The term lipid encompasses various biomolecules such as fats, waxes, glycerides and phospholipids. Lipids can be hydrophobic or amphiphilic by nature, and they have many critical physiological roles in living organisms, including as sources of energy storage, in metabolism and as structural components of biological membranes, including neural membranes ^[1][70]. These lipids possess a hydrophilic head and hydrophobic tail and are ubiquitous in cell and organelle membranes as glycerophospholipids (GPLs).

Sphingomyelin (SM) lipids are a subclass of phospholipids abundant in biological membranes and essential for the function and development of the nervous system ^[2][72]. It is a major structural element of neural membranes and regulates cell growth and differentiation. Infants fed a formula containing milk fat globule membrane (MFGM) enriched with SM were reported with better cognitive development compared to infants fed a standard formula ^[3][4][73,74]. Similarly, preschool children who regularly consumed a milk formula enriched with MFGM polar lipids displayed a lower frequency of febrile episodes, hinting that intake of these PL may improve behavioural regulation ^[5][75].

The acidic phospholipid class known as phosphatidylserine (PS) is enriched in the cerebral cortex and plays a critical role in neural structure and function ^[6][7][76,77]. The distribution of phospholipids across the cell membrane is significant for correct cellular functioning and health, and disruption of the normal asymmetric distribution of PS on the membrane results in the initiation of apoptosis ^[8][9][78,79]. In this regard, levels of PS asymmetry were significantly decreased in the brains of patients with AD and mild cognitive impairment (MCI) ^[8][78]. Dietary supplementation with PS and docosahexaenoic acid (DHA) improved oxidative parameters and spatial memory function in rat pups ^[10][80], confirming that supplementation is beneficial for the functioning of the developing brain. Another study found that daily intake of soybean-derived PS over 12 weeks in elderly volunteers with impaired memory function resulted in significantly improved outcomes of learning and memory ^[11][81].

Phosphatidylcholine (PC) is an important dietary source of the B-group vitamin choline, a precursor of the neurotransmitter acetylcholine ^[12][82]. An ex vivo investigation showed that a higher intake of PC was associated with better cognitive function (as assessed by improved performance on verbal and memory tests) and a lower risk of dementia in middle-aged Finnish men ^[13][83]. Another study examined the effect of PC-containing diets (including on the cognitive function of male BALB/c mice, with dementia-like characteristics induced by injection with scopolamine ^[14][84]. It was found that PC intake could effectively attenuate brain damage caused by treatment with scopolamine, as assessed by cognitive tests such Morris water maze task ^[14][84].

Region-specific differences in the spatial localisation of lipid molecules, including phosphatidylcholine, have been detected in AD mouse models compared to wild-type control mice ^[15][85]. This indicates that alterations in the spatial localisation of lipids in the brain play an important role in the pathology of neurodegenerative disease and lipid levels. Further, metabolomics profiling identified significant changes in phosphatidylcholines in the APOE ɛ4 genotype in AD patients ^[16][86].

Ether lipids and phospholipids are of major physiological significance, forming a component of the biological membrane and being involved in signalling pathways. Examples of this class of lipids include platelet-activating factor (PAF), alkylglycerols and plasmalogens. The levels of ether lipids have been linked with neurodegenerative disease. Analysis of brain lipid content in human patients ^[17][87] and AD mouse models have found that levels of certain plasmalogen species are significantly altered ^[18][88]. Aside from AD, Parkinson’s disease has also been associated with altered lipid levels. A clinical investigation of Parkinson’s disease found that oral administration of purified ether phospholipids improved clinical symptoms ^[19][89].

Consumption of fish-derived omega-3 polyunsaturated fatty acids (PUFAs) has been linked with a lower incidence of subclinical brain abnormalities in older adults ^[20][90]. For example, the autosomal dominant neurodegenerative disorder Huntington’s disease is characterised by severe cognitive decline and dementia. In addition, a study has shown that the administration of deuterium polyunsaturated fatty acids (D-PUFA) significantly improved cognitive decline through antioxidant activity and reduction of lipid peroxidation ^[21][91].

A recent study using rat models showed that milk fat globule membrane supplementation during pregnancy promotes neurodevelopment in offspring by modulating the gut microbiome and downregulating levels of pro-inflammatory cytokines and lipopolysaccharide (LPS) in the circulation ^[22][92]. Similarly, oral supplementation of phosphatidylserine (PS) improved learning and memory function in young rats and upregulated the production of the neurotrophic factors BDNF and IGF-1 in the hippocampus ^[23][93]. Moreover, a 2022 study demonstrated that the omega-6 PUFA linoleic acid is highly neuroprotective and reduces inflammation in in vitro models of Parkinson’s disease ^[24][94].

Lipids are involved in several critical signalling pathways, acting as signalling activators, mediators and enzyme substrates. Membrane lipids are crucial components of signal transduction pathways, which are often highly interconnected and interconvertible ^[25][106]. The phosphatases and lipid kinase molecules are some of the most important signalling components. Phosphoinositide 3-kinase (PI3K) is a prominent example of a lipid phosphorylation pathway since mutations in this pathway have been associated with cancer ^[26][107]. Lipid molecules can also act as mediators and bind G-protein coupled receptors (GCPRs) on the cell surface. These include phosphoglycerides, leukotrienes, lysophospholipids, and the phospholipid platelet activating factor (PAF). PAF binds the PAF receptor and triggers downstream activation, thereby regulating processes such as the immune response, cell proliferation and apoptosis, making it an important mediator of these downstream signalling events ^[27][108].

The sterol class of lipids, particularly cholesterol, are essential components of cellular membranes. Cholesterol is a major structural component of lipid rafts, and thus its metabolism strongly influences membrane fluidity ^[28][109] and several membrane signalling pathways ^[29][30][110,111]. Cholesterol has recently been shown to interact with scaffold proteins such as NHERF1 and thus regulate cellular signalling and trafficking pathways ^[31][112].

Saturated fatty acids (SFA), such as palmitic acid and stearic acid, have significant roles in cognitive function. Several studies have shown that palmitic acid can induce neuroinflammation and microglial activation, thus promoting neurodegeneration ^[32][33][34][113,114,115]. On the other hand, stearic acid seems neuroprotective ^[35][116]. For example, a recent study reported that hydroxy stearic acid (5-PAHSA) is neuroprotective in vitro and in vivo ^[36][117]. Thus, these SFA differentially impact neurological health and function.

Monounsaturated fatty acids (MUFA) also have a beneficial impact on brain health. For example, oleic acid is an omega-6 MUFA enriched in oils such as olive oil. Intake of this fatty acid has been shown to protect against oxidative stress in vivo ^[37][118] and reduce Aβ secretion in APP-transgenic mice ^[38][119]. Similarly, a 2018 study reported that deuterium-reinforced linoleic acid in the diet of Huntington’s disease model mice caused reduced lipid peroxidation and improved performance in cognitive tests ^[21][91]. Another study in rat models of multiple sclerosis reported improvement in oxidative stress parameters in the brain of rats fed conjugated curcumin-linoleic acid, as well as improved memory scores ^[39][120].

Dietary lipids are hydrolysed by pancreatic lipases in the lumen of the intestine and taken up through transporter proteins located in enterocytes, the absorptive cells of the gut. Before this, however, the lipids are emulsified by bile salts to facilitate their hydrolysis into products such as free fatty acids, glycerols and monoglycerides. Following uptake by enterocytes, these hydrolysed products are transported to the endoplasmic reticulum (ER), where they are resynthesized into lipids by processes such as esterification. These lipids are subsequently either stored as lipid droplets in the cytosol or secreted out of the ER in the form of lipoprotein particles known as chylomicrons ^[40][121].

Lipids are abundantly present in the nervous system, with hundreds of lipid species present in the neural tissues. Polar lipids, notably phospholipids and sphingolipids, form major structural components of cellular membranes, including neural tissues. Neural membranes are rich in long-chain saturated fatty acids (LC-SFA) palmitic and stearic acids. Many studies have confirmed the importance of polar lipids in early neurodevelopment and cognitive function. In addition to acting as cell membrane components, polar lipids have roles in vesicular trafficking, signalling transduction and synaptic plasticity ^[41][42][122,123]. Sphingolipids are particularly enriched in the brain, and studies have shown that the profile of sphingomyelin in the brain shifts with factors such as ageing and dietary intake of lipids ^[43][44][45][124,125,126].

It has been shown that PUFAs are relatively less abundant in brain tissue than in other organs, with MUFAs significantly enriched in the brain ^[46][127]. Saturated fatty acids are also abundant in the brain and play structural and metabolic roles in neural tissues; as lipid raft components in plasma membranes and cell signalling molecules in pathways such as NF-κB ^[47][128].

The relationship between AD pathology and a high-fat diet (HFD) or obesity is not fully clear, with some studies suggesting that obesity promotes Aβ pathology ^[48][49][129,130]. At the same time, other evidence points towards an HFD as protecting the BBB and promoting cognitive function ^{[50][51][52][53]}[131,132,133,134].

It is established that systemic inflammation is linked to ageing and worsened cognitive function. The inflammatory potential of diet is thus able to predict the risk of incident dementia ^[54][135] and highlights the importance of preventive dietary interventions in reducing the incidence of dementia and other chronic diseases. Indeed, numerous investigations have shown that dietary intake of foods containing beneficial fats with antioxidant and anti-inflammatory properties has a neuroprotective effect and promotes cognitive function. It appears that dietary lipid source is a critically important factor in health outcomes, with n-6 and n-3 long-chain polyunsaturated fatty acids (LC-PUFA) having important neuroprotective properties ^[55][56][136,137], while saturated fats negatively impact brain health and contribute to neuroinflammation ^[57][138]. An epidemiological study reported that intake of n-3 PUFAs, especially α-linolenic acid, was inversely associated with ND-related mortality ^[58][139]. Notbaly, studies have demonstrated the clinical significance of phospholipid subclasses phosphatidylcholine and phosphatidylethanolamine levels in the brain. Ageing has been linked with decreased levels these phospholipids in brain regions of elderly subjects ^[59][140]. Moreover, it appears that phospholipid supplementation positively affects memory and stress performance, as found in human studies ^[60][61][141,142].

Supplementation with the omega-3 PUFA docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA) is beneficial for mood disorders and neurodegenerative disease. EPA and DHA are known to promote neurite outgrowth and affect synaptic plasticity in rat hippocampal neurons ^[62][63][143,144]. Dietary supplementation with EPA and DHA has been shown to improve age-related inflammatory signalling and cognitive function ^[10][64][65][80,145,146]. Many studies have demonstrated the role of omega-6 PUFA, such as linoleic acid and arachidonic acid, in neurodegeneration and neuroinflammation. It appears that the intake of linoleic acid, a PUFA abundant in corn and soybean oils, is neuroprotective and anti-inflammatory in models of Parkinson’s disease (PD) ^[24][66][94,147]. Arachidonic acid is an omega-6 PUFA mainly found in animal sources, such as meats, poultry, eggs and seafood, and plays important roles in membrane fluidity, neurodevelopment and neuronal signal transduction ^[67][148]. Similar to previously discussed lipids, arachidonic acid has neuroprotective properties. For example, it inhibits cytotoxicity in vitro in cell models of PD ^[66][147]. Another study reported that dietary supplementation with arachidonic acid added to DHA improves impairment in social interactions in children with autism spectrum disorders ^[68][149].

The lipid class of sterols is abundantly present in the brain, and many sterols possess neuroprotective properties. For example, cholesterol metabolism and homeostasis are closely linked with brain health and function. Cholesterol levels in the brain affect crucial processes such as neurodevelopment and neuronal signalling. Evidence also suggests that dysregulated cholesterol homeostasis contributes to neurodegenerative disease pathology ^[69][70][150,151]. The role of phytosterols such as stigmasterol, campesterol and β-sitosterol in reducing ND pathology has been highlighted in recent investigations. This group of sterols are naturally present in plants, which possess neuroprotective and cholesterol-lowering properties and can cross the blood–brain barrier, thereby contributing to cognitive health. A 2013 study showed that consuming stigmasterol-enriched diets in mice leads to reduced Aβ production, indicating that intake of this phytosterol protects against AD pathology ^[71][152]. Dietary intake of marine sterols such as fucosterol, a compound derived from brown algae, is noted for its antioxidant ^[72][153] and anti-inflammatory properties ^[73][154]. Fucosterol has also been shown to decrease Aβ oligomer aggregation and thus reduce Aβ pathology in AD ^[74][155]. Another sterol compound derived from seaweed with similar neuroprotective properties is saringosterol, derived from Sargassum fusiforme. In AD model mice, dietary supplementation with 24(S) saringosterol prevented memory decline and reduced Aβ deposition ^[75][156]. Thus, phytosterols also represent an important source of anti-inflammatory lipids that can be adopted as part of a dietary regimen to combat neuroinflammation.

Oxysterols are various oxidation products of sterols, a prominent example of which is 7-ketosterol (7-KC). 7-KC is a toxic compound that leads to deleterious processes, such as the generation of reactive oxygen species (ROS) and cellular death and damage ^[76][157], and has been found in arterial plaques and other disease tissues. There is evidence that 7-KC contributes to AD pathology by causing microglial dysfunction and impaired clearance of amyloid plaques ^[77][78][158,159]. 7β-hydroxycholesterol (7β-OHC) is another cholesterol oxidation product like 7-KC, and similarly to 7-KC, is also implicated in age-related disease and inflammatory processes. However, studies have shown that it is similar to counter the harmful effects of these oxysterols, including cytotoxicity and mitochondrial stress, by consumption of nutrients such as tocopherols ^[77][79][80][158,160,161]. Alpha and gamma-tocopherols can cross the blood–brain barrier and counter the neurotoxic effect of oxysterols ^[81][82][83][162,163,164]. The impact of sterols on brain health is thus quite significant, with beneficial phytosterols conferring neuroprotection, although oxidation products like 7-KC are deleterious and neurotoxic.

The current knowledge of dietary lipids and ND suggests a positive impact on disease pathology. A study with AD mouse models found that maternal supplementation with DHA-enriched fish oil improved cognitive function and prevented neuronal dysfunction in the cortex ^[84][165]. Similarly, another study found that DHA supplementation reduces AD pathology and Aβ oligomer aggregation ^[85][96]. An investigation of Parkinson’s rat models found that pre-treatment with DHA protected against dopaminergic neuronal death ^[86][166]. A similar study with PD mice showed that fish oil supplementation decreased lipid peroxidation and improved dopaminergic neuronal turnover ^[87][95].

Oils containing tocopherols, such as alpha-tocopherol, are enriched in the Mediterranean diet. These are rich in oleic acid and linoleic acid and have significant antioxidant properties. There is ample evidence for many tocopherols, most notably olive oil, in preventing Alzheimer’s disease. One population study ^[88][167] found that the consumption of olive oil was linked with a lower risk of death and protection from cognitive decline and stroke. This may be attributed to the highly bioactive phenolic compounds present in olive oil, such as oleuropein aglycone and oleocanthal, which can reduce Aβ pathology and decrease neuroinflammation and oxidative stress ^[89][90][91][168,169,170]. Indeed, the intake of extra virgin olive oil has been proven to improve cognitive performance in subjects with mild cognitive impairment ^[92][171].

Argan oil is another type of highly bioactive vegetable oil abundant in alpha-tocopherols. Studies in rat models have demonstrated the potential of argan oil to protect against certain neuropsychiatric disorders due to its ability to inhibit oxidative stress, improve mitochondrial function and modulate inflammation ^[93][172]. One study using 158 N murine oligodendrocytes as a neurodegeneration model reported that argan oil treatment reduced 7-KC-induced cytotoxicity ^[94][173]. Milk thistle oil is another primary source of alpha tocopherols, and it is similarly reported to ameliorate the oxidative stress effects of oxysterols such as 7β-hydroxycholesterol ^[95][174], which are increased in patients with ageing-related diseases ^[96][175].

There is also some evidence for supplementation with dietary lipids to improve the pathology of Huntington’s disease (HD), a rare autosomal dominant disorder characterised by progressive loss of nervous system function. Indeed, dysregulation in lipid metabolism and increased insulin resistance have been linked to the disease ^[70][97][151,176]. In a mouse model of HD, omega-3 fatty acids such as EPA have improved motor function (but not neurodegeneration) ^[98][177]. However, the evidence so far is insufficient to draw a conclusion about the role of dietary lipids in HD, and studies with greater sample sizes and more robust designs are required to fill the research gap.