Contributing factors

Contributing factors are substances, contexts, or conditions that have roles in the causation or promotion of Alzheimer’s disease.

Diet and food components

Diet is commonly considered the most important determinant of health and disease. An unhealthy diet can promote Alzheimer’s disease by driving the core mechanisms of the disease progression.

Key ways diet and food components promote Alzheimer’s disease:

Refined carbohydrates and high glycemic load foods (sugar, white flour products, sweetened beverages)

These foods act by:

• increasing blood glucose and insulin levels (Kanoski & Davidson, 2011; Beeri et al., 2008)
• increasing oxidative stress and inflammation (Kanoski & Davidson, 2011)
• impairing blood–brain barrier function – which allows inflammatory molecules greater access to the brain (Kanoski & Davidson, 2011)
• increasing advanced glycation end products (AGEs) – which promotes amyloid-β aggregation and AGE-mediated modification of tau that favours neurofibrillary tangle formation (Li et al., 2012).

Industrial seed oils (soybean, corn, sunflower oils)

These oils (e.g. soybean, corn and sunflower oils) are rich in linoleic acid. Excessive dietary linoleic acid may increase formation of oxidized linoleic acid metabolites which:

• promote lipid peroxidation (oxidative damage to fats), inflammation and mitochondrial dysfunction (Taha, 2020).
• alter neuronal cell membrane composition – which disrupts receptor signalling and impairing synaptic function (Grimm et al., 2013).

Trans fats (margarine, processed baked goods, fried fast foods),

These fats act by:

• disrupting cell membrane structure (Morris et al., 2003)
• increasing systemic inflammation (Kalmijn et al., 1997)
• promoting increased amyloid deposition (Morris et al., 2003)

Ultra-processed foods (packaged snacks, processed meats, ready meals, additives)

These foods are associated with accelerated cognitive decline in cohort studies (Monteiro et al., 2019; Srour et al., 2019). They are often a combination refined carbohydrates, seed oils, additives and chemicals which:

• increase inflammation and oxidative stress (Srour et al., 2019)
• disrupt gut microbiota (dysbiosis) – which increases intestinal permeability (“leaky gut”) and allows endotoxins (e.g., LPS) into circulation (Monteiro et al., 2019; Chassaing et al., 2015)

Food additives and chemicals (emulsifiers, artificial sweeteners, preservatives)

These substances act by (Chassaing et al., 2015):

• disrupting gut microbiota – which leads to dysbiosis
• increase intestinal permeability – which allows inflammatory compounds into circulation
• potentially directly affecting brain signalling and inflammation

Advanced glycation end products (AGEs) from cooked foods (grilled, fried, roasted meats; processed foods)

These molecules act by:

• directly increasing AGE burden in the body (Uribarri et al., 2010)
• binding to RAGE receptors – which increases oxidative stress and inflammation, and promotes amyloid-β transport into the brain (West et al., 2014)
• cross-linking proteins – which impairs normal protein function and clearance (Uribarri et al., 2010)

Alcohol

Alcohol is a neurotoxin that affects metabolism, the brain, and the immune system. Chronic or heavy use may increase the risk and progression of Alzheimer’s disease through multiple mechanisms.

Key ways alcohol promotes Alzheimer’s disease include:

• increasing intestinal permeability – which allows gut toxins to enter the bloodstream (León et al., 2022), resulting in systemic and brain inflammation
• increasing gut-derived endotoxins (LPS) – which amplifies systemic and brain inflammation (León et al., 2022)
• activating microglia and TLR pathways – which leads to sustained brain inflammation (Chandrashekar et al., 2023; León et al., 2022)
• increasing pro-inflammatory cytokines – which results in neuronal injury and impaired signalling (León et al., 2022; Seemiller et al., 2024)
• increasing reactive oxygen species (ROS) – which damages lipids, proteins, and DNA (León et al., 2022; Seemiller et al., 2024)
• reducing antioxidant defenses – which increases vulnerability to oxidative injury (León et al., 2022)
• impairing mitochondrial function – which decreases ATP production and neuronal energy supply (León et al., 2022)
• causing thiamine deficiency – which impairs brain energy metabolism, reducing ATP production and increasing oxidative stress (Chandrashekar et al., 2023)
• impairing insulin and IGF-1 signalling (Chandrashekar et al., 2023) – which leads to impaired brain glucose metabolism
• disrupting blood–brain barrier integrity – which allows toxins and immune cells to enter the brain (Chandrashekar et al., 2023)
• decreasing acetylcholine – which results in less effective communication between neurons (Chandrashekar et al., 2023)
• impairing glutamate regulation – which increases neuronal overstimulation and injury (Seemiller et al., 2024)
• increasing amyloid-β production – which promotes plaque formation (Chandrashekar et al., 2023)
• decreasing amyloid-β clearance – which leads to accumulation in brain tissue (Chandrashekar et al., 2023)
• activating the enzymes CDK5 and GSK3β – which promotes excessive tau phosphorylation, leading to neurofibrillary tangles (León et al., 2022)
• increasing ER stress and cellular injury – which promotes neuronal death (Seemiller et al., 2024)
• promoting progressive neuronal loss – which results in cognitive decline and dementia (Seemiller et al., 2024)

Toxins

Toxins from air, food, water, and everyday products can enter the body and affect the brain. Many of them act through the same core pathways:

Key ways toxins promote Alzheimer’s disease include:

• disrupting blood–brain barrier function – allowing toxins and inflammatory molecules greater access to the brain (Hussain et al., 2023; Babić Leko et al., 2023; Choudhury et al., 2023)
• increasing oxidative stress – which damages lipids, proteins, and DNA (Dhapola et al., 2023; Lee et al., 2018)
• increasing neuroinflammation – through microglial activation and inflammatory signalling (Dhapola et al., 2023; Alemany et al., 2021)
• impairing mitochondrial function – which reduces energy production and increases neuronal vulnerability (Dhapola et al., 2023; Choudhury et al., 2023)
• promoting amyloid-β accumulation and tau pathology (Dhapola et al., 2023; Mir et al., 2020)

Over time, these changes can damage neurons, impair synaptic function, and contribute to cognitive decline and Alzheimer’s disease (Rao et al., 2023; Dhapola et al., 2023)

Addressing toxin exposure

• Reduce exposure from food
  • Prioritize lower-pesticide options
  • Use resources such as the Environmental Working Group’s Dirty Dozen and Clean Fifteen lists
• Identify and reduce environmental exposures
  • Avoid air pollution and household chemicals
• Support detoxification pathways
  • Consume a nutrient-dense diet with adequate protein intake
  • Include fibre-foods such as psyllium, ground flaxseed, chia, and pectin-rich foods – to support toxin binding and elimination through the gut
  • Supplement nutrients that provide antioxidants and support liver function
• Consider practitioner guidance when needed – especially for higher or chronic exposures

Medications

• Certain medications can impair memory, attention, and thinking, particularly in older adults and people with existing cognitive impairment.
• In some cases these effects may mimic or worsen Alzheimer’s symptoms.
• A medication review with a physician or pharmacist is an important part of evaluating potentially reversible contributors to cognitive decline.

Medication classes that can contribute to cognitive impairment include (AGS Beers Panel, 2023; Belessiotis-Richards et al., 2025; Cognitive Health and Older Adults, 2024):

• medications with strong anticholinergic (acetylcholine blocking) effects (especially certain antihistamines, bladder medications, tricyclic antidepressants, antispasmodics, and some Parkinson’s medications)
• benzodiazepines and non-benzodiazepine sleeping medications
• opioid pain medications
• antipsychotic medications
• certain anti-seizure medications
• sedating antihistamines and muscle relaxants
• systemic corticosteroids
• Parkinson’s medications with central nervous system effects
• medications that cause metabolic disturbances, such as hypoglycemia (low blood sugar), hyponatremia (low sodium), or excessive lowering of blood pressure
• statin medications (medications that lower cholesterol in the blood) (Wagstaff et al., 2003)

Suboptimal neurotrophic support

Neurotrophic support refers to signals that help neurons survive, grow, and maintain connections. Low neurotrophic support is the context of reduced neurotrophic signals.

Key ways low neurotrophic support promotes Alzheimer’s disease include:

• Decreased NGF signalling – reduces TrkA (tropomyosin receptor kinase A) activation, resulting in:
  • decreased activation of survival signalling pathways (Pentz et al., 2021)
  • decreased growth and maintenance of neurons
  • decreased cholinergic neuron survival (Pentz et al., 2021)
  • decreased expression of genes needed for cholinergic function, impairing acetylcholine production and signalling (Pentz et al., 2021)
  • damage to axons (the long extensions of brain cells that carry signals), disrupting communication between brain cells (Pentz et al., 2021)
• Decreases BDNF (brain-derived neurotrophic factor) levels, resulting in:
  • reduced synaptic plasticity which impairs learning and memory
  • decreased neurogenesis and neuronal survival (Amidfar et al., 2020; Xue et al., 2022)
  • increased susceptibility to amyloid-β-induced synaptic dysfunction (Amidfar et al., 2020)
  • reduced neurotransmitter release which impairs neuronal communication (Amidfar et al., 2020)
  • progressive neuronal atrophy, contributing to degeneration of vulnerable brain regions (Amidfar et al., 2020)
• Decreased ghrelin activity, which:
  • impairs insulin signalling
  • increases tau hyperphosphorylation (Jeon et al., 2019; Tian et al., 2023)
  • increases Aβ toxicity, oxidative stress, and inflammation, promoting synaptic dysfunction and cognitive decline (Jeon et al., 2019)
  • increases apoptosis signalling, promoting neuronal loss (Jeon et al., 2019)
  • reduces synaptic plasticity, impairing learning and memory (Jeon et al., 2019)

Hormone imbalance

Hormones are chemical messengers that regulate brain metabolism, inflammation, and neuronal function. Hormone imbalances reduce neuroprotection and increase processes that drive neurodegeneration.

Key ways hormone imbalances promote Alzheimer’s disease include:

Decreased estrogen levels which results in:

• reduced synaptic plasticity (impairs memory and learning)
• decreased neuroprotection
• increased inflammatory signalling
• increased neuroinflammation (Brann et al., 2022)
• increased release of mitochondrial danger signals – which activates immune responses (Mishra et al., 2023)
• reduced mitochondrial protection, resulting in increased oxidative stress and increased excitotoxic damage (Hara et al., 2015)
• disrupted cellular transport and signalling, which impairs synaptic function (Uddin et al., 2020)

Decreased testosterone levels, which results in:

• reduced synaptic function and connectivity
• impaired brain energy metabolism
• reduced cerebral blood flow – which decreases oxygen and nutrient delivery to the brain (Sundermann et al., 2020)
• increased inflammation and oxidative stress (Sundermann et al., 2020)
• increased amyloid-β accumulation
• increased neurodegeneration and cognitive decline (Sundermann et al., 2020)

Increased cortisol levels, which results in:

• chronic activation of the stress-response axis
• damage to the hippocampus – which impairs memory
• hippocampal atrophy, which contributes to cognitive decline (Yeram et al., 2021)
• increased neuroinflammation (Rao et al., 2023)
• stimulation of microglia, resulting in increased inflammatory damage to neurons (Seemiller et al., 2024)
• impaired brain waste clearance
• increased amyloid-β production and aggregation
• increased tau hyperphosphorylation
• increased neuronal vulnerability, which leads to degeneration (Pietrzak et al., 2017; Yeram et al., 2021; Yao et al., 2021)

Decreased progesterone activity, which results in:

• reduced anti-inflammatory signalling
• increased microglial activation (Cekic et al., 2009)
• increased vulnerability to glutamate toxicity
• increased vulnerability to amyloid toxicity (Cekic et al., 2009)

Impaired thyroid hormone function, which results in:

• reduced neurogenesis (the formation of new neurons) and neurodifferentiation (their development into specialized neurons) – which impairs normal brain function (Salehipour et al., 2023)
• disrupted hippocampal function (impairs memory and learning)
• altered brain glucose metabolism (reduces energy availability) (Salehipour et al., 2023)
• increased oxidative stress in neurons
• cellular stress in the hippocampus, which contributes to dysfunction (Salehipour et al., 2023)
• altered amyloid precursor protein processing
• increased amyloid-β accumulation and tau phosphorylation – which promotes pathology (Figueroa et al., 2021; Salehipour et al., 2023)

Homocysteine

Homocysteine is an amino acid produced in the body during the normal metabolism of methionine, another amino acid. It has important roles in metabolism, but in excess is harmful to the body.

Homocysteine levels are regulated by:

1. converting it to methionine
2. converting it into other molecules, like glutathione

Causes of elevated homocysteine include:

• deficiencies of vitamin B2, B6, folate, vitamin B12, choline, and betaine
• genetic issues (polymorphisms/SNPs) that affect methionine and folate cycle enzymes

Key ways elevated homocysteine promotes Alzheimer’s disease include:

• inhibiting methylation reactions – by increasing the methionine cycle intermediate S-adenosylhomocysteine (SAH), which results in:
  • altered DNA methylation – contributing to neurotoxicity and brain atrophy (Sah et al., 2023)
  • neuronal DNA damage and apoptosis (Hama et al., 2020)
  • impaired phospholipid (cell membrane building block) synthesis (Hama et al., 2020)
• reacting with oxygen – which produces harmful reactive oxygen and nitrogen species that damage cells and increase oxidative stress (Hayden & Tyagi, 2022; Stefaniak et al., 2022)
• damaging the endothelium (the thin layer of cells that lines the inside of blood vessels) – which results in decreased nitric oxide, increased vasoconstriction, and reduced cerebral blood flow (Elsherbiny et al., 2020; Hama et al., 2020)
• disrupting the blood–brain barrier – which allows toxins and inflammatory mediators into the brain (Lauer et al., 2022; Hermann & Sitdikova, 2021)
• promoting chronic inflammation – which activates microglia to promote increased cytokine production (Elsherbiny et al., 2020; Hermann & Sitdikova, 2021)
• increasing amyloid-β production and toxicity (Lauer et al., 2022)
• increasing tau phosphorylation (Luzzi et al., 2021; Rizzo & Marino, 2023)
• activating NMDA receptors (glutamate receptors involved in learning and memory) – which increases cellular calcium influx, triggering excitotoxicity (damage to nerve cells caused by excessive stimulation) (Wan et al., 2022; Hama et al., 2020)
• promoting brain atrophy – through cumulative vascular and neuronal damage (Hama et al., 2020; Rizzo & Marino, 2023)

Mineral imbalances

Minerals and metals such as copper, iron, and zinc are essential for brain function. Imbalances in their levels or distribution can contribute to Alzheimer’s disease manifestation.

Key ways mineral imbalances promote Alzheimer’s disease include:

• disrupting mineral balance and distribution – which alters bioavailability (the amount available for brain cells to use) and impairs synaptic signalling (Puentes-Díaz et al., 2023)
• increasing oxidative stress – which damages lipids, proteins, and DNA and impairs mitochondrial function (Hussain et al., 2023; Hamid et al., 2022)
• promoting mitochondrial dysfunction – which reduces ATP production and promotes apoptosis (Squitti et al., 2023)
• activating inflammasomes (inflammatory protein complexes) and cytokines – which sustains chronic neuroinflammation (Hamid et al., 2022)
• contributing to blood–brain barrier (BBB) dysfunction (Babić Leko et al., 2023) – which can increase metal and toxin entry into the brain and accelerate neurodegeneration
• promoting amyloid and tau pathology (Babić Leko et al., 2023)
• impairing synaptic and neuronal function – which reduces synaptic plasticity and cognition (Socha et al., 2021)
• promoting amyloid deposition – potentially as a protective mechanism to sequester excess metals (Puentes-Díaz et al., 2023)

Elevated copper also:

• increases reactive oxygen species (ROS) – which causes direct neuronal oxidative damage (Choudhury et al., 2023; Vasefi et al., 2020)
• impairs neuronal energy metabolism – by disrupting mitochondrial function and reducing ATP production (Squitti et al., 2023)
• inhibits NMDA and AMPA receptors (glutamate receptors that mediate fast excitatory signalling between neurons) – reducing glutamate signalling, which impairs synaptic function, memory, and learning (Dhapola et al., 2023)
• impairs autophagy – which prevents the breakdown and removal of abnormal amyloid-β and tau proteins (Dhapola et al., 2023)
• binds amyloid-β (Aβ) – to form toxic copper–Aβ complexes (Puentes-Díaz et al., 2023)

Elevated iron also:

• increases β-secretase activity – which promotes plaque formation (Puentes-Díaz et al., 2023)
• disrupts calcium signalling – which impairs neuronal function (Puentes-Díaz et al., 2023)
• amplifies calcium-driven mitochondrial stress – by increasing oxidative damage, leading to energy failure and neuronal death (Puentes-Díaz et al., 2023)

Elevated zinc also:

• promotes Aβ aggregation into fibrils – which stabilizes amyloid plaques (Hamid et al., 2022)
• disrupts copper and iron balance – which impairs metal-dependent enzyme function (Choudhury et al., 2023)

Insulin resistance

Insulin is a hormone that regulates the use and storage of sugar and carbohydrates as well as fats and protein by the body.

Insulin resistance is the state in which the body’s cells become less responsive to insulin.

Key ways insulin resistance promotes Alzheimer’s disease include:

• reducing insulin receptor expression at the blood–brain barrier – which decreases insulin entry into the brain (Jiang et al., 2023), and results in decreased synaptic plasticity and neuronal survival (Figueroa et al., 2021; Mietelska-Porowska et al., 2022)
• increasing oxidative stress – which damages neuronal membranes and proteins (Kshirsagar et al., 2021)
• disrupting mitochondrial function – which reduces energy (ATP) production, leading to neuronal dysfunction (Akhtar & Sah, 2023)
• increasing the production of advanced glycation end products (AGEs) – which trigger inflammatory signalling that damages blood vessels and neurons (Wei et al., 2021)
• indirectly activating microglia – which increase inflammation (Kshirsagar et al., 2021)
• disrupting blood–brain barrier function – which impairs cerebral blood flow regulation, reduces nutrient delivery and waste removal (Rhea et al., 2023), and reduces amyloid clearance from the brain (Yoon et al., 2023)
• reducing insulin-degrading enzyme (IDE) availability for amyloid β degradation – which occurs because insulin and amyloid β share IDE for breakdown. High insulin levels cause degradation of insulin over amyloid β (Norwitz et al., 2021)
• activating the enzyme glycogen synthase kinase-3 beta (GSK-3β) – which increases tau phosphorylation and promotes neurofibrillary tangle formation (Kshirsagar et al., 2021; Akhtar & Sah, 2023)
• increasing amyloid-β accumulation – through reduced IDE-mediated degradation, impaired microglial clearance, increased production via inflammatory signalling, and reduced clearance across the blood–brain barrier (Wei et al., 2021; Norwitz et al., 2021; Yoon et al., 2023)

Infections

Infections are the invasion and growth of bacteria, viruses, fungi, or parasites in the body. They activate the immune system to eliminate the threat, but when persistent or recurrent, they lead to ongoing inflammation and tissue damage.

Key ways infections promote Alzheimer’s disease include:

• damaging the blood–brain barrier (BBB) – which increases permeability and allows pathogens and inflammatory molecules into the brain (Whitson et al., 2024)
• activating microglia and astrocytes (resident brain immune and support cells) – which shifts them into a pro-inflammatory state that leads to neuronal damage, neuroinflammation, and synaptic loss (Butler & Walker, 2021; Vasefi et al., 2020)
• increasing reactive oxygen species (ROS) – which damages brain lipids, proteins, and DNA, and promotes amyloid and tau pathology (Mancuso et al., 2022)
• increasing Aβ production – as part of the innate immune response in which Aβ acts as an antimicrobial peptide (Barichello et al., n.d.; Vasefi et al., 2020)
• altering Aβ transport – by decreasing LRP1-mediated clearance and increasing RAGE-mediated influx (“Oral Porphyromonas gingivalis Infections Increase the Risk of Alzheimer’s Disease,” 2023)
• promoting tau hyperphosphorylation – particularly through HSV-1 infection (Yong et al., 2021; Vasefi et al., 2020)

Gram-negative bacteria:

• release lipopolysaccharide (LPS) – which (Whitson et al., 2024):
  • activates inflammatory signalling pathways
  • increases amyloid production and deposition

Oral pathogens (e.g., P. gingivalis):

• increase systemic inflammation – may enter circulation and reach the brain, activating microglia and inflammatory pathways (Putri & Bachtiar, 2021; Prajjwal et al., 2023)

Herpes simplex virus type 1 (HSV-1):

• can remain dormant in the nervous system, reactivate repeatedly over time – which drives inflammation, oxidative stress, and amyloid accumulation (Vasefi et al., 2020; Mancuso et al., 2022)

Dysbiosis

Dysbiosis is an imbalance in the composition and function of gut bacteria. It occurs when beneficial microbes are reduced and harmful or pro-inflammatory microbes increase.

Dysbiosis disrupts gut barrier function, immune regulation, and metabolic signalling, which promotes inflammation and other harmful effects in the brain.

Key ways gut bacteria issues promote Alzheimer’s disease include:

• promoting chronic systemic and neuroinflammation – which activates pro-inflammatory cytokines, and stimulates microglial activation and inflammatory signalling in the brain (Jiang et al., 2023; Romanenko et al., 2021)
• disrupting intestinal barrier integrity (“leaky gut”) (Chu et al., 2022; Bhratee et al., 2023)
• increasing lipopolysaccharide (LPS) exposure – which promotes inflammatory signalling by:
  • activating RAGE signalling in the brain (Jiang et al., 2023)
  • mimicking amyloid-β signalling in microglia, amplifying neuroinflammation (Bello-Corral et al., 2021)
• promoting activation of the intestinal NLRP3 inflammasome, which contributes to Alzheimer’s disease pathogenesis (Romanenko et al., 2021)
• impairing blood–brain barrier function – which allows inflammatory cytokines to enter the brain (Chu et al., 2022; Bello-Corral et al., 2021)
• promoting chronic immune activation (Jiang et al., 2023)
• promoting metabolic and signalling dysfunction – which (Bhratee et al., 2023):
  • disrupts insulin signalling
  • increases oxidative stress, GSK-3β activity, and astrocyte activation
  • enhances amyloid-β aggregation
• disrupting production of gut-derived metabolites – including short-chain fatty acids, bile acids, branched-chain amino acids, and neurotransmitters, which influence cognition and Alzheimer’s disease progression (Jiang et al., 2023)

Depression

Depression is a common mental health condition marked by a persistent low mood and loss of interest or pleasure, along with changes in thinking, behaviour, and physical function.

Depression is best understood as both a contributing factor and a clinical signal of Alzheimer’s disease processes (Rao et al., 2023; Huang et al., 2024).

Shared underlying causes

Depression and Alzheimer’s disease often arise from overlapping biological disturbances including:

• chronic inflammation and immune dysregulation
• oxidative stress and stress-hormone dysregulation
• neurotransmitter imbalances, including serotonin, noradrenaline, and acetylcholine
• metabolic and mitochondrial dysfunction
• vascular and blood–brain barrier dysfunction

These shared disturbances create a biological environment that increases vulnerability to both depression and neurodegeneration.

Key ways depression contributes to Alzheimer’s disease include:

• increasing cortisol levels (Hasan et al., 2023) – which can damage the hippocampus, impair memory formation, and increase neuronal susceptibility to stressors
• increasing pro-inflammatory cytokines and oxidative stress – which activate microglia and contribute to neuronal injury, synaptic loss, tau pathology, neurodegeneration, and cognitive decline (Rao et al., 2023; Hasan et al., 2023; Huang et al., 2024)
• decreasing BDNF and other growth factors (Hasan et al., 2023) – which reduces synaptic plasticity and impairs neuron repair and regeneration
• decreasing serotonin and noradrenaline – which impairs mood regulation and cognition (Hasan et al., 2023)
• reducing acetylcholine signalling – which worsens memory and learning (Modrego et al., 2023)
• altering calcium signalling and NMDA receptor activity – which impairs synaptic communication and reduces learning and memory capacity (Hasan et al., 2023)
• promoting vascular dysfunction – through endothelial dysfunction and increased blood-brain barrier permeability, contributing to neuroinflammation and cognitive decline (Wu et al., 2022).
• disrupting glymphatic function (Hu et al., 2024) – which decreases amyloid-β clearance

Addressing depression
View ISOM’s Depression webpages

Hearing loss

Hearing loss reduces auditory input and increases the effort required to understand sound. This leads to brain under-stimulation and sustained cognitive strain, which promote neurodegeneration.

Key ways hearing loss promotes Alzheimer’s disease include:

• increased compensatory brain activity – which recruits non-auditory brain regions, including the frontal cortex, to support attention, working memory, and language processing during listening (Glick & Sharma, 2017)
• altered neuronal activity in the medial temporal lobe – which may promote Alzheimer’s neuropathology (Tarawneh et al., 2022)
• altered synaptic activity and disrupts neural connectivity – which impairs information processing (Tarawneh et al., 2022)

Factors that contribute to Alzheimer’s disease and also cause hearing loss (Tarawneh et al., 2022):

• mitochondrial dysfunction – which decreases cellular energy and increases oxidative stress, resulting in hair cell damage and loss (hearing decline) and neuronal dysfunction and degeneration (cognitive decline)
• microvascular dysfunction – which reduces blood flow, oxygen and nutrient delivery, and waste removal, resulting in inner ear damage and neurodegeneration
• chronic inflammation – which leads to cochlear and auditory pathway damage

Downstream brain effects of hearing loss (Tarawneh et al., 2022):

• alters synaptic activity and neural network efficiency – which leads to impaired information processing
• increases compensatory brain activity – which shifts processing to non-auditory regions and reduces overall network stability and efficiency
• increases reliance on memory systems – which increases demand on the hippocampus and medial temporal lobe, contributing to functional strain and eventual atrophy

Factors that contribute to Alzheimer’s disease and also cause hearing loss (Tarawneh et al., 2022)

• Mitochondrial dysfunction – which decreases cellular energy and increases oxidative stress, resulting in hair cell damage and loss (hearing decline) and neuronal dysfunction and degeneration (cognitive decline)
• Increased oxidative stress – which leads to degeneration of auditory structures and neurodegeneration
• Chronic inflammation – which leads to cochlear and auditory pathway damage
• Vascular dysfunction – which reduces blood flow, oxygen and nutrient delivery, and waste removal, and results in inner ear damage and neurodegeneration

Social isolation

Social isolation refers to reduced social contact and engagement. It has roles in increasing stress, inflammation, hypothalamic-pituitary-adrenal (HPA) axis activation, and promoting neurodegeneration.

Key ways social isolation promotes Alzheimer’s disease include:

• increasing cortisol through chronic stress – which disrupts hippocampal and prefrontal cortex function, and promotes amyloid plaque formation (Drinkwater et al., 2022; Ren et al., 2023)
• increasing inflammatory signalling (Drinkwater et al., 2022; Ren et al., 2023) – which activates microglia, and damages neurons and synapses
• increasing oxidative stress (Drinkwater et al., 2022) – which worsens inflammation and neuronal injury
• decreasing BDNF levels – which decreases neurogenesis, synaptic plasticity and weakens brain resilience (Drinkwater et al., 2022)
• decreasing AMPA receptor expression (a type of glutamate receptor) – which impairs synaptic signalling and reduces neuronal communication (Drinkwater et al., 2022)
• increasing amyloid and tau accumulation – through the combined effects of cortisol, inflammation, and oxidative stress (Drinkwater et al., 2022)

Poor sleep

Poor sleep reduces the brain’s ability to repair and clear waste. Over time, this leads to toxin buildup, inflammation, and neuronal damage.

“Poor sleep” includes:

• short sleep duration
• fragmented sleep
• loss of deep sleep
• sleep-disordered breathing (e.g., apnea)

The glymphatic system is most efficient during sleep.

Key ways poor sleep promotes Alzheimer’s disease include:

• decreasing time spent in slow-wave sleep – which reduces peak glymphatic activity (Turner et al., 2023)
• impairing AQP4 channel function – which reduces glymphatic flow efficiency and waste clearance
• causing hypoxia (repeated drops in oxygen levels) – which increases oxidative stress and damages neurons, especially in the hippocampus (Owen et al., 2021)
• increasing inflammatory signalling in the brain – which promotes neuronal injury and disease progression (Astara et al., 2024; Turner et al., 2023)
• increasing BACE-1 activity – via hypoxia, oxidative stress, and inflammation, which increases amyloid-β production (Astara et al., 2024)
• promoting tau hyperphosphorylation – via increased tau kinase activity (e.g., GSK-3β, CDK5), hypoxia effects, oxidative stress, inflammation, and increased synaptic activity (prolonged wakefulness = more synaptic activity = more tau release) (Astara et al., 2024)
• reducing glymphatic clearance of amyloid-β – which promotes amyloid accumulation in the brain (Turner et al., 2023; Astara et al., 2024; Hu et al., 2024; Hussain et al., 2023)
• reducing glymphatic clearance of phosphorylated tau – which promotes tau accumulation (Hussain et al., 2023; Astara et al., 2024)

Addressing poor sleep

View ISOM’s Insomnia webpages