High-Fat Diet—Shared Environmental Risk Factor for Amyotrophic Lateral Sclerosis and Multiple Sclerosis

Abstract

Background: Amyotrophic lateral sclerosis (ALS) and multiple sclerosis (MS) are, in essence, neurodegenerative disorders with significant individual, social, and economic burdens worldwide. Despite having different clinical onset and evolution, the two diseases share common risk factors and underlying pathophysiological mechanisms. Environmental risk factors are particularly interesting, considering the available effective counter strategies. High-fat diets remain a significant element that negatively impacts the onset and evolution of several disorders, including ALS and MS. Focusing on changeable disease-related aspects is increasingly appealing in the context of a lack of an effective treatment. Methods: This review aims to offer an updated overview of the influence of high-fat diets in modulating the risk of onset and progression of ALS and MS, based on the search of three relevant online databases. Results: In the first part, the shared pathophysiological mechanisms of ALS and MS are shown, and significant differences between the two disorders are highlighted. Subsequently, the most relevant research on this topic conducted in animal models and humans is presented, bringing additional proof of the critical role of high-fat diets in neurodegeneration. Finally, based on current knowledge, the authors offer potential therapeutic approaches and future relevant research directions to better control nutrition in ALS and MS patients, hoping to increase survival and quality of life. Conclusions: High-fat diets negatively impact the onset and evolution of ALS and MS.

1. Introduction

Neurodegenerative disorders (NDDs) are a heterogeneous group of diseases affecting the central nervous system (CNS) and are characterized by the progressive death of neurons that lead to the decrease and final loss of several motor, sensory, and cognitive functions [1]. While Alzheimer’s disease and Parkinson’s disease remain the most frequent NDDs [2], other pathologies such as amyotrophic lateral sclerosis (ALS) and, from a certain point of view regarding its evolution, multiple sclerosis (MS), are also of great interest considering their significant individual, social, and economic burden [3,4].

ALS, also known as Lou Gehrig’s disease, is the result of the progressive loss of upper and lower motor neurons, being clinically characterized by muscle weakness and eventually respiratory failure, with most patients being deceased within 2–3 years of symptom onset [5]. It affects approximately 2 per 100,000 people globally, with a lifetime risk of 1 in 350, with these figures expected to increase due to improved diagnostics and changing demographics [6]. Only 5–10% of the cases have a positive family history, with both genetic causes (such as SOD-1 [superoxide dismutase-1] and FUS [fused in sarcoma)] mutations) and environmental risk factors (smoking, pollution, heavy metals) [7] being considered for the majority of ALS patients. Besides the symptomatic treatment, only Riluzole, Edaravone, and Tofersen are approved for clinical use [8]; however, they have an unsatisfactory impact on quality of life and survival, with limited efficacy in modifying ALS history and preventing disease progression [9].

MS is traditionally known as the most common autoimmune demyelinating disorder of the CNS, affecting young adults (35.9 per 100,000 population) and leading to progressive neurodegeneration during its evolution [10]. Still, increasing evidence highlights its neurodegenerative aspects, based on the progressive neuronal loss, axonal degeneration, and brain atrophy observed in advanced MS stages, these being hallmarks shared with other NDDs. According to the most recent epidemiological data, the global incidence is 2.1 per 100,000 persons/year, and the worldwide prevalence is over 2.8 million MS patients, with figures expected to rise in the near future [11]. This disorder also imposes high socioeconomic costs on healthcare systems [12]. For example, in 2022 in the United States, the MS-related total economic burden was USD 85.4 billion, with a direct medical cost of USD 63.3 billion [13]. MS significantly impacts patients’ quality of life, causing diverse neurological symptoms: vision and balance problems, motor and sensory deficits, urinary problems, and cognitive impairment, the heterogeneous clinical picture being explained by the demyelinating plaques that can affect various CNS regions. In the last decades, there has been an effervescence of disease-modifying therapies (DMTs) that have shown efficacy in counteracting the clinical and radiological activity of MS; still, DMTs have little to no effect on disease progression independent of such acute episodes and on the underlying neurodegenerative processes [14].

While ALS and MS are different entities in clinical presentation, underlying pathophysiology, and treatment opportunities, there are still shared risk factors and molecular mechanisms that have raised researchers’ interest in recent years. One relevant example is the impact of high-fat diet in the onset and evolution of both disorders in the context of the increasing importance of nutrition and nutritional interventions in modulating neurological disorders, most probably via the intensely discussed gut–brain axis [15,16]. In this context, this review aims to offer an updated overview of the role of high-fat diet in ALS and MS risk and progression. The shared pathophysiological mechanisms of ALS and MS are presented in the first part, together with a comparative analysis of the significant differences between the two pathologies. Subsequently, the authors highlight the most relevant research on this topic conducted in animal models and humans, bringing additional proof of the negative impact of a high-fat diet on neurodegeneration. In the final part, based on the currently available knowledge, potential therapeutic approaches and future relevant research directions used to better control nutrition in ALS and MS patients are offered, with the hope of increasing the survival and the quality of life of these patients.

2. Materials and Method

Despite this not being a systematic review, to include in this work the most relevant studies related to high-fat diets’ impact on ALS and MS, the authors conducted a systematic search in the most relevant online databases, namely, PubMed/Medline (https://pubmed.ncbi.nlm.nih.gov/, accessed on 30 November 2024), ScienceDirect (https://www.sciencedirect.com/, accessed on 30 November 2024), and Google Scholar (https://scholar.google.com/, accessed on 30 November 2024). To cover all significant aspects (pathophysiological mechanisms, trials in animal models, clinical trials) covered in the review, different combinations of the following relevant terms were used: ‘amyotrophic lateral sclerosis’, ‘multiple sclerosis’, ‘high-fat diet’, ‘neuroinflammation’, ‘oxidative stress’, ‘neurodegenerative disease’. The inclusion criteria comprised original, peer-reviewed English language studies conducted on patients and in silico, in vitro, and in vivo models, published up to the present. In addition, some narrative and systematic reviews were also included, mainly when covering aspects lacking original research. The authors admit that this search and inclusion strategy might lead to the exclusion of some potentially valuable studies, which represents the main limitation of this paper.

3. Comparative Overview of ALS and MS Pathophysiological Mechanisms

According to the classical definition, ALS is a progressive NDD characterized by the dysfunction of both upper and lower motor neurons, being long considered a motor system disease. Despite its typical focal beginning in the upper or lower limbs and bulbar or respiratory regions, ALS progresses causing widespread muscle weakness, with a restrictive respiratory failure marking its terminal stage [17]. Understanding the link between upper and lower motor neuron dysfunction is crucial for deciphering ALS pathogenesis, with three main theories currently existing: the dying-forward hypothesis (that suggests that ALS originates in the cortex and spreads to lower neurons), the dying-back hypothesis (that proposes the beginning of the degeneration in the lower motor neuron), and the independent hypothesis (which states that upper and lower motor neuron degenerate independently in a random and contiguous pattern) [18].

While its etiology is still incompletely elucidated, the onset and evolution of ALS appear to result from a complex interaction between genetic and environmental factors, which subsequently leads to disruptions in critical molecular pathways and sustained neurodegeneration. Research suggests a multi-step phenomenon with up to six consecutive phases/factors necessary for the development of ALS-related neurodegeneration [19]. Among the genetic contributors, mutations in the C9orf72, TARDBP (encoding TDP-43), and fused in sarcoma (FUS) genes lead to the dysregulation of RNA metabolism, resulting in abnormal protein translation and the formation of intracellular neuronal aggregates [20]. Mutations in the SOD-1 gene further exacerbate neurodegenerative processes by inducing oxidative stress, causing mitochondrial dysfunction and leading to defective axonal transport with the formation of subsequent intracellular aggregates [21]. These genetic disturbances intersect with critical pathogenic pathways for ALS, such as glutamate excitotoxicity [22]. The dysfunction of the astrocytic excitatory amino acid transporter 2 (EAAT2) leads to reduced glutamate uptake from the synaptic cleft, and excess glutamate subsequently activates Ca²⁺-dependent enzymatic pathways [23]. Environmental factors, including toxins and metabolic stressors, may also exacerbate these molecular disruptions, promoting neuroinflammation. Activated microglia release proinflammatory cytokines that amplify neurotoxicity and contribute to disease progression [24].

Regarding environmental factors, diet remains a highly discussed issue, with micro- and macronutrients from different diets being hypothetically linked to many pathological modifications in ALS. Several environmental toxins, such as β-methylamino-L-alanine (BMAA) found in seafood and cycad seeds, have been linked to ALS, particularly in regions like Guam and the Kii peninsula of Japan [25]. Additionally, excessive consumption of high-fat foods, particularly in countries like Sweden and Scotland, is associated with a higher incidence of ALS, although the exact role of dietary fat remains debated [26]. Meanwhile, oxidative stress and mitochondrial dysfunction are known to play critical roles in the disease’s progression, with evidence suggesting that diets rich in antioxidants may help reduce oxidation. Curcumin, creatine, and coenzyme Q10 (CoQ10) have shown promise in animal studies for their antioxidant properties, but their efficacy in humans remains uncertain [27]. Dietary sources of heavy metals such as lead, cadmium, and mercury have also been studied for their potential connection to ALS [28,29]. Bioaccumulation and biomagnification in the food chain, particularly in seafood, could lead to increased exposure to these metals, which are suspected to promote neurodegeneration through oxidative damage and excitotoxicity. Although evidence linking mercury exposure to ALS is inconclusive, some studies suggest that individuals with ALS might be more susceptible to toxic metals due to genetic predispositions [30]. The overall role of diet in ALS is complex, with factors such as antioxidant intake potentially slowing disease progression, while exposure to neurotoxins could increase the risk of disease onset.

Contrary to ALS, the pathophysiology of MS seems to be better understood, although incompletely elucidated. This autoimmune disease is characterized by the formation of plaques in the CNS, leading to neuroinflammation, demyelination, axonal damage, and neuronal loss. The disease results from autoreactive immune cells, particularly CD8+ T cells, CD4+ Th1 cells, and Th17 cells, crossing the blood–brain barrier (BBB) and triggering autoimmune reactions in the CNS [31]. The failure of peripheral immune tolerance, possibly due to impaired regulatory T cells and dysfunctional autoreactive T cells, contributes to MS development. Additionally, B cells play a crucial role by producing oligoclonal immunoglobulins (OCBs) in the cerebrospinal fluid (CSF), with memory B cells significantly contributing to disease progression [32]. According to the viral hypothesis, infected B cells may also serve as ‘reservoirs’ for latent viral infections, such as by Epstein–Barr Virus (EBV), which was demonstrated to play a significant role in MS pathogenesis [33]. EBV-infected B cells not only evade immune control systems and apoptosis but also become capable of more efficiently presenting antigens to CD8+ T cells. Microglia and macrophages contribute to neurodegeneration by releasing cytokines like tumor necrosis factor-α (TNF-α) and interleukin-1β (IL-1β), promoting oxidative stress, excitotoxicity, and mitochondrial damage [34]. However, microglia were also shown to have anti-inflammatory properties, aiding in remyelination [35]. While MS onset results from the mixed impact of genetic and environmental factors, disease progression results from the complex interactions between immune cells, latent viral infections, and inflammatory processes.

Similar to ALS, studies on dietary interventions in MS are still to reach a clear conclusion. Although no specific diet is scientifically proven to treat MS, certain foods and supplements are recommended for their potential benefits. These include fish, low-fat foods, whole grains, vitamins, and omega-3 fatty acids [36]. Some evidence suggests that carotenoids, polyphenols, and other bioactive molecules from vegetables may have anti-inflammatory and antioxidant effects [37]. Vitamin D deficiency is recognized as a risk factor for MS [38], while the role of low levels of vitamin B12, initially thought to be linked to increased disability in MS patients, still remains elusive [39]. Although diets and alternative therapies cannot replace conventional MS treatments, a healthy diet might reduce inflammation and improve physical deficits, potentially serving as a complementary therapy. Further research is required to determine how dietary supplementation can slow MS progression and delay its onset.

ALS and MS share common pathophysiological pathways, including oxidative stress and neuroinflammation, which contribute to neuronal damage in both conditions. Oxidative stress, characterized by an imbalance between reactive oxygen species and antioxidant defenses, leads to cellular injury and mitochondrial dysfunction, critical neurodegeneration components in both MS and ALS [40,41]. In MS, oxidative stress is closely tied to the inflammatory environment generated by pathologically reactive immune cells, resulting in demyelination, axonal injury, and the formation of plaques [42]. Similarly, in ALS, oxidative damage is associated with motor neuron death, although the sources of oxidative stress may differ, with protein misfolding, mitochondrial dysfunction, and excitotoxicity playing more significant roles [43]. Neuroinflammation is a shared feature of both diseases, with microglial activation contributing to disease progression [44]. In MS, activated microglia release pro-inflammatory cytokines and reactive species, exacerbating the immune-mediated destruction of myelin [45], while in ALS, microglial activation leads to neurotoxic effects on motor neurons, perpetuating their degeneration [46].

Despite these shared mechanisms, highlighted in Figure 1, the two diseases diverge significantly in their specific pathophysiological processes and damaged neural structures. MS is primarily an autoimmune disorder orchestrated by T and B cells [47]. The pathological hallmark of MS is the formation of demyelinating plaques, where inflammatory cells infiltrate and cause destruction, impairing the transmission of nerve signals [48]. In contrast, ALS is predominantly a motor neuron disease characterized by the progressive degeneration of upper and low motor neurons. In ALS, neurodegeneration is driven by mechanisms such as glutamate excitotoxicity, mitochondrial dysfunction, and the accumulation of toxic proteins like SOD-1, contributing to motor neuron death [49].

Understanding the similarities and differences between the pathophysiological processes of MS and ALS can be intuitive for comprehending how high-fat diets might negatively impact and exacerbate these disorders. In the following sections, the authors reveal the most relevant studies that prove the role of high-fat diets in the onset and development of MS- and ALS-related neurodegeneration, subsequently showing how dietary changes might help slow disease progression.

4. Relevant Research in Animal Models and Humans

4.1. High-Fat Diets and MS

Research on the association between high-fat diets and MS has been conducted in both animal models and humans.

Table 1. Most relevant studies on the high-fat diet–MS association.

	Author (Year)	Cohort Details	Measured Outcomes	Limitations	Conclusions
Research in animal models	Davanzo et al. (2023) [50]	C57BL/6 J females randomized into two groups (a standard diet or a high-fat diet)	Spinal cord lesions and pro-inflammatory biomarkers	EAE animal model No difference in innate or adaptive immune cell compartments	Spinal cord lesions in myelinated regions and BBB disruption Higher levels of pro-inflammatory cells
	Shahi et al. (2022) [51]	19 HLA-DR3 transgenic mice randomized into three groups (prediet, high-fat diet, normal chow)	Gut microbiota depletion Microbiome analysis Intestinal permeability and inflammatory mediator measurement	EAE animal model	Mice on high-fat diet showed gut microbiota alterations, increased gut permeability, and systemic inflammation
	Timmermans et al. (2014) [52]	20 Female EAE mice randomized into two groups (normal rodent chow versus Western-type diet)	Immunohistochemical staining and real-time PCR to determine immune cell infiltration and inflammatory mediators	EAE animal model	Activation of the renin–angiotensin system, increased immune cell infiltration and inflammatory mediator production in high-fat diet-treated EAE mice
Research in humans	Asgharzadeh et al. (2024) [53]	467 MS patients, 260 controls, age under 15 Azeri population	Dietary demographic questionnaire	Use of questionnaires Homogeneous small cohort	MS patients had a significantly higher consumption of high-fat foods

summarizes the most relevant research on this topic, highlighting the studies’ methodology, limitations, and conclusions.

Despite its limitations, the experimental autoimmune encephalomyelitis (EAE) mouse model is a frequently used animal model for MS-related research, playing a role also in studies on the high-fat diet–MS association. EAE mice receiving a high-fat diet are precious models for a more in-depth understanding of the pathophysiological mechanisms underlying this association. Research conducted by Timmermans et al. showed the significant role of the activated renin–angiotensin system, the increased pro-inflammatory response, and the impact of infiltrated immune cells resulting from the high intake of dietary fats [52]. More recently, fundamental studies demonstrated the increasing role of the gut–brain axis in the correlation between fat diet and MS, the alteration of intestinal microbiota and intestinal permeability modulating the systemic inflammation that subsequently sustains the CNS inflammatory state [51]. Another relevant structure, the blood–brain barrier, also suffers structural and functional damage. This leads to high levels of inflammatory cells entering the CNS, favoring the formation and aggravation of the demyelinating plaques [50].

The preliminary conclusions from the studies conducted in animal models are still to be confirmed in humans via larger cohorts of MS patients. Despite the comprehensive literature search, the authors found only one relevant research study that specifically addressed the role of high-fat diets as a risk factor for MS onset and progression. In this regard, the study conducted by Asgharzadeh et al. is worth mentioning, with the group of MS patients registering a significantly higher high-fat food consumption compared to the healthy controls [53]. As this observation is only correlational, there is an increasing need for further, more extensive cohort studies and interventional studies to confirm the correlation between MS and high-fat food intake.

4.2. High-Fat Diets and ALS

The issue of high-fat diets in ALS is more complex than in MS, with the negative high-fat diet–MS association. Given the catabolic nature of the changes in the metabolism of ALS patients, a high-fat diet seems to play a dual role: in the first stages of the disease, high-fat diets may sustain neuroinflammation and increase oxidative stress, playing a pivotal role as a risk factor for the development and advancement of the disease, while in the final stages of ALS, a high-fat diet might be beneficial, restoring biological imbalances and even slightly extending the lifespan. The metabolic dysfunctions found in the most frequently used ALS mouse models comprise reduced body weight, reduced fat and muscle mass, and an imbalanced caloric intake. Thus, a high-caloric intake, including a high-fat diet, could be an option for improving the general condition of these animals. In this regard, worth mentioning is the research conducted by Coughlan et al., in which a novel ALS mouse model received a high-fat jelly diet, with a promising positive impact on sudden death prevention and survival extension [54]. Several studies were conducted on the implications of hypercaloric diets in ALS mouse models, with results showing the potential for improvement of the nutritional status and prolonged life [55].

Regarding research conducted on ALS patients, the findings on the role of lipids in ALS prognosis are conflicting. On the one hand, higher frequencies of hyperlipidemia, increased triglycerides, and altered cholesterol ratios were reported in ALS patients compared to controls, with higher cholesterol levels associated with more prolonged survival [56]. On the other hand, no clear association between lipid levels and ALS survival has been established, while some authors linked dyslipidemia to worsened respiratory function [56]. Worth mentioning is the work of Dorst et al. (see

Table 2. Most relevant studies on the high-fat diet–ALS association.

	Author (Year)	Cohort Details	Type of Diet	Measured Outcomes	Limitations	Conclusions
Research in animal models	Coughlan et al., 2016 [54]	39 TDP-43A315T male mice randomized into three groups	High-fat jelly diet low-fat jelly diet standard pellet diet	Assessment of lifespan and disease progression in vivo	New animal model for the study of ALS	High-fat diet prevented sudden death and extended survival in this animal model
Research in humans	Dorst et al., 2022 [57]	64 Patients with possible, probable, or definite ALS randomized into four groups	High-caloric fatty supplements ultra-high-caloric fatty supplements ultra-high-caloric, carbohydrate-rich supplements control group	Follow-up over four weeks for gastrointestinal side effects and weight modification	Small and heterogeneous cohort	Despite gastrointestinal side effects, a non-significant trend for weight gain was observed in the groups receiving high-caloric supplements

), where the authors compared a high-fat diet to other high-caloric dietary supplementations, assessing the patient’s tolerability and the impact on weight gain [57]. Several similar studies were conducted in the last decade, with mixed results [58]; however, the focus was on hypercaloric intake, with no differentiation of high-fat diets, making it challenging to draw relevant conclusions.

5. Dietary Changes as Potential Therapeutic Interventions

Despite the incomplete understanding of the physiology of MS and ALS and the conflicting results regarding the dual role of high-fat diets in ALS, dietary changes have long been regarded as adjuvant therapeutic measures with increased potential (see

Table 3. Diet-based therapies in ALS and MS.

Targeted Disorder	Dietary Intervention	Findings	Evidence/Limitations
Amyotrophic lateral sclerosis	Curcumin	Antioxidant and anti-inflammatory effects; potential synergy with Riluzole	Mixed human trial results Nausea and gastrointestinal side effects.
	Creatine	Neuroprotection in animal models	Limited improvements in human trials Further research required
	CoQ10	Antioxidant with mitochondrial benefits	Safe Potential drug interactions and gastrointestinal side effects.
	Phytochemicals (e.g., carotenoids, resveratrol, terpenoids)	Antioxidative and anti-inflammatory effects; cognitive benefits (resveratrol)	Preliminary evidence from in vitro and animal studies Further human trials needed
Multiple sclerosis	Low-saturated-fat diets	Benefits on weight, cholesterol levels, fatigue (Swank, Wahls diets)	Small pilot studies High dropout rate Limited data on long-term adherence and efficacy
	Plant-based diets	Improved fatigue and quality of life in MS patients	Evidence from systematic reviews Variability in diet composition and patient adherence
	Antioxidants	Mixed results for neuroprotection	Limited large-scale evidence Variable study designs and outcomes
	Polyunsaturated fatty acids (PUFAs)	Uncertain impact on relapse rates or disability	Mixed evidence Further research required

). The proof is the many trials conducted in recent years, particularly in MS patients. For example, the work of Villa et al. highlighted the benefits of low-saturated-fat (Swank) and modified Paleolithic elimination (Wahls) diets on weight, cholesterol levels, and perceived fatigue in MS patients [59]. More interesting are the results obtained by Dean et al. in their pilot study, despite the small number (n = 12) of initially included patients and the high dropout rate (50%), where patients followed a low-saturated-fat diet for the median duration of 37 months. The patients who were able to follow the diet registered a decrease in their EDSS scores, no relapses, and a stable disease according to the imaging criteria of yearly magnetic resonance imaging (MRI) scans [60]. According to a systematic review, plant-based diets were demonstrated to be helpful in MS patients, together with low-fat and ketogenic diets [61]. Moreover, a Cochrane review from 2020 addressing the influences of dietary interventions on MS-related outcomes demonstrated the most relevant directions of the dietary interventions used in MS patients [62]. According to recent works, diet might also improve complementary symptoms in MS patients, such as fatigue, improving the patient’s quality of life [63,64]. Most clinical trials focused on supplementation to increase polyunsaturated fatty acids (PUFAs), the administration of antioxidant supplements, or dietary programs. Other nutritional supplements such as biotin, acetyl L-carnitine, riboflavin, probiotics, and palmitoylethanolamide were also tested in smaller trials. There is uncertain evidence on whether PUFA administration modulates the relapse rate, disability, or overall clinical status in MS patients. Similarly, insufficient evidence exists to determine whether supplementation with antioxidants or other dietary interventions significantly impacts MS.

When considering ALS, certain foods and compounds might prevent ALS onset or slightly slow its progression, mainly by countering the significant factors of neuronal degeneration, oxidative stress, and chronic inflammation. Several nutraceuticals share common pathophysiological pathways with different types of fats, becoming potential therapeutic strategies that may mitigate the adverse effects of a high-fat diet. Among the promising nutraceuticals intensely studied in recent years, curcumin showed promising effects due to its antioxidant and anti-inflammatory properties. While animal studies suggest that increasing the levels of antioxidants like glutathione and curcumin potentially reduces neuroinflammation and oxidative stress, interventions in humans have led to mixed results [65]. Some trials have shown that curcumin, in combination with Riluzole, may extend survival in ALS patients, though side effects like nausea have been noted [66]. Moreover, dimethoxy curcumin has shown protective effects on mitochondrial function in cellular ALS models, explaining mitochondria’s role in ALS development and a possible action pathway for curcumin [67]. Other supplements currently under investigation in ALS patients are creatine and CoQ10. Creatine has been shown to offer neuroprotection in animal models, but human studies report only limited improvements, with further research needed [68]. CoQ10, an essential antioxidant to mitochondrial function, was tested in various neurodegenerative conditions, including ALS [69]. Though generally safe, CoQ10 may interact with certain drugs and cause gastrointestinal side effects [70]. Other antioxidants, such as vitamins C and E, have mixed evidence for neuroprotection in ALS. Ongoing research also involves the role of phytochemicals such as carotenoids, polyphenols, and terpenoids as antioxidant compounds that could help reduce neuroinflammation and prevent neuronal damage [71]. Resveratrol, a polyphenol, has demonstrated cognitive benefits by increasing sirtuin 1 (SIRT1) levels, a gene regulator, while terpenoids showed antioxidative potential in vitro [72]. Despite promising findings, establishing the effectiveness of these phytochemicals in ALS requires more in-depth research on larger cohorts of patients.

6. Conclusions and Future Research Directions

ALS and MS remain two relevant pathologies in the heterogeneous group of NDDs, with their prevalence expected to increase in the following decades. Despite intensive research regarding the causative factor leading to neurodegeneration, there are still many unknowns, and an effective disease-stopping therapy is lacking. Still, several risk factors are known, with environmental factors such as high-fat diet having appeared as a prominent research topic in recent years. In MS, high-fat diets have without doubt a negative impact on the disease onset and evolution; however, the relation between high-fat diet and ALS is dependent on ALS stage: in earlier phases, high-fat diets increase oxidative stress and neuroinflammation, sustaining the rapid neurodegeneration of the motor neurons, while in the terminal stages, high-fat diets, together with other high-caloric diets, seem to prolong disease duration.

Based on the current literature on the impact of a high-fat diet in ALS and MS, there are at least three directions that future studies should focus on in the near future. Regarding studies in humans, large-cohort, randomized clinical trials are mandatorily needed to assess the real impact of high-fat diets on the onset and evolution of MS and, particularly, in the later stages of ALS. Also, as high-fat diets differ in composition (types of fat, absolute percentages), future studies in humans should deliver clearer methodologies to follow the impact of saturated/unsaturated/trans fats on the pathophysiological processes. Simultaneously, fundamental research in cellular and animal models should be continued, with the scope of a more in-depth understanding of the molecular pathways involved. Finally, the most promising area of research is related to the dietary changes and multiple diets that should thoroughly be studied in MS and ALS patients as add-on therapies that may significantly impact patients’ quality of life and disease duration.