Prevention and / or treatment of neurodegenerative diseases

Abstract

A composition comprising at least one carotenoid selected from the group consisting of lutein, zeaxanthin and meso-zeaxanthin; and at least one omega-3 fatty acid for use in the prevention and / or treatment of dementia in a human subject.

Description

[Technical Field]

[0001] The present invention relates to the use of a combination of substances for the prevention and / or treatment of neurodegenerative diseases, in particular dementia, in human subjects. [Background technology]

[0002] Alzheimer's disease (AD) is the most common type of dementia, followed by vascular dementia. There are 850,000 people with AD in the UK and 5.5 million in the US. The overall prevalence of the disease is expected to continue to increase with age and population growth [1]. Despite considerable research efforts, the cause of the disease remains unknown. However, established risk factors include age, family history of the disease, and education [1]. Putative risk factors include smoking, physical inactivity, and social isolation

[32] . The effectiveness of current drug treatments (medications) is severely limited and varies between individuals. Furthermore, the effects of current medications are at best palliative, as they do not halt disease progression. The UK NHS suggests the following preventative measures: smoking cessation, limiting alcohol intake, eating a healthy, well-balanced diet, and maintaining physical and mental activity.

[0003] There is a wealth of research on the effects of the Mediterranean diet, a diet characterized by a high intake of vegetables and olive oil, and moderate intakes of fish, dairy products, and wine. There is agreement that adherence to such a diet is associated with better cognitive performance [2-7] and a reduced risk of dementia, particularly AD [8-12], but there is no clear evidence of the exact foods responsible.

[0004] Some studies have pointed to benefits from omega-3 fatty acids, including docosahexaenoic acid (DHA), which is found in high concentrations in fish oils and fatty fish, such as salmon and herring. Significant concentrations of DHA are present in the human brain, where it forms a structural component within this neural tissue. High intakes of omega-3 fatty acids are associated with better cognitive performance

[13] and a reduced risk of dementia [14-17]. However, intervention studies have shown conflicting results, with some demonstrating improved cognition [18, 19] and others demonstrating no beneficial effects [20, 21].

[0005] Other target foods include the carotenoids lutein (L) and zeaxanthin (Z). These carotenoids are derived from the diet and are found in certain fruits and vegetables (e.g., spinach, broccoli, peppers, and melons) [Reference 22]. In humans, L and Z are found in high concentrations in the eye (specifically, the central part of the retina known as the macula; they are referred to as "macular pigment" or "macular carotenoids") and the brain [References 23, 24]. High carotenoid intake has been found to reduce the risk of AD [References 25, 27]. Some studies administering L and Z have shown improvements in different cognitive domains [References 28, 29], while other randomized trials have shown no benefit [Reference 30].

[0006] Another macular carotenoid is meso-zeaxanthin (MZ), a stereoisomer of zeaxanthin. The chemical structures of L, Z, and MZ are shown in Figure 1.

[0007] Vitamin E is also present in the brain, and high plasma concentrations of vitamin E are associated with a reduced risk of AD.

[31] There are no reports of successful treatment of AD following administration of this vitamin.

[0008] In summary, there is general agreement that substances exist in the brain that play a role in preventing AD, but attempts to identify and / or use them have so far been unsuccessful.

[0009] Compositions containing all three macular carotenoids (L, Z, and MZ) are commercially available as nutritional supplements. One example of such a supplement is sold under the trade name Macushield® and consists of capsules containing the three macular carotenoids L, Z, and MZ in amounts of 10 mg, 2 mg, and 10 mg per capsule, respectively. WO 2013 / 005037 discloses the use of such a composition for improving visual performance in a human subject, where the composition optionally further comprises fish oil and / or omega-3 fatty acids.

[0010] U.S. Patent Application Publication No. 2016 / 0067203 (Lion Corporation) discloses and claims a composition for improving cognitive function, the composition comprising docosahexaenoic acid (DHA) in combination with lutein, zeaxanthin, and capsanthin.

[0011] This specification includes the results of a "passive avoidance test" conducted using mice fed with the test composition or the control composition for three months (see, in particular, Example 5 in Table 2 of the prior art document). The mice received a mild electric shock when they entered the dark compartment, and learned to avoid the dark compartment when the test was repeated. The prior art specification also presents data suggesting that the amount of amyloid beta protein in the brain was reduced in the test mice compared to controls (Table 3) (however, the number of animals included in this experiment was very small, n=3 and n=4, respectively), and therefore the results are not statistically significant.

[0012] There is no data from studies on human subjects. Furthermore, there is no evidence that the exemplary compositions could improve cognitive function in subjects already suffering from cognitive impairment or stabilize the condition of the subject.

[0013] WO 2006 / 116755 (Trustees of Tufts College) discloses and claims a composition having "synergistic amounts of lutein and DHA for use in improving cognitive function." The claims are based on a study in which 50 human subjects (all female) were given a supplement containing (i) a placebo; (ii) DHA or lutein; or (iii) a combination of DNA and lutein once daily for a period of four months. Various cognitive function tests were performed at the beginning and end of the supplement intake period, and the results are shown in Table 2 of that prior art document. All compositions, except the placebo, provided statistically significant (<0.05) improvements in verbal fluency tests (thus, there is no evidence of any synergy between DHA and lutein).

[0014] Additionally, however, subjects receiving the DHA / lutein combination demonstrated statistically significant improvements in the Shopping List Memory Test and the MIR ("Memory-in-Reality") Apartment Test. For the latter, however, it is clear from Figure 4 of that prior art publication that baseline scores were unusually low for that group, and thus the large improvement was likely unrelated to supplementation. Finally, there is no evidence that the DHA / lutein combination could have any beneficial effect on subjects with existing cognitive impairment. Summary of the Invention [Means for solving the problem]

[0015] The inventors have found that macular carotenoids, such as meso-zeaxanthin (MZ), lutein (L) and zeaxanthin (Z), or a mixture of omega-3 fatty acids, when given separately, individually have no effect on the progression of dementia, but when given together are remarkably and surprisingly effective in halting or slowing the progression of the disease and improving cognitive function.

[0016] Accordingly, in a first aspect, the present invention provides a composition comprising at least one carotenoid selected from the group consisting of lutein, zeaxanthin and meso-zeaxanthin; and at least one omega-3 fatty acid, for use in the prevention and / or treatment of dementia in a human subject.

[0017] More particularly, the composition is for use in the prevention and / or treatment of Alzheimer's disease.

[0018] In a second aspect, prevention provides a method of preventing and / or treating dementia, particularly Alzheimer's disease, in a human subject, comprising administering to the human subject an effective amount of a composition comprising at least one carotenoid selected from the group consisting of lutein, zeaxanthin and meso-zeaxanthin; and an effective amount of a composition selected from the group consisting of lutein, zeaxanthin and meso-zeaxanthin; and an effective amount of a composition comprising at least one omega-3 fatty acid.

[0019] In one embodiment, in the first and second aspects of the present invention, the at least one carotenoid comprises lutein. In one embodiment, the at least one carotenoid comprises any combination of at least two of the above carotenoids (i.e., L and Z, L and MZ, or Z and MZ). Preferably, one of the "at least two carotenoids" comprises lutein. In a preferred embodiment, in the first and second aspects of the present invention, a composition comprising each of lutein, zeaxanthin, and meso-zeaxanthin is used.

[0020] More preferably, in the first and second aspects of the present invention, a composition comprising lutein, zeaxanthin, meso-zeaxanthin and at least one omega-3 fatty acid is used, such that all four of the above substances can be obtained by a human subject by administration of a single composition, which represents a preferred embodiment of the present invention.

[0021] When two separate compositions (i.e., one composition for at least one carotenoid and one composition for at least one omega-3 fatty acid) are used, they are desirably administered substantially simultaneously (i.e., within 5 minutes of each other) or at least concurrently (i.e., on the same day). When two separate compositions are used in the practice of the invention, they are preferably both administered to a subject via the same route (preferably both orally), although administration of one composition by a first route and the other composition by a second route is contemplated.

[0022] In the first or second aspect of the invention, one or more compositions (as appropriate) may be administered to a human subject by any suitable route, for example, intravenously, however preferably the compositions are administered orally and advantageously the compositions are formulated to be suitable for oral administration.

[0023] One or more compositions (as appropriate) can be administered to a human subject who does not yet exhibit any symptoms of dementia (e.g., Alzheimer's disease) with the goal of preventing the subject from developing dementia or delaying the time when the subject will begin to develop one or more symptoms of dementia (e.g., Alzheimer's disease). Either of these can be considered to "prevent" dementia, or specifically Alzheimer's disease, firstly indefinitely and secondly for at least a certain period of time. The length of time that the development of one or more symptoms of dementia / Alzheimer's disease can be delayed may depend on the age of the subject at the time of administration of the composition and other factors that affect the subject's susceptibility to dementia (e.g., genotype, diet, smoking history, etc.). Preferably, the development of one or more symptoms of dementia is delayed for at least 6 months, more preferably at least 12 months, and most preferably at least 18 months. In particular, the one or more symptoms of dementia typically include or consist of cognitive impairment (e.g., as can be assessed by the MMSE, discussed below). The inventors believe that administration of sufficient amounts of one or more macular carotenoids and one or more omega-3 polyunsaturated fatty acids (particularly DHA and / or eicosapentaenoic acid, EPA) to a human subject who does not yet exhibit any symptoms of Alzheimer's disease may indefinitely prevent the development of Alzheimer's disease in the subject.

[0024] Alternatively, the composition can be administered to a subject who already exhibits one or more symptoms of dementia (particularly Alzheimer's disease) for the purpose of preventing or delaying the progression of the disease. Preventing disease progression means that the severity of one or more existing symptoms of dementia does not increase. In particular, preventing disease progression preferably comprises or consists of substantially preventing the progression of cognitive impairment in the subject. Delaying disease progression means that the severity of the symptoms increases more slowly than would occur in the absence of intervention (i.e., administration of the composition of the present invention). Preventing or delaying the progression of dementia (e.g., Alzheimer's disease) is considered to be treating the disease for this purpose.

[0025] Diagnosis of dementia is known to be difficult. A useful diagnostic aid is the Mini-Mental State Examination or "MMSE" (Tombaugh & McIntyre 1992 J. Am. Geriatr. Soc. 40, 922-935). For the present purpose, a subject can be considered to have dementia if the subject obtains an MMSE score of 25 or less and can exclude any other causes of cognitive impairment (e.g., head injury, chronic alcohol abuse, fever, urinary tract infection, etc.).

[0026] The prevention of cognitive impairment progression in a subject as a result of administering the composition of the present invention can be confirmed by performing a Mini-Mental State Examination. In a preferred embodiment, a subject who already suffers from dementia (i.e., has an MMSE score of 25 or less) and takes the composition of the present invention will experience a reduction in MMSE score of 2 points or less over an 18-month period, more preferably 1 point or less over an 18-month period, and most preferably 0 points over an 18-month period.

[0027] As already mentioned, the composition comprises at least one omega-3 fatty acid. For the present purposes, unless the context dictates otherwise, the term "fatty acid" is intended to include not only the free acid of the fatty acid, but also its derivatives (such derivatives include in particular esters, especially esters formed with glycerol (monoglycerides, diglycerides, and preferably triglycerides)), and salts. Preferred salts include monocations, such as Na + , K. + or NH4 + The most preferred salts are those containing metal monocations. The free fatty acids or triglycerides are the most preferred forms of the compounds.

[0028] The omega-3 fatty acid component of the composition preferably comprises an omega-3 polyunsaturated fatty acid or a derivative thereof, most preferably docosahexaenoic acid (DHA) or a derivative thereof. The composition may contain two or more omega-3 fatty acids. The composition may include eicosapentaenoic acid (EPA). In one embodiment, the composition includes both DHA and EPA.

[0029] A convenient source of omega-3 fatty acids is fish oil.Therefore, in a preferred embodiment, the composition comprises fish oil.Fish oil has a significant odor, so it may be preferable to use commercially available deodorized fish oil.Another source of omega-3 fatty acids is peanut oil.Without being bound by any particular theory, the present inventors believe that DHA is the most active omega-3 fatty acid in terms of preventing and / or treating dementia.Peanut oil does not contain a significant amount of DHA, and therefore is not preferred for the purpose of the present invention.

[0030] Other sources of fatty acids include algae (see Ji et al., 2015, “Omega-3 Biotechnology: A green and sustainable process for omega-3 fatty acids production,” Front Bioeng. Biotechnol. 3, 158).

[0031] The compositions can be formulated in "bulk" form, e.g., mixed with conventional foodstuffs, such as dairy foodstuffs (e.g., incorporated into butter or ice cream) or non-diary foodstuffs (e.g., margarine, vegetable stock, or fish stock preparations). More preferably, however, the compositions are formulated in unit dosage forms, preferably those suitable for oral ingestion by a human subject, e.g., tablets, capsules, gels, liquids, powders, etc. One or more macular carotenoids can be granulated, e.g., as microcapsules, prior to inclusion in the formulation.

[0032] Conveniently, but not necessarily, the compositions can be packaged in a foil blister pack of the type known to those skilled in the art. Desirably, one or two doses are taken daily, with the amount of active agent in each dose adjusted accordingly.

[0033] The compositions may conveniently contain conventional diluents well known to those skilled in the art, in particular vegetable oils such as sunflower, safflower, corn oil and rapeseed oil, excipients, fillers etc. Such substances include calcium and / or magnesium stearate, starch or modified starch.

[0034] Other conventional compounding agents, such as any one or more of the following non-exclusive list, may be present in the composition: acidity regulators; anti-caking agents (e.g., sodium aluminosilicate, calcium or magnesium carbonate, calcium silicate, sodium or potassium ferricyanide), antioxidants (e.g., vitamin E, vitamin C, polyphenols), coloring agents (e.g., artificial coloring agents, such as FD&C Blue No. 1, Blue No. 2, Green No. 3, Red No. 40, Red No. 3, Yellow No. 5, and Yellow No. 6; and natural coloring agents, caramel, annatto, cochineal, betanin, turmeric, saffron, paprika, and the like); color retention agents; emulsifiers; flavors; flavor enhancers; preservatives; stabilizers; sweeteners, and thickeners.

[0035] Other optional components of the composition include vitamins and / or minerals. Preferably, the composition includes vitamin E. Preferably, the composition includes at least one B vitamin. Preferably, the composition includes vitamin E and at least one B vitamin.

[0036] Typically, one or more compositions (as appropriate) are administered at least once a week, preferably at least twice a week, more preferably three times a week, and most preferably once a day.In a typical embodiment, at least one unit dosage form of the composition is taken once a day.Those skilled in the art will recognize that the frequency of intake can be adjusted to take into account the concentration of active agents (one or more macular carotenoids, omega-3 fatty acids) present in the formulation.The administration of the composition can be adjusted accordingly.

[0037] Preferably, to prevent the onset of one or more symptoms of dementia, the composition should be administered to subjects under the age of 50, an age at which dementia is fairly rare.

[0038] To achieve a prophylactic effect, the composition should preferably be administered, typically at least two or three times per week or once daily, for a period of at least six months, preferably at least twelve months, and even more preferably at least eighteen months. For the treatment of patients who already exhibit one or more symptoms of dementia, the composition should preferably be administered indefinitely, as long as the patient is able to take the composition.

[0039] For present purposes, the "active agents" in the composition are considered to be one or more macular carotenoids and at least one omega-3 fatty acid.

[0040] The precise concentration of active agent in the compositions of the present invention is not critical: a beneficial effect on a subject may be obtained by ingesting a high dose of a composition containing a low concentration of active agent, or vice versa.

[0041] When a macular carotenoid composition contains two or more carotenoids, the ratio of each of them in the composition is not considered critical and can vary widely. For example, the proportion of either MZ or lutein in the composition can range from 10% to 90% (of the macular carotenoids present in the composition). The proportion of zeaxanthin can typically range from about 5 to 45% (of the macular carotenoids present in the composition). One particular composition has an MZ:lutein:zeaxanthin ratio of 10:10:2 (or 45%, 45%, 10%), although this is not required. Another typical composition has a ratio (MZ:L:Z) of 12:10:2.

[0042] One preferred composition for use in the practice of the present invention is in unit dosage form, with each unit dose containing 10 mg meso-zeaxanthin, 10 mg lutein, 2 mg zeaxanthin, and fish oil (preferably 1 mg). g Contains fish oil.

[0043] Another preferred composition for use in the practice of the present invention is in unit dosage form, with each unit dose containing 15 mg meso-zeaxanthin, 5 mg lutein, 1 mg zeaxanthin, and fish oil (preferably 1 mg). g Contains fish oil.

[0044] Desirably, the average daily dose of the composition provides a total macular carotenoid content of at most 100 mg, preferably at most 75 mg, and most preferably at most 50 mg. Desirably, the average daily dose of the composition provides a minimum total macular carotenoid content of at least 18 mg, more preferably at least 20 mg, and most preferably at least 22 mg. Such concentrations are known to be well tolerated and show substantially no adverse effects.

[0045] Advantageously, the average daily dose of the composition is between 10 mg and 2 g More preferably, in the range of 20 mg to 2 g and most preferably in the range of 25 mg to 1 gram of omega-3 fatty acids.

[0046] The omega-3 fatty acid content can be provided entirely by DHA or by a combination of two or more omega-3 fatty acids, one of which is preferably DHA. DHA desirably comprises at least 50%, preferably at least 55%, more preferably at least 60%, and most preferably at least 65% of the omega-3 fatty acid content of the composition.

[0047] The invention will now be further described by way of illustrative examples and with reference to the accompanying drawings, in which: [Brief explanation of the drawings]

[0048] [Figure 1] 1 is a schematic representation of the structural formulas for lutein, zeaxanthin, and meso-zeaxanthin. [Figure 2] 1 is a graph of serum lutein concentration (μmol / L) over time (months). [Figure 3] 1 is a graph of serum meso-zeaxanthin concentration (μmol / L) over time (months). [Figure 4] Graph of either DHA or EPA response (arbitrary units) over time (months). [Figure 5] 1 is a pie chart illustrating the severity of dementia symptoms in patients at 0 or 18 months. [Figure 6] 1 is a pie chart illustrating the severity of dementia symptoms in patients at 0 or 18 months. [Figure 7] 1 is a pie chart illustrating the severity of dementia symptoms in patients at 0 or 18 months. [Figure 8] 1 is a pie chart illustrating the severity of dementia symptoms in patients at 0 or 18 months. [Example]

[0049] This example relates to scientific research trials carried out at the Nutrition Research Centre Ireland (NRCI).

[0050] Patients with AD were recruited from University Hospital Waterford (UHW) through the Age-Related Care Unit. This study was conducted with due consideration of the ethical requirements of the recruited patients. The aims and methods of this study were in full accordance with widely recognized international texts and codes of practice, such as the Declaration of Helsinki and Good Research Practice. To ensure proper informed consent and to obtain consent from vulnerable subjects, such as patients with AD, a protocol was developed specifically for this study in accordance with appropriate ethical regulations.

[0051] Briefly, we conducted three study experiments: two in patients with AD and one in age-matched control subjects (without AD).

[0052] In Study Group 1, patients with AD (n=12) were given a once-daily supplement containing macular carotenoids but no omega-3 fatty acids. The supplement was in the form of capsules of a commercially available formulation ("Macushield"™). Each capsule contained approximately 10 mg of lutein ("L"), 10 mg of meso-zeaxanthin ("Z"), and 2 mg of zeaxanthin ("Z"). One capsule per day was administered under the supervision of a patient caregiver for a period of 18 months.

[0053] In study group 2 (n=13), the AD patients were essentially the same as those used in study group 1, but 1 gThe subjects received a once-daily dietary supplement containing 100 mg of fish oil (containing approximately 430 mg of DHA and 90 mg of EPA). The fish oil was of high quality and was obtained from Epax® (Epax Norway AS, Alesund, Norway). Again, supplement intake was monitored by the patient's caregiver and continued for 18 months.

[0054] The third study group (n=31) were age-matched controls with no evidence of dementia. This group did not take any dietary supplements.

[0055] All subjects were assessed at the start of the study to provide a baseline. Characteristics assessed included some / most of the following depending on study arm: (i) serum concentrations of L, Z, and MZ; (ii) macular pigment (MP) concentration in the macula at 0.23 degrees retinal eccentricity (“MP0.23”) (see below for explanation); (iii) MP volume (MP volume under the curve) (see below); (iv) LPC22:6 and LPC20:5 (which are measures of phospholipids in the blood that contain either DHA or EPA, respectively—see below); and (v) Medical Assessment of Dementia (+ / - "MMSE"). Baseline values ​​for these characteristics are shown in Table 1 below.

[0056] The MP was measured by dual-wavelength autofluorescence (AF) using a Spectralis HRA+OCT MultiColor instrument (Heidelberg Engineering GmbH, Heidelberg, Germany) as described by Akuffo et al. (2014 Ophthalmic Epidemiol. 21, 111-123). Pupil dilation was performed before measurement, and patient details were entered into Heidelberg Eye Explorer (HEYEX) version 1.7.1.0 software. Dual-wavelength AF in this instrument uses two excitation wavelengths: one well absorbed by MP (486 nm, blue) and one not absorbed (518 nm, green) (Trieschmann et al., 2006, Graefes Arch. Clin. Exp. Ophthalmol. 244, 1565-1574; Dennison et al., 2013 Exp. Eye Res. 116, 190-198). The following acquisition parameters were used: fast scan resolution, 2-second circular buffer size, internal fixation, 30-second video, and manual brightness control. Alignment, focus, and illumination were initially adjusted in infrared mode. Once the image was evenly illuminated, the laser mode was switched from infrared to blue and green laser AF. HEYEX software was used to align and average the video images to generate MP density maps. MP abundance was calculated as the MP average magnification of the area under the curve up to 7° of eccentricity.

[0057] LPC22:6 and LPC20:5 assays were performed as follows: Samples were extracted and analyzed as previously published (Koulman, et al. 2014. "The development and validation of a fast and robust dried blood spot-based lipid profiling method to study infant metabolism". Metabolomics 10:1018-25). All samples were injected into an Exactive Orbitrap (Thermo, Hemel Hempstead, UK) using a Triversa Nanomate (Advion, Ithaca, US).

[0058] [Table 1]

[0059] Evaluation method Biochemical response: For biochemical assessment, samples were obtained at baseline and again after 6 months of supplementation. Serum MZ, L, and Z concentrations were assessed by high-performance liquid chromatography (HPLC) of plasma. Markers of DHA and EPA were assessed by liquid chromatography (LC) mass spectrometry (MS) metabolomic and lipidomic analyses of blood samples using previously validated methods detailed above.

[0060] MMSE: This was performed under the supervision of the attending clinician and is a validated technique. MMSE results were used to guide the diagnosis of AD during patient recruitment. AD status was defined as follows: MMSE score 0–10 = severe AD; MMSE score 11–20 = moderate AD; MMSE score 21–25 = mild AD; 26 + = no AD. In addition to the MMSE performed at the start of the study, each patient was assessed for health and AD status for 18 months if possible.

[0061] result Macular carotenoid levels First, it should be noted that the mean serum lutein concentration in Study 2 subjects (0.154 ± 0.084 μmol / L) was significantly lower than that in the control group (0.297 ± 0.179), and this difference was statistically significant (p = 0.010) as determined by an independent samples t-test.

[0062] Figure 2 shows the mean serum lutein concentrations at baseline and after 6 months for Study Group 1 (black circles) and Study Group 2 (white circles). It is readily apparent that serum lutein concentrations increased over the 6-month period for both groups. However, Group 2 subjects (receiving MC and fish oil supplements) exhibited a significantly greater increase in serum lutein, which was statistically significant (p=0.002).

[0063] A similar picture was found for serum levels of MZ in Study 1 and 2 subjects (see Figure 3): both groups exhibited a clear increase in serum MZ at 6 months compared to baseline; however, Study 2 subjects showed a greater increase than Group 1 subjects, which was also statistically significant (p=0.06).

[0064] Omega-3 fatty acid response The results for serum DHA (black circles) and serum EPA (white circles) are shown in Figure 4 for the subjects in study group 2 at baseline and after 6 months. It can be seen that EPA concentrations increased, and DHA concentrations increased significantly. Because the fish oil supplement used in the study contained more DHA than EPA, a greater response in DHA levels could be expected.

[0065] Medical response Patients were medically evaluated at baseline and 18 months after supplementation. Medical evaluations were performed by qualified AD nurses under the supervision of a medical consultant. In addition, patient caregivers were interviewed 18 months after patients began supplementation. Baseline AD status was confirmed by a medical consultant.

[0066] Figures 5 and 6 show the AD status for Study Group 1 subjects at baseline (Figure 5) and at 18 months (Figure 6). Figures 7 and 8 show the AD status for Study Group 2 subjects at baseline (Figure 7) and at 18 months (Figure 8).

[0067] Additionally, individual subject data for the two study arms are presented in Table 2.

[0068] [Table 2-1] [Table 2-2]

[0069] As can be seen from the pie charts (Figures 5 and 6, data from Study 1, carotenoid-only intervention) and Table 2, AD progression was evident in this group over the 18-month period, with the health status of 42% of patients declining to the point where they could not continue in the study. Reasons for dropout included patients moving to nursing homes due to AD progression; patients being unable to continue due to severe ill health; severe cognitive decline; and no longer being able to follow instructions.

[0070] However, as seen in Figures 7 and 8 (data from Study 2, carotenoid and fish oil intervention) and Table 2, there was significantly less progression of AD, and caregivers reported improvements in cognitive function, visual function, and general health. Notably, no patients dropped out of Study 2, and the comments received were as follows: memory improved, vision improved, AD did not worsen.

[0071] conclusion The examples provided herein suggest that AD may be a nutrient deficiency disease. The nutrients in question are carotenoids (lutein and zeaxanthin) and DHA, which have been identified in the human brain. These nutrients have the potential to support brain health and reduce the risk of AD through their antioxidant, anti-inflammatory, and structural roles. The inventors hypothesize that AD is a nutrient deficiency disease, and that the favorable medical responses observed in this study are due to the correction of this deficiency. However, in the setting of disease onset, correction of nutrient deficiency cannot reverse the disease; however, stabilization of brain health and function was achieved, consistent with the halting of AD progression in patients supplemented with carotenoids and fish oil.

[0072] The inventors suggest that AD is a disease of deficiency of two nutritional components: a. the macular pigments lutein and zeaxanthin, obtained from eating green leafy vegetables (e.g., spinach and kale), and b. DHA, obtained from eating fatty fish (e.g., salmon).

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Claims

1. 1. A composition for use in preventing or delaying the progression of cognitive impairment in a human subject having an MMSE score of 25 or less, comprising: Composition A comprising each of lutein, zeaxanthin, and meso-zeaxanthin; and Composition B comprising at least one selected from the group consisting of a free acid of an omega-3 fatty acid, a salt of a free acid of an omega-3 fatty acid, and an ester formed with glycerol of a free acid of an omega-3 fatty acid, wherein each unit dose of the composition comprises 15 milligrams of the meso-zeaxanthin, 5 milligrams of the lutein, and 1 milligram of the zeaxanthin; an average daily dose of the composition providing a total amount of the free acid of the omega-3 fatty acid, salts of the free acid of the omega-3 fatty acid, and esters formed with glycerol of the free acid of the omega-3 fatty acid of at least 520 milligrams and no more than 2 grams; The composition is adapted to be administered to the human subject for a period of at least 18 months.

2. The composition for use according to claim 1, wherein the composition is a single composition comprising each of the lutein, the zeaxanthin, the meso-zeaxanthin, and at least one selected from the group consisting of free acids of the omega-3 fatty acids, salts of free acids of the omega-3 fatty acids, and esters of free acids of the omega-3 fatty acids with glycerol.

3. A composition for use according to claim 1 or 2, wherein at least one selected from the group consisting of the free acid of the omega-3 fatty acid, a salt of the free acid of the omega-3 fatty acid, and an ester formed with glycerol of the free acid of the omega-3 fatty acid comprises docosahexaenoic acid.

4. the composition comprises fish oil; The composition for use according to any one of claims 1 to 3, wherein at least one selected from the group consisting of the free acid of the omega-3 fatty acid, a salt of the free acid of the omega-3 fatty acid, and an ester formed with glycerol of the free acid of the omega-3 fatty acid is a component of the fish oil.

5. A composition for use according to any one of claims 1 to 4, wherein at least one selected from the group consisting of free acids of the omega-3 fatty acids, salts of free acids of the omega-3 fatty acids, and esters formed with glycerol of free acids of the omega-3 fatty acids comprises at least two fatty acids.

6. A composition for use according to any one of claims 1 to 5, wherein at least one selected from the group consisting of free acids of the omega-3 fatty acids, salts of free acids of the omega-3 fatty acids, and esters formed with glycerol of free acids of the omega-3 fatty acids comprises docosahexaenoic acid and eicosapentaenoic acid.

7. A composition for use according to any one of claims 1 to 6, wherein at least one selected from the group consisting of the free acid of the omega-3 fatty acid, the salt of the free acid of the omega-3 fatty acid, and the ester formed with glycerol of the free acid of the omega-3 fatty acid is a salt or a triglyceride.

8. The composition for use according to claim 7 , wherein the salt comprises a monocation.

9. The composition for use according to claim 8 , wherein the salt comprises a metal monocation.

10. The composition for use according to any one of claims 1 to 9, wherein the composition is formulated to be suitable for oral ingestion and is administered orally.

11. The composition for use according to any one of claims 1 to 10, wherein the composition is administered once a day.

12. The composition for use according to any one of claims 1 to 11, wherein the composition is in unit dose form.

13. each unit dose of the composition contains 1 g of fish oil; The composition for use according to claim 12, wherein at least one selected from the group consisting of the free acid of the omega-3 fatty acid, a salt of the free acid of the omega-3 fatty acid, and an ester formed with glycerol of the free acid of the omega-3 fatty acid is a component of the fish oil.

14. each unit dose of the composition comprises 20 milligrams to 2 grams of docosahexaenoic acid; 13. The composition for use according to claim 12, wherein at least one selected from the group consisting of the free acid of the omega-3 fatty acid, the salt of the free acid of the omega-3 fatty acid, and the ester formed with glycerol of the free acid of the omega-3 fatty acid comprises docosahexaenoic acid.

15. 15. The composition for use according to any one of claims 1 to 14, wherein the composition further comprises one or more of the following: an acidity regulator, an anti-caking agent, such as sodium aluminosilicate, calcium carbonate, magnesium carbonate, calcium silicate, sodium ferricyanide, potassium ferricyanide, or any combination thereof; an antioxidant, such as vitamin E, vitamin C, polyphenols, or any combination thereof; a coloring agent, such as artificial coloring, FD&C Blue No. 1, Blue No. 2, Green No. 3, Red No. 40, Red No. 3, Yellow No. 5, and Yellow No. 6; and a natural coloring agent, such as caramel, annatto, cochineal, betanin, turmeric, saffron, paprika, or any combination thereof; a color retention agent; an emulsifier; a flavor; a flavor enhancer; a preservative; a stabilizer; a sweetener; and a thickener.

16. The composition for use according to any one of claims 1 to 15, wherein the composition is in the form of a tablet or capsule.

17. the composition comprises at least one selected from the group consisting of the lutein, the zeaxanthin, the meso-zeaxanthin, the free acids of the omega-3 fatty acids, salts of the free acids of the omega-3 fatty acids, and esters of the free acids of the omega-3 fatty acids with glycerol, and a diluent, carrier, or excipient; 17. The composition for use according to any one of claims 1 to 16, wherein at least one component selected from the group consisting of the free acid of the omega-3 fatty acid, the salt of the free acid of the omega-3 fatty acid, and the ester formed with glycerol of the free acid of the omega-3 fatty acid comprises an omega-3 polyunsaturated fatty acid or a corresponding salt or triglyceride.

18. 18. The composition for use according to claim 17, wherein the omega-3 polyunsaturated fatty acid or corresponding salt or triglyceride comprises docosahexaenoic acid or a salt or triglyceride of docosahexaenoic acid.

19. the composition comprises each of the lutein, the zeaxanthin, and the meso-zeaxanthin, as well as docosahexaenoic acid and / or eicosapentaenoic acid; at least one component selected from the group consisting of free acids of omega-3 fatty acids, salts of free acids of omega-3 fatty acids, and esters formed with glycerol of free acids of omega-3 fatty acids comprises docosahexaenoic acid and / or eicosapentaenoic acid; 19. The composition for use according to any one of claims 1 to 18, wherein the composition is formulated in a unit dose form for once-daily oral administration, for use in preventing or delaying the progression of cognitive impairment in a subject who already exhibits one or more symptoms of Alzheimer's disease prior to administration of the composition.

20. The method of claim 20, wherein at least one selected from the group consisting of free acids of omega-3 fatty acids, salts of free acids of omega-3 fatty acids, and esters of free acids of omega-3 fatty acids with glycerol comprises docosahexaenoic acid and eicosapentaenoic acid; 20. The composition for use according to any one of claims 1 to 19, wherein the average daily dose of the composition provides at least 430 milligrams of docosahexaenoic acid and at least 90 milligrams of eicosapentaenoic acid.

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