Ch 12: Alzheimers Disease Flashcards
Pathophysiology of Alzheimers
- Beta-amyloid placque deposition
- Tangles of dead nerve cells
- Inflammation is key. High CRP and IL6 are strong predictors!
- Beta-amyloid causes mitochondrial dysfunction
Risk Factors for Alzheimers
- Age (most important)
- APOE-4: with two genes especially
- Weight (U-shaped)
- CVD, DM, Insulin resistance, HTN, smoking
- OSA (strong link. Treating helps at any stage of Alzheimers!)
- TBI
- Chronic stress
- Fam Hx
- Lower education
- Low glutathione (GSH)
- Hormonal imbalance
- Methylation defects
- Mild cog impairment
- Toxicities
- Gut dysbiosis
Nutritional Risk Factors for Alzheimers
- High glycemic index
- Low Omega 3
- Low B12 and B6
- Niacin deficiency (causes Pellagra - Dementia, Diarrhea, Dermatitis)
- Thiamine Deficiency (Wernicke-Korsakoff)
- Selenium deficiency (2 brazil nuts per day - overdose is possible!)
- Vitamin E deficiency (mixed data)
- Copper Excess (more risky with supplemental copper over dietary copper, since dietary in organic form is processed by the liver and bound to ceruloplasmin, versus free copper from supplements)
- Zinc deficiency (zinc protects from copper excess)
- Vitamin D Deficiency (supplementation reduces risk of falls! Doesnt slow progression)
APOE4 Genomics and Alzheimers
- Apolipoproteint E4 is a known risk factor
- Risk with this genotype varies widely based on other genetic factors
- Risk is higher in APOE4 individuals who also have a BCHE-K variant
Methylation and Alzheimers
- Impaired methylation associated with dementia
- Elevated homocysteine is a risk factor for dementia
- However lowering homocysteine with synthetic B-vitamins has not been shown to slow dementia progression
Which environmental toxins are posited to increase risk of Alzheimer’s?
- Aluminum
- Lead
- Mercury
- Organophosphate pesticides
- Extremely low-frequency electromagnetic fields
- Molds (leading to Chronic Inflammatory Response Syndrome)
Which common viral infection has a strong correlation with Alzheimer’s?
- HSV-1
- People with more flares have higher risk of AD
- Treating with antivirals mitigates the risk!
- Links is highest in APOE4-positive poeople
- HSV1 DNA has been found in placques; HSV-1 cells accumulate Beta-amyloid
- Increases neuro-inflammation
Key differences between Mild Cognitive Impairemnt and Alzheimer’s
- People with MCI have normal overall cognition (they may hust have memory problems which they can usually recognize)
- People with MCI have normal functioning per measures of ADLs
What are the screening tools used for Alzheimers
- MMSE = most popular but now copyrighted
- Mini-Cog
- MoCA: free, but can get trained for a small fee
The A/T/N diagnostic criteria for Alzhemiers
- Amyloid biomarkers
- pathologic Tau
- Neurodegenerative changes
Alzheimers is now recognized as a contiuum, where cognitive decline happens over a long period of time and biomarkers simultaneously progress and do so before clinical symptoms begin.
Components of diagnostic workup for Alzheimers
- Physical exam (stroke, signs of vitamin deficiency)
- Routine labs: CBC, CMP, B12, folate, TSH, syphilis, HIV
- Integrative testing: glucose and A1c, Zinc & copper, CRP, hormones (pregnenolone, DHEA, testosterone in both sexes), comprehenisve nutritional assessment including oxidaive and fatty acid analysis
- Oxidative stress assays: reduced glutathione, lipid peroxidases, CoQ12, 8-hydroxydeoxygyanosine, cysteine-to-cystine ratio, superoxide dismutase
- If susupicion: total body lead or mercury
- Heavy metal serum testing will miss cases because of rapid sequestration to tissue
- consider mold testing (complement 4A, transforming growth factor-B1)
- APOE4 screening
- PET or MRI
- Dental exam (remove amalgams, treat periodontal disease - overgrowth of Porphyromanos gingivalis can lead to neuroinflammationl; treating periodontitis can improve alzheimer’s progression!)
What is the MIND diet for Alzheimers?
- A hybrid of Mediterranean and DASH (“The Mediterranean-DASH Intervention for Neurological Delay)
- Specifies consumptions of berries and leafy greens
- Limited amount of animal-based foods (fish, poultry).
- Not low-fat (olive oil, nuts)
How does Intermittent Fasting help in Alzheimer’s?
- Reduces oxidative damage and inflammation
- At minimum 14-hours, but ideally 16 to 18
- Ketogenesis thought to be neuroprotective
- ketogenesis may be enhanced by MCTs (coconut oil, purified MCT oils) or ketone supplements (ketone salts or esters - but the salts can lead to “keto flu”)
- monitor lipids though!
What is the most abundant membrane lipid?
- It is the Omega-3 called DHA!
- DHA and EPA can be synthesized by humans from ALA
- EPA modulates membrane fluidity and neuronal synaptic plasticity
- Fish intake reduces risk of AD, but fish oil supplementation does not!
What are the key components to an Alzheimer’s prevention and treatment diet?
1.Low–glycemic index diet.
2.Reduction of proinflammatory foods such as red meat, dairy, and sugar.
3.High amounts of fresh fruits and vegetables, including high-antioxidant foods such as berries, turmeric, and green tea.
4.High amounts of foods rich in omega-3 fatty acids.
5.Overnight fasting to promote ketogenesis.
6.Consider ketogenic diets with selected patients
Important components of an exercise prescription for AD
- mix of aerobic, strength, balance, and stretching for 30-60min per day
- as disease progresses, focus on balance and strnegth to prevent falls, sarcopenia, contractures
What is benefit of yoga and tai chi in Alzheimers
- Yog acan improve immediate and delayed recall!
- In people with Alzheimers, yoga doesnt affect cognitive function but improves physical health, depression, and agitation
- Tai Chi increases brain volume and reduces risk of cognitive decline
Role of Cortisol in Alzheimers
- Cortisol blocks glutamate uptake by the glial cell, –> increased accumulation of glutamate in the synapses –> activating N-methyl-D-aspartate (NMDA) receptors, –> influx of calcium into the postsynaptic neuron –> increases oxidative stress –> neuronal death.
- HPA axis dysfunction contributes to Alzheimers
- Cortisol levels and dexa-suppression tests not clinically useful in Alzheimer
- Salivary cortisol associated with smaller hippocampal values
What are some forms of meditation beneficial in Alzhemiers or cognitive impairment
- Transcendental meditation
- Kirtan Kriya (breathing, finger movement, and primal chanting)
- Tibetan sound meditation
The choice of what to recommend depends on local resources and preferences!
Can CVD risk reduction affect Alzheimer’s risk
Yes!
Treating HTN with antihypertensives can reduce risk of dementia.
Appropriate way to supplement B-vitamins for Alzheimers
- Goal B12 is > 500
- Consider testing intracellular B12 levels (functional assays)
- Use activated B12 and Folate: methylcobalamin and 5-methyltetrahydrofolate
- Ideally give 1000mcg of each
- Give B12 in morning (avoid sleep disruptions(
- Do not use synthetic folate unless negative MTHFR status is confirmed due to negative effects of unmetabolized folate!!
Cautions: in people with O-methyltransferase SNPs, giving methylcobalamin can cause anxiety or agitation (due to higher levels of dopa and NE). Mitigate by giving hydroxy- or adeno-B12 or lower levels of methyl B12
Should you use Vitamin E or C supplements in Alzheimers
- No. Conflicting results
- Would not use unless there is nutritional testing that shows deficiency
- Otherwise, recommend getting it from diet - likely a positive interaction with other phytochemicals
- Consider using a multivitamin or antioxidant formula that contains mixed tocopherols to contain all 8 natural isoforms
What to look for in a multivitamin for Alzheimers?
*No additional copper and iron
*Natural forms of vitamin E 200 to 400 IU—mixed tocopherols
*Methylated forms of folate at least 400mcg
*Activated forms of vitamin B12—methyl, hydroxy, or adeno at least 500mcg
*Zinc at least 15mg
*Selenium 100 to 200mcg
Is Choline supplementation beneficial in Alzheimers?
- One study showed strong results, but a Cochrane overall did not show benefit but concluded we need more studies
- Choline intake in childhood critical for brain development
Why measure Delta-6 Desaturase?
- Patients with decreased levels can benefit from intake of gamma-linoleic acid via borage, eveing primrose, or black current oils. This helps balance fatty acid profiles
In general, could also consider a 4:1 omega 6:3 balanced supplement for anyone with Alzheimer’s with at least 1-3g of combined DHA/EPA, where at least 50% is DHA.
Krill oil has not been studied for AD
What does NAC do?
- It is a precursor to glutathione (low neuronal levels of GSH found in AD)
- May be important in prevention and treatment of Alzheimers
- NAC can cross the BBB and lead to increased intracellular GSH
- Essential role in antioxidant defense
- Liposomal and bioavailable forms better reach the brain
- Take NAC 500-1000mg 5 days per week. Well tolerated, occasional GI side effects.
Huperzine A
- Anticholinesterase inhibitor
- From Chinese club moss
- Improved cognitive function and ADLS in patients with AD
- May have other neuroprotectice effects
- Approved in China for AD therapy
- Dose: 100-400mg mcg BID. Use in people who wanted to try anticholinesterase inhibitors but have side effects.
- Cautions: intestinal sx. Do not combine with any anticholinesterase inhibitor meds.
Turmeric, Green Tea
- lower rates of AD in populations that consume high doses of turmeric or green tea
- Should use these in liberal amounts as part of antiinflammatory diets
- Matcha is more potent
- Use oil with turmeric to enhance absorption
Coffee and black tea consuption has mixed results
Hormonal supplementation in Alzheimers
- Only if levels are low
- DHEA and pregnenolone
- In theory would provide anticortisol effects and improve hippocampal perfusion. No studies showing change in cognitive performance
Melatonin in Alzheimers
- Mixed evidence as to whether it improves cognitive function
- Can improve sleep and agitation symptoms
- 0.5mg - 10 mg (start low dose and increase gradually)
What are Medical Foods in Alzheimer’s
- Axona: MCT. Induces ketogenesis and provides ketone bodies to brain to optiize mitochrondrial electron transport. Gas and diarrhea.
- CerefolinNAC: activated B12 and folatea nd NAC. FDA approved for vitamin-deficienies associated with memory loss
- Souvenaid: comprehensive formulat to target acetylcholine deficiency, neuron membrane integrity, oxidative stress resistance, metabolic activity. Studies show confliting results.
Pharmacotherapy for Alzheimers
Acetylcholinesterase inhibitors:
Donepezil (all stages)
Rivastigmine (Mild-mod)
Galantamine (mild-mod)
Side effects - bradycardia, GI bleed, syncope, nausea, diarrhea, HA
Gingko has theoretical interaction but not seen in clinical studies
NMDA-receptor antagonist (Memantine): mod-severe.
Side effects: dizzy, headache, fatigue, diarrhea, constipated. usually well tolearted!
Alkalinizing agents may decrease memantine clearance!
Many end up getting SSRIs too for mood and behavioral problems
Antipsychotics can increase delirium and mortality.
Integrative therapy for behavioral problems in Alzheimers
- Music
- animal-assisted therapy
- Reiki. Can be taught to caregivers.
- Assisting caregiversn
Which herz light therapy in Alzheimers and what brain wave does it promote
40-Hz light therapy (flickering) may promote gamma brain wave, may remove amyloid placque, but human studies underway
Cannabinoids and Alzheimers
- useful for palliation but not disease-modifying
- cannabidiol (CBD) does seem to have neuroprotective effects in animal models
- THC linked to memory concerns and brain volume loss
Gingko Biloba in Alzheimers
- no association in studies
- but improves microvascular circulation and free radical scavenging
- Use in patients with a vascular component
- Theoretical risk of bleeding with Coumadin; monitor INR
- DOsage 60-120 / day
Alpha-lipoic acid (ALA)
Endogenous mitochondrial molecule, antioxidant effect, phase II detoxification by activation of Nrf2. Chelation effect of heavy metals in the brain.
Cautions: Acidic, high doses can irritate stomach and should be taken with food
Coenzyme Q10
Coenzyme Q10 Endogenous mitochondrial molecule, energy production, dynamic antioxidant
Mild GI symptoms in doses over 300mg
Acetyl L Carnitine
Enhances acetylcholine production and stimulates membrane phospholipid synthesis. Conflicting data
Occasional mild GI bloating and body odor. Well tolerated
Magnesium-L-threonate
Synaptoprotective effects in the hippocampus in animal models. Recent small RCT showed improved
Lithium orotate
Earth crust mineral with neuroprotective properties. Appears to have very broad positive effect on autophagy, oxidative stress, inflammation, and mitochondrial function
5-10mg
Nicotinamide riboside
Mitochondrial energy support, increase in SirT1 function, animal studies, RCT under way
Ecklonia cava (brown algae)
Potent modulator of gut microbiome suppressing neuroinflammation. In late 2019, oligomannate pharmaceutical extract of brown algae was approved by Chinese government for treatment of AD based on large phase 3 trial. US trial is under way
Resveratrol
Neuroprotective effect by increase in SirT1 function
Not reported, possible interaction with Coumadin
Bacopa monnieri
Neuroprotective, possible neuroregenerative effects. RCT showing improved memory in healthy elderly
Theoretical hormonal side effects if hypersensitization develops (not reported)
Spearmint extract, standardized to contain 15% of rosmarinic acid
Promotes antioxidant status in both neuronal cells and hippocampal tissue, in small randomized studies shown benefit in healthy older adults and those with subjective cognitive impairment
Gotu kola
Neuroprotective against oxidative stress and amyloid associated toxicity. Conflicting clinical data, positive small trials but negative meta-analysis
nausea, GI upset
Lemon balm
Acetylcholine receptor activity enhancement in the central nervous system. Also anxiolytic and mild sedative effects
Saffron
Neuroprotective against oxidative stress, possibly protective against aggregation and deposition of amyloid-beta
Reishi
Cordyceps
Lion’s Mane
Neuroprotective against oxidative stress and amyloid associated toxicity.
Possible neuroregenerative mechanisms. Number of positive small trials including systematic review suggestive of benefit.
In clinical practice often combined in capsules or powdered form.
Cordyceps: mild GI upset and dry mouth, known to increase risk of bleeding,
