Cell-type-directed network-correcting combination therapy for Alzheimer’s disease
Reversing Alzheimer’s damage: Two cancer drugs demonstrate surprising power
Since MR which is basically genetic studies are one of the best tools in medicine for predicting disease and finding drugs (drugs which have genetic support have higher likelihood of succeeding), could slow progress in Alzheimer’s Disease and dementia be because of genetic research underpinning cognitive decline with age being controversial?
Recently, claims of improved prediction of cognitive ability: predictor correlation of ~ 0.4 or 0.5 with actual IQ scores. I wrote ~15 years ago that we would surpass this level of prediction, given enough data. I have maintained for a long time that complex trait prediction is largely data-limited. Progress has been slow as there is almost zero funding to accumulate cognitive scores in large biobanks. This is because of persistent ideological attacks against this area of research.
Almost all researchers in genomics recognize human cognitive ability as an important phenotype. For example, cognitive decline with age should be studied carefully at a genetic level, which requires creation of these datasets. However most researchers are AFRAID to voice this in public because they will be attacked by leftists.
I note that as the Overton window opens some cowardly researchers who were critical of GP [genomic prediction] in its early days (even for disease risk reduction!) are now supporting companies that openly advertise embryo IQ selection.
https://x.com/hsu_steve/status/1951263974747488601#m
I don’t personally care that much about IQ/intelligence, health seem like most important especially in the age of AI, I don’t think anyone believes their kids or grandkids will be smarter than AI. But controversy surrounding genetic research for cognitive abilities might slow down some forms of research that can help with cognitive aging.
Genetics is the most important area of medicine for sure, except randomized trials of course.
Neurofilament light chain (NfL) is a new blood test that can be used to screen for neurodegenerative conditions. It has good sensitivity but lacks specificity. Linked below is a short article from Mayo. The neuroscientist notes that:
“If NfL is elevated, the patient’s cognitive decline is likely due to neurodegeneration. If NfL is normal, then the most likely cause of cognitive decline is a non-neurodegenerative process,” Dr. Algeciras says.
”“A blood test for NfL is a feasible screening tool that can reduce the number of tests that physicians order up front, which will obviously have an economic benefit.”
In other words, it can be used for screening, and then if the result is elevated, additional tests can be done to determine the cause. It may allow people to catch a neurodegenerative process early.
Marek Diagnostics offers it through Labcorp for $406.
https://news.mayocliniclabs.com/2022/05/17/nflc-test-in-focus/
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A new study, which included 2,100 older Americans at risk of dementia, found significant improvement in cognition by incorporating regular moderate to high-intensity physical exercise, adherence to what’s known as the mind diet, such as grains, leafy greens, and berries, mandatory social engagement, as well as cardiovascular health monitoring.
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Alzheimer’s disease may start in your gut, new research finds
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Lithium Battery of Tests
Did researchers just find a glimmer of hope in the quest to fight Alzheimer’s? “Seven years of investigation by scientists at Harvard Medical School have revealed that the loss of the metal lithium plays a powerful role in Alzheimer’s disease, a finding that could lead to earlier detection, new treatments and a broader understanding of how the brain ages. Researchers led by Bruce A. Yankner, professor of genetics and neurology at Harvard Medical School, reported that they were able to reverse the disease in mice and restore brain function with small amounts of the compound lithium orotate, enough to mimic the metal’s natural level in the brain.” Research on reversing Alzheimer’s reveals lithium as potential key.
Open access paper:
Lithium deficiency and the onset of Alzheimer’s disease
The earliest molecular changes in Alzheimer’s disease (AD) are poorly understood1,2,3,4,5. Here we show that endogenous lithium (Li) is dynamically regulated in the brain and contributes to cognitive preservation during ageing. Of the metals we analysed, Li was the only one that was significantly reduced in the brain in individuals with mild cognitive impairment (MCI), a precursor to AD. Li bioavailability was further reduced in AD by amyloid sequestration. We explored the role of endogenous Li in the brain by depleting it from the diet of wild-type and AD mouse models. Reducing endogenous cortical Li by approximately 50% markedly increased the deposition of amyloid-β and the accumulation of phospho-tau, and led to pro-inflammatory microglial activation, the loss of synapses, axons and myelin, and accelerated cognitive decline. These effects were mediated, at least in part, through activation of the kinase GSK3β. Single-nucleus RNA-seq showed that Li deficiency gives rise to transcriptome changes in multiple brain cell types that overlap with transcriptome changes in AD. Replacement therapy with lithium orotate, which is a Li salt with reduced amyloid binding, prevents pathological changes and memory loss in AD mouse models and ageing wild-type mice. These findings reveal physiological effects of endogenous Li in the brain and indicate that disruption of Li homeostasis may be an early event in the pathogenesis of AD. Li replacement with amyloid-evading salts is a potential approach to the prevention and treatment of AD.
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Also discussed there:
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low dose lithium orotate would seem to be a no-brainer
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Cerebrospinal fluid lipoprotein-mediated cholesterol delivery to neurons is impaired in Alzheimer’s disease and involves APOE4
https://www.jlr.org/article/S0022-2275(25)00127-0/fulltext
Pop sci article:
Scientists Uncover Hidden Link Between Cholesterol Flow and Alzheimer’s Disease
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Lead researcher Mary Ni Lochlainn, King’s College London (KCL), and colleagues asked whether adding a daily prebiotic to a modest protein supplement and light resistance exercise could affect cognition in older twins.
The team enrolled 36 pairs, each aged 60 or older, and assigned one twin to inulin plus fructooligosaccharides while the co-twin received a placebo, all under double blind conditions.
Everyone received the same branched chain amino acid protein powder and simple at home strength moves.
The 12 week protocol ran remotely using video visits, online questionnaires, and posted kits for cognitive testing and stool samples.
The twin design reduced genetic and early environmental noise. That choice made any between twin differences more likely to reflect the supplement rather than family background or shared habits.
Fructooligosaccharides and memory
The prebiotic group scored higher on a combined cognition factor and made fewer errors on the PAL test, a visual paired associated task sensitive to early Alzheimer’s related change.
That pattern fits with decades of work showing PAL detects subtle episodic memory problems before many standard clinic scales do.
“We are excited to see these changes in just 12 weeks. This holds huge promise for enhancing brain health and memory in our ageing population,” said Dr. Lochlainn.
The specific test improvement matters because paired associates learning taps the ability to form new connections between locations and patterns.
That is a core function that erodes early in Alzheimer’s, so even small gains on this task are notable in people over 60.
Open access paper:
Effect of gut microbiome modulation on muscle function and cognition: the PROMOTe randomised controlled trial
Abstract
Studies suggest that inducing gut microbiota changes may alter both muscle physiology and cognitive behaviour. Gut microbiota may play a role in both anabolic resistance of older muscle, and cognition. In this placebo controlled double blinded randomised controlled trial of 36 twin pairs (72 individuals), aged ≥60, each twin pair are block randomised to receive either placebo or prebiotic daily for 12 weeks. Resistance exercise and branched chain amino acid (BCAA) supplementation is prescribed to all participants. Outcomes are physical function and cognition. The trial is carried out remotely using video visits, online questionnaires and cognitive testing, and posting of equipment and biological samples. The prebiotic supplement is well tolerated and results in a changed gut microbiome [e.g., increased relative Bifidobacterium abundance]. There is no significant difference between prebiotic and placebo for the primary outcome of chair rise time (β = 0.579; 95% CI −1.080-2.239 p = 0.494). The prebiotic improves cognition (factor score versus placebo (β = −0.482; 95% CI,−0.813, −0.141; p = 0.014)). Our results demonstrate that cheap and readily available gut microbiome interventions may improve cognition in our ageing population. We illustrate the feasibility of remotely delivered trials for older people, which could reduce under-representation of older people in clinical trials. ClinicalTrials.gov registration: NCT04309292
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Thx, I forwarded your article to my eye doc and he shared this related paper:
“Biomarkers from retinal OCTA images can provide useful information for clinical decision-making and diagnosis of AD and MCI.”
Apparently he has been taking OCTA images on my eyes (who knew!?!). He has been doing it with the idea that once he acquires the ability, he will go back to our past results and use AI algorithms to pick up early signs of dementia.
(He’s Bay Area for anyone local who interested).
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Today I had the back of my eyes and retinas photographed - small healthy blood vessels - nothing out of place. No cateract development, optic nerve great. Cost was $39. Cheap.
After seeing this article on eye exams - glad I paid the small extra for pics over the free look - drops to dialate and look. Like having a record for any future changes is great…
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Glad you had the test and that is an excellent price!
Also, PSA: I had not had my eyes dilated in many years, but I actually met someone who had eye cancer and then passed… a simple eye exam would have found it early.
My doc found a tiny spot on my eye and sent me to Stanford just to make sure it was nothing, and now I go every year.
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More on the amazing supplement lithium orotate.
Lithium deficiency may be the hidden spark behind Alzheimer’s | ScienceDaily
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Regarding the article “More than simply leftovers: a new link between remnant cholesterol and dementia” posted by @A_User, I wanted to see where my lipids put me, compared to the people in this study. In case anyone else is interested in doing this, below is the information that I used.
The article states:
When the population was stratified by remnant-C quartiles, higher remnant-C concentrations were incrementally associated with higher risks of developing all-cause dementia, Alzheimer’s disease, and vascular dementia after adjusting for age, sex, and additional confounders such as income level, BMI, comorbidities, statin and fibrate use, and total cholesterol concentration.
Per Wikipedia:
Remnant cholesterol corresponds to all cholesterol not found in high-density lipoprotein (HDL-C) and low-density lipoprotein (LDL-C). It is calculated as total cholesterol minus HDL-C and LDL-C.
The full text of the paper on the study covered in the article is linked from PubMed: Association of remnant cholesterol with risk of dementia: a nationwide population-based cohort study in South Korea - PubMed.
The quartiles in this study have the following mean (SD) remnant-C values, in mg/dL (from table 1 in the paper):
Quartile 1: 14.66 (1.83)
Quartile 2: 19.49 (1.33)
Quartile 3: 24.67 (1.74)
Quartile 4: 35.53 (6.62)
If you don’t fall in quartile 1, you may want to examine table 2 in the paper for hazard ratios.
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