Certainly in the brain tissue, because there it’s the astrocytes that produce cholesterol, not the hepatic tissue for example. That’s why I feel calcium signaling in astrocytes is key, and perhaps somehow atorvastatin is disrupting it, while simvastatin is not. If one could figure out what the difference is, it would be a huge step forward in unraveling the PD pathology.
Simvastatin worsened symptoms in a recent RCT in PD.
So the veterans study was a false signal? Interesting. OK, so maybe there is no discordance between the effects of statins on PD. In a way that’s a relief, because it was making my head hurt trying to figure out the mechanism that could account for the difference. Whew! However, this doesn’t take away from the original question, and actually makes it stronger: why do statins worsen PD?
Cholesterol is produced in the astrocytes, and if statins inhibit that production, and worsen PD, then what is the linking mechanism? It would imply something downstream from that, but presumably before the ApoE transporters get involved.
Reduction of Lewy body pathology by oral cinnamon
“Upon oral administration, cinnamon markedly reduced the level of insoluble α-syn in nigra, hippocampus and brain stem of A53T mice. We also demonstrated that sodium benzoate (NaB), a metabolite of cinnamon, a widely used food additive and a FDA-approved drug for glycine encephalopathy, was also capable of reducing α-syn deposits in A53T mice. In addition, both cinnamon and NaB treatments showed improvement in their motor and cognitive functions. Glial activation plays an important role in the pathogenesis of various neurodegenerative disorders including PD, DLB and MSA, and we found suppression of microglial and astroglial activation in the nigra of A53T mice upon cinnamon treatment. Moreover, neuroprotective proteins like DJ-1 and Parkin are known to reduce the formation of Lewy bodies in the CNS. Accordingly, we observed upregulation and/or normalization of DJ-1 and Parkin in the nigra of A53T mice by treatment with cinnamon and NaB. Together, these results highlight a new therapeutic property of cinnamon and suggest that cinnamon and NaB may be used to halt the progression of α-synucleinopathies.“
High LDL and apoB are protective in PD. That’s the most likely reason according to me.
OK, what part is protective and how? LDL transports cholesterol in the body, and ApoE in the brain. How does high LDL level protect the brain (in PD)? LDL doesn’t cross the BBB. I don’t believe that cholesterol transporting particles in the brain somehow protect against PD. Statins in the brain don’t affect LDL, but cholesterol synthesis. And incidentally, damaged ApoE, or I should say ineffective ApoE 4 variant is seen more often in AD, and might accellerate PD progression:
APOE ε4 influences Parkinson disease progression
GBA and APOE Impact Cognitive Decline in Parkinson’s Disease: A 10-Year Population-Based Study
Does anyone have access to the full text of this paper?
Comparative pharmacological study of free radical scavenger, nitric oxide synthase inhibitor, nitric oxide synthase activator and cyclooxygenase inhibitor against MPTP neurotoxicity in mice
Interpretation
Our findings suggest that exenatide is safe and well tolerated. We found no evidence to support exenatide as a disease-modifying treatment for people with Parkinson’s disease. Studies with agents that show better target engagement or in specific subgroups of patients are needed to establish whether there is any support for the use of GLP-1 receptor agonists for Parkinson’s disease.
https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(24)02808-3/fulltext
It’s available on Sci-Hub.
Some ISPs block scihub.
Caution, Chinese paper:
The link between renal failure and Parkinson’s disease: Researchers illuminate the underlying mechanisms
Quote:
"Essentially, the researchers found that the kidneys of patients presenting renal failure contained a large amount of the protein α-synuclein. They were then able to shed light on how this α-synuclein accumulation could lead to PD, specifically following the spread of this protein to the brain.
Zhang and his colleagues also showed that severing the connections between the kidneys and the brain in male mice blocked the accumulation of α-synuclein in the brain following renal failure. In the future, their study could inspire further research exploring the processes they uncovered, which could contribute to the development of therapeutic interventions aimed at slowing down or stopping the progression of PD and potentially other LBDs.
“The most notable finding of our study is that α-synuclein may originate from the kidney and spread to the brain,” added Zhang. “These observations suggest that eliminating circulating α-synuclein may be a possible way to halt the progression of PD. In our next studies, we will study the molecular mechanisms that mediate the deposition of α-synuclein in the kidney as well as the mechanisms that mediate the spread of α-synuclein pathology from the kidney to the brain.”
While obviously, mapping out the exact pathology of PD is of critical importance, the big drawback is the length of time it takes to accomplish that and develop appropriate interventions, new drugs etc., all taking years/decades, time PD patients don’t have.
I was therefore very happy to find this new approach to repurposing already FDA approved drugs for different indications toward PD treatment.
A network-based systems genetics framework identifies pathobiology and drug repurposing in Parkinson’s disease
https://www.nature.com/articles/s41531-025-00870-y
“Using the following criteria: (1) A stronger network proximity (Z < −3, p.adj.BH [q] <0.05); (2) Existing preclinical and experimental evidence of drugs related to PD; and (3) U.S. Food and Drug Administration (FDA)-approved drugs, we highlighted 12 candidate drugs, including Simvastatin, Fluvastatin, N-Acetylglucosamine, Azathioprine, Riluzole, Clotiazepam, Cyanocobalamin, Bromazepam, Hydroxocobalamin, Lacosamide, Pyridoxine, and Alprazolam (Fig. 6 and Supplementary Table S7)”
What caught my attention in particular was simvastatin and fluvastatin(?!). So, maybe simvastatin is not dead yet for PD?
High ApoB is protective from PD. So statin use seems protective but if you adjust for baseline ApoB it’s not.
A friend of mine just published this btw: Ten years preceding a diagnosis of neurodegenerative disease in Europe and Australia: medication use, health conditions, and biomarkers associated with Alzheimer’s disease, Parkinson’s disease, and amyotrophic lateral sclerosis 2025
A higher level of triglycerides was associated with a lower risk of AD, whereas a higher level of Apolipoprotein B was associated with a lower risk of PD, 5–10 years later.
A higher level of triglycerides was associated with a lower risk of AD 5–10 years later [0.69 (0.50–0.95)] (Table 2; Tables S30–S32). Similar association was found for Apolipoprotein B (ApoB) and PD [0.60 (0.37–0.97)]. Compared with controls, patients with AD had higher levels of ApoB [1.13 (1.01–1.25)], ApoB/apolipoprotein A (ApoA) ratio [1.16 (1.04–1.30)], low-density lipoprotein (LDL) [1.17 (1.02–1.35)], and LDL/high-density lipoprotein (HDL) ratio [1.13 (1.03–1.23)] measured >10 years earlier. In contrast, patients with PD had lower levels of ApoB [0.85 (0.72–1.00)], triglycerides [0.79 (0.67–0.92)], and leukocyte [0.69 (0.51–0.94)] than controls. We did not observe clear associations for ALS.
Could you please provide functioning links to the article(s) not just to the graphs because I would like to read the full text and make my own judgement.
Thanks
So is it a binary choice? Increased risk of CVD vs AD/PD?
Just click on “Source”.