Orthomolecular Interventions
Orthomolecular interventions are nutrients and actions that promote health by supporting the body’s specific biochemical needs.
Beneficial dietary approaches
Dietary approaches influence many of the biological processes involved in Alzheimer’s disease and cognitive decline. They have actions that support brain health and can help reduce the risk and progression of cognitive decline.
Actions of the Mediterranean diet in preventing and addressing Alzheimer’s disease include:
- improving cardiovascular health – which reduces the risk of Alzheimer’s disease and related dementias (Ellouze et al., 2023)
- improving cerebral blood flow – which enhances oxygen and nutrient delivery to the brain and supports healthy cognitive aging (Ellouze et al., 2023)
- improving mitochondrial function – which supports neuronal energy production and healthy brain aging (Ellouze et al., 2023)
- reducing oxidative stress and neuroinflammation (Ellouze et al., 2023; Chu et al., 2022)
- supporting neurogenesis and neuronal survival (Chu et al., 2022)
- providing neuroprotective nutrients – which support multiple pathways involved in brain health (Chu et al., 2022) including:
- B vitamins
- antioxidants
- polyphenols (plant compounds)
- omega-3 fatty acids
Actions of intermittent fasting in preventing and addressing Alzheimer’s disease include:
- promoting the transition to ketone metabolism – which provides an alternative energy source for neurons when cerebral glucose availability is reduced (Elias et al., 2023)
- suppressing inflammatory signalling pathways and lowering pro-inflammatory cytokine production (Chu et al., 2022)
- reducing oxidative stress (Elias et al., 2023)
- activating cellular stress-response pathways – which enhances antioxidant defenses, DNA repair, and cellular resilience (Elias et al., 2023)
- suppressing mTOR signalling – which enhances cellular resilience and improves mitochondrial function and ATP production (Chu et al., 2022)
- improving mitochondrial function – which increases ATP production and supports neuronal energy metabolism (Chu et al., 2022)
- increasing autophagy – which removes damaged proteins and cellular components that contribute to Alzheimer’s pathology (Chu et al., 2022)
- reducing amyloid accumulation – through β-hydroxybutyrate-mediated effects on gene regulation and amyloid-related cellular pathways (Chu et al., 2022)
- enhancing synaptic plasticity and hippocampal neurogenesis (Chu et al., 2022)
- modulating the gut microbiome – which improves neurotransmitter balance in the brain (Chu et al., 2022)
Actions of a ketogenic diet in preventing and addressing Alzheimer’s disease include:
- providing ketone bodies as an alternative brain fuel – which improves neuronal energy production when cerebral glucose metabolism is impaired (Castro et al., 2023)
- reducing neuroinflammation – which helps limit inflammation-induced blood–brain barrier breakdown by (Chu et al., 2022; Norwitz et al., 2021):
- activating PPAR-γ (a receptor that regulates genes involved in metabolism, inflammation, and cellular function)
- suppressing NF-κB signalling
- reducing the production of pro-inflammatory cytokines
- improving mitochondrial function – which increases ATP production and activates antioxidant pathways that reduce oxidative stress (Chu et al., 2022)
- supporting synaptic maintenance – which helps preserve communication between neurons and supports cognitive function (Lilamand et al., 2021)
- decreasing amyloid deposition, enhancing amyloid clearance, reducing amyloid toxicity, and limiting tau-related pathology (Chu et al., 2022; Lilamand et al., 2021)
- supporting neuronal growth and repair – through ketone-mediated changes in gene expression that increase BDNF production and support learning and memory (Norwitz et al., 2021; Chu et al., 2022)
Vitamin B1 (Thiamine)
Actions of vitamin B1 in preventing and addressing Alzheimer’s disease include:
- supporting activity of thiamine-dependent enzymes involved in glucose metabolism – which helps maintain ATP production and mitochondrial function, reducing neuronal energy deficits (Fessel, 2021; Peres et al., 2022; Gibson et al., 2016)
- supporting acetyl-CoA (a key metabolic molecule) production – which supports ATP production and may support acetylcholine neurotransmission (Fessel, 2021; Gibson et al., 2016)
Benfotiamine
Benfotiamine is a fat-soluble derivative of vitamin B1 (thiamine) that is absorbed more efficiently than thiamine and produces higher, longer-lasting thiamine levels in the body.
Actions of benfotiamine reported in human clinical studies and supported by animal studies include (Gibson et al., 2020; Pan et al., 2010):
- reducing cognitive decline in people with mild Alzheimer’s disease (Gibson et al., 2020)
- reducing amyloid-β plaque formation and tau phosphorylation – by suppressing glycogen synthase kinase-3 (GSK-3) activity (Pan et al., 2010)
Vitamin B3 (Niacin)
The active biologically active forms of vitamin B3, together with related NAD⁺ precursors, help maintain cellular levels of nicotinamide adenine dinucleotide (NAD⁺). NAD⁺ is an essential coenzyme involved in cellular energy production, DNA repair, antioxidant defence, and other processes that help maintain brain health.
The different forms of vitamin B3 and related NAD⁺ precursors do not all act through the same mechanisms:
- Nicotinic acid (niacin) → increases NAD⁺ and activates HCAR2
- Nicotinamide → increases NAD⁺ but has little or no HCAR2 activation
- Nicotinamide riboside (NR) and NMN → primarily increase NAD⁺ without HCAR2 activation
Increasing intracellular NAD⁺ supports processes involved in neuronal health, including:
- supporting mitochondrial health and energy production (Linus Pauling Institute, 2018)
- supporting cellular energy metabolism (Linus Pauling Institute, 2018)
- acting as a mitochondrial antioxidant (Morris et al., 2004)
- supporting DNA repair (Linus Pauling Institute, 2018; Morris et al., 2004)
- supporting calcium homeostasis (Linus Pauling Institute, 2018; Morris et al., 2004)
- supporting myelination and dendritic growth (Morris et al., 2004)
Activating HCAR2
HCAR2 is a receptor expressed on immune cells, including brain microglia. Activation by niacin (nicotinic acid) helps regulate neuroinflammation, promotes amyloid-β clearance, and may help reduce neuronal loss (Moutinho et al., 2020).
Vitamin B6, folate, and vitamin B12
Vitamin B6, folate, and vitamin B12 work together to keep homocysteine levels in balance through different but complementary processes.
Combined actions of vitamin B6, folate, and vitamin B12 in preventing and addressing Alzheimer’s disease include:
- supporting methionine cycle (a biochemical pathway that recycles methionine) function – by enabling the reactions that recycle homocysteine and regenerate methionine, which supports methylation-dependent brain function (Gregory et al., 2016; Smith et al., 2018; Zhang et al., 2021; El-Mezayen et al., 2022)
- supporting homocysteine metabolism – by converting it to methionine (folate, vitamin B12) or into cysteine (vitamin B6), which helps reduce homocysteine-associated vascular and neuronal damage (Gregory et al., 2016; Smith et al., 2018; Zhang et al., 2021; El-Mezayen et al., 2022)
- supporting methylation reactions – which help maintain normal DNA methylation, gene regulation, neuronal function, and brain health (Zhang et al., 2021; El-Mezayen et al., 2022)
Other actions of vitamin B6 in preventing and addressing Alzheimer’s disease include:
- Serving as a cofactor (a helper molecule that helps enzymes work) in the synthesis and metabolism of neurotransmitters – including serotonin, dopamine, norepinephrine, GABA, glutamate, glycine, D-serine, and histamine (Kennedy, 2016).
- maintaining excitatory–inhibitory neurotransmission (balancing stimulating and calming signals) – by enabling the conversion of glutamate into GABA (Kennedy, 2016)
- Supporting glutathione synthesis by helping convert homocysteine into cysteine, a key building block of glutathione (Gregory et al., 2016)
Other actions of folate in preventing and addressing Alzheimer’s disease include:
- supporting DNA methylation – which influences Alzheimer’s disease-related gene regulation (Zhang et al., 2021)
- reducing oxidative stress – which protects neurons from oxidative injury (Zhang et al., 2021)
- Reducing amyloid-β production and the buildup of amyloid plaques in the brain – by regulating the activity of the enzymes β-secretase and γ-secretase (Fuso et al., 2007; Zhang et al., 2021).
- inhibiting tau phosphorylation – by modulating kinase and phosphatase activity (Sontag and Sontag, 2014; Zhang et al., 2021)
Other actions of vitamin B12 in preventing and addressing Alzheimer’s disease include:
- maintaining blood–brain barrier integrity – by reducing homocysteine-associated vascular injury (El-Mezayen et al., 2022)
- protecting mitochondria from oxidative stress and amyloid-β toxicity – by scavenging reactive oxygen species (highly-reactive oxygen-containing molecules), preserving glutathione, and preventing mitochondrial dysfunction (Lauer et al., 2022)
- regulating calcium signalling – which protects neurons from amyloid-β-induced oxidative injury (Lauer et al., 2022)
- reducing amyloid-related damage – by preventing amyloid-β from forming harmful clumps and helping break up existing deposits (Lauer et al., 2022; Wang et al., 2023)
- reducing tau-related damage – by preventing tau proteins from clumping together into tangles inside brain cells (Lauer et al., 2022)
- reducing neuroinflammation – by modulating inflammatory cytokine activity (El-Mezayen et al., 2022; Lauer et al., 2022)
- supporting neurotransmitter production, myelin formation, and neuronal communication – which helps maintain and repair neural structures (Lauer et al., 2022)
Vitamin C
Actions of vitamin C in preventing and addressing Alzheimer’s disease include:
- reducing oxidative stress – by:
- scavenging reactive oxygen species, which decreases oxidative damage to neurons (Dey & Singh, 2022; Marino et al., 2023)
- increasing antioxidant capacity, which protects lipids, proteins, and DNA from injury (Marino et al., 2023)
- binding reactive metals – which decreases free radical formation (Marino et al., 2023)
- reducing oxidative stress in mitochondria – which supports mitochondrial function and neuronal survival (Marino et al., 2023)
- suppressing neuroinflammation – by:
- modulating microglial activation, which reduces pro-inflammatory signalling (Marino et al., 2023)
- protecting synapses and neurons from inflammatory damage (Hamid et al., 2022)
- reducing amyloid-β production – by influencing APP processing and suppressing BACE-1 activity, which decreases amyloid-β generation (Marino et al., 2023; Hamid et al., 2022)
- inhibiting amyloid-β fibril formation – which:
- reduces amyloid aggregation (Heo et al., 2013; Marino et al., 2023)
- lowers neuronal toxicity (Heo et al., 2013)
- enhancing cholinergic neurotransmission – by reducing acetylcholinesterase activity (Heo et al., 2013)
- supporting norepinephrine synthesis – which supports attention, mood, and stress response (Hamid et al., 2022)
- regulating glutamate signalling – which reduces excitotoxic neuronal injury (Marino et al., 2023)
- modulating NMDA receptor activity – which stabilizes synaptic signalling (Marino et al., 2023)
- preserving nitric oxide – by scavenging superoxide, a highly reactive oxygen species, thereby improving endothelial function (Marino et al., 2023)
- reducing peroxynitrite formation (a highly reactive molecule formed when superoxide reacts with nitric oxide) – by preserving nitric oxide and lowering oxidative stress (Marino et al., 2023).
- maintaining healthy cerebral blood vessels – by reducing endothelial dysfunction and oxidative injury (Marino et al., 2023; Heo et al., 2013)
- improving nitric oxide signalling – which increases cerebral blood flow (Heo et al., 2013)
- preventing oxidative damage to LDL cholesterol – which helps reduce inflammation and injury to blood vessels (Marino et al., 2023)
- strengthening blood–brain barrier integrity – which limits toxin and immune cell entry (Heo et al., 2013; Marino et al., 2023)
- supporting myelination and neuronal function – by supporting myelin formation and regulating gene expression through DNA demethylation (Marino et al., 2023)
- protecting against aluminum-induced neurotoxicity – by reducing oxidative damage associated with aluminum exposure (Dey & Singh, 2022)
Vitamin D
Actions of vitamin D in preventing and addressing Alzheimer’s disease include:
- suppressing pro-inflammatory signalling – by reducing pro-inflammatory cytokines and NF-κB activation, which decreases chronic brain inflammation, microglial overactivation, and neuronal damage (Cekic et al., 2009; Kouba et al., 2023)
- enhancing anti-inflammatory signalling – by increasing IL-10, IL-4, and TGF-β, which promotes the resolution of chronic neuroinflammation (Kouba et al., 2023)
- reducing oxidative stress – by enhancing antioxidant defenses, reducing reactive oxygen species, and activating Nrf2 signalling (Cekic et al., 2009; Kouba et al., 2023)
- reducing amyloid-β buildup – by decreasing its production and helping the brain clear it away (Kouba et al., 2023; Lasoń et al., 2023)
- reducing harmful tau buildup – by decreasing the formation of tau tangles, which helps slow damage to brain cells (Thiel et al., 2023)
- reducing intracellular calcium overload – which prevents excitotoxic neuronal death (Chakkera et al., n.d.)
- increasing neurotrophic factor expression (e.g., glial cell line-derived neurotrophic factor GDNF) – which:
- promotes neuronal growth and survival, and supports repair after injury (Cekic et al., 2009; Lasoń et al., 2023)
- reduces apoptosis, which preserves neuronal integrity and slows neurodegeneration (Lasoń et al., 2023)
- supporting myelination and neuronal proliferation (Lasoń et al., 2023)
- regulating neurotransmitter synthesis and signalling – by:
- modulating neurotransmitter activity and balance (Thiel et al., 2023)
- supporting synaptic plasticity and communication between neurons (Kouba et al., 2023)
- contributing to improved cognitive function and neuronal signalling (Thiel et al., 2023)
Vitamin E
Actions of vitamin E in preventing and addressing Alzheimer’s disease include:
- scavenging free radicals and reducing lipid peroxidation in neuronal membranes (Browne et al., 2019)
- activating Nrf2 signalling – which enhances endogenous (produced within the body) antioxidant defenses (Wang et al., 2023)
- protecting neurons from amyloid-β–induced oxidative damage (Ayoub et al., 2023; Wang et al., 2023)
- regulating genes involved in oxidative stress and inflammation (Boccardi et al., 2016)
- inhibiting COX and 5-LOX pathways – which decreases production of prostaglandins (signalling molecules) and inflammatory signalling (Lloret et al., 2019; Boccardi et al., 2016)
- increasing the production of IL-2 (an immune signalling protein that regulates T-cell activity) – which supports immune regulation (Lloret et al., 2019)
- strengthening the blood–brain barrier – by reducing oxidative damage in the cells lining blood vessels, increasing the proteins that keep the barrier tightly sealed (tight junctions), and restoring blood–brain barrier function after amyloid-β damage (Lam et al., 2016; Ayoub et al., 2023)
- supporting the conditions required for effective autophagy (cellular cleanup and recycling process) – which may reduce amyloid-β accumulation (Wang et al., 2023)
- reducing amyloid-β accumulation – by increasing amyloid-β clearance, reducing its production, and protecting against amyloid-induced toxicity (Ayoub et al., 2023; Wang et al., 2023)
- supporting the activity of PP2A (an enzyme that removes excess phosphate groups from proteins) – which helps maintain normal tau regulation (Boccardi et al., 2016)
- supporting cholesterol metabolism – by protecting LDL and membrane cholesterol from oxidative damage (Boccardi et al., 2016)
Choline
Choline is an essential nutrient.
Actions of choline in preventing and addressing Alzheimer’s disease include:
- increasing acetylcholine production – which supports memory formation, attention, and cognitive processing
- maintaining neuronal membrane integrity – by supporting phospholipid synthesis, which preserves membrane structure and signalling (Paules et al., 2025)
- decreasing pro-inflammatory signalling in the brain – by reducing microglial activation (Dave et al., 2023)
- reducing insulin resistance in the brain – which supports normal insulin signalling (Dave et al., 2023)
- supporting methylation – which lowers homocysteine levels and reduces vascular damage (Choline | Linus Pauling Institute, 2014)
Chromium
Actions of chromium in preventing and addressing Alzheimer’s disease include:
- increasing insulin sensitivity (Akhtar & Sah, 2023) – which improves glucose uptake into neurons and supports cellular energy production
- modulating GSK-3β activity – which may decrease tau phosphorylation and reduce neurofibrillary tangle formation (Akhtar & Sah, 2023)
- downregulating the NF-κB pathway – which decreases pro-inflammatory cytokine production, resulting in (Akhtar & Sah, 2023):
- reduced activation of microglia and astrocytes
- decreased chronic neuroinflammation that drives neuronal damage
- decreasing oxidative stress and lipid peroxidation – which (Akhtar & Sah, 2023):
- stabilizes mitochondrial membrane potential (the electrical charge across the mitochondrial membrane that is needed to produce ATP)
- improves mitochondrial function
- protects neuronal membranes
- enhances neuronal survival
Magnesium
Actions of magnesium in preventing and addressing Alzheimer’s disease include:
- modulating inflammatory signalling – low magnesium status increases inflammation, while adequate magnesium helps reduce pro-inflammatory activity (Magnesium | Linus Pauling Institute, 2024)
- enabling glutathione synthesis – which increases antioxidant capacity, and protects lipids, proteins, and DNA (Magnesium | Linus Pauling Institute, 2024)
- improving insulin sensitivity – by helping cells respond better to insulin and use glucose more effectively, which improves glucose uptake and overall energy regulation (Hosseini Dastgerdi et al., 2022)
- supporting ATP production – by acting as a cofactor for ATP synthesis and forming Mg-ATP, the biologically active form of cellular energy (Magnesium | Linus Pauling Institute | Oregon State University, 2014)
- regulating NMDA receptors – by controlling how much calcium enters nerve cells during signalling and closing the channels after activation (Ben Zaken et al., 2020)
- supporting synaptic plasticity, learning, and memory – by maintaining normal NMDA receptor signalling during excitatory neurotransmission (Ben Zaken et al., 2020)
- reducing glutamate-driven excitotoxicity – which decreases neuronal overstimulation, calcium overload, and neuronal degeneration (Tao et al., 2022)
- improving endothelial function – by regulating nitric oxide production and endothelial cell activity, which supports vascular function and blood flow (Fatima et al., 2024)
Selenium
- enabling the activity of antioxidant selenoenzymes (e.g., glutathione peroxidase and thioredoxin reductase) – which scavenge reactive oxygen species; reduce lipid, protein, and DNA damage; and protect neurons from oxidative injury and death (Gireadă et al., 2022; Pereira et al., 2022)
- reducing pro-inflammatory cytokine signalling – which suppresses neuroinflammation (Pereira et al., 2022; Gireadă et al., 2022).
- supporting mitochondrial function – by increasing ATP production and reducing mitochondrial reactive oxygen species (Zhang et al., 2023)
- reducing the interaction of copper and iron with amyloid-β – which decreases amyloid toxicity (Gireadă et al., 2022; Zhang et al., 2023)
- decreasing β-secretase and γ-secretase activity – which reduces amyloid-β production (Gireadă et al., 2022; Zhang et al., 2023)
- inhibiting the activity of the enzyme GSK-3β – which decreases tau hyperphosphorylation and neurofibrillary tangle formation (Gireadă et al., 2022; Zhang et al., 2023)
- reducing tau aggregation – through the activity of intracellular antioxidant selenoenzymes (including glutathione peroxidase and thioredoxin reductase) (Gireadă et al., 2022)
- activating FoxO signalling pathways – which support memory consolidation and synaptic function (Zhang et al., 2023)
- enhancing synaptic function – by increasing the expression of synaptic proteins involved in synapse structure and signalling (including PSD95 and synaptophysin), thereby supporting communication between neurons (Zhang et al., 2023)
Zinc
Actions of zinc in preventing and addressing Alzheimer’s disease include:
- supporting antioxidant enzyme activity – by serving as a cofactor for copper-zinc superoxide dismutase (Cu/Zn SOD), which reduces oxidative damage to neurons (Zinc | Linus Pauling Institute | Oregon State University, 2014)
- reducing amyloid-β buildup – by decreasing its formation and supporting zinc-dependent enzymes that help break down and clear amyloid-β (Rivers-Auty et al., 2021)
- promoting neuronal survival and synaptic plasticity – by supporting zinc-dependent enzymes such as MMP-9 (Rivers-Auty et al., 2021) that activate brain-derived neurotrophic factor (BDNF)
- supporting copper-zinc balance – which helps limit inflammation and oxidative stress associated with neurodegenerative processes (Escobedo-Monge et al., 2021)
Omega-3 fatty acids
Actions of omega-3 fatty acids in preventing and addressing Alzheimer’s disease include:
- reducing oxidative stress (Huang et al., 2022)
- suppressing neuroinflammation – by reducing pro-inflammatory cytokines and microglial activation (Huang et al., 2022)
- reducing thrombosis (blood clot formation) – which may improve cerebral blood flow and oxygen delivery to brain tissue (Huang et al., 2022)
- promoting neurogenesis – which supports neuronal repair and brain function (Huang et al., 2022)
- enhancing macrophage energy production and phagocytosis – which promotes immune-mediated clearance of amyloid-beta and cellular debris (Lau et al., 2020)
- promoting AQP4-mediated glymphatic clearance – which enhances removal of amyloid-beta from the brain (Lau et al., 2020)
- supporting proteostasis – the process which maintains protein quality control and reduces the accumulation of misfolded proteins, including amyloid-beta (Lau et al., 2020)
Short-chain fatty acids
Short-chain fatty acids (SCFAs) are produced primarily in the large intestine when beneficial bacteria ferment dietary fibre and resistant starches.
The three principal short-chain fatty acids—acetate, propionate, and butyrate—influence several processes important for brain health. Although each have supportive actions, butyrate has shown the strongest evidence for therapeutic potential in neurodegenerative disorders (Chakraborty et al., 2024).
Actions of short-chain fatty acids in preventing and addressing Alzheimer’s disease include:
- suppressing neuroinflammation – by (Fernando et al., 2019; Chen et al., 2022):
- activating GPR43 (FFAR2) and FFAR3 receptors
- reducing microglial activation
- decreasing inflammatory cytokine production
- shifting microglia toward an anti-inflammatory state
- promoting the resolution of inflammation – by increasing regulatory T cells (immune cells that calm inflammation) and removing neutrophils (inflammatory immune cells) when they are no longer needed (Chen et al., 2022)
- strengthening the blood–brain barrier – by increasing tight junction proteins and reducing inflammation and oxidative stress (Chen et al., 2022)
- suppressing pathways involved in amyloid-beta formation – which decreases plaque development (Chen et al., 2022)
- enhancing the intestinal hormone glucagon-like peptide-1 (GLP-1) signalling – which supports neuronal survival and helps protect neurons from amyloid-beta toxicity (Chen et al., 2022)
- improving glucose metabolism and mitochondrial function – which increases cellular energy production and reduces metabolic stress (Chen et al., 2022)
- inhibiting histone deacetylases (enzymes) – which restores expression of genes involved in neuronal survival, learning, and memory (Chen et al., 2022)
- increasing the expression of BDNF and GDNF (neurotrophic signalling proteins) – which supports synaptic function, memory, and neuronal survival (Fernando et al., 2019; Chen et al., 2022)
Medium-chain fatty acids
Medium-chain fatty acids (MCFAs) are saturated fatty acids typically containing 6–12 carbon atoms, and include caproic acid, caprylic acid, capric acid, and lauric acid.
Compared with long-chain fatty acids, MCFAs are absorbed and metabolized more rapidly due to their shorter chain length.
Actions of medium-chain fatty acids in preventing and addressing Alzheimer’s disease include:
- increasing ketone availability to the brain – by generating ketone bodies that bypass impaired cerebral glucose metabolism and provide an alternative fuel for neuronal ATP production (Castro et al., 2023)
- improving mitochondrial function – by helping mitochondria produce energy more efficiently and supporting the brain’s energy needs (Castro et al., 2023)
- protecting against oxidative stress – by limiting oxidative damage to lipids, proteins, and DNA (Castro et al., 2023)
- suppressing neuroinflammation – by reducing microglial activation and pro-inflammatory cytokine production (Lilamand et al., 2021)
Acetyl-L-carnitine (ALCAR)
Acetyl-L-carnitine (ALCAR) is a naturally occurring compound formed from acetyl-CoA and L-carnitine.
ALCAR is commonly used in neurological and metabolic contexts due to its ability to cross the blood–brain barrier and participate in mitochondrial energy metabolism (Bigio et al., 2024).
Actions of ALCAR in preventing and addressing Alzheimer’s disease include:
- increasing neuronal ATP production – which improves cellular function and helps counter the energy deficits associated with Alzheimer’s disease (Pennisi et al., 2020)
- stabilizing neuronal membranes and synapses – which improves membrane function, enhances communication between neurons, and supports cognitive processing (Pennisi et al., 2020)
- improving acetylcholine signalling – which supports memory, learning, attention, and cognitive function (Pennisi et al., 2020)
- supporting neuronal growth and survival – by enhancing neurotrophic signalling (Pennisi et al., 2020)
- reducing oxidative stress – which helps protect neurons from free radical damage and neurodegeneration (Pennisi et al., 2020)
- reducing excitotoxicity – which helps protect neurons from degeneration (Pennisi et al., 2020)
Alpha-lipoic acid
Alpha-lipoic acid (ALA) is a naturally occurring compound synthesized in human mitochondria and functions as a cofactor in key enzymatic reactions involved in energy metabolism.
Actions of alpha-lipoic acid in preventing and addressing Alzheimer's disease include:
- removing harmful reactive oxygen species (ROS) and binding metal ions – which reduces oxidative stress and inhibits the formation of highly damaging hydroxyl radicals (Lam et al., 2016; Dey & Singh, 2022)
- supporting glutathione-dependent antioxidant defenses – by increasing reduced glutathione levels, which enhances protection against oxidative damage (Brown, 2017; Lam et al., 2016)
- suppressing neuroinflammation – which helps reduce ongoing neuronal damage (Brown, 2017; Lam et al., 2016)
- preserving blood–brain barrier integrity – by reducing oxidative stress and neuroinflammation (Lam et al., 2016)
- supporting mitochondrial function and cellular energy production (Brown, 2017)
- improving communication between brain cells – by increasing the production of acetylcholine (a neurotransmitter important for learning and memory) and enhancing its signalling (Dey & Singh, 2022; Brown, 2017; Lam et al., 2016)
Curcumin
Curcumin is a substance that comes from the plant Curcuma longa – which is commonly called commonly called turmeric.
Actions of curcumin in preventing and addressing Alzheimer’s disease include:
- protecting neurons from oxidative stress – by activating the Nrf2/ARE pathway (which switches on the body’s antioxidant defenses), and increasing the production of protective antioxidants (Wang et al., 2023)
- regulating nitric oxide signalling – which reduces oxidative injury and supports neuronal survival (Wang et al., 2023)
- enhancing DNA repair – which limits cumulative neuronal damage (Wang et al., 2023)
- maintaining healthy calcium levels inside brain cells – which helps prevent calcium overload, reduces damage caused by overactive nerve signalling, and protects brain cells (Wang et al., 2023)
- inhibiting the formation of neurofibrillary tangles and BACE1 activity – which reduces amyloid plaque development and amyloid-induced neurotoxicity (Dey & Singh, 2022; Wang et al., 2023)
- suppressing GSK3β activity – which further limits the formation of neurofibrillary tangles (Wang et al., 2023)
Melatonin
Actions of melatonin in preventing and addressing Alzheimer’s disease include:
- scavenging free radicals, reducing lipid peroxidation, and enhancing endogenous antioxidant defenses – which limits oxidative neuronal injury (Dey & Singh, 2022; Rao et al., 2023)
- preserving mitochondrial function – which supports neuronal energy production and helps maintain normal cellular function (Lam et al., 2016; Rao et al., 2023)
- inhibiting NF-κB signalling, reducing pro-inflammatory cytokine production, and suppressing astrocyte activation – which limits inflammatory neuronal damage (Roy et al., 2022)
- maintaining blood–brain barrier integrity – which limits the entry of toxins and inflammatory molecules into the brain (Lam et al., 2016)
- inhibiting amyloid-β production and aggregation – which reduces plaque formation and amyloid-induced neurotoxicity (Dey & Singh, 2022; Roy et al., 2022)
- modulating GSK-3β and PP2A activity – which limits neurofibrillary tangle formation (Dey & Singh, 2022; Roy et al., 2022)
- regulating apoptosis pathways – which decreases programmed neuronal death (Roy et al., 2022; Lam et al., 2016)
- promoting neuroplasticity and synaptic plasticity – by improving dendritic structure, neuronal morphology, and synaptic density (Roy et al., 2022)
Resveratrol
Resveratrol is a natural plant compound (a phytochemical) found in a variety of plant foods.
Actions of resveratrol in preventing and addressing Alzheimer’s disease include:
- activating the enzyme SIRT-1 – which contributes to improved cerebrovascular function and suppresses pro-inflammatory signalling (Xu Lou et al., 2023; Dhapola et al., 2023)
- activating the enzyme AMPK – which supports cellular energy metabolism (Dhapola et al., 2023)
- inhibiting the NLRP3 inflammasome and reducing microglial and astrocyte activation (Norwitz et al., 2021) – which helps limit chronic neuroinflammation, neuronal damage, and synaptic dysfunction
- improving cerebrovascular function and reducing vascular inflammation (Xu Lou et al., 2023)
- improving cellular energy metabolism – by supporting healthy glucose metabolism, increasing neuronal energy availability, and reducing metabolic stress associated with cognitive decline (Dhapola et al., 2023)
- protecting neurons in people with the APOE ε4 genetic variant – by helping prevent metabolic crisis when both glucose and lipid metabolism are impaired (Norwitz et al., 2021)
Probiotics
Probiotics are specific live bacteria and yeasts that have beneficial effects on the body.
Actions of probiotics in preventing and addressing Alzheimer’s disease include:
- regulating gut microbiota composition – which suppresses systemic inflammation through the gut-brain axis and may reduce amyloid-β accumulation (Bhratee et al., 2023; Romanenko et al., 2021)
- strengthening gut barrier integrity – which reduces intestinal permeability (Romanenko et al., 2021)
- supporting short-chain fatty acid (SCFA) production by supporting a healthy balance of gut bacteria (Romanenko et al., 2021)
- regulating cognition-related nutrients and the metabolism of dietary polyphenols – which supports brain health and delays neurodegeneration (Romanenko et al., 2021)
- increasing production of neurotransmitters such as GABA and influencing vagal and endocrine signalling – which supports cognitive function (Bhratee et al., 2023)
- regulating BDNF, dopamine, serotonin, and GABA – which supports neuronal survival, synaptic plasticity, cognitive function, and behaviour (Maccioni et al., 2022)
- enhancing insulin sensitivity and lipid metabolism – which supports cerebral energy metabolism and cognitive function (Vinuesa et al., 2021)
Coenzyme Q10 (CoQ10)
CoQ10 is a mitochondrial cofactor and lipid-soluble antioxidant that plays an essential role in cellular energy production.
Actions of CoQ10 in preventing and addressing Alzheimer’s disease include (Fišar & Hroudová, 2024; Bagheri et al., 2023):
- supporting mitochondrial electron transport and ATP production – which helps maintain cellular energy levels.
- preserving mitochondrial integrity – by protecting mitochondrial membranes and promoting the formation of new mitochondria
- reducing oxidative stress – by scavenging reactive oxygen species, limiting lipid peroxidation, and regenerating vitamin E
- maintaining healthy calcium levels inside brain cells – which helps keep mitochondria functioning properly and protects brain cells from damage and death.
- reducing neuroinflammation
- reducing neuronal apoptosis
- supporting cholinergic neurotransmission
- supporting autophagy – which may facilitate the removal of damaged cellular components and protein aggregates
- reducing amyloid-β and tau pathology
These orthomolecular interventions are intended to support the body’s natural biochemical processes by addressing nutritional deficiencies, reducing oxidative stress, supporting mitochondrial function, and promoting healthy brain function.
The Basic First Steps section highlights the foundational lifestyle and dietary strategies that form the basis of a comprehensive approach to supporting brain health.
