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Alzheimer's Disease

Overview

Alzheimer's disease shares overlapping biological dysfunctions with other neurocognitive disorders, including mitochondrial impairment, chronic inflammation, oxidative stress, impaired methylation, and neurotransmitter imbalance (see Tardy et al. 2020). Mediterranean-leaning and plant-forward dietary strategies have been associated with slower cognitive decline and improved neuroprotection trajectories (see Agarwal et al. 2023; Morris et al. 2015; Ashley Holub 2022).

Biological Target Matrix

Inflammation

SubstanceFoodsMechanism of Action
GenisteinAnti-inflammatory and anti-neuroinflammatory properties; reduces neuroinflammation
DHA (Docosahexaenoic Acid)Precursor to specialized pro-resolving mediators (SPMs) including protectins and maresins; terminates inflammation without immunosuppression
EPA (Eicosapentaenoic Acid)Potent anti-inflammatory; precursor to E-series resolvins; specialized pro-resolving mediators (SPMs) terminate inflammation without immunosuppression, downregulate COX-2, inhibit neutrophil infiltration, enhance macrophage clearance
Omega-3 Fatty AcidsSpecialized Pro-Resolving Mediators (SPMs) - resolvins, protectins, maresins terminate inflammation without immunosuppression, downregulate COX-2, inhibit neutrophil infiltration, enhance macrophage clearance, limit glutamate-induced excitotoxicity
BerberineReduces LPS translocation and dampens LPS-driven inflammation through antimicrobial effects on pathobionts
EGCG (Green Tea Catechin)Polyphenol antioxidant and anti-inflammatory effects; reduces inflammatory signaling
AcetateSupports immune regulation and anti-inflammatory processes
ButyrateHas anti-inflammatory effects, potentially reducing neuroinflammation; deficiencies linked to many neurological disorders including ADHD
PropionateHelps reduce neuroinflammation and protects the blood-brain barrier; enhances cognitive function
Short-Chain Fatty Acids (SCFAs)Butyrate has anti-inflammatory effects, potentially reducing neuroinflammation; propionate helps reduce neuroinflammation and protects the blood-brain barrier
Urolithin APowerful antioxidant; supports anti-inflammatory effects
Quercetin (and Isoquercetin)Anti-inflammatory, anti-neuroinflammatory, and neuroprotective properties; supports gut barrier integrity and TLR4 suppression
Vitamin C (Ascorbate)Antioxidant properties; supports anti-inflammatory effects
β-CaroteneAnti-inflammatory properties; supports immune regulation
LuteinAnti-inflammatory properties; supports immune regulation
LycopeneAnti-inflammatory properties; supports immune regulation
ZeaxanthinAnti-inflammatory properties; supports immune regulation
Curcumin (Turmeric)Anti-inflammatory and neuroprotective effects; supports BDNF expression through polyphenol synergy
Hydroxytyrosol (Olive Polyphenol)Strong anti-inflammatory profile; contributes to neuroprotective effects of extra-virgin olive oil
OleocanthalNF-κB inhibition; strong anti-inflammatory effects similar to ibuprofen; contributes to neuroprotective effects of extra-virgin olive oil
OleuropeinAnti-inflammatory properties; contributes to neuroprotective effects of extra-virgin olive oil
Saffron (Crocin, Safranal)Anti-inflammatory effects
ALA (Alpha-Linolenic Acid)Essential omega-3 precursor; limited conversion to DHA/EPA; contributes to omega-3 pool for anti-inflammatory effects
DPA (Docosapentaenoic Acid)Important in vascular health, repair, and immune modulation; emerging brain-health roles (less studied than EPA and DHA)
Arachidonic Acid (AA, n-6)Omega-6 PUFA that gives rise to eicosanoids with predominantly pro-inflammatory actions; overall dietary n-6:n-3 balance affects inflammatory tone
Linoleic Acid (LA, n-6)Essential omega-6 fatty acid; precursor to arachidonic acid and eicosanoids; excessive n-6:n-3 ratios may skew toward pro-inflammatory eicosanoids
CopperParticipates in redox enzymes and antioxidant networks
ZincSupports immune signaling; gut barrier integrity disrupted by nutrient deficiencies including zinc

Mitochondrial Support

SubstanceFoodsMechanism of Action
ButyrateSupports mitochondrial function, enhancing brain energy metabolism; aids in reducing cholesterol and neuroinflammation
Short-Chain Fatty Acids (SCFAs)Butyrate supports mitochondrial function, enhancing brain energy metabolism; aids in reducing cholesterol and neuroinflammation
Urolithin ASupports mitochondrial resilience and mitophagy; improves cognitive endurance; may extend to executive function
Quercetin (and Isoquercetin)Enhances mitochondrial baseline activity and energy production; supports mitochondrial function
TaurineProtects mitochondrial function under oxidative stress; stabilizes mitochondrial membranes; supports ATP production
MagnesiumSupports enzymes involved in glycolysis and the Krebs cycle (processes that generate ATP from glucose); binds to ATP and all triphosphates in cells to activate them
Vitamin B5 (Pantothenic Acid)Forms CoA (coenzyme A), required for β-oxidation and TCA cycle acetyl-CoA flux; deficiency impairs ATP production impacting brain energy
OleuropeinOleuropein aglycone (the active form) supports mitophagy, SIRT1 activation, and AMPK activation; enhances mitochondrial function, autophagy, and neuroprotective effects through modulation of mitochondrial dynamics and antioxidant pathways
Vitamin B1 (Thiamine)Essential for mitochondrial glucose metabolism in the brain leading to ATP production; supports PDH (pyruvate dehydrogenase) and α-KGDH (alpha-ketoglutarate dehydrogenase) function
Vitamin B12 (Cobalamin)Crucial role in conversion of methylmalonyl-CoA to succinyl-CoA, a key step in mitochondrial energy production; deficiency leads to buildup of methylmalonic acid and odd-chain fatty acids, which are neurotoxic
Vitamin B2 (Riboflavin)Forms FMN/FAD coenzymes, supporting oxidative metabolism and redox balance; facilitates metabolism of B12, B6, and niacin; supports antioxidant enzymes
Coenzyme Q10 (CoQ10)Electron transport chain cofactor; supports ATP production; antioxidant protection for neurons
CreatineSupports ATP recycling via phosphocreatine system; buffers high-energy demand in neurons; enhances mitochondrial energy buffering
Capric Triglyceride (Tridecanoin)Capric triglyceride (C10) is converted to ketones (beta-hydroxybutyrate) in the liver, which serve as an alternative energy substrate for mitochondria; ketones can be used by brain mitochondria when glucose metabolism is impaired, supporting ATP production and mitochondrial function
Caproic Triglyceride (Tricaproin)Caproic triglyceride (C6) is converted to ketones (beta-hydroxybutyrate) in the liver, which serve as an alternative energy substrate for mitochondria; ketones can be used by brain mitochondria when glucose metabolism is impaired, supporting ATP production and mitochondrial function
Caprylic Triglyceride (Trioctanoin)Caprylic triglyceride (C8) is converted to ketones (beta-hydroxybutyrate) in the liver, which serve as an alternative energy substrate for mitochondria; ketones can be used by brain mitochondria when glucose metabolism is impaired, supporting ATP production and mitochondrial function
MCT (Medium-Chain Triglycerides)MCTs are converted to ketones (beta-hydroxybutyrate) in the liver, which serve as an alternative energy substrate for mitochondria; ketones can be used by brain mitochondria when glucose metabolism is impaired, supporting ATP production and mitochondrial function
IronCritical for oxygen delivery to the brain via hemoglobin; supports mitochondrial function and energy production
ManganeseSupports mitochondrial antioxidant defense through MnSOD activity
SeleniumProtects mitochondria from oxidative damage through antioxidant enzyme activity
Vitamin B3 (Niacin; Niacinamide)Replenishes NAD+, supporting oxidative phosphorylation, sirtuin signaling, and mitochondrial biogenesis; key for neuronal energy metabolism

Neurochemical Balance

SubstanceFoodsMechanism of Action
CholineEssential precursor for acetylcholine synthesis, supporting memory, learning, and neuroplasticity; supports membrane phospholipid biosynthesis (PC) which is critical for membrane fluidity and neurotransmitter receptor function; phospholipid methylation (PLM) alters membrane structure, facilitating faster neuronal recovery and influencing ion channel behavior in gamma oscillations linked to attention and cognition
GenisteinEnhances endocannabinoid activity; modulates dopamine, glutamate, and GABA signaling pathways
DHA (Docosahexaenoic Acid)Accounts for ~10–15% of total brain fatty acids, but represents 20–30% of fatty acids in neuronal phospholipids such as PE and PS, and more than 90% of the brain's omega-3 PUFA; critical for membrane fluidity, synaptic vesicle fusion, and neurodevelopment; transported across BBB as LPC-DHA via MFSD2A
EPA (Eicosapentaenoic Acid)Modulates dopamine and serotonin signalling; synergises with DHA but has independent mechanisms; membrane fluidity and neurotransmitter receptor function
Omega-3 Fatty AcidsMembrane fluidity and neurotransmitter receptor function, ion channel behavior and gamma oscillations, support neurotransmission and phospholipid methylation
PropionateStimulates secretion of norepinephrine and may influence dopamine regulation; promotes synthesis of key neurotransmitters
Short-Chain Fatty Acids (SCFAs)Propionate stimulates secretion of norepinephrine and may influence dopamine regulation; SCFAs promote synthesis of dopamine and serotonin
GlycineActs as an inhibitory neurotransmitter; improves sleep latency and quality; supports GABA pathways and neurotransmitter balance
L-TheanineSupports GABAergic tone and neurotransmitter balance
TaurineModulates calcium handling; influences GABAergic tone; supports neurotransmitter balance
Phosphatidylserine (PS)Supports neuronal membrane dynamics and signaling
CalciumEssential for nerve impulse transmission and neurotransmission
MagnesiumBroad cofactor for neurotransmitter synthesis and receptor modulation (e.g., NMDA, GABA); functions as an NMDA receptor antagonist and GABA receptor modulator; assists enzymes involved in synthesis of dopamine and serotonin
IodineThyroid hormones regulate synthesis and regulation of key neurotransmitters (dopamine and serotonin), supporting cognitive function and development
Vitamin C (Ascorbate)Supports norepinephrine synthesis; transported in brain via SVCT2
Saffron (Crocin, Safranal)Thought to boost serotonin; supports mood regulation and cognitive function
CopperCofactor in dopamine β-hydroxylase, supporting catecholamine synthesis; supports norepinephrine synthesis
ZincImportant for DNA synthesis, cell division, and neurotransmitter regulation, particularly in modulating dopamine—a key neurotransmitter implicated in ADHD; acts as an allosteric modulator of the GABA receptor; supports glutamate regulation
Vitamin B12 (Cobalamin)Supports neurotransmitter production through methylation; essential for myelin synthesis
Vitamin B6 (Pyridoxine → PLP)Cofactor for synthesis of dopamine, serotonin, GABA, and glutamate; supports rate-limiting steps in catecholamine synthesis; requires PDXK activation with magnesium and ATP support
Vitamin B9 (Folate; 5-MTHF)Supports neurotransmitter synthesis through methylation; cofactor for dopamine synthesis alongside iron, B6, and omega-3s
Capric Triglyceride (Tridecanoin)Ketones produced from capric triglyceride provide ATP through mitochondrial metabolism; ATP is essential for neurotransmitter synthesis, release, and reuptake, indirectly supporting neurochemical balance by ensuring adequate energy for neuronal function
Caproic Triglyceride (Tricaproin)Ketones produced from caproic triglyceride provide ATP through mitochondrial metabolism; ATP is essential for neurotransmitter synthesis, release, and reuptake, indirectly supporting neurochemical balance by ensuring adequate energy for neuronal function
Caprylic Triglyceride (Trioctanoin)Ketones produced from caprylic triglyceride provide ATP through mitochondrial metabolism; ATP is essential for neurotransmitter synthesis, release, and reuptake, indirectly supporting neurochemical balance by ensuring adequate energy for neuronal function
MCT (Medium-Chain Triglycerides)Ketones produced from MCTs provide ATP through mitochondrial metabolism; ATP is essential for neurotransmitter synthesis, release, and reuptake, indirectly supporting neurochemical balance by ensuring adequate energy for neuronal function
IronEssential cofactor for tyrosine hydroxylase, the rate-limiting enzyme in the conversion of tyrosine to dopamine; critical for catecholamine synthesis
TyrosolNeuroprotective effects; contributes to brain health benefits of extra-virgin olive oil
TyrosineCatecholamine precursor (dopamine, norepinephrine); brain transport via LAT1 competes with other LNAAs; iron is an essential cofactor for tyrosine hydroxylase, the rate-limiting enzyme in conversion of tyrosine to dopamine; cofactors include iron, B6, folate, omega-3s, and BH₄ (tetrahydrobiopterin) to support rate-limiting steps in catecholamine synthesis
PhenylalanineEssential amino acid that converts to tyrosine and supports catecholamine synthesis (dopamine, norepinephrine); participates in LAT1 competition at the blood-brain barrier
TryptophanPrecursor for serotonin and melatonin; brain entry competes at LAT1 with other large neutral amino acids (LNAAs); carbohydrate-rich, low-protein meals raise the plasma tryptophan:LNAA ratio because insulin pushes competing LNAAs out to muscles; can feed NAD+ synthesis via the kynurenine pathway
Phosphatidylcholine (PC)Major neuronal membrane phospholipid central to membrane fluidity, receptor function, and acetylcholine synthesis; DHA/EPA incorporated into PC are converted to lysophosphatidylcholine (LPC), a key transport form across the BBB
PotassiumCritical for membrane potential, nerve signaling, and neuronal excitability; adequate intake balances sodium effects
SodiumSupports fluid balance, nerve impulse transmission, and muscle function; balance with potassium is relevant for blood pressure and neuronal excitability

Oxidative Stress

SubstanceFoodsMechanism of Action
GenisteinPrevents neuronal death; increases hippocampal glutathione (GSH) and superoxide dismutase (SOD); lowers lipid peroxidation, ROS, and nitric oxide production
Omega-3 Fatty Acids
EGCG (Green Tea Catechin)Supports antioxidant defenses; part of antioxidant network
ButyrateEnhances mitochondrial function during oxidative stress; supports antioxidant activity
Short-Chain Fatty Acids (SCFAs)Support antioxidant activity; butyrate enhances mitochondrial function during oxidative stress
Urolithin APowerful antioxidant; supports antioxidant defenses
Quercetin (and Isoquercetin)Effective antioxidant agent that scavenges reactive oxygen species; supports antioxidant defenses
Vitamin C (Ascorbate)Key water-soluble antioxidant; works within antioxidant network with vitamin E, CoQ10, and polyphenols
β-CaroteneAntioxidant properties; scavenges reactive oxygen species and stabilizes cell membranes
LuteinAntioxidant properties; scavenges reactive oxygen species and stabilizes cell membranes
LycopeneAntioxidant properties; scavenges reactive oxygen species and stabilizes cell membranes
ZeaxanthinAntioxidant properties; scavenges reactive oxygen species and stabilizes cell membranes
Curcumin (Turmeric)Antioxidant properties; supports antioxidant defenses
Hydroxytyrosol (Olive Polyphenol)Potent antioxidant polyphenol; supports antioxidant defenses
OleuropeinAntioxidant polyphenol; works within the polyphenol network in olive oil
Saffron (Crocin, Safranal)Contains antioxidant crocin; supports antioxidant defenses
ALA (Alpha-Linolenic Acid)Essential omega-3 fatty acid; contributes to antioxidant and membrane support
Arachidonic Acid (AA, n-6)Contributes to inflammatory and oxidative stress pathways when in excess relative to omega-3s
Linoleic Acid (LA, n-6)Essential fatty acid; balance with omega-3s is emphasized for optimal inflammatory tone
CopperIncluded in antioxidant enzyme networks; interacts with iron metabolism affecting oxidative stress
ZincEssential mineral that serves as a cofactor for antioxidant enzymes; works synergistically with other antioxidants; heavy metals are detoxified by metallothionein (MT) metal carrier proteins that must bind with zinc and copper
Coenzyme Q10 (CoQ10)Part of antioxidant network; works synergistically with vitamin E, vitamin C, lipoic acid, and glutathione
ManganeseEssential cofactor for MnSOD (SOD2), supporting detoxification of superoxide within the mitochondrial matrix
SeleniumSupports glutathione peroxidase (GPx) and other antioxidant systems, protecting membranes and mitochondria from oxidative damage
TyrosolAntioxidant properties; supports antioxidant defenses
OleaceinAntioxidant properties; activates NRF2 pathway; supports antioxidant defenses and neuroprotection
Vitamin A (Retinoids; β-Carotene precursor)Provitamin A carotenoids (β-carotene) act as antioxidants in neural tissue; contribute to antioxidant network
Vitamin E (Tocopherols/Tocotrienols)Lipid-phase antioxidant; protects polyunsaturated fatty acids in membranes from peroxidation; works within antioxidant network with vitamin C, CoQ10, and polyphenols

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