Alzheimer's disease is progressive dementia with amyloid plaques, neurofibrillary tangles, and gliosis. Mainstream research centers on genetics (APOE), amyloid clearance, and acetylcholine drugs.

In The problem of Alzheimer's disease as a clue to immortality, in Ray Peat's framework dementia is failed brain energy and protective inhibition: the aging brain faces the same oxygen, PUFA, estrogen, and glucose deficits that injure the fetal brain, not a separate "entropyz-only" fate.[1][2]

The toxicity of estrogen and of the unsaturated fats has been known for most of the twentieth century, and much has been learned about their interactions in the aging process.

— Ray Peat[3]

Fetal brain injury and aged brain parallels

[edit]

At six months gestation the human fetal brain has about twice as many cells as at birth; in old age glial cells multiply while neurons die and brain DNA mass can exceed young-adult levels in Peat's cited measurements.[4] Factors shrinking the brain at birth also injure the degenerating aged brain in his list: hypoxia, excess PUFA, estrogen excess, progesterone deficiency, and glucose lack.[5]

Excessive supply of unsaturated fats in our diet, acting as a false-signal system, overcomes cholesterol, pregnenolone, and progesterone which are our main long-range defenses, and the resulting cascade of ineffective and defective reactions leads to lower and lower energy production, reduced function, and death.

— Ray Peat[6]

Many people experience regenerative improvement when circumstances align, such as mountain air in spring with adequate social support optimizing basic regulatory systems.[7]

Inhibiting prostaglandin E2 receptor EP2 on myeloid cells restores glucose oxidation, reduces neuroinflammation, and reverses age-related cognitive decline in mice, a pathway upstream of COX-derived PGE2 that aspirin also suppresses.[8]

Gut LPS, miRNA-30b, and neurofilament loss

[edit]

Microbiome-derived LPS upregulates miRNA-30b-5p in stressed neuronal-glial cells, suppressing neurofilament light chain and promoting cytoskeletal atrophy and synaptic disorganization seen in Alzheimer's pathology.[9]

PUFA, estrogen, and iron

[edit]

Excess dietary unsaturated fats act as false environmental signals, overwhelming cholesterol, pregnenolone, and progesterone defenses and lowering energy production.[10]

The most highly unsaturated fats, including DHA, accumulate with aging, and their toxic fragments are increased in Alzheimer's disease.

— Ray Peat[11]

Iron reacts with reductants and unsaturated oils to form lipid peroxides; absorption rises with estrogen and Hypothyroidism in Peat's regulatory summary.[12] Endotoxin synergizes with unsaturated fats; naloxone opposes some toxic effects in citations on the same page.[13]

In post-mortem tissue from controls aged 40 to 80 and from Alzheimer's and ALS cases, regional ferritin, a proxy for stored iron, tracked the burden of TDP-43 protein pathology, which appeared from the fourth decade and spread to the hippocampus after 60.[14]

Plaques as a protective response

[edit]

Brain fatty-acid profiling found six unsaturated fatty acids, including linoleic, arachidonic, docosahexaenoic and oleic acids, dysregulated in brains with differing degrees of Alzheimer's pathology.[15] A 2006 report that oligomeric amyloid-β*56 impairs memory in mice became one of the most-cited pillars of the amyloid hypothesis and redirected billions in drug development toward amyloid targets.[16] Decades of drugs targeting beta-amyloid and tau plaques directly have almost uniformly failed to help patients. The plaques may be a protective response rather than the primary cause of the disease. Tau protein has an independent, physiological role in glial cells: it is required for glia to form lipid droplets that sequester peroxidized lipids exported from stressed neurons, and glia lacking tau cannot protect neurons from this oxidative damage, a mechanism confirmed across fruit flies, rat astrocytes, and human glial cells.[17] This fits the PUFA/endotoxin model above: plaque formation may be the brain's attempt to contain lipid peroxidation and oxidative damage from excess unsaturated fat and endotoxin exposure, rather than a random pathological byproduct.

Protective inhibition and hormones

[edit]

Ordinary sleep is framed as restorative protective inhibition; weakened glycogen and energy charge with aging parallels hypothyroid night stress.[18] Case histories in part 2 include progesterone restoring function in labeled epileptic dementia and thyroid with pregnenolone and progesterone clearing senile confusion within days.[19]

One study has found that the only hormone abnormality in a group of Alzheimers patients' brains was an excess of DHEA... These observations suggest that DHEA should be used with caution. Supplements of pregnenolone and thyroid seem to be the safest way to optimize DHEA production.

— Ray Peat[20]

Before structural plaque burden is advanced, the priority is normalizing temperature, Magnesium, CO₂, sleep, and red light, then cautious thyroid and Progesterone rather than excess DHEA.[21][22] Cytochrome oxidase defects appear in Alzheimer's tissue in work Peat cited.[23] See Harm reduction.

Allopregnanolone (a progesterone/pregnenolone-pathway neurosteroid) is in active clinical development as a regenerative therapeutic for early Alzheimer's, with phase 1b/2a trials showing it promotes neurogenesis and restores hippocampal volume and cognitive markers rather than merely slowing decline.[24]

LSD microdosing trials

[edit]

Intermittent low-dose LSD (5–20 µg every four days for 21 days) was safe and tolerable in a phase 1 trial positioned toward Alzheimer's disease, with proposed anti-inflammatory mechanisms via 5-HT2A signaling.[25]

PET imaging linked greater serotonin transporter loss and amyloid-beta deposition together to late-life depression risk, supporting a shared serotonin/amyloid pathway between depression and Alzheimer's rather than treating them as unrelated conditions that happen to co-occur.[26]

Dopamine and neprilysin

[edit]

Activating ventral tegmental dopamine neurons or L-DOPA treatment raises neprilysin and reduces β-amyloid plaques in Alzheimer's mouse models, with chronic L-DOPA improving memory performance.[27]

High estradiol-to-progesterone ratios during perimenopause downregulate mitochondrial OXPHOS genes and reduce brain ATP; progesterone supplementation normalizes the ratio and restores synaptic function in Alzheimer-model mice.[28]

Vitamin K2 vitamer MK7R hypermethylates and downregulates PSEN1, BACE1, IL-1β, and IL-6 while raising protective ADAM10/ADAM17 expression in neuroblastoma models of amyloidogenesis and neuroinflammation.[29]

Autophagy-deficient human neurons die from NAD+ depletion driven by hyperactive SIRT and PARP enzymes; NAD precursor supplementation rescues mitochondrial energetics and survival.[30]

Vitamin K and neuronal differentiation

[edit]

Retinoic-acid-conjugated vitamin K analogues (Novel VK) cross the blood-brain barrier, convert to MK-4 more efficiently than natural K, and induce neural progenitor differentiation with stronger potency than menaquinone alone in Alzheimer's rodent models.[31]

Cervical lymphatic shunting

[edit]

A surgical cervical shunting procedure to unclog cerebral lymphatic drainage pathways (CSULS) produced measurable improvement in six Alzheimer's patients as of 2024, with transient delirium the only complication, resolving within 72 hours, and gains in attention and reaction speed across all six. In the reported first case (a 70-year-old woman treated at Shanghai Jiao Tong University's Alzheimer's disease center), five weeks post-surgery showed reduced tau-PET signal and improved glucose metabolism on FDG-PET, most evident in the right frontal lobe with additional gains in the left temporal lobe, alongside improved Mini-Mental Status Examination score (5→7), Clinical Dementia Rating, and depression scores.[32]

Intermittent CO2 and glymphatic clearance

[edit]

In a small human study (n=12), masks delivering intermittent ~5% CO2 alternating with normal air every 35 seconds for 30 minutes appeared to boost the brain's glymphatic clearance of tau and amyloid-beta, evidenced by elevated plasma amyloid-beta after sessions.[33]

Mitochondrial metabolism and acetyl-CoA

[edit]

In transgenic C. elegans expressing pan-neuronal human amyloid beta, metabolic stress (not amyloid aggregation per se) was the primary pathogenic event driving dysfunction, supporting metabolic failure as causally upstream of amyloid pathology rather than merely a downstream consequence of it.[34]

Pharmacologic NAD+ restoration (P7C3-A20) reversed advanced amyloid and tau pathology and restored cognition in multiple Alzheimer's mouse models.[35] In aged SAMP8 mice, experimental compounds that maintain brain acetyl-CoA levels (partly by inhibiting acetyl-CoA carboxylase 1) preserved mitochondrial gene expression, increased histone acetylation at memory-relevant sites, and improved cognitive performance, linking aging and dementia to shared defects in brain mitochondrial metabolism rather than irreversible plaque pathology alone.[36]

Gut barrier, vitamin A, and amyloid

[edit]

Vitamin A status in APP/PS1 mice modulates gut microbiota, intestinal permeability, and circulating inflammatory cytokines, with deficiency associated with higher brain amyloid-β deposition.[37]

Nitrate exposure

[edit]

Systemic LPS can produce amyloid plaques and cognitive deficits in mice without infectious prion protein, suggesting inflammatory endotoxin load as an upstream driver of protein-misfolding pathology.[38] Drinking-water nitrate below current EU limits (as low as 5 mg/L) associates with higher dementia incidence in a large Danish cohort.[39]

Glucocorticoid challenge enhances Aβ synthesis via 5-lipoxygenase; inhibiting or genetically removing 5-LO prevents dexamethasone-induced amyloid elevation in vitro and in mice.[40]

Blocking constitutively active 5-HT7 receptors with the inverse agonist amisulpride prevented pathological tau buildup and cognitive deficits in preclinical Alzheimer models.[41]

Repeated low-grade LPS exposures in middle-aged mice produced lasting deficits in inhibitory avoidance and Morris water-maze performance with disrupted hippocampal LTP, modeling infection-burden effects on cognitive aging.[42]

A large observational cohort linked vitamin D supplementation before cognitive decline to substantially lower subsequent dementia incidence and longer dementia-free survival.[43]

Decade-long low-dose aspirin use in coronary patients correlated with roughly one-third lower Alzheimer disease incidence and two-thirds lower vascular dementia in observational analysis.[44]

Mendelian-randomization and observational analyses supported a causal protective effect of higher vitamin D on dementia and stroke risk, with up to 17% of dementia potentially preventable by correcting deficiency.[45]

Transcranial photobiomodulation at 1068 nm raised ATP-related cognitive measures in healthy adults; separate pilot trials reported symptomatic gains in mild dementia.[46]

People with mild cognitive impairment had lower carbohydrate oxidation and higher fat oxidation at rest than healthy elders, a low-energy pattern seen early in Alzheimer's.[47]

A one-year benfotiamine trial produced significantly less ADAS-cog decline than placebo in patients with mild Alzheimer disease.[48]

Endotoxin hypothesis

[edit]

Elevated blood and CSF LPS in Alzheimer's patients may promote amyloid expression, tau phosphorylation, and microglial neurotoxicity via gut, lung, or periodontal bacterial sources.[49]

In a blood study, plasma LPS was about three times higher in 18 Alzheimer's patients than in healthy controls, and LPS tracked with activation of circulating monocytes. The controls were about 24 years younger, so age may explain part of the gap.[50]

In post-mortem brain tissue, gingipains, protein-cutting enzymes made by the gum-disease bacterium Porphyromonas gingivalis, were found in nearly all Alzheimer's brains and in about half of brains from people without dementia. In mice, infecting the mouth with the bacterium led it into the brain and raised amyloid-beta, and blocking gingipains reduced brain inflammation and nerve loss.[51] In rats, repeated P. gingivalis in the bloodstream made the blood-brain barrier leakier.[52] In aged mice, bacterial membrane vesicles from the same species, given by mouth, reached the hippocampus, activated microglia and impaired memory.[53] See Teeth.

Methylene blue (hydromethylthionine)

[edit]

Pharmacokinetic reanalysis of phase III trials found concentration-dependent cognitive and anti-atrophy effects at 8 mg/day hydromethylthionine monotherapy, with no added benefit from the high doses and smaller effects when added to symptomatic AD drugs.[54]

Repetitive negative thinking

[edit]

Repetitive negative thinking (RNT), a shared process across rumination and worry and a proposed "Cognitive Debt" risk pathway, associated with decline in global cognition, immediate memory, and delayed memory in 292 older adults with longitudinal assessments. In PET subsets, higher RNT tracked with greater global amyloid (PREVENT-AD and IMAP+) and entorhinal tau deposition; associations held after adjusting for anxiety and depression symptoms.[55]

Lithium

[edit]

In a large Danish nationwide study, long-term lithium exposure from drinking water was linked to a lower incidence of dementia at the highest levels tested, but a higher incidence at some middle levels, a non-linear relationship that doesn't support a simple dose-response story, and confounding by other differences between municipalities couldn't be ruled out. Alzheimer's disease specifically showed the same pattern.[56]

In post-mortem human brain tissue, lithium was the only metal measured that was significantly lower in the prefrontal cortex of people with mild cognitive impairment and with Alzheimer's disease, and amyloid deposits bound lithium and reduced its availability. In wild-type and Alzheimer-model mice, a diet that cut cortical lithium by about half increased amyloid and phospho-tau deposits and sped memory loss. Low-dose lithium orotate, a salt that binds amyloid less than lithium carbonate, prevented these changes and the memory loss in Alzheimer-model mice and aging wild-type mice (human tissue and mouse study).[57] The orotate results come from mice only.

B vitamins and omega-3 status

[edit]

In the VITACOG trial, older adults with mild cognitive impairment took placebo or daily B vitamins (folic acid, vitamin B6, and vitamin B12) for two years. In a retrospective analysis of that RCT, the B vitamins meaningfully slowed the rate of brain atrophy compared to placebo, but only in people whose baseline plasma omega-3 (EPA plus DHA) was already high; people with low baseline omega-3 saw no benefit.[58] Cognition followed the same pattern: among trial participants with high omega-3 status, those on B vitamins were much less likely to show cognitive decline than those on placebo, while with low omega-3 status the B vitamins made no difference (post hoc analysis of the RCT).[59] Both are subgroup analyses by a baseline blood marker, and high plasma omega-3 can also reflect other differences in diet and health.

[On lowering homocysteine] A diet rich in folic acid, B12, B6, and good thyroid function. Milk, eggs, orange juice are helpful foods.

— Ray Peat[60]

Some recent work on the anti-inflammatory effect of fish oil (Omega-3) shows that they accumulate with aging. Alzheimer's or dementia patients have a much higher level of these in the brain. They spontaneously oxidize into toxic, anti-metabolic substances—neuroprostanes—and in the process of oxidizing, they suppress the immune system.

— Ray Peat[61]

Vitamin E

[edit]

In brains donated by older adults, more gamma-tocopherol, a form of vitamin E, went with less amyloid and fewer tangles, while alpha-tocopherol on its own showed no link (autopsy study).[62] A blood test gives a rough read on brain vitamin E: in centenarians, serum alpha- and gamma-tocopherol rose with the tocopherol content of the frontal and temporal cortex (autopsy study).[63] See Vitamin E: Dementia.

Thyroid hormone, vitamins A and E, niacinamide (to inhibit systemic lipolysis), magnesium, calcium, progesterone, sugar, saturated fats, and gelatin all contribute in basic ways to prevention of the inflammatory states that eventually lead to the amyloid diseases.

— Ray Peat[64]

Steroids, cortisol, and amyloid

[edit]

In Peat's view, Alzheimer's disease may involve an early loss of pregnenolone production in the brain, without a matching loss of thyroid function.[65] The brain is one of the body's largest steroid-forming organs, with progesterone, DHEA and pregnenolone far more concentrated there than in the blood, and making these neurosteroids is one of its major uses of oxygen.[66]

Brains affected by Alzheimer's disease metabolize glucose poorly, and high cortisol adds to that defect and to the death of nerve cells.[67] Radiation also promotes the formation of amyloid, the plaque-forming protein incriminated in Alzheimer's disease and in degenerative lung, kidney and pancreatic disease.[68]

See also

[edit]


References

[edit]
  1. ↑ "The problem of Alzheimer's disease as a clue to immortality - Part 1," Ray Peat article
  2. ↑ "The problem of Alzheimer's disease as a clue to immortality - Part 2," Ray Peat article
  3. ↑ The problem of Alzheimer's disease as a clue to immortality Part 1, Ray Peat newsletter
  4. ↑ "The problem of Alzheimer's disease as a clue to immortality - Part 1," Ray Peat article
  5. ↑ "The problem of Alzheimer's disease as a clue to immortality - Part 1," Ray Peat article
  6. ↑ The problem of Alzheimer's disease as a clue to immortality Part 1, Ray Peat newsletter
  7. ↑ "The problem of Alzheimer's disease as a clue to immortality - Part 1," Ray Peat article
  8. ↑ Minhas PS, Andreasson KI, et al. "PGE2-EP2 signaling drives brain aging," Nature. 2021. PMID 33473210.
  9. ↑ Pogue AI, et al. "LPS, miRNA-30b, and neurofilament light chain," Front Neurol. 2022. doi:10.3389/fneur.2022.900048.
  10. ↑ "The problem of Alzheimer's disease as a clue to immortality - Part 1," Ray Peat article
  11. ↑ Fats, functions and malfunctions., Ray Peat newsletter
  12. ↑ "The problem of Alzheimer's disease as a clue to immortality - Part 1," Ray Peat article
  13. ↑ "The problem of Alzheimer's disease as a clue to immortality - Part 1," Ray Peat article
  14. ↑ Waldron FM et al. 2026. "Brain iron as a surrogate biomarker of pathological TDP-43 identifies brain region-specific signatures in aging, and disease," Acta Neuropathol Commun. 2026. doi:10.1186/s40478-026-02433-5. Cross-sectional; hippocampal involvement rose 4.5-fold after age 60; significant ferritin associations were region-specific.
  15. ↑ Snowden SG, Ebshiana AA, Hye A, et al. "Association between fatty acid metabolism in the brain and Alzheimer disease neuropathology and cognitive performance: A nontargeted metabolomic study," PLoS Med. 2017;14(3):e1002266. doi:10.1371/journal.pmed.1002266. PMID 28323825.
  16. ↑ Lesné S, Ashe KH, et al. "Aβ*56 impairs memory in mice," Nature. 2006. PMID 16541076.
  17. ↑ Goodman LD, et al. "Tau is required for glial lipid droplet formation and resistance to neuronal oxidative stress," Nat Neurosci. 2024;27:1918-1933.
  18. ↑ "The problem of Alzheimer's disease as a clue to immortality - Part 2," Ray Peat article
  19. ↑ "The problem of Alzheimer's disease as a clue to immortality - Part 2," Ray Peat article
  20. ↑ Progesterone Pregnenolone & DHEA - Three Youth-Associated Hormones, Ray Peat newsletter
  21. ↑ "The problem of Alzheimer's disease as a clue to immortality - Part 2," Ray Peat article
  22. ↑ "Progesterone Pregnenolone & DHEA - Three Youth-Associated Hormones," Ray Peat article
  23. ↑ "The problem of Alzheimer's disease as a clue to immortality - Part 1," Ray Peat article
  24. ↑ Hernandez GD, Brinton RD, et al. "Allopregnanolone: regenerative therapeutic to restore neurological health," Neurobiol Stress. 2022. doi:10.1016/j.ynstr.2022.100502.
  25. ↑ Family N, et al. "Safety of microdose LSD in volunteers," Psychopharmacology. 2020. doi:10.1007/s00213-019-05417-7.
  26. ↑ Smith GS, Workman CI, Protas H, et al. "Positron emission tomography imaging of serotonin degeneration and beta-amyloid deposition in late-life depression," Transl Psychiatry. 2021. doi:10.1038/s41398-021-01539-9.
  27. ↑ Watamura N, Kakiya N, Fujioka R, et al. "The dopaminergic system promotes neprilysin-mediated degradation of amyloid-β in the brain," Sci Signal. 2024;17(848):eadk1822. doi:10.1126/scisignal.adk1822. PMID 39106321.
  28. ↑ Sun Y, Peng Y, Hart RP, et al. "Estradiol-progesterone ratio and Alzheimer's pathology," Nat Commun. 2025. doi:10.1038/s41467-025-66726-4.
  29. ↑ Orticello M, Cavallaro RA, Antinori D, et al. "Amyloidogenic and Neuroinflammatory Molecular Pathways Are Contrasted Using Menaquinone 4 (MK4) and Reduced Menaquinone 7 (MK7R) in Association with Increased DNA Methylation in SK-N-BE Neuroblastoma Cell Line," Cells. 2023;13(1):58. doi:10.3390/cells13010058. PMID 38201262.
  30. ↑ Sun Y, et al. "NAD depletion in autophagy-deficient neurons," Cell Rep. 2023. doi:10.1016/j.celrep.2023.112372.
  31. ↑ Hirota Y, et al. "Vitamin K-retinoic acid hybrids for neurodegeneration," ACS Chem Neurosci. 2025. doi:10.1021/acschemneuro.5c00111.
  32. ↑ Li X, Zhang C, Fang Y, Xin M, Shi J, Zhang Z, Wang Z, Ren Z. "Promising outcomes 5 weeks after a surgical cervical shunting procedure to unclog cerebral lymphatic systems in a patient with Alzheimer's disease," Gen Psychiatr. 2024;37(3):e101641. doi:10.1136/gpsych-2024-101641. PMID 39816183.
  33. ↑ Vakhtin AA, Lin HC, Pirio Richardson SE, Shaff NA, Ryman SG. "Harnessing brain rhythms to activate the glymphatic pathway via controlled breathing and intermittent CO2," J Cereb Blood Flow Metab. 2026. doi:10.1177/0271678X251399120.
  34. ↑ Teo E, Ravi S, Barardo D, et al. "Metabolic stress is a primary pathogenic event in transgenic Caenorhabditis elegans expressing pan-neuronal human amyloid beta," eLife. 2019. doi:10.7554/eLife.50069.
  35. ↑ Chaubey K, Vázquez-Rosa E, Tripathi SJ, et al. "Pharmacologic reversal of advanced Alzheimer's disease in mice and identification of potential therapeutic nodes in human brain," Cell Rep Med. 2026;7(1):102535. doi:10.1016/j.xcrm.2025.102535. PMID 41435831.
  36. ↑ Currais A, et al. "Elevating acetyl-CoA levels reduces aspects of brain aging," eLife. 2019;8:e47866. PMID 31742554.
  37. ↑ Wang ZL, et al. "Vitamin A, gut barrier, and amyloid pathology," Front Nutr. 2024. doi:10.3389/fnut.2024.1367086.
  38. ↑ Goldansaz H, Ametaj BN, et al. "LPS and prion protein neurodegeneration," Int J Mol Sci. 2025. doi:10.3390/ijms26136245.
  39. ↑ Bondonno CP, et al. "Nitrate intake and incident dementia," Alzheimers Dement. 2025. doi:10.1002/alz.70995.
  40. ↑ Puccio S, Chu J, Praticò D. "Involvement of 5-lipoxygenase in the corticosteroid-dependent amyloid beta formation: in vitro and in vivo evidence," PLoS One. 2011;6(1):e15163. doi:10.1371/journal.pone.0015163. PMID 21253592.
  41. ↑ Jahreis G, Ponimaskin E, et al. "Amisulpride as disease-modifying therapy in tauopathies," Alzheimers Dement. 2023. doi:10.1002/alz.13090.
  42. ↑ Engler-Chiurazzi EB, Russell AE, Povroznik JM, et al. "Intermittent systemic exposure to lipopolysaccharide-induced inflammation disrupts hippocampal long-term potentiation and impairs cognition in aging male mice," Brain Behav Immun. 2023;108:279-291. doi:10.1016/j.bbi.2022.12.013. PMID 36549577.
  43. ↑ Ghahremani P, Ismail Z, et al. "Vitamin D supplementation and incident dementia," Alzheimers Dement (Amst). 2023. doi:10.1002/dad2.12404.
  44. ↑ Nguyen TA, et al. "Low-dose aspirin and dementia in CHD," Alzheimers Res Ther. 2022. doi:10.1186/s13195-022-01017-4.
  45. ↑ Navale SM, et al. "Vitamin D and brain health," Am J Clin Nutr. 2022. doi:10.1093/ajcn/nqac107.
  46. ↑ Dougal A, et al. "Transcranial near-infrared light and memory performance," Photobiomodul Photomed Laser Surg. 2021. doi:10.1089/photob.2020.4956.
  47. ↑ Morris JK, et al. "Mitochondrial respiration in mild cognitive impairment," Function. 2021. doi:10.1093/function/zqab045.
  48. ↑ Gibson GE, et al. "Benfotiamine and cognitive decline in Alzheimer disease," J Alzheimers Dis. 2020. doi:10.3233/JAD-200896.
  49. ↑ Brown DR, et al. "The endotoxin hypothesis of Alzheimer's disease," Mol Neurodegener. 2024. doi:10.1186/s13024-024-00722-y. PMID 38561809.
  50. ↑ Zhang R et al. 2009. "Circulating endotoxin and systemic immune activation in sporadic amyotrophic lateral sclerosis (sALS)." J Neuroimmunol 206(1-2):121-124. PMID 19013651. PMC2995297. Plasma LPS 61±42 pg/mL in AD (n=18, mean age 78.9) vs 21±6 in controls (mean age 54.5); monocyte HLA-DR 943±417 vs 495±136, p<0.001; LPS vs HLA-DR in AD r=0.69. Primary cohort was sALS; AD was a disease-control group.
  51. ↑ Dominy SS, Lynch C, Ermini F, et al. "Porphyromonas gingivalis in Alzheimer's disease brains: Evidence for disease causation and treatment with small-molecule inhibitors," Sci Adv. 2019;5(1):eaau3333. doi:10.1126/sciadv.aau3333. PMID 30746447. Post-mortem tissue microarrays plus mouse study; RgpB in 96% (51/53) and Kgp in 91% (49/54) of AD samples vs 39% (18/46) and 52% (26/50) of non-demented controls; gingipain load correlated with tau and ubiquitin.
  52. ↑ Lei S, Li J, Yu J, et al. "Porphyromonas gingivalis bacteremia increases the permeability of the blood-brain barrier via the Mfsd2a/Caveolin-1 mediated transcytosis pathway," Int J Oral Sci. 2023;15(1):3. doi:10.1038/s41368-022-00215-y. PMID 36631446. Rat study; tail-vein injection three times a week for 8 weeks; more Evans blue and albumin in brain tissue; plus in vitro barrier model.
  53. ↑ Gong T, Chen Q, Mao H, et al. "Outer membrane vesicles of Porphyromonas gingivalis trigger NLRP3 inflammasome and induce neuroinflammation, tau phosphorylation, and memory dysfunction in mice," Front Cell Infect Microbiol. 2022;12:925435. doi:10.3389/fcimb.2022.925435. PMID 36017373. Mouse study; 14-month-old mice, 4 mg/kg outer membrane vesicles by gavage every other day for 8 weeks; lower hippocampal tight-junction proteins, higher IL-1β and tau phosphorylation.
  54. ↑ Schelter BO, Shiells H, Baddeley TC, et al. "Concentration-Dependent Activity of Hydromethylthionine on Cognitive Decline and Brain Atrophy in Mild to Moderate Alzheimer's Disease," J Alzheimers Dis. 2019;72(3):931-946. doi:10.3233/jad-190772. PMID 31658058. doi:10.3233/JAD-190772.
  55. ↑ Marchant NL, Lovland LR, Jones R, et al. "Repetitive negative thinking is associated with amyloid, tau, and cognitive decline," Alzheimers Dement. 2020;16(7):1025-1034. doi:10.1002/alz.12116. PMID 32508019.
  56. ↑ Kessing LV, Gerds TA, Knudsen NN, Jørgensen LF, Kristiansen SM, Voutchkova D, Ernstsen V, Schullehner J, Hansen B, Andersen PK, Ersbøll AK. "Association of lithium in drinking water with the incidence of dementia," JAMA Psychiatry. 2017;74(10):1005-1010. doi:10.1001/jamapsychiatry.2017.2362. PMID 28832877. PMCID PMC5710473. Nationwide nested case-control study.
  57. ↑ Aron L, Ngian ZK, Qiu C, Choi J, Liang M, Drake DM, Hamplova SE, Lacey EK, Roche P, Yuan M, Hazaveh SS, Lee EA, Bennett DA, Yankner BA. "Lithium deficiency and the onset of Alzheimer's disease," Nature. 2025;645(8081):712-721. doi:10.1038/s41586-025-09335-x. PMID 40770094. PMCID PMC12443616. Human post-mortem brain tissue and mouse study.
  58. ↑ Jernerén F, Elshorbagy AK, Oulhaj A, Smith SM, Refsum H, Smith AD. "Brain atrophy in cognitively impaired elderly: the importance of long-chain ω-3 fatty acids and B vitamin status in a randomized controlled trial," American Journal of Clinical Nutrition. 2015;102(1):215-221. doi:10.3945/ajcn.114.103283. PMID 25877495. Retrospective analysis of the VITACOG RCT.
  59. ↑ Oulhaj A, Jernerén F, Refsum H, Smith AD, de Jager CA. "Omega-3 fatty acid status enhances the prevention of cognitive decline by B vitamins in mild cognitive impairment," Journal of Alzheimer's Disease. 2016;50(2):547-557. doi:10.3233/JAD-150777. PMID 26757190. PMCID PMC4927899. Post hoc analysis of the VITACOG RCT.
  60. ↑ Ray Peat, "Vitamins & Minerals: Lowering Homocysteine", Ray Peat Forum
  61. ↑ Ray Peat, "EastWest Healing: The Science Behind The Dangers of Polyunsaturated Fats", EastWest Healing, 2010, 31:26
  62. ↑ Morris MC, Schneider JA, Li H, Tangney CC, Nag S, Bennett DA, Honer WG, Barnes LL. "Brain tocopherols related to Alzheimer's disease neuropathology in humans," Alzheimers Dement. 2015;11(1):32-39. doi:10.1016/j.jalz.2013.12.015. PMID 24589434. PMCID PMC4148466. Autopsy study, Rush Memory and Aging Project: 115 deceased participants, 113 analyzed (two extreme tocopherol values excluded), mean age at death 88.5. Tocopherols measured in midfrontal and inferior temporal cortex and two subcortical regions; models adjusted for age, sex, education, APOE-ε4 and death-to-autopsy interval. Per log10 unit of brain γ-tocopherol: amyloid load β = −2.10 (P = .002), neurofibrillary tangle severity β = −1.16 (P = .02). α-Tocopherol alone was not associated; high α-tocopherol went with more amyloid when γ-tocopherol was low and less amyloid when γ-tocopherol was high (P for interaction = 0.03). Observational; cannot show cause.
  63. ↑ Tanprasertsuk J, Mohn ES, Matthan NR, Lichtenstein AH, Barger K, Vishwanathan R, Johnson MA, Poon LW, Johnson EJ. "Serum Carotenoids, Tocopherols, Total n-3 Polyunsaturated Fatty Acids, and n-6/n-3 Polyunsaturated Fatty Acid Ratio Reflect Brain Concentrations in a Cohort of Centenarians," J Gerontol A Biol Sci Med Sci. 2019;74(3):306-314. doi:10.1093/gerona/gly125. PMID 29893813. Georgia Centenarian Study, n = 47, serum vs matched frontal and temporal cortex; adjusted for sex, race, cognitive status, BMI, hypertension and diabetes; significant serum-brain relationship (p < 0.05) for α- and γ-tocopherol, carotenoids, total n-3 PUFA and n-6/n-3 ratio; inconsistent for total n-6 PUFA; none for retinol, saturated, monounsaturated or trans fats.
  64. ↑ "BSE, Mad Cow, Scrapie, etc.: Stimulated amyloid degeneration and the toxic fats," raypeat.com
  65. ↑ Ray Peat, "Multiple sclerosis and other hormone-related brain syndromes," raypeat.com.
  66. ↑ Ray Peat, "Ask the Herb Doctor: Dementia and Progesterone", https://www.toxinless.com/kmud-121221-dementia-progesterone.mp3, 12:52
  67. ↑ Ray Peat, "Serotonin: effects in disease, aging and inflammation," raypeat.com.
  68. ↑ Ray Peat, "Politics & Science: Ionizing Radiation in Context Part 2", https://www.toxinless.com/polsci-090427-radiation-2.mp3, 9:01