, liver serum and imaging measures (ultrasound and transient elastography), metabolic dysfunction-associated fatty liver disease (MAFLD), non-alcoholic fatty liver disease (NAFLD) and fibrosis phenotypes, and brain structure were determined in 3,493 non-demented and stroke-free participants in 2009-2014. This resulted in subgroups of n=3,493 for MAFLD (mean age 69±9 years, 53%♀), n=2,938 for NAFLD (mean age 70±9 years, 56%♀) and n=2252 for fibrosis (mean age 65±7 years, 54%♀). Imaging markers of small vessel disease and neurodegeneration, cerebral blood flow (CBF) and brain perfusion (BP) were acquired from brain MRI (1.5-tesla). General cognitive function was assessed by Mini-Mental State Examination and the g-factor. Multiple linear and logistic regression models were used for liver-brain associations and adjusted for age, sex, intracranial volume, cardiovascular risk factors and alcohol use.Higher gamma-glutamyltransferase(GGT) levels were significantly associated with smaller total brain volume (TBV, standardized mean difference (SMD), -0.02, 95% confidence interval (CI) (-0.03; -0.01); p=8.4·10 ), gray matter volumes, and lower CBF and BP. Liver serum measures were not related to small vessel disease markers, nor to white matter microstructural integrity or general cognition. Participants with ultrasound-based liver steatosis had a higher fractional anisotropy (FA, SMD 0.11, 95%CI(0.04; 0.17), p=1.5·10 ) and lower CBF and BP. MAFLD and NAFLD phenotypes were associated with alterations in white matter microstructural integrity (NAFLD ~ FA, SMD 0.14, 95%CI(0.07; 0.22), p=1.6·10 ; SMD NAFLD ~ mean diffusivity, -0.12, 95%CI(-0.18; -0.05), p=4.7·10 ) and also with lower CBF and BP (MAFLD ~ CBF, SMD -0.13, 95%CI(-0.20; -0.06), p=3.1·10 ; SMD MAFLD ~ BP, -0.12, 95%CI(-0.20; -0.05), p=1.6·10 ). Furthermore, fibrosis phenotypes were related to TBV, gray and white matter volumes.Presence of liver steatosis, fibrosis and elevated serum GGT are associated with structural and hemodynamic brain markers in a population-based cross-sectional setting. Understanding the hepatic role in brain changes can target modifiable factors and prevent brain dysfunction.This article is protected by copyright. All rights reserved.

Increasing evidence suggests that both amyloid-β metabolism disorders in the liver and cerebral hypoperfusion play an important role in the pathogenesis of Alzheimer's disease (AD). However, the relevance of liver function alterations to cerebral blood flow (CBF) of patients with AD remains unclear.We aimed to investigate the associations between liver function changes and CBF of patients with AD.We recruited 17 patients with sporadic AD. In addition to physical and neurological examinations, detection of AD biomarkers in cerebrospinal fluid by enzyme-linked immunosorbent assay and CBF assessment by arterial spin labeling sequence of magnetic resonance image scans as well as measure of liver function markers in serum by routine laboratory testing were conducted. Neuropsychological tests were evaluated, including Mini-Mental State Examination and Montreal Cognitive Assessment. Linear and rank correlations were performed to test the associations of liver function alterations with regional CBF of AD.We found that liver function markers, especially total protein, the ratio of albumin to globin, globin, alkaline phosphatase, and aspartate aminotransferase were significantly associated with regional CBF of AD patients.These findings demonstrated significant associations between perfusion in certain brain regions of AD and alterations of liver function markers, particularly proteins and liver enzymes, which might provide implications to the pathogenesis and treatment of AD.© 2024 – The authors. Published by IOS Press.

Alzheimer's disease (AD) is a complex neurodegenerative disorder characterized by a multi-factorial etiology that is not completely understood. Donepezil is a first-line acetylcholinesterase inhibitor used for the treatment of AD that has been found, in addition to its potent acetylcholinesterase inhibitory effect, to act through other non-cholinergic mechanisms such as affecting mitochondrial biogenesis through peroxisome proliferator-activated receptor gamma coactivator (PGC1α). Mitochondrial biogenesis and PGC-1α, at least in part, are associated with hepatic fatty acid oxidation and ketogenesis. Whether donepezil regulates ketogenesis in AD treatment remains unclear. Ketogenesis is important in the progression of AD and is a critical consideration during the therapeutic strategy selection for AD. Thus, our goals were to determine the differences in ketone bodies in patients with AD who were taking donepezil treatment and those who were not, to elucidate the potential effect of AD and donepezil therapy on ketone body metabolic parameters, and to discover the effect of donepezil therapy on ketogenesis in patients with AD.Cross-sectional analysis was performed on plasma collected from 145 individuals, namely, elderly adults as healthy controls (n=30), newly diagnosed patients with AD (n=30), patients with AD who responded to donepezil therapy (n=48) and patients with AD who did not respond to donepezil therapy (n=37). Gas chromatography-mass spectrometry was performed to quantify the lipids in the plasma. The level of β-hydroxybutyrate, a metabolite, was determined by liquid chromatographytandem mass spectrometry, and to gain further insight into the effect of donepezil on ketogenesis, the effects of donepezil were investigated in a mouse model.The level of β-hydroxybutyrate decreased in AD patients, and donepezil elevated the plasma level of β-hydroxybutyrate. Donepezil increased the plasma and liver levels of β-hydroxybutyrate in mice as well as the hepatic expression of PGC-1α and the mitochondrial expression of HMG-CoA synthetase 2 (HMGCS2) in response to fasting, causing a subsequent increase in ketogenesis.Our study revealed that impaired ketogenesis is a metabolic feature of AD. Donepezil had effects on ketogenesis in mice and reversed the decrease in the level of β-hydroxybutyrate found in patients with AD.Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

Ganoderma lucidum (G. lucidum) polysaccharide-1 (GLP-1) is one of the polysaccharides isolated from the fruiting bodies of G. lucidum. Inflammation in the brain-liver axis plays a vital role in the progress of cognitive impairment. In this study, the beneficial effect of GLP-1 on d-galactose (d-gal) rats was carried out by regulating the inflammation of the brain-liver axis. A Morris water maze test was used to assess the cognitive ability of d-gal rats. ELISA and/or western blot analysis were used to detect the blood ammonia and inflammatory cytokines levels in the brain-liver axis. Metabolomic analysis was used to evaluate the changes of small molecule metabolomics between the brain and liver. As a result, GLP-1 could obviously ameliorate the cognitive impairment of d-gal rats. The mechanism was related to the decreasing levels of TNF-α, IL-6, phospho-p38MAPK, phospho-p53, and phospho-JNK1 + JNK2 + JNK3, the increasing levels of IL-10 and TGF-β1, and the regulation of the metabolic disorders of the brain-liver axis. Our study suggests that G. lucidum could be exploited as an effective food or health care product to prevent and delay cognitive impairment and improve the quality of life.

Luteolin is a widely distributed flavone herbs and vegetables. It has anti-oxidant and anti-inflammatory activities and improves glucose metabolism by potentiating insulin sensitivity and improving β-cell function and mass. Alzheimer's disease (AD) is induced by the deposition of amyloid-beta (Aβ) in the hippocampus and the formation of neurotoxic Aβ plaques. The Aβ deposition is associated with increased formation of Aβ from amyloid precursor protein by up-regulation of β-secretase and β-site amyloid precursor protein-cleaving enzyme 1 (BACE1). Furthermore, Aβ accumulation is increased by brain insulin resistance. The impairment of insulin/IGF-1 signaling mainly in the hippocampus and brain insulin resistance is connected to signals originating in the liver and gut microbiota, known as the gut microbiota-liver-brain axis. This indicates that the changes in the production of short-chain fatty acids by the gut microbiota and pro-inflammatory cytokines can alter insulin resistance in the liver and brain. Luteolin is detected in the brain tissues after passing through the blood-brain barrier, where it can directly influence neuroinflammation and brain insulin resistance and modulate Aβ deposition. Luteolin (10-70 mg/kg bw for rodents) can modulate the systemic and brain insulin resistance, and it suppresses AD development directly, and it influences Aβ deposition by activation of the gut microbiota-liver-brain axis. In this review, we evaluate the potential of luteolin to mitigate two potential causes of AD, neuroinflammatory processes, and disruption of glucose metabolism in the brain. This review suggests that luteolin intake can enhance brain insulin resistance and neuroinflammation, directly and indirectly, to protect against the development of Alzheimer's-like disease, and the gut microbiota-liver-brain axis is mainly involved in the indirect pathway. However, most studies have been conducted in animal studies, and human clinical trials are needed.© 2020 International Union of Biochemistry and Molecular Biology.

Brain energy metabolism is impaired in Alzheimer's disease (AD), which may be mitigated by a ketogenic diet. We conducted a randomized crossover trial to determine whether a 12-week modified ketogenic diet improved cognition, daily function, or quality of life in a hospital clinic of AD patients.We randomly assigned patients with clinically confirmed diagnoses of AD to a modified ketogenic diet or usual diet supplemented with low-fat healthy-eating guidelines and enrolled them in a single-phase, assessor-blinded, two-period crossover trial (two 12-week treatment periods, separated by a 10-week washout period). Primary outcomes were mean within-individual changes in the Addenbrookes Cognitive Examination - III (ACE-III) scale, AD Cooperative Study - Activities of Daily Living (ADCS-ADL) inventory, and Quality of Life in AD (QOL-AD) questionnaire over 12 weeks. Secondary outcomes considered changes in cardiovascular risk factors and adverse effects.We randomized 26 patients, of whom 21 (81%) completed the ketogenic diet; only one withdrawal was attributed to the ketogenic diet. While on the ketogenic diet, patients achieved sustained physiological ketosis (12-week mean beta-hydroxybutyrate level: 0.95 ± 0.34 mmol/L). Compared with usual diet, patients on the ketogenic diet increased their mean within-individual ADCS-ADL (+ 3.13 ± 5.01 points, P = 0.0067) and QOL-AD (+ 3.37 ± 6.86 points, P = 0.023) scores; the ACE-III also increased, but not significantly (+ 2.12 ± 8.70 points, P = 0.24). Changes in cardiovascular risk factors were mostly favourable, and adverse effects were mild.This is the first randomized trial to investigate the impact of a ketogenic diet in patients with uniform diagnoses of AD. High rates of retention, adherence, and safety appear to be achievable in applying a 12-week modified ketogenic diet to AD patients. Compared with a usual diet supplemented with low-fat healthy-eating guidelines, patients on the ketogenic diet improved in daily function and quality of life, two factors of great importance to people living with dementia.This trial is registered on the Australia New Zealand Clinical Trials Registry, number ACTRN12618001450202. The trial was registered on August 28, 2018.