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Clinical specialization is not only a force for progress, but it has also led to the fragmentation of medical knowledge. The focus of research in the field of Alzheimer’s disease (AD) is neurobiology, while hepatologists focus on liver diseases and lipid specialists on atherosclerosis. This article on AD focuses on the role of the liver and lipid homeostasis in the development of AD. Amyloid-β (Aβ) deposits accumulate as plaques in the brain of an AD patient long before cognitive decline is evident. Aβ generation is a normal physiological process; the steady-state level of Aβ in the brain is determined by balance between Aβ production and its clearance. We present evidence suggesting that the liver is the origin of brain Aβ deposits and that it is involved in peripheral clearance of circulating Aβ in the blood. Hence the liver could be targeted to decrease Aβ production or increase peripheral clearance.
In an ever more algorithmically-driven world, medical super-specialization often leads to blinkered thought and academic compartmentalization of medical care. Those with multisystem disorders are often looked after by a clutch of different specialists, while the rush to medical specialization leaves little time for those giving care to think laterally. Few neurologists or neuropsychiatrists dual accredit in General Internal Medicine and time precludes them following advances in other specialties. Among hepatologists, little thought is given to the extrahepatic sequelae of liver disease, while still fewer in the discipline recognize that many diseases which traditionally are thought to be specific to other organs may actually have a major hepatic component. Alzheimer’s disease (AD), the most common form of dementia, is a case in point. In the second most common neurodegenerative disorder, Parkinson’s disease, new research is suggesting a role for the microbiota-gut-brain axis in alpha-synuclein pathology in the brain (reviewed in ).
This review of AD, written from the perspective of hepatology and lipidology, presents evidence suggesting that the liver is the origin of brain amyloid-β (Aβ) deposits and that it is involved in peripheral clearance of circulating Aβ in the blood. Furthermore, useful new drugs for dementia may be focused on decreased hepatic production or increased peripheral clearance of Aβ protein.
AD affects more than 40 million people globally and is expected to hit 75.6 million by 2030. AD is the sixth leading cause of mortality in the United States, accounting for 3.6% of all deaths in 2014 . In the United Kingdom, almost one in eight people (12.8%) died from AD in 2018; it is the biggest killer in women at 15.3% and the second biggest killer in men at 8%. The most common form of AD, which occurs sporadically late in life (late-onset AD, LOAD) is typified by deposition of Aβ within the brain [3, 4]. Aβ generation is a normal physiological process; the steady-state level of Aβ in the brain is determined by the balance between Aβ production and its clearance and an imbalance in the Aβ production/excretion rate is the basis of increased Aβ levels in AD.
Altered production or clearance of a protein might be a trait (that is, lifelong) marker that precedes build-up of the protein in inclusions or aggregates.
Three loci that modify Aβ accumulation and deposition in the brains of a mouse model of AD have been previously described: amyloid-β protein precursor (AβPP), presenilin 1 (PSEN1), and presenilin 2 (PSEN2). Mutations in these loci result in abnormal processing of AβPP and increased generation of Aβ42, which aggregates as insoluble β-pleated sheets . One of these, the PSEN2 gene encoding presenilin 2, a component of the γ-secretase activity is responsible for generating Aβ by proteolysis. Activity of mouse PSEN2, as measured by levels of mRNA accumulation, has unexpectedly been shown to be heritable in the liver, but not the brain, suggesting that the liver is the origin of brain Aβ deposits . Sutcliffe and colleagues showed that peripheral administration of the anticancer drug, Imatinib, commonly known as Gleevac (a specific inhibitor of a number of tyrosine kinase enzymes), resulted in a 50% reduction in plasma and brain Aβ levels. As Imatinib does not cross the blood-brain barrier (BBB), this provided evidence that Aβ produced peripherally was contributing to brain Aβ. Imatinib lowers Aβ levels through indirect inhibition of γ-secretase activity . Imatinib also renders AβPP less susceptible to proteolysis by β-secretase (BACE) without inhibiting BACE enzymatic activity or the processing of other BACE substrates . However, plasma levels of Aβ42 did not change in patients with chronic myeloid leukemia treated with Imatinib , bringing into question whether it may have a role in individuals with Aβ dyshomeostasis.
The important study by Sutcliffe et al.  built on earlier findings that peripherally derived Aβ40 and Aβ42 can cross the BBB and that circulating Aβ could thus contribute to neurotoxicity [10, 11]. The implication that Aβ homeostasis was an interconnected system involving the liver and BBB to regulate brain Aβ was discussed at the time  but needs re-emphasizing now, with the addition of new data from the last decade.
The AβPP gene is located at chromosome 21q21 and individuals with Down’s syndrome, which results from trisomy of chromosome 21, develop AD neuropathology (reviewed in ). Individuals with partial trisomy of chromosome 21, which does not include the AβPP gene, fail to develop AD neuropathology, demonstrating that excess Aβ production is sufficient to cause AD (Fig. 1). In addition, recent tissue-specific metabolomic analysis revealed that the liver was the earliest affected organ in AβPP/PS1 mice during amyloid pathology progression . Genetic variants affecting AβPP and Aβ processing are associated not only with early-onset autosomal dominant AD but also with LOAD .
Generation of the AβPP by β- and γ-secretases occurs in early endosomes, followed by routing of Aβ to multivesicular bodies in HeLa and N2a cells and subsequently, a minute fraction of Aβ peptides can be secreted from the cells in association with exosomes . Exosomes are extracellular membrane vesicles actively secreted by cells into the circulation that are involved in cell-to-cell communication in normal homeostasis. They can carry cargo across the BBB  and are carriers of Aβ in AD . The BBB keeps neurotoxic plasma derived components out of the central nervous system, but recent studies suggest an early BBB breakdown in AD . The receptor for advanced glycation end products (RAGE) has been implicated in the transport of Aβ across the BBB [11, 20]. Inhibiting RAGE has been shown to have significant therapeutic benefit in AD models . High dietary advanced glycation end products have also been found to accelerate Aβ deposition in an AD murine model mediated by overexpression of RAGE .
LOAD, the common form of AD, is characterized by an overall impairment in Aβ clearance . Aβ clearance is a complex event that involves more than neurons and microglia . Peripheral clearance of brain-derived Aβ exists physiologically. Efflux of Aβ to peripheral blood accounts for 50% of total brain Aβ clearance in humans , suggesting that the physiological Aβ clearance capacity of the peripheral system provides an important mechanism against Aβ accumulation in the brain. Hence, dysfunction of peripheral Aβ clearance may contribute to the development of AD.
In a murine model of AD using parabiosis (the anatomical joining of two animals for physiological research), it has been shown that parabiosis reduces brain Aβ burden through clearance by peripheral tissues and organs, including the liver . In this model, it was calculated that the periphery can remove 40% of Aβ burden in the brain, similar to other estimates of the importance of peripheral physiological Aβ clearance . Studies in another model system found a short half-life of both Aβ40 and Aβ42 after injection of only 2.5–3.0 min with the liver being the major organ responsible for plasma clearance, accounting for > 60% of the peptide uptake. Indeed, it was suggested that the capability of the liver to take-up, catabolize, and excrete large doses of Aβ, several orders of magnitude above its physiologic concentration may explain not only the femtomolar plasma levels of Aβ, but also the minor fluctuation observed with age and disease stages .
There are several potential pathways for the efflux of brain Aβ into the periphery. These include clearance via the glial-lymphatic (glymphatic) system  and transport across the BBB, mediated by low-density lipoprotein receptor-related peptide 1 (LRP1) [29, 30] and the low-density-lipoprotein receptor (LDLR). In animal models of AD, lack of LDLR enhances amyloid deposition in the brain , while LDLR overexpression increases the rate that Aβ enters the blood from the brain .
In plasma, a soluble form of LRP1 (sLRP1) is the major transport protein for peripheral Aβ . Improving the binding of Aβ to a sLRP1 variant has been shown to increase the efficiency of Aβ clearance , suggesting that this binding prevents re-entry of Aβ to the brain. Impaired sLRP1 binding of plasma Aβ has also been reported to be an early biomarker for mild cognitive impairment preceding AD . Brain-derived Aβ in the arterial blood is cleared physiologically when it goes through the capillary bed of the peripheral organs and tissues, including the liver . LRP1 is the major receptor responsible for the saturable uptake of plasma free Aβ40 by the liver . The remarkable therapeutic effect of the ayurvedic agent, Withania somnifera (also known as poison gooseberry or winter cherry, from the nightshade family), mediated through upregulation of liver LRP indicates that targeting the periphery offers a unique mechanism for Aβ clearance as this therapy reverses the behavioral deficits and pathology seen in AD models . Atorvastatin has also been shown to upregulate liver LRP1 and this effect is mediated by the sterol response element-binding protein-2 (SREBP-2) in vitro and in vivo . Statins can reduce AD risk and the effect varies with statin molecule, sex, and race/ethnicity .
Transthyretin, a protein involved in the transport of thyroid hormones and retinol, has been proposed as a protective protein in AD . Transthyretin acts as a carrier of Aβ at the BBB and liver using LRP1 .
Thus, LRP1 is involved in three stages of the homeostatic control of Aβ clearance including 1) cell-surface LRP1 at the BBB and cerebrovascular cells, mediating brain-to-blood Aβ clearance, 2) circulating LRP1 providing a key endogenous peripheral ‘sink’ activity for plasma Aβ which prevents free Aβ access to the brain , and 3) LRP1 in the liver mediating systemic Aβ clearance  (Fig. 2).
In a human study using amyloid PET with [11C]PiB, the C667T polymorphism of the LRP1 gene has been shown to be moderately, but significantly associated with global and regional amyloid deposition . This finding is compatible with the Aβ hypothesis that impaired amyloid clearance contributes to amyloid deposition in LOAD.
LRP1 is capable of recognizing a wide variety of structurally-distinct ligands; Apolipoprotein E (ApoE) is one. ApoE polymorphic alleles are major genetic determinants of AD. Individuals carrying the epsilon (ɛ) 4 allele (APOE ɛ4) are at increased risk of AD, compared to those carrying the more common ɛ3 allele, whereas the ɛ2 allele decreases risk. Thus, at age 85 years, the lifetime risk of AD without reference to APOE genotype is 11% in males and 14% in females, compared to 51% for male APOE4 homozygotes and 60% for female APOE4 homozygotes, consistent with autosomal co-dominant inheritance of a moderately penetrant gene variant . In a murine model, Aβ was mainly sequestered in the liver and its peripheral clearance was by influenced by ApoE . A number of subsequent studies suggest that ApoE4 inhibits Aβ clearance and/or is less efficient in mediating Aβ peripheral clearance compared with ApoE3 and ApoE2  (reviewed in [48, 49]). A biologically inspired nanostructure, ApoE3-reconstituted high-density lipoprotein, with high binding affinity to Aβ, rescues memory loss of mice with AD by accelerating the clearance of Aβ .
ApoE expression is transcriptionally induced through the action of the nuclear receptors peroxisome proliferator-activated receptor gamma (PPARγ) and liver X receptor (LXR) in coordination with retinoid X receptors (RXRs).
In the liver, LRP1 functions in concert with LDLR in the clearance of ApoE-containing particles circulating in plasma . Biliary clearance of Aβ is not only mediated by LRP1, but also by the drug efflux pump, P-glycoprotein encoded by ABCB1 gene . P-glycoprotein dysfunction in BBB active efflux of xenobiotics has been shown by imaging studies in individuals with early AD . This raises the possibility that common pharmacological inhibitors of P-glycoprotein, such as amiodarone, lansoprazole, omeprazole, and other proton-pump inhibitors, tamoxifen and verapamil , could impact on Aβ clearance. A recent in vitro study using synthetic fluorescein-labelled Aβ40 and Aβ42 spiked into human liver homogenates has shown that Aβ degradation rates are lower in AD-derived homogenates as compared with those from non-demented control subjects, even after accounting for the covariates of age, sex, and APOE genotype. The authors conclude that their results “support the possibility that impaired hepatic Aβ degradation could be a factor contributing to increased brain Aβ accumulation and AD” . In addition, serum-based bile acid metabolites are associated with AD biomarkers, providing further evidence that bile acid pathways play a role in AD pathophysiology .
Plasma assays as screening tests for AD
Plasma Aβ levels tend to be nearer the lower limits of detection, but there is emerging consensus that “recent improvements in technologies to assess plasma levels of amyloid beta indicate that a single sample of blood could provide an accurate estimate of brain amyloid positivity” . For example, measurement of plasma Aβ biomarkers by immunoprecipitation coupled with mass spectrometry has recently been shown to correlate with brain Aβ burden and levels of Aβ42 in cerebrospinal fluid (CSF) . The biomarkers measured were ratios of AβPP669-711/Aβ42 and Aβ40/Aβ42 and their composites, confirming that plasma Aβ might reflect brain amyloid deposition. Another group has shown that the secondary structure distribution of Aβ in blood plasma, measured by an immuno-infrared sensor, is an excellent biomarker for AD, reflecting the Aβ burden in the brain . The performance of Elecsys (Roche Diagnostics, Basel, Switzerland) immunoassays to measure plasma Aβ42 and Aβ40 has also recently been shown to predict Aβ status in all stages of AD and their accuracy can be increased by analyzing APOE genotype . A recently reported promising approach is measuring exosome-bound Aβ; this has shown to better reflect PET imaging of brain amyloid plaques than unbound or total circulating Aβ and hence enable early diagnosis and disease monitoring .
A rapidly growing body of research suggests that disturbances in the circadian system precede the emergence of the characteristic cognitive and motor symptoms of AD . Aggregation of Aβ into extracellular plaques in the brain likely begins 20 years before the onset of dementia. Aβ concentrations in both humans and mouse models show Aβ concentrations rise during wakefulness and fall during sleep, that is, an Aβ diurnal pattern. Studies on sleep raise the possibility that altering sleep quality might impact Aβ deposition and may also regulate the clearance of Aβ from the brain . Indeed, sleep has been identified as a factor which alters the production and/or clearance of Aβ in stable isotope labelling kinetic (SILK) studies measuring Aβ turnover in blood and within the brain . SILK studies have shown that the Aβ42:Aβ40 turnover rate positively correlates with amyloid plaque load and demonstrate that understanding Aβ dynamics in different compartments including CSF, blood, and brain tissue is crucial to improving therapy. Thus, studies showing significantly lower levels of CSF Aβ42 in AD patients with more severe cognitive impairment  are unable to provide information on changes in Aβ turnover occurring either during the circadian cycle or during the progression of disease.
The clearance of amyloid from the brain during sleep is primarily via the glymphatic pathway [66, 67]. These lymphatic vessels exit the cranium along veins and arteries associated with the middle meningeal arteries, transporting waste via the deep cervical lymph nodes to the systemic circulation (reviewed in ). Initial functional studies in the sleeping brain have shown the importance of the glymphatic pathway in animal models. More recent research has demonstrated glymphatic efflux in patients with AD .
Proper functioning of the circadian system is determined by the orchestration of the suprachiasmatic nucleus in the hypothalamus and synchronized peripheral clocks in local tissues, including the liver. Mass spectrometry analyses of the mouse liver proteome has shown that many secreted proteins accumulate with a diurnal rhythm . Circadian post-transcriptional and post-translational mechanisms play a key role in the temporal orchestration of liver-specific metabolic pathways . Among those enriched in the liver cycling proteome are primary bile acid biosynthesis, bile secretion, protein processing in the ER, PPAR signaling pathway, and metabolism of xenobiotics. Hence poor sleep may be impacting on the hepatic production and biliary clearance of Aβ, as well as directly on the brain. The unfolded protein response (UPR) and circadian rhythm are intimately linked in the liver  and the UPR is emerging as a pharmaceutical candidate to combat neurodegenerative diseases . It would hence be of interest to measure the diurnal pattern of plasma biomarkers of AD in relation to therapy.
THERAPEUTIC IMPLICATIONS OF PERIPHERAL PRODUCTION AND CLEARANCE OF Aβ
The aim of the G8 summit held in London in 2013 was “to create disease modifying treatment to stop, slow, or reverse the condition”, but, under the current conditions, only drugs currently in late phase I or later will have a chance of being approved by 2025 . Drug development is costly, as is exemplified by anti-Aβ monoclonal antibodies (mAbs), some of which have progressed to evaluation in phase II and phase III trials . To date, the most promising is Aducanumab (BIIB037; Biogen, Inc., Cambridge, MA), a fully human IgG1 mAb, which selectively reacts with Aβ aggregates, including soluble oligomers and insoluble fibrils . This mAb has been shown to enter the brain, bind parenchymal Aβ, and reduce soluble and insoluble Aβ in a dose-dependent manner. However, some medications that are already licensed for other indications may be beneficial in AD by altering the peripheral pathways involved in the physiological homeostasis of Aβ. Therapies which could be repurposed include both licensed drugs and herbal remedies, for example:
Tauroursodeoxycholic acid (TUDCA) is the taurine conjugate of ursodeoxycholic acid (UDCA), a US Food and Drug Administration (FDA)-approved hydrophilic bile acid for the treatment of certain cholestatic liver diseases . There is a growing body of research on the mechanism(s) of TUDCA and its potential therapeutic effect on a wide variety of non-liver diseases , including amyotrophic lateral sclerosis . In a mouse model of AD, TUDCA supplementation has been shown to reduce hippocampal and pre-frontal amyloid deposition . TUDCA affects biliary excretion and may predominantly act by altering the production/clearance dynamics of Aβ in the periphery. In AD patients an altered bile acid profile (increased ratio of deoxycholic acid:cholic acid, which reflects 7α-dehydroxylation of cholic acid by gut bacteria), has been shown to associate with cognitive decline, suggesting a possible role of gut-liver-brain axis in the pathogenesis of AD , analogous to Parkinson’s disease . TUDCA is now being used in a phase II trial in combination with another repurposed drug, sodium phenylbutyrate, produced by Amylyx Pharmaceuticals Inc. (Cambridge, Mass, USA) (AMX0035), supported by the Alzheimer’s Drug Discovery Foundation and the Alzheimer’s Association.
Bile acids (chenodeoxycholic acid and cholic acid) are physiological ligands/activators of the nuclear receptors, farnesoid-X-receptor, pregnane-X-receptor (PXR) and constitutive androstane receptor, while lithocholic acid is a ligand for the Vitamin D receptor (VDR) and PXR . These receptors generally form heterodimers with RXR .
Other nuclear receptor agonists
PPARγ may act as a master regulator of the transcription of several genes involved in LOAD pathogenesis . PPARγ agonists such as the glitazone, pioglitazone, prescribed for the treatment of type 2 diabetes, promote amyloid clearance in animal models of AD . A phase II study of pioglitazone in AD showed that it is safe and well tolerated and two large phase III trials are ongoing . In patients with diabetes, pioglitazone treatment is a time- and dose-dependent protective factor against dementia . Cilostazol enhances LRP1 expression in liver by activating PPARγ through the peroxisome proliferator response element in the LRP1 promoter . In mice, combined PPARγ /LXR agonist treatment also reduces soluble and deposited forms of Aβ .
The RXR agonist, bexarotene (brand name: Targretin), which is approved by both the FDA and European Medicines Agency (EMA) for use in cutaneous T cell lymphoma, stimulates physiological Aβ clearance mechanisms, resulting in the rapid reversal of a broad range of Aβ-induced deficits in mouse models .
VDR - 1,25-dihydroxyvitamin D3(1,25(OH)2D3) treatment has been shown in vitro to enhance both Aβ40 efflux across the BBB and hepatic uptake by HepG2 cells, accompanied by increased LRP1 expression. It was suggested that the effect was exerted via the nuclear VDR and could explain how 1,25(OH)2D3 exerts neuroprotection against AD .
Genistein is an isoflavone derived from the dyer’s broom plant, Genista tinctoria, which activates PPARs. Treatment of an AD mouse model with genistein results in improvement in various parameters of cognition, associated with a lowering of Aβ levels in brain and in the number and the area of amyloid plaques . The authors conclude that “our results strongly suggest that controlled clinical trials should be performed to test the effect of genistein as treatment of human AD”.
Newly identified flavonoids which selectively target another nuclear receptor/pathway, LXRβ have also been found to reduce total brain Aβ and plaque burden in AβPP/PS1 double transgenic mice .
Silymarin, the main flavonoid extracted from milk thistle, has long been used as a medicinal herb for liver diseases. In a mouse model, it has been shown that Silymarin treatment was associated with a decline in Aβ oligomer production . Silymarin can control the production of Aβ by inhibiting the precursor substance of Aβ, AβPP, and has potential for the treatment of AD .
Gene silencing and genome editing
The property of a therapeutic agent in AD to penetrate the BBB has generally been regarded as a prerequisite for new drugs . Recognition of the importance of the liver in Aβ production and clearance means that targeting the liver might be a promising therapeutic approach.
The last decade has witnessed renewed interest in novel therapeutic agents aiming to prevent the production of disease-causing proteins at the level of mRNA, reviewed in . Broadly, two oligonucleotide-based technologies are being deployed in this way, antisense oligonucleotides (ASO) and small interfering RNAs (siRNA), which respectively prevent translation or trigger RNA induced silencing complex (RISC)-dependent cleavage of a specific RNA target. A large number of disease targets reside in the liver where they are susceptible to modulation by oligonucleotide therapies . The ASO mipomersen, targeting apolipoprotein B in the liver to treat familial hypercholesterolemia, was among the first such agents to be marketed . The recent entry of large numbers of gene silencing agents into clinical trials owes much to the development of conjugates that enable specific delivery of the oligonucleotide to the cytoplasm of the desired target cell, allowing lower doses with fewer side effects. In particular, addition of N-Acetylgalactosamine conjugates, which bind with high specificity and affinity to the asialoglycoprotein receptor on hepatocytes has elicited robust gene silencing in vivo .
Proof of concept for silencing the production of a form of aberrant amyloid by the liver in order to prevent or reverse damage to the nervous system is provided by the rare metabolic disease, hereditary transthyretin amyloidosis. In this condition, mutant transthyretin is produced in the liver resulting in amyloid fibril deposition in various organs and heterogeneous clinical symptoms including peripheral neuropathy and cardiomyopathy . Patirisan, a gene silencing agent delivered to the hepatocyte in a lipid nanoparticle, reduces the production of abnormal transthyretin and can halt or even reverse the process. Both Patirisan, an siRNA and Inotersen, an untargeted ASO, are approved by the FDA and EC for this disorder .
Whereas gene silencing provides a temporary fix, all be it with single dose duration of action above six months now regularly achievable, the ability to permanently alter the human genome remains an attractive possibility for patients with deleterious genetic mutations. This has been made possible by a series of technologies collectively known as genome editing for which CRISPR-Cas9 was the archetype. In murine models, liver-directed somatic genome editing with CRISPR-Cas9 is a novel and versatile approach with therapeutic potential in metabolic disorders . The proof of principle that a gene can be targeted in mammalian hepatocytes in vivo would suggest that sequence-specific gene editing might be viable in humans [104–107]. In the future, liver-specific gene editing may be used to alter hepatic gene transcription for therapeutic purposes in AD. It is tempting to speculate that mutations in AβPP, PSEN1 , and ApoE4  could be targeted with these technologies. In addition, as lifelong overexpression of wild-type AβPP causes AD in individuals with trisomy 21 (Down’s syndrome), so the normal hepatic AβPP gene could be targeted in AD to decrease production and alter the balance in favor of Aβ42 clearance.
LIVER DISEASES AND DEMENTIA
It is recognized that hepatic functionality should be considered when Aβ balance is addressed . This is reflected in the situation of orthotopic liver transplantation (OLT) where the recipient passes through an anhepatic phase to reperfusion of the new organ. Postoperative cognitive dysfunction is observed in 11% to 44% of OLT patients and is unrelated with the success of a surgery. It is associated with an increase in the serum biomarkers of dementia including Aβ protein 24 h after surgery , presumably reflecting alterations in the clearance of Aβ as a result of OLT.
90% of people who die from liver disease are under the age of 70, but the majority of AD cases occur late in life (>65 years). However, a recent large epidemiological study demonstrated that comorbidities significantly associated with mild cognitive impairment and dementia were cirrhosis (OR 3.29, CI 1.29–8.41), cerebrovascular disease (OR 3.35, CI 2.62–4.28), asthma (OR 1.56, CI 1.07–2.27), and diabetes mellitus (OR 1.24, CI 1.07–1.44) . In addition, some studies have shown associations of AD with specific liver diseases.
Hepatitis C virus (HCV)
Chronic HCV infection has been found to be associated with dementia in a large population-based cohort (Hazard ratio 1.36 [95% CI 1.27–1.42]) . More recently, a predictor of cirrhosis in chronic HCV infection, an elevated aspartate aminotransferase to alanine aminotransferase ratio, has been reported to be associated with AD diagnosis (Odds ratio: 7.932) . ApoE, a critical player in Aβ homeostasis, is intimately involved in production of infectious HCV particles  and is important in HCV cell entry. HCV may cross the BBB leading to neuroinflammation and neuropsychiatric symptoms . We have reported ApoE deficiency in HCV associated depression . Interestingly low plasma levels of ApoE are associated with increased risk of future AD and all dementia in the general population, independent of ɛ2/ɛ3/ɛ4 APOE genotype .
NAFLD, metabolic syndrome, and type 2 diabetes
Non-alcoholic fatty liver disease (NAFLD) is a chronic liver disease which is increasing in prevalence, in tandem with the obesity epidemic. NAFLD defines a spectrum of conditions from simple steatosis to non-alcoholic steatohepatitis and cirrhosis and is regarded as the hepatic manifestation of the metabolic syndrome. Hepatic insulin resistance is associated with NAFLD and is a major factor in the pathogenesis of type 2 diabetes and the metabolic syndrome .
Various epidemiological studies have shown that metabolic syndrome and type 2 diabetes   are correlated with AD. In addition, short sleep duration and poor sleep quality are associated with an increased risk of both NAFLD  and AD .
In murine models, correlations between a high fat diet and elevated brain and serum Aβ42 have been observed , and NALFD induces signs of AD in wild-type mice and accelerates pathological signs of AD . Advanced glycation end-products exacerbate progression of experimental NAFLD  and AD .
An imbalance in the Aβ production/excretion rate underlies the increased brain concentrations of Aβ in AD. There is evidence suggesting that the liver is the origin of brain Aβ deposits and that it is involved in peripheral clearance of plasma Aβ. LRP-1 is the major receptor responsible for the saturable uptake of plasma free Aβ by the liver. A number of medications that are already licensed for other indications and herbal remedies that are currently available improve the Aβ balance in animal models via decreased hepatic production or increased biliary clearance. Hepatic functionality should be considered when Aβ balance is addressed and future developments could include liver-directed somatic genome editing and/or therapeutic gene silencing. Cirrhosis, chronic hepatitis C infection, and NAFLD, the hepatic manifestation of metabolic syndrome, are associated with an increased risk of AD, despite chronic liver disease leading to an early death (under the age of 70 years) in 90% of patients and LOAD manifesting after the age of 65 years.
Clinical specialization, subspecialization, and subsubspecialization has some advantages in terms of creating standards but could be said to be leading to a growing fragmentation of medical care . Hence, when a variant in the ATP-binding cassette A7 (ABCA7) gene which encodes for a phospholipid transporter, is shown to be associated with LOAD , subsequent research focuses on brain mRNA and protein expression . Conversely, hepatologists, who have highly focused knowledge and skills, do not see patients with dementia or keep abreast with the scientific progress in the field of AD. Most patients with long-term conditions and co-morbidities want physicians who see them as a whole person and can deliver holistic care. Perhaps the time has come for a more physiological approach to AD, looking at the integrative function of organs and a multidisciplinary approach to reversing the epidemic?
MFB and STR are grateful to the National Institute for Health Research Biomedical Research Centre at Imperial College London for infrastructure support [grant number 2011-NIHR 7068]. STR was supported by a Wellcome Institutional Strategic Support Grant at Imperial College London.
Authors’ disclosures available online (https://www.j-alz.com/manuscript-disclosures/19-0848r2).
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text:
Why should I get a mammogram?
With breast cancer as the number one type of cancer in women and the second leading cause of death due to cancer in American women, screening for breast cancer is critical. That’s why getting a mammogram is so important. Mammography has been proven to detect early breast cancer and is the only screening tool known to reduce mortality from breast cancer.
There are several different screening options available. These include:
Screening mammography: Screening mammography typically begins at age 40 and is performed annually. It can start earlier if there’s a strong family history of breast cancer. If there is an abnormal finding on the mammogram, the patient would return for additional imaging called a diagnostic mammogram. She may also require a possible ultrasound, and if needed, a biopsy.
Digital breast tomosynthesis: Many breast centers now have three-dimensional breast imaging known as digital breast tomosynthesis. The advantage of 3-D imaging is that it reduces overlapping tissue, which often obscures lesions on conventional 2-D mammography. This is especially true in women with dense breast tissue. Compared to mammography alone, cancer detection is much higher when mammography and tomosynthesis are combined.
Screening ultrasound: Whole breast screening ultrasound is another screening tool used for women, especially if they have dense breast tissue. This, too, is done in conjunction with screening mammography.
Breast MRI: Breast MRI is another screening tool used to look for breast cancer. Because it is much more sensitive than both mammography and ultrasound, it’s more likely to pick up subtle cancers that can’t be detected on a mammogram. However, this imaging modality is expensive and often not covered by insurance. Patients who’ve already been diagnosed with breast cancer, high risk patients such as those with strong family history of breast cancer or those who have been diagnosed with precancerous conditions, or patients who’ve had chest irradiation for a prior cancer are those who usually get a screening breast MRI.
The best way to survive breast cancer is to screen for it every year with a mammogram. Monthly breast self-examinations are just as important; if you have any breast concerns, address them as soon as possible with your doctor because early detection is the key to survival.
About the Author
Dr. Josie Kim is a radiologist at Advocate Good Samaritan Hospital in Downers Grove, Ill.

domain: medical


text:
Betfred Super League have struck up a deal with pizza firm Papa John’s.
The agreement will see players provided food while games remain behind Closed Doors. The company has already had advertising on advertising boards around the game as well as Super League’s online video content.
Chief Commercial Officer Rhodri Jones said: “It’s great to be partnering with Papa John’s during the behind closed doors period, and it’s important to be able to provide our players with the chance to refuel after a tough game.
“As we have seen since the restart, Betfred Super League games are getting faster and harder and I know the players are grateful when they see so many pizzas to choose from after a tough 80 minutes.”
Papa John’s Marketing Director Giles Codd added: “We are delighted to be partnering with the Betfred Super League this season.
“Ensuring the players and officials are fed safely post-match is paramount and our teams are well-drilled in safely delivering fresh, hot and tasty pizza after successfully adapting to the situation we find ourselves in during this global pandemic.”

domain: game


SiroSilo Industrial can provide you with different types of FFS machines, such as vertical form fill seal machines and horizontal form fill seal machines.
FFS machines complete film unwinding to bag sealing in one stop, with a max. speed of up to 300 bags/min, which greatly improves packaging efficiency.
SiroSilo form fill seal machine is popular in food, hardware, electronics, medicine, cosmetics, fertilizer, agriculture and other industries. According to practical test, the following products are packable with FFS machine:
Drinks, jams, detergents, soy sauce, etc.
Flour, condiments, milk powder, pesticides, etc.
Seeds, sugar, grains, etc.
Peanuts, chewing gum, potato chips, pet food, etc.
If the item you want to pack is not listed above, please contact us, we can customize a suitable form-fill-seal machine for you.
FFS Machine Purchasing Guide
FFS Machine Meaning
FFS machine stands for form fill seal machine, which is a common packaging equipment, it completes the processes of bag forming, product filling, bag sealing in one stop.
In its operation process, product weighing is essential, specific dosing/metering equipment undertakes this task. Common dosing equipment includes multihead weighers, auger fillers, and metering pumps.
According to the bag forming directions, 2 types of FFS machines are available:
- Horizontal FSS Machine
- VFFS Packing Machine
FFS machines are good at packaging a variety of food, pharmaceuticals and other products suitable for flexible bag packaging, including:
- Grains (e.g. rice, beans)
- Granules (e.g. detergents, fertilizers, sugar)
- Hardware Fittings (e.g. nuts, bolts, screws)
- Liquids (e.g. water, milk, juice, wine)
- Powder (e.g. spice powder, milk powder, coffee powder)
- Snacks (e.g. chips, dried fruit, crackers, namkeen)
- Viscous Liquid (e.g. cooking oil, ghee, ketchup, mayonnaise, salad dressing, body wash)
Form Fill Seal Machines Diagram
With reference to the following schematic diagram of a vertical form fill seal machine, let’s introduce its main components one by one.
- Film Unwinding Shaft
The tension of the dancer roller drives the unwinding shaft to rotate for plastic film unwinding.
The brake device installed on the shaft receives the PLC signal to control the unwinding process.
- Tension Control Dancer Roller
It generates the tension for film unwinding.
- Photoelectric Sensor
Detect the color mark on the film, control the stroke of the film.
- Rotary Encoder
The rubber roller follows the rotation of the film, drives the encoder to rotate, rotary encoder detects the actual stroke of the film.
- Inkjet Printer
Coding equipment, receive PLC signal to print date and batch number on the film.
- Film Pulling Shaft
Follow the rotation of the main shaft and pull the film down at a constant speed.
- Vertical Sealing Bar
After the film has passed through the forming tube, the bag has taken shape, the two outer edges of the film overlap each other.
Then the vertical sealing bar seals the outer edges and presses down, completing the vertical heat sealing.
- Product Inlet
The product weighed by the dosing equipment enters the vertical form fill seal machine from this port.
- Horizontal Sealing Shaft
Drive the horizontal sealing jaws to stick to the plastic film for sealing cyclically.
- Horizontal Sealing Jaws
They seal the formed bag’s top opening and cut it off, at the same time, form the next bag’s bottom seam.
- Horizontal Sealing Jaws Driver
Drive the horizontal sealing jaws to move up and down to achieve continuous sealing.
How Does FFS Machine Work?
FSS machines include horizontal and vertical types, and their working principles are quite similar.
Vertical form fill seal machines are relatively more common, so let’s take a form fill seal machine as an example, explaining how it works in detail.
The vertical form fill seal machine converts a rollstock flexible packaging material into a bag, fills the product, and then seals the bag. One machine completes these three processes in succession automatically.
Combined with the upstream metering, dosing, filling equipment, vertical form fill seal machines are suitable for packaging blocky, flaky, granular, stalk, powder, liquid and viscous liquid materials.
The VFFS bagging machine’s product inlet is located inside the bag maker, the machine carries out bag making and product filling vertically from top to bottom.
It mainly consists of:
- Transmission System
- Film Pulling System
- Product Inlet
- Metering Device
- Horizontal and Vertical Sealing Device
The working principle of the vertical packaging machine is summarized as follows:
The roll film placed on the unwinding shaft passes through the guide roller and the tensioning device, the trademark on the film is detected by the photoelectric sensor, and then rolled into a film cylinder through the forming tube surface.
First, the vertical sealing bar seals the film cylinder’s longitudinal adjoining edges, thus obtaining a sealed bag with a top opening.
The metering device fills the measured products into the top-open bag through the product inlet, and then the horizontal sealing jaws seals the top opening and cuts it off to get a packaging bag, and at the same time, form the bottom seal of the next bag.
To sum up, the workflow of the vertical form-fill-seal machine mainly includes the following steps:
- Film Unwinding and Transmission
- Film Tensioning
- Date & Batch Number Printing
- Film Tracking
- Bag Forming
- Product Filling
- Bag Sealing
- Bag Dischaging
Types of FFS Machines
According to the direction of bag forming, FFS machines include the following two kinds:
- Vertical Form Fill Seal Machine
The bag forming tube is perpendicular to the ground, and the plastic film is pulled by the film pulling shaft from top to bottom through the forming tube, forming a shaped bag.
- Horizontal Form Fill Seal Machine
The rectangular bag forming tube is parallel to the ground, and the plastic film is pulled by the film pulling shaft from left to right through the forming tube, forming a shaped bag.
According to the different properties of the materials contained in the bags, the FFS machines mainly include the following three types:
- Granule Filling Machine
- Powder Filling and Sealing Machine
- Liquid Filling and Sealing Machine
According to the different shapes of forming bags, FFS machines mainly include the following categories:
- Pillow Pouch
- 3 Side Seal Pouches
- 4 Side Seal Pouches
- Gusset Pouch
- Flat Bottom Pouch
- Standup Pouch (with zipper/spout/euro slot/handle, etc.)
VFFS Packing Machine
There are two types of VFFS packing machines: continuous motion and intermittent motion.
The continuous motion VFFS packing machine can achieve continuous sealing without stopping, its packing efficiency is higher;
The intermittent motion VFFS packing machine requires a short pause every time it seals, its packing is less efficient, but it’s cheaper.
The working principles of these two VFFS packing machines are basically the same, it mainly includes three steps.
- Bag Forming
Unwind the flexible film roll, the film enters the forming tube after being driven by the guide roller and the dancer roller. The film forms a round bag on the forming tube, and seals the two vertical seams, and the upper part is open.
- Product Filling
The product is dropped from the metering device into the forming bag via the upper opening. The metering device needs to be purchased additionally.
Usually, a multi-head scale is used for granular materials, an auger weigher is used for powder materials, and a metering pump is selected for liquid materials.
- Bag Sealing
After the material filling is completed, the horizontal sealing jaws will seal the upper part of the forming bag and also form the bottom seal of the next bag.
Vertical packaging machines generally have two cutting methods, namely, mark cutting and fixed-length cutting. The two cutting methods are easy to switch, and cutting method option depends on the packaging film.
The packaging film is either with a photo eye mark or not. The packaging film without a photo eye mark is cut to a fixed length; otherwise, it is cut by detecting photo eye mark.
In most VFFS machines, the vertical sealing bar and horizontal sealing jaws consist of a nichrome wire, the wire has an intermittent current flow through it, it heats the sealing bar and jaws to the proper temperature.
It is necessary to carefully adjust this temperature, as well as the dwell time, to provide enough heat at the ideal temperature to melt the plastic without overheating.
This is to avoid overheating causing the film to wrinkle or even burn through.
Horizontal FFS Machine
The following picture is a schematic diagram of a horizontal form fill seal machine.
- Product Feeding Conveyor
- Transmission System
- Packaging Material Rollstock
- Vertical Sealing Device
- Horizontal Sealing and Cutting Device
- Pressing Brush
- Control Console
- Output Device
In order to explain the process of the horizontal form fill seal machine more intuitively, please check the following picture first:
- Rolled Film
- Guide Roller
- NIP Roller
- Vertical Sealing Roller
- Horizontal Sealing and Cutting Device
The workflow of the horizontal form fill seal machine is:
The roll film 1 is folded into a pillow shape by the former 3 through the guide roller 2, and is clamped by the NIP roller 5 and fed to the right;
At the same time, the vertical sealing roller 6 seals the longitudinal seam;
Product 4 is pushed into the pillow-shaped bag by the push plate on the conveyor belt, and is transferred to the right;
Finally, the sealing and cutting process is completed by the horizontal sealing and cutting device 7, and the pillow-shaped packaging bag as shown in the figure below is obtained.
FFS Liquid Filling Machine
The FFS liquid filling machine is controlled by the PLC program, and the whole process of bag making, material weighing & filling, bag sealing, batch number & date printing, tear notch adding, bag cutting off, and bag counting can be completed automatically.
The packaging and sealing form can be customized into three-side sealing, four-side sealing, pillow-shaped sealing, etc.
Such machine has the following features:
- Beautiful bag shape;
- Convenient adjustment of bag size, packaging weight, and sealing and cutting temperature;
- Direct heat sealing and cutting;
- Fast packaging speed;
- High weighing accuracy;
- No sealing pollution;
- Prevent material leakage.
You can also choose devices such as vacuuming and punching. For materials that are easy to solidify, a constant temperature insulation system can be selected.
The FFS liquid filling machine has a wide range of applications, mainly used for packaging various seasonings, oils, beverages and other liquid materials in the food & condiment industry, including:
Food seasoning, jam, honey, shampoo, hot pot ingredients, bean paste, chili sauce, beef sauce, etc.
Soy sauce, edible vinegar, milk, cooking wine, liquor, sterilized beverages, fruit juice, milk, yogurt, soy milk, etc.
Referring to the picture below, you can clearly understand the process flow of the liquid FFS machine.
The liquid material is injected into the aging tank (including an automatic stirring device, which can be heated and kept warm).
The rotor pump automatically pumps the liquid material to the high-level mixing tank (controlled by the material level of the mixing tank).
The liquid filling machine can automatically make and form bags (optional accessories such as punching, gusset, vacuuming, etc.), automatically measure and fill according to the set weight, and complete automatic sealing and cutting, weight dosing is realized by measuring cup or metering pump.
The packaged bag comes out from the liquid filling machine, the checkweigher automatically detects its weight (optional equipment).
The qualified bag is finally transported to the manual packing station by the outfeed conveyor.
FFS Powder Packing
Powder packaging is generally completed on a vertical packaging machine. The FFS powder packing machine and the auger weigher can automatically complete all processes such as bag making, powder weighing, powder filling, bag sealing, and bag cutting.
The amount of powder is mostly measured by the volume method, and some models are also equipped with a reliable photoelectric detection system. When using packaging materials printed with photoelectric marks, a complete trademark pattern can be obtained.
The powder packaging machine is suitable for small bag packaging of medicine, food, chemical industry, pesticide, etc. It is suitable for the production of powder drugs, sugar, coffee, fruit, tea, monosodium glutamate, salt, seeds, desiccant, milk powder, starch, pesticides, veterinary drugs, premixes, additives, condiments, feeds, enzymes, etc.
The automatic FFS powder packing machine directly sends the powder materials into the auger weigher through the screw elevator, and completes the automatic measurement, filling, automatic packaging and sealing, and finished product delivery according to the set weight.
The SiroSilo FFS powder packing machine has won the favor of many customers around the world with the following properties.
- Auger filler completes metering, filling, etc., suitable for powder materials;
- The servo drive system, high precision, and stable performance;
- The stainless steel material tank is easy to clean, equipped with safety protection, and meets the requirements of enterprise safety management;
- Intelligent & accurate temperature control, and the sealing is beautiful and smooth.
- PLC control double-pull or single-pull film feeding system, motor-driven deviation correction of sealing and cutting position, large display touch screen, which maximizes the control accuracy, reliability, and intelligence;
- This machine and metering equipment can automatically complete the whole packaging process of metering, feeding, filling bag making, gas flush (vacuuming), date printing, bag counting;
- Perfect automatic alarm function to minimize loss and help to troubleshoot in time;
- The styles of packaging are diversified, such as back seal, gusset, even bag, punching, and so on.
Automatic FFS Machine
The automatic FFS machine is one of the film bag-making and packaging machines. It is often used for automatic quantitative packaging of irregular bulk products such as granules, powders, liquids, pastes, soups, and sauces.
Both bag making and packaging are realized synchronously during the machine operation, the material falls vertically along the filling tube into the cylindrical bag, and then is sealed to complete the independent packaging of the product in one-stop, which has strong applicability, good durability, and wide application.
There are mainly the following types of automatic FFS machines:
- Liquid Filling Sealing Machine
The metering pump is used for automatic quantitative packaging, and the liquid material is fed directly from the tank through the conduit into the packaging bag.
The material does not contact the packaging equipment during the entire filling process, and the cleanliness and hygiene are high. The precision is high and the speed is fast, which can meet the automatic quantitative filling of various fluid products.
- FFS Powder Packing Machine
Using special high-precision auger weigher, volumetric scale is conducive to material filling and rapid metering, often used for automatic packaging of non-viscous and easy-flowing powder products.
FFS powder packing machine needs to be combined with an automatic feeding machine, powder metering machine, discharging conveyors, and other devices to form an automatic packaging line.
The FFS powder packing machine can meet the general packaging of products with similar characteristics, and realize the purpose of one machine for multiple purposes.
- Granule Filling Machine
According to the material characteristics, packaging accuracy, and speed requirements, volumetric measuring cups, linear scales, and combination scales can be used for weighing, which can realize both compact packaging of small vertical packaging machines and automatic weighing of large granule packaging machines.
Heavy packaging is also suitable for solid particle bars, flakes, and spherical special-shaped materials.
The automatic FFS machine has won the global clients’ favor due to the following attractive features.
- The whole machine is controlled by a microcomputer program, and the touch screen displays the operation in Chinese and English. The working process can be seen in real-time, which is intuitive, simple, and easy to maintain.
- Small footprint, high space utilization, easy placement and layout, realizing the optimal combination of upstream and downstream production lines, and equipment that conforms to Industry 4.0 standards.
- It can work independently without a lot of supporting equipment, and it can be equipped with an air compressor and power supply according to the model to meet the equipment operation.
- It is easy to clean and sterilize, and the contact parts between the automatic FFS machine and the material are all made of high-quality 304 food-grade stainless steel, which fully guarantees product safety.
- The unique sealing bar is combined with a special temperature control system to ensure that the product is firmly sealed and well sealed, which is beneficial to the circulation and storage of the product.
- The film-pulling drive system and plc program control system can ensure high productivity under various materials and specifications. Small vertical packaging machine has a variety of bag styles, such as three-side sealing, four-side sealing, back sealing, chained bag, punching, and other styles.
Rotary FFS Machine
The rotary FFS machine is mainly composed of a coding machine, PLC control system, bag opening guide device, a vibration device, dust removal device, solenoid valve, temperature controller, vacuum generator or vacuum pump, frequency converter, and output system.
The optional configurations are material measuring and filling machine, working platform, checkweigher, material elevator, vibrating feeder, finished product conveyor, and metal detector.
The range of bag materials is extremely wide, including paper-plastic composite materials, plastic-plastic composite materials, aluminum-plastic composite materials, PE composite materials, etc., and the loss of packaging materials is low.
Because the premade bags are used, the bag pattern is perfect, and the sealing quality is good, thus improving the product grade;
It can also be used for multiple purposes in one machine, and only need to match different measuring devices according to different materials, it can achieve granule, powder, block, liquid, soft cans, toys, hardware, and other products fully automatic packaging.
Detergent, wine, soy sauce, vinegar, juice, beverage, ketchup, jam, chili sauce, bean paste.
Peanuts, jujubes, potato chips, rice noodles, nuts, candy, chewing gum, pistachios, melon seeds, nuts, pet food, etc.
Condiments, additives, crystalline seeds, seeds, granulated sugar, soft white sugar, chicken essence, grains, agricultural products.
Flour, seasoning, milk powder, glucose, chemical seasoning, pesticide, fertilizer.
The rotary FFS machine has the characteristics of fast packaging speed and a good packaging effect. It is suitable for standard stand-up pouches, and can also be adapted to the zipper and special-shaped mask bags through customized transformation. It is a right-hand man for large-scale, high-speed packaging.
The rotary FSS machine mainly includes the following working steps:
- Pick-up Doypack
The machine picks up a doypack to the gripper, if the photoelectric eye detects no pouch, the machine sounds an alarm.
In this way, it effectively reduces the labor intensity;
- Print Date Code
Ribbon detection, if the ribbon runs out, alarm pops up on the touch screen, ensure the normal date coding;
- Open Pouch
Open the pouch to detect, if the bag is not open, the machine doesn’t fill material, avoids wasting material;
- Fill Material
Inspect first, if no material, no filling, and no sealing, avoids wasting bag;
- Heat Sealing
Alarm for the abnormal temperature to ensure sealing quality;
- Cooling, Shaping & Discharging
Ensure that the seal is beautiful.
The rotary FSS machine replaces manual packaging and realizes packaging automation for large enterprises and small and medium-sized enterprises.
The operator only needs to put the pre-made bags one by one, and place hundreds of bags at the bag magazine of the equipment at one time, and the mechanical grip will automatically take the bags, print the date, open the bags, send the signal to the measuring device and drop it, then seal the pouch and output the packaged pouch.
Customers can also add custom functions such as emergency stop against door opening, automatic card insertion, abnormal discharge, and others according to packaging requirements.
The whole process of packaging doesn’t require manual operations, which effectively improves production efficiency for your company, saves labor costs and management costs, and greatly reduces costs.
The following outstanding features of the rotary FSS machine have attracted many customers to contact SiroSilo for product information and quotations.
- PLC control, equipped with touch screen HMI interface, easy to operate.
- Frequency conversion speed regulation, and the speed can be adjusted at will within the specified range.
- Automatic detection function, if the bag is not opened or the bag is incomplete, no material is added, no heat sealing, the bag can be reused, no material is wasted, and the production cost is saved for the user.
- Safety device, when the working air pressure is abnormal or the heating tube fails, it will alarm.
- With the horizontal bag feeding method, the bag storage device can store more bags, which has lower requirements on the quality of the bags, and the rate of bag separation and bag loading is high.
- The adjustment of the bag width is controlled by motor. Press and hold the control button to adjust the width of each group of clamps at the same time, which is easy to operate and saves time.
- Some imported engineering plastic bearings are used, no need to refuel and reduce the pollution to materials.
- Adopt oil-free vacuum pump to avoid pollution of production environment.
- The zipper bag opening mechanism is specially designed for the characteristics of the zipper bag mouth to avoid deformation or damage of the bag mouth.
- The loss of packaging materials is low. The machine uses premade bags with perfect packaging bag patterns and good sealing quality, thus improving the product quality.
- In line with the hygiene standards of the food processing industry, the parts on the machine that are in contact with materials or packaging bags are processed with stainless steel or other materials that meet food hygiene requirements to ensure food hygiene and safety.
- Wide range of packaging. By choosing different measuring instruments, it can be applied to the packaging of liquid, sauce, granule, powder, irregular block and other materials.
- The packaging bag is suitable for a wide range of applications. It can be applied to prefabricated bags and paper bags made of multi-layer composite films, silica, aluminum foil, single-layer PE, PP and other materials.
Form Fill Seal Machines Manufacturers
According to the search results of Google Adwords, the following manufacturers of FFS machines are the most common.
- TNA vffs
- Viking/Viking Masek
Without a doubt, these producers are the top players in this niche. If you want to customize the highest-end, best-performing form-fill-seal machine, they are the best choice.
We SiroSilo Industrial is also one of the professional form fill seal machine manufacturers in China, with our own R&D team and factory, we are capable of supplying high-quality form fill seal machines at a competitive price.
Please contact us to get a quote for comparison: firstname.lastname@example.org.
Form Fill Seal Machine Price
Form fill seal machines are usually customized according to the actual packaging requirements of customers, and the prices of customized machines vary greatly, so it is difficult to give a specific price range.
In addition, the price of form fill seal machine is related to many factors, mainly including:
- FFS machine type (horizontal or vertical)
- Type of product packaged (powder, liquid, paste or paste, granules)
- Bag type (three-side seal, four-side seal, gusset)
- Bag size
- Premade pouches or not
When you determine your requirements for the above factors, ask the FFS machine supplier to provide a reasonable quotation according to your requirements.
I found some information about the price of the FFS machine from the Internet, and the price information is shown in the following four pictures. You can use the prices in these four pictures as a reference.
The FFS machine manufacturer in the 1st pictures is from Europe, and the FFS machine manufacturer in the 2nd picture is from China.
SiroSilo could also supply the following products:


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