Urea's role in dementia

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Julie G
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Urea's role in dementia

Postby Julie G » Wed Dec 13, 2017 7:58 am

Good morning, beautiful people! I'm confused :?. Over the past few days I've been reading press releases like this and this claiming urea Is the MAJOR cause of dementia. I tracked down the primary source (below) and see that it's based on a paper using a sheep model focused on Huntington's disease, in which cognitive symptoms can also be present, although it's primarily a motor disorder.

Brain urea increase is an early Huntington’s disease pathogenic event observed in a prodromal transgenic sheep model and HD cases
http://www.pnas.org/content/early/2017/12/05/1711243115
Abstract
The neurodegenerative disorder Huntington’s disease (HD) is typically characterized by extensive loss of striatal neurons and the midlife onset of debilitating and progressive chorea, dementia, and psychological disturbance. HD is caused by a CAG repeat expansion in the Huntingtin (HTT) gene, translating to an elongated glutamine tract in the huntingtin protein. The pathogenic mechanism resulting in cell dysfunction and death beyond the causative mutation is not well defined. To further delineate the early molecular events in HD, we performed RNA-sequencing (RNA-seq) on striatal tissue from a cohort of 5-y-old OVT73-line sheep expressing a human CAG-expansion HTT cDNA transgene. Our HD OVT73 sheep are a prodromal model and exhibit minimal pathology and no detectable neuronal loss. We identified significantly increased levels of the urea transporter SLC14A1 in the OVT73 striatum, along with other important osmotic regulators. Further investigation revealed elevated levels of the metabolite urea in the OVT73 striatum and cerebellum, consistent with our recently published observation of increased urea in postmortem human brain from HD cases. Extending that finding, we demonstrate that postmortem human brain urea levels are elevated in a larger cohort of HD cases, including those with low-level neuropathology (Vonsattel grade 0/1). This elevation indicates increased protein catabolism, possibly as an alternate energy source given the generalized metabolic defect in HD. Increased urea and ammonia levels due to dysregulation of the urea cycle are known to cause neurologic impairment. Taken together, our findings indicate that aberrant urea metabolism could be the primary biochemical disruption initiating neuropathogenesis in HD.

My confusion arises over previous work, suggesting that gout (hyperuricemia) may actually PROTECT against dementia. Here's a press release from several years ago on the topic. Below see full-text of original paper:

Gout and the Risk of Alzheimer’s Disease: A Population-Based Cohort Study
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4560667/
Abstract
Objective

While gout is associated with cardiovascular (CV)-metabolic comorbidities and their sequelae, the antioxidant effects of uric acid may have neuroprotective benefits. We evaluated the potential impact of incident gout on the risk of developing Alzheimer’s disease (AD) in a general population context.

Methods

We conducted an age-matched, sex-matched, entry-time-matched and body mass index (BMI)-matched cohort study using data from The Health Improvement Network, an electronic medical record database representative of the UK general population, from 1 January 1995 to 31 December 2013. Up to five non-gout individuals were matched to each case of incident gout by age, sex, year of enrolment and BMI. We compared incidence rates of AD between the gout and comparison cohorts, excluding individuals with prevalent gout or dementia at baseline. Multivariate hazard ratios (HRs) were calculated, while adjusting for smoking, alcohol use, physician visits, social deprivation index, comorbidities and medication use. We repeated the same analysis among patients with incident osteoarthritis (OA) as a negative control exposure.

Results

We identified 309 new cases of AD among 59 224 patients with gout (29% female, mean age 65 years) and 1942 cases among 238 805 in the comparison cohort over a 5-year median follow up (1.0 vs 1.5 per 1000 person-years, respectively). Univariate (age-matched, sex-matched, entry-time-matched and BMI-matched) and multivariate HRs for AD among patients with gout were 0.71 (95% CI 0.62 to 0.80) and 0.76 (95% CI 0.66 to 0.87), respectively. The inverse association persisted among subgroups stratified by sex, age group (<75 and ≥75 years), social deprivation index and history of CV disease. The association between incident OA and the risk of incident AD was null.

Conclusions

These findings provide the first general population-based evidence that gout is inversely associated with the risk of developing AD, supporting the purported potential neuroprotective role of uric acid.

Anybody else confused? Does the answer lie in the difference between urea and uric acid outlined here. Is it possible that one (uric acid) is protective while the other (urea) is harmful? Or, just another red herring...

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Re: Urea's role in dementia

Postby rws » Wed Dec 13, 2017 8:38 am

Julie G wrote:Does the answer lie in the difference between urea and uric acid outlined here. Is it possible that one (uric acid) is protective while the other (urea) is harmful? Or, just another red herring...


Very possible. Both substances are very different chemically, and we know that even slight changes in chemical structure make a big difference. It's only the name.

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Re: Urea's role in dementia

Postby Julie G » Wed Dec 13, 2017 5:17 pm

Very possible. Both substances are very different chemically, and we know that even slight changes in chemical structure make a big difference. It's only the name.

Thanks, rsw. YES, although they’re very different, they both serve to eliminate excess nitrogen. Urea from the catabolism of proteins and uric acid from the catabolism of purine nucleotides Adenine and Guanine - the As and Gs in our DNA. I’m also guessing that elevated levels of each have very different clinical presentations.

Here's a really helpful blog post by Self-Hacked on urea that dives into the related SNPs with a confirmed link to Alzheimer’s. Interesting stuff. 23andMe reports on many and I score badly although my BUN is typically low to mid-range. Back to uric acid, since a diet high in purines is thought to contribute to gout, it makes me wonder if targeting specific purine-rich foods (like seafood and organ meats) could protect against AD?

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Re: Urea's role in dementia

Postby sarahb12 » Wed Dec 13, 2017 5:45 pm

I wonder if ppl with gout lock it in places other than the brain.

I wonder what countermeasures might work (or make worse) For gout, I know water and acidic stuff (like tart cherry juice) helps.


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Julie G
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Re: Urea's role in dementia

Postby Julie G » Thu Dec 14, 2017 9:51 am

I wonder if ppl with gout lock it in places other than the brain.

I wonder what countermeasures might work (or make worse) For gout, I know water and acidic stuff (like tart cherry juice) helps.

Hey, Sarah! If I'm reading the tea leaves correctly, it looks like gout (high uric acid) is neuroprotective. Not sure we'd want to use countermeasures...

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Re: Urea's role in dementia

Postby sarahb12 » Sun Dec 17, 2017 11:40 pm

Right. That's what I was trying to say - it locks it in the gouty places, thereby keeping it out of the brain.
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Re: Urea's role in dementia

Postby Julie G » Mon Dec 18, 2017 3:57 pm

Duh, gotcha ;). You mention methylene blue in the brain infection thread. FWIW, I also think it could serve as an aid in high urea as it also addresses ammonia and nitrite poisoning...

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Re: Urea's role in dementia

Postby Gilgamesh » Mon Dec 18, 2017 10:55 pm

I just found out I have extremely low uric acid (2.7 mg/dL).... Another thing to worry about (though I think I'll let this one slide).

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Re: Urea's role in dementia

Postby Vikingman » Sun Feb 09, 2020 5:57 pm

I discovered in Viome that my uric acid pathways were stressed and they recommended eating less high purine foods. I was eating tons of sardines and lots of purine foods and inflammation in my knees and shoulders really flared up. Could hardly walk on some days. I cut out the purines and now all the inflammation is gone in my knees and shoulders. Life is so much better. I was wanting to get my DHA from Salmon Roe but that looks like one of the highest sources of purine foods in existence. Also I see that you are thinking uric acid is possible protective against Alzheimer's possibly. I would much rather have debilitating joints than Alzheimer's. Maybe I can just eat the salmon roe and get the good and bad consequences.

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Re: Urea's role in dementia

Postby apoe4thebetter » Fri Jan 22, 2021 4:29 pm

Just found this thread and wanted to ask if there is a preferred reference range for uric acid for E4s? I didn’t see anything about uric acid in either of Dr. Bredesen's books (might have missed it). I would understand if the confusing data about it caused it to be omitted for now as one of the “holes in the roof”.

Other experts I’ve heard (eg. Dr. Peter Attia, Dr. Rick Johnson) recommend lower uric acid numbers because of its potential negative effects, and I realize that their recommendations are to a different audience. This thread is the first time I had heard the flip side that uric acid is an antioxidant and may be neuroprotective. For now my preference is to keep it on the lower side, but I’d be interested to know if there is a preferred uric acid range for E4s?
apoe4thebetter | 3/4 | currently doing keto experiments to work through A1c and LDL challenges


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