The 26 remaining compounds decreased in dementia patients (P < 0.05) (Fig. 1 B–E). They consisted of four subgroups (B to E), having distinct characteristics. Group B compounds include ET and five other trimethyl-ammonium compounds. To our knowledge, except for ET (17), these are all not previously reported as dementia markers, probably because they are enriched in RBCs and scarcely studied in connection with dementia. ET is an antioxidant, a thiourea derivative of trimethyl-histidine. Two other ET-related, but less abundant, compounds, S-methyl-ET and trimethyl-histidine (hercynine), also declined strikingly in blood of dementia patients.
Group C compounds also decreased in dementia patients. These included ATP, NADP+ (oxidoreductive coenzyme), GSSG (redox compound), pantothenate (vitamin B5), S-adenosyl-methionine (SAM; methyl donor) (21), and gluconate (zinc carrier) (22). They are related to energy, redox reactions, methylation, and metal ions. Group C compounds were all enriched in RBCs, and four of the six are not previously reported as dementia markers. Two of them (SAM and GSSG) were previously shown to be AD-related (21, 23).
Trimethyl-tryptophan (hypaphorine), trimethyl-phenylalanine, glycerophosphocholine, dodecanoyl-carnitine (24), and trimethyl-tyrosine, all of which contain trimethyl-ammonium ions, also declined. The extent of reduction for trimethyl-tryptophan (0.10) and trimethyl-tyrosine (0.08) was striking. These reductions may be due to instability or reduced synthesis, or to reduced import in dementia patients. Of the nine compounds that contain a trimethyl-ammonium moiety, six of them that contain ET are enriched in RBCs and classified as group B compounds (Table 1).
Twelve group D metabolites (Table 1) are enriched in blood plasma and seven of them were previously reported to be dementia or AD markers. They include standard amino acids, glutamine (19, 25), phenylalanine (19, 26), tyrosine (19), histidine (19, 25), methionine, and tryptophan (regular amino acids) (18, 19), a pyrimidine nucleoside, uridine (27), and organic acids, 2-hydroxybutyrate (lipid-degradation product) and keto(iso)leucine (keto acid). Caffeine is a known dementia marker (28). Dimethyl-xanthine is a metabolite of caffeine. These greatly declined in dementia and are highly correlated with and isolated from other metabolites (see below) so they are designated as group E. Consistency of group D plasma metabolites as dementia markers but not group B and C RBC metabolites validated the method of searching dementia markers that we employed in the present study. The great majority of metabolites enriched in RBCs were not identified in the previous studies.
Nine trimethylated ammonium compounds were diminished in dementia patients.
Of nine trimethylated compounds that decreased in dementia, six are enriched in RBCs (SI Appendix, Fig. S2). Three of them (betaine, glycerophosphocholine, and dodecanoyl-carnitine) are present in plasma and are synthesized in the human body, whereas the other six, containing an aromatic moiety, are derived from food (29, 30). Most strikingly, six of these nine compounds are highly abundant (H, H-M, or H-L) in plasma and RBCs in healthy subjects, and are highly correlated so that their behavior may be highly coordinated. Hence, the sharp declines of these amphipathic compounds (possessing both hydrophilic and lipophilic properties and forming the basis of lipid polymorphism) in blood of dementia patients may strongly affect the physicochemical properties of neuronal systems.
Seven metabolites increased in dementia.
Interestingly, the seven metabolites of group A, comprising three nucleosides and four amino acid derivatives, increased in dementia (Fig. 1A). None was highly abundant and none was enriched in RBCs, and their increase in dementia occurred in plasma. Indoxyl-sulfate, kynurenine, and quinolinic acid (18) are involved in tryptophan metabolism and possibly act as excitatory toxins in the brain (31, 32), while N6-acetyl-lysine is implicated in histone and nonhistone protein modification (33). Pseudouridine, adenosine (19), and dimethyl-guanosine are degradation products of RNAs present in urine and are thought to be oxidized (34, 35). Increases of these metabolites in dementia are of great interest, as some are reportedly toxic in the central nervous system (CNS) and may lead to impairment of the brain (36⇓–38).
more on plasmalogens - Plasmalogens — MED-LIFE DISCOVERIES
Oral Supplementation of an Alkylglycerol Mix Comprising Different Alkyl Chains Effectively Modulates Multiple Endogenous Plasmalogen Species in Mice - PubMed
A study that looked at 2,252 adults aged 60 or older living in the US found that metabolic syndrome—defined as a combination of three or more symptoms, such as hyperglycemia, high blood pressure, or abdominal obesity—may hamper visual-spatial skills, attention, and processing speed. Participants with more features of metabolic syndrome performed worse on the test than others, with the most detrimental features being high blood glucose and blood pressure. In a study of 1,759 postmenopausal women in Denmark, high blood glucose levels and insulin resistance diminished verbal fluency, concentration, and memory. In Finland, a study that followed 3,695 adults aged 30-80 for more than a decade found that those with insulin resistance experienced the steepest declines in verbal fluency. Health records of 80,000 South Koreans aged over 60 revealed an 11 times higher chance of Alzheimer’s among people with metabolic syndrome.
Since insulin is so important in the brain, and severe insulin resistance underlies Type-2 diabetes, it follows that brain health worsens as diabetes sets in. Using data from more than 6,000 older adults who were part of the oft-cited Rotterdam cohort, one study found that diabetes almost doubles the risk of dementia. And a growing body of research suggests that diabetes significantly raises the risk of Alzheimer’s and more than doubles the risk of vascular dementia. A UK study of nearly 450,000 people aged between 40 and 69 looked at the relationship between blood glucose levels and the incidence of cognitive decline and dementia. People with prediabetic levels had 1.5 times the risk of vascular dementia compared to those whose blood sugar was in the normal range, and the risk was almost three times as much among those diagnosed with diabetes.
This result was backed up by a Spanish study that tested skills including verbal fluency and short-term memory in more than 1,800 adults with Type-2 diabetes and found that cognitive performance was better among patients who kept their blood glucose below a certain threshold. Evidence from Sweden has shown that dementia is diagnosed earlier in people with Type-2 diabetes, suggesting that young people with diabetes should be screened regularly to enable interventions that might delay cognitive decline.
photobiomodulation (could be an interesting intervention) esp at 40hz. MIT even published a few things on it
vielight also sticks the lgiht up the nose where it more easily accesses the regions (like EC) that the plaques and tangles of alzheimer’s disease first spreads from
https://www.nature.com/articles/s41598-019-46490-4
vielight allows you to try them out for 180 days before returning
https://twitter.com/BrainRepair_VGB
https://www.nature.com/articles/s41583-020-0269-3
https://colemanlab.brc.cam.ac.uk/blog/30-years-of-programmed-axon-death
MAYBE some of these: https://www.reddit.com/r/Peptides/comments/nkj7jq/peptides_for_cognition/ (super-experimental)
NAD+ supplements: NAD+ in Brain Aging and Neurodegenerative Disorders - PMC (CONTENT WARNING: SINCLAIR)
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coffee and dementia - https://www.frontiersin.org/articles/10.3389/fnagi.2021.744872/full
Another meta-analysis found that low (1–2 cups/day vs. <1 cup/day) but not high (>3 cups/day) coffee consumption was associated with a significantly reduced risk of AD and dementia [15].
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N-PEP-12, derived from cerebrolysin, is a peptide preparation produced enzymatically from purified nerve cell proteins that have been demonstrated to have multiple neurochemical and neurophysiological effects, many of which mimic the effects of NGF. N-PEP-12 has two main differences from CBL. First, it can be administered orally, whereas CBL administration is intravenous. Second, N-PEP-12 is less potent than CBL (Hernández-Hernández et al., 2018; Flores et al., 2020; Balea et al., 2021). In experimental studies using aged rats, N-PEP-12 has been shown to exert neuroprotective and pro-cognitive effects, increasing NTs, synapsis, plasticity biomarkers, the density of dendritic spines, and the total dendritic length in neurons of the PFC (layers 3 and 5) and hippocampi (CA1 and CA3). Thus, N-PEP-12 improves recognition memory and promotes neuronal plasticity (Hernández-Hernández et al., 2018; Balea et al., 2021).
look up more on superagers! they haven’t done longitudinal data on the subjects (tested them when younger) so the research is kinda sus but try it anyways
Ideally you want to be a superager (google for more info). They are rare but do exist. Scientists study ‘super-aging’ minds for clues to possible interventions . What Makes Someone a SuperAger?: Research: Feinberg School of Medicine: Northwestern University . Youthful memory capacity in old brains: anatomic and genetic clues from the Northwestern SuperAging Project - PubMed
Sapkota though that increasing the amount of long aquaporin 4 might increase waste clearance. Therefore, he screened 2,560 compounds for the ability to increase readthrough of the aquaporin 4 gene. He found two: apigenin, a dietary flavone found in chamomile, parsley, onions, and other edible plants; and sulphaquinoxaline, a veterinary antibiotic used in the meat and poultry industries.
Sapkota and Dougherty teamed up with Alzheimer’s researchers and co-authors John Cirrito, PhD, an associate professor of neurology, and Carla Yuede, PhD, an associate professor of psychiatry, of neurology, and of neuroscience, to figure out the relationship between long aquaporin 4 and amyloid beta clearance.
The scientists studied mice that were genetically engineered to have high levels of amyloid in their brains. They treated the mice with apigenin; sulphaquinoxaline; an inert liquid; or a placebo compound that has no effect on readthrough. Mice treated with either apigenin or sulphaquinoxaline cleared amyloid beta significantly faster than those treated with either of the two inactive substances.
“There’s a lot of data that says reducing amyloid levels by just 20% to 25% stops amyloid buildup, at least in mice, and the effects we saw were in that ballpark,” Cirrito said. “That tells me that this could be a novel approach to treating Alzheimer’s and other neurodegenerative diseases that involve protein aggregation in the brain. There’s nothing that says this process is specific for amyloid beta. It may be enhancing, say, alpha-synuclein clearance, too, which could benefit people with Parkinson’s disease.”
Sulphaquinoxaline is not safe for use in people. Apigenin is available as a dietary supplement, but it’s not known how much gets into the brain. Cirrito cautions against consuming large amounts of apigenin in an attempt to stave off Alzheimer’s. The scientists are working on finding better drugs that influence the production of the long form of aquaporin 4, testing several derivatives of sulphaquinoxaline and additional compounds.
Newest study no association, nothing on cellular level
RCT showed no effect of a single administration of tadalafil on CBF.
https://alz-journals.onlinelibrary.wiley.com/doi/full/10.1002/alz.12559
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some say… microdosing LSD (https://www.frontiersin.org/articles/10.3389/fnsyn.2020.00034/full ). Also supposedly LSD/DOI can clear out amyloid plaque
(Neuromyst). I try 40Hz at 3.7 mA
Brainstrobe light: Copy of Brain Strobe Light
(these are unlikely to be powerful enough, but w/e)
ONLINE COGNITIVE TESTS
https://wais-iv-symbol-search-f568d4.netlify.app/
https://www.reddit.com/r/cognitiveTesting/comments/jmzth2/comprehensive_online_resources_list/
https://www.reddit.com/r/cognitiveTesting/comments/10ivsqu/opening_the_tri_52_test/
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