Alberto Espay
@albertoespay.bsky.social
Neurology professor at the University of Cincinnati, an advocate of precision and rescue medicines for Parkinson's & Alzheimer's. Author #BrainFables.
Pinned
Alberto Espay
@albertoespay.bsky.social
· Jun 27
Physics of Protein Aggregation in Normal and Accelerated Brain Aging
Soluble monomeric proteins precipitate via nucleation into insoluble amyloids in response to age-related exposures (e.g., microbes, nanoparticles). Persistent soluble-to-insoluble phase transition de....
onlinelibrary.wiley.com
How does physics inform neurodegeneration? Supersaturation lowers the nucleation barrier for the precipitation of monomeric proteins into their pathological state. In normal aging, replacement matches loss; in accelerated aging, it does not. (1/4)
onlinelibrary.wiley.com/doi/10.1002/...
onlinelibrary.wiley.com/doi/10.1002/...
For decades, we have tried to suppress γ-secretase, lower Aβ42 levels, or remove amyloid from the brain. We show that PSEN1 mutations already reduce γ-secretase activity and lower Aβ42. Why restoring Aβ42 is the way forward for #Alzheimers, via @Brain1878
academic.oup.com/brain/articl...
academic.oup.com/brain/articl...
Restoring amyloid-β42 and γ-secretase function in Alzheimer’s disease
Espay et al. challenge the view that Alzheimer’s disease is caused by increased gamma-secretase activity and overproduction of Aβ42. Instead, they suggest
academic.oup.com
November 6, 2025 at 7:15 PM
For decades, we have tried to suppress γ-secretase, lower Aβ42 levels, or remove amyloid from the brain. We show that PSEN1 mutations already reduce γ-secretase activity and lower Aβ42. Why restoring Aβ42 is the way forward for #Alzheimers, via @Brain1878
academic.oup.com/brain/articl...
academic.oup.com/brain/articl...
Increasing synuclein pathology as a treatment for corticobasal syndrome?
Facetious, yes ... but that’s one logical takeaway when learning that CBS patients positive for αSyn-SAA show milder disease, slower progression, and lower NfL.
movementdisorders.onlinelibrary.wiley.com/doi/10.1002/...
Facetious, yes ... but that’s one logical takeaway when learning that CBS patients positive for αSyn-SAA show milder disease, slower progression, and lower NfL.
movementdisorders.onlinelibrary.wiley.com/doi/10.1002/...
A Biomarker‐Based Classification of Corticobasal Syndrome
Background Corticobasal syndrome (CBS) is a clinically defined syndrome with progressive movement and cortical dysfunction, caused by various underlying pathologies, most commonly tau-predominant pa...
movementdisorders.onlinelibrary.wiley.com
November 1, 2025 at 11:33 AM
Increasing synuclein pathology as a treatment for corticobasal syndrome?
Facetious, yes ... but that’s one logical takeaway when learning that CBS patients positive for αSyn-SAA show milder disease, slower progression, and lower NfL.
movementdisorders.onlinelibrary.wiley.com/doi/10.1002/...
Facetious, yes ... but that’s one logical takeaway when learning that CBS patients positive for αSyn-SAA show milder disease, slower progression, and lower NfL.
movementdisorders.onlinelibrary.wiley.com/doi/10.1002/...
Proposing three principles to guide #Parkinson research:
1. Quantify monomeric & pathological α-synuclein
2. Prioritize human evidence over animal models
3. Use clinical trials to test hypotheses, not just molecules
@ajlees.bsky.social
movementdisorders.onlinelibrary.wiley.com/doi/10.1002/...
1. Quantify monomeric & pathological α-synuclein
2. Prioritize human evidence over animal models
3. Use clinical trials to test hypotheses, not just molecules
@ajlees.bsky.social
movementdisorders.onlinelibrary.wiley.com/doi/10.1002/...
Beyond Pathology: α‐Synuclein Homeostasis and Three Principles to Guide Research
Click on the article title to read more.
movementdisorders.onlinelibrary.wiley.com
October 16, 2025 at 3:50 AM
Proposing three principles to guide #Parkinson research:
1. Quantify monomeric & pathological α-synuclein
2. Prioritize human evidence over animal models
3. Use clinical trials to test hypotheses, not just molecules
@ajlees.bsky.social
movementdisorders.onlinelibrary.wiley.com/doi/10.1002/...
1. Quantify monomeric & pathological α-synuclein
2. Prioritize human evidence over animal models
3. Use clinical trials to test hypotheses, not just molecules
@ajlees.bsky.social
movementdisorders.onlinelibrary.wiley.com/doi/10.1002/...
Can #Alzheimers happen when β-amyloid protection fails? This is one conclusion drawn by the authors of a new Human Connectome Project study, which shows that higher β-amyloid load is associated with better cognition, fitness, tissue integrity & perfusion.
onlinelibrary.wiley.com/doi/10.1111/...
onlinelibrary.wiley.com/doi/10.1111/...
Clinical and MRI Correlates of β‐Amyloid Load Inconsistent With Its Presumed Neurotoxicity in Cognitively Healthy Ageing
At low levels, β-amyloid—a protein commonly present in brains of patients with Alzheimer's disease – appears to actually support overall tissue integrity, blood flow, brain function and cognitive abi....
onlinelibrary.wiley.com
September 28, 2025 at 5:23 PM
Can #Alzheimers happen when β-amyloid protection fails? This is one conclusion drawn by the authors of a new Human Connectome Project study, which shows that higher β-amyloid load is associated with better cognition, fitness, tissue integrity & perfusion.
onlinelibrary.wiley.com/doi/10.1111/...
onlinelibrary.wiley.com/doi/10.1111/...
Reposted by Alberto Espay
Remember kids: "Pathology does not mean disease. Most individuals with pathology will never have disease"
Wonderful letter from @albertoespay.bsky.social
"In the reality we inhabit, we have made Lewy pathology not just a marker of PD, but its very maker!
journals.sagepub.com/doi/10.1177/...
Wonderful letter from @albertoespay.bsky.social
"In the reality we inhabit, we have made Lewy pathology not just a marker of PD, but its very maker!
journals.sagepub.com/doi/10.1177/...
‘Pathology is disease’ Parkinson's mythology: The ‘brain-first-body-first’ case study - Alberto J. Espay, Andrew J. Lees, 2025
journals.sagepub.com
September 20, 2025 at 5:52 PM
Remember kids: "Pathology does not mean disease. Most individuals with pathology will never have disease"
Wonderful letter from @albertoespay.bsky.social
"In the reality we inhabit, we have made Lewy pathology not just a marker of PD, but its very maker!
journals.sagepub.com/doi/10.1177/...
Wonderful letter from @albertoespay.bsky.social
"In the reality we inhabit, we have made Lewy pathology not just a marker of PD, but its very maker!
journals.sagepub.com/doi/10.1177/...
We neurologists fall in love with our hypotheses: they never die. The latest: Depending on where Lewy pathology is first found, one of 2 #Parkinsons types exists. @ajlees and I explain the newest inconsistency in this “brain-first/body-first” hypothesis.
journals.sagepub.com/doi/10.1177/...
journals.sagepub.com/doi/10.1177/...
Sage Journals: Discover world-class research
Subscription and open access journals from Sage, the world's leading independent academic publisher.
journals.sagepub.com
September 19, 2025 at 7:03 PM
We neurologists fall in love with our hypotheses: they never die. The latest: Depending on where Lewy pathology is first found, one of 2 #Parkinsons types exists. @ajlees and I explain the newest inconsistency in this “brain-first/body-first” hypothesis.
journals.sagepub.com/doi/10.1177/...
journals.sagepub.com/doi/10.1177/...
Remember the “time saved” modeling for #Alzheimers infusions introduced a year ago? Extrapolating the observed curves, patients would increase their months ‘saved’ to 7.5. The #lecanemab data have shattered the optimistic model prediction—Details on this discrepancy follow (🧵1 of 5).
September 5, 2025 at 9:01 PM
Remember the “time saved” modeling for #Alzheimers infusions introduced a year ago? Extrapolating the observed curves, patients would increase their months ‘saved’ to 7.5. The #lecanemab data have shattered the optimistic model prediction—Details on this discrepancy follow (🧵1 of 5).
Losing your mind by forgetting 𝘵𝘩𝘦 password
www.nature.com/articles/d41...
www.nature.com/articles/d41...
A mind-reading brain implant that comes with password protection
A brain–computer interface decodes in near-real time the imagined speech of people who have difficulty enunciating words.
www.nature.com
September 3, 2025 at 1:45 PM
Losing your mind by forgetting 𝘵𝘩𝘦 password
www.nature.com/articles/d41...
www.nature.com/articles/d41...
Reposted by Alberto Espay
15 years (and 12 editions) later, here we are again for our annual 4-day intensive course on the diagnosis and treatment of #movementdisorders.
This year we're in charming Milan, hosted by the conference centre of Humanitas University.
More info here: www.mdscourse.com
This year we're in charming Milan, hosted by the conference centre of Humanitas University.
More info here: www.mdscourse.com
July 12, 2025 at 3:15 PM
15 years (and 12 editions) later, here we are again for our annual 4-day intensive course on the diagnosis and treatment of #movementdisorders.
This year we're in charming Milan, hosted by the conference centre of Humanitas University.
More info here: www.mdscourse.com
This year we're in charming Milan, hosted by the conference centre of Humanitas University.
More info here: www.mdscourse.com
In #Alzheimers news: “4 years on #lecanemab, the benefit tripled” … “3 years on #donanemab, the benefit doubled”, as summed by @Alzforum from #AAIC25 reported data. How the graphical illusion hides the acceleration of cognitive decline (9-part thread).
www.alzforum.org/news/confere...
www.alzforum.org/news/confere...
August 28, 2025 at 3:10 PM
In #Alzheimers news: “4 years on #lecanemab, the benefit tripled” … “3 years on #donanemab, the benefit doubled”, as summed by @Alzforum from #AAIC25 reported data. How the graphical illusion hides the acceleration of cognitive decline (9-part thread).
www.alzforum.org/news/confere...
www.alzforum.org/news/confere...
Amylyx halted the ORION trial in #PSP: no benefit from AMX0035 (sodium phenylbutyrate + taurursodiol).
The question: a false negative trial (inadequate drug) or a true negative (protein aggregation + mitochondrial dysfunction not driving PSP)?
investors.amylyx.com/news-release...
The question: a false negative trial (inadequate drug) or a true negative (protein aggregation + mitochondrial dysfunction not driving PSP)?
investors.amylyx.com/news-release...
Amylyx Pharmaceuticals to Discontinue ORION Program of AMX0035 for Progressive Supranuclear Palsy (PSP) | Amylyx Pharmaceuticals, Inc.
- AMX0035 did not show differences compared to placebo on primary or secondary outcomes at Week 24 - AMX0035 continued to be generally well-tolerated CAMBRIDGE, Mass. --(BUSINESS WIRE)--Aug. 27, 2025-...
investors.amylyx.com
August 27, 2025 at 8:25 PM
Amylyx halted the ORION trial in #PSP: no benefit from AMX0035 (sodium phenylbutyrate + taurursodiol).
The question: a false negative trial (inadequate drug) or a true negative (protein aggregation + mitochondrial dysfunction not driving PSP)?
investors.amylyx.com/news-release...
The question: a false negative trial (inadequate drug) or a true negative (protein aggregation + mitochondrial dysfunction not driving PSP)?
investors.amylyx.com/news-release...
Reposted by Alberto Espay
"These findings suggest that restoring, not reducing, γ-secretase activity & monomeric Aβ42 levels above a compensation threshold could offer disease-modifying therapeutic benefits"; More data from @albertoespay.bsky.social & colleagues
academic.oup.com/brain/advanc...
academic.oup.com/brain/advanc...
Restoring amyloid-β42 and γ-secretase function in Alzheimer’s disease
Espay et al. challenge the view that Alzheimer’s disease is caused by increased gamma-secretase activity and overproduction of Aβ42. Instead, they suggest
academic.oup.com
August 26, 2025 at 10:21 PM
"These findings suggest that restoring, not reducing, γ-secretase activity & monomeric Aβ42 levels above a compensation threshold could offer disease-modifying therapeutic benefits"; More data from @albertoespay.bsky.social & colleagues
academic.oup.com/brain/advanc...
academic.oup.com/brain/advanc...
Reposted by Alberto Espay
Some scholars have become so preoccupied with turning reality into definitions that they have totally lost sight of what Parkinson’s disease and Alzheimer’s disease actually are.
They are so fixated with galaxies they can no longer see the stars
They are so fixated with galaxies they can no longer see the stars
June 10, 2025 at 8:35 AM
Some scholars have become so preoccupied with turning reality into definitions that they have totally lost sight of what Parkinson’s disease and Alzheimer’s disease actually are.
They are so fixated with galaxies they can no longer see the stars
They are so fixated with galaxies they can no longer see the stars
Plagiarism = copying words without credit.
'Idea plagiarism' = stealing insights without credit.
With AI “remixing” text, sources get obscured, making idea theft easier. Copying words is bad, but copying findings or methods may be worse.
Via @nature.com
www.nature.com/articles/d41...
'Idea plagiarism' = stealing insights without credit.
With AI “remixing” text, sources get obscured, making idea theft easier. Copying words is bad, but copying findings or methods may be worse.
Via @nature.com
www.nature.com/articles/d41...
What counts as plagiarism? AI-generated papers pose new risks
Researchers argue over whether ‘novel’ AI-generated works use others’ ideas without credit.
www.nature.com
August 25, 2025 at 2:18 PM
Plagiarism = copying words without credit.
'Idea plagiarism' = stealing insights without credit.
With AI “remixing” text, sources get obscured, making idea theft easier. Copying words is bad, but copying findings or methods may be worse.
Via @nature.com
www.nature.com/articles/d41...
'Idea plagiarism' = stealing insights without credit.
With AI “remixing” text, sources get obscured, making idea theft easier. Copying words is bad, but copying findings or methods may be worse.
Via @nature.com
www.nature.com/articles/d41...
Key findings of critical new research in #Parkinsons and #Alzheimers disease -with corrected conclusions.
1/7🧵
www.nature.com/articles/s41...
1/7🧵
www.nature.com/articles/s41...
Phosphorylated α-synuclein in CSF and plasma does not reflect synucleinopathy - npj Parkinson's Disease
npj Parkinson's Disease - Phosphorylated α-synuclein in CSF and plasma does not reflect synucleinopathy
www.nature.com
August 15, 2025 at 4:38 PM
Key findings of critical new research in #Parkinsons and #Alzheimers disease -with corrected conclusions.
1/7🧵
www.nature.com/articles/s41...
1/7🧵
www.nature.com/articles/s41...
Looking forward to tomorrow's noon EST debate at Indiana University on 'proteinopathies' as cause (Dr. Malu Tamsey) versus consequence (me). Here is the link:
August 10, 2025 at 3:47 PM
Looking forward to tomorrow's noon EST debate at Indiana University on 'proteinopathies' as cause (Dr. Malu Tamsey) versus consequence (me). Here is the link:
The scorecard on the “diagnostic revolution” of #Alzheimers blood biomarkers based on 885 studies: sobering.
⚠️ Good lab accuracy, not real-world benefit
⚠️ No gains for patients or caregivers
Availability ≠ necessity. Don't do it just because you can.
www.bmj.com/content/390/...
⚠️ Good lab accuracy, not real-world benefit
⚠️ No gains for patients or caregivers
Availability ≠ necessity. Don't do it just because you can.
www.bmj.com/content/390/...
August 9, 2025 at 3:43 PM
The scorecard on the “diagnostic revolution” of #Alzheimers blood biomarkers based on 885 studies: sobering.
⚠️ Good lab accuracy, not real-world benefit
⚠️ No gains for patients or caregivers
Availability ≠ necessity. Don't do it just because you can.
www.bmj.com/content/390/...
⚠️ Good lab accuracy, not real-world benefit
⚠️ No gains for patients or caregivers
Availability ≠ necessity. Don't do it just because you can.
www.bmj.com/content/390/...
SOD1 is aggregated in #Parkinsons brains
New mouse data: copper lowers SOD1 aggregation
Conclusion: 'SOD1 pathology is a treatment target'
Alternative: SOD1 aggregates with copper deficiency
Chasing pathology leads nowhere. Restoring function might.
actaneurocomms.biomedcentral.com/articles/10....
New mouse data: copper lowers SOD1 aggregation
Conclusion: 'SOD1 pathology is a treatment target'
Alternative: SOD1 aggregates with copper deficiency
Chasing pathology leads nowhere. Restoring function might.
actaneurocomms.biomedcentral.com/articles/10....
Copper supplementation mitigates Parkinson-like wild-type SOD1 pathology and nigrostriatal degeneration in a novel mouse model - Acta Neuropathologica Communications
Misfolded wild-type superoxide dismutase 1 (disSOD1) protein is implicated in the death of substantia nigra (SN) dopamine neurons in Parkinson disease. Regionally reduced copper availability, and subs...
actaneurocomms.biomedcentral.com
July 27, 2025 at 6:01 PM
SOD1 is aggregated in #Parkinsons brains
New mouse data: copper lowers SOD1 aggregation
Conclusion: 'SOD1 pathology is a treatment target'
Alternative: SOD1 aggregates with copper deficiency
Chasing pathology leads nowhere. Restoring function might.
actaneurocomms.biomedcentral.com/articles/10....
New mouse data: copper lowers SOD1 aggregation
Conclusion: 'SOD1 pathology is a treatment target'
Alternative: SOD1 aggregates with copper deficiency
Chasing pathology leads nowhere. Restoring function might.
actaneurocomms.biomedcentral.com/articles/10....
July 11, 2025 at 10:50 PM
Biomarker fetishism alert: A new @jama.com Neurology paper claims higher education worsens your Alzheimer’s biomarker profile—without mentioning cognition even once.
Readers beware: more such articles will continue to pollute the literature as “objective.”
jamanetwork.com/journals/jam...
Readers beware: more such articles will continue to pollute the literature as “objective.”
jamanetwork.com/journals/jam...
Education and Accelerated Tau Accumulation in Alzheimer Disease
This cohort study investigates if higher educational attainment is associated with rate of tau accumulation.
jamanetwork.com
July 8, 2025 at 3:56 PM
Biomarker fetishism alert: A new @jama.com Neurology paper claims higher education worsens your Alzheimer’s biomarker profile—without mentioning cognition even once.
Readers beware: more such articles will continue to pollute the literature as “objective.”
jamanetwork.com/journals/jam...
Readers beware: more such articles will continue to pollute the literature as “objective.”
jamanetwork.com/journals/jam...
Reposted by Alberto Espay
Reposted by Alberto Espay
"We suggest this search is in vain. The problem lies not in the population but in the framework itself"
Shots fired!
@albertoespay.bsky.social & colleagues ask probing questions regarding αSyn-SAA-based staging for #Parkinsons progression
movementdisorders.onlinelibrary.wiley.com/doi/10.1002/...
Shots fired!
@albertoespay.bsky.social & colleagues ask probing questions regarding αSyn-SAA-based staging for #Parkinsons progression
movementdisorders.onlinelibrary.wiley.com/doi/10.1002/...
Refutation of the αSyn‐SAA‐Based Staging for Parkinson's Progression (Neuronal α‐Synuclein Disease‐Integrated Staging System [NSD‐ISS])
Click on the article title to read more.
movementdisorders.onlinelibrary.wiley.com
July 1, 2025 at 5:14 PM
"We suggest this search is in vain. The problem lies not in the population but in the framework itself"
Shots fired!
@albertoespay.bsky.social & colleagues ask probing questions regarding αSyn-SAA-based staging for #Parkinsons progression
movementdisorders.onlinelibrary.wiley.com/doi/10.1002/...
Shots fired!
@albertoespay.bsky.social & colleagues ask probing questions regarding αSyn-SAA-based staging for #Parkinsons progression
movementdisorders.onlinelibrary.wiley.com/doi/10.1002/...
High p-tau217 in #Alzheimers? It's a cause.
High p-tau217 in premature infants? It's protective.
Same protein change, different stories.
If we didn't conflate marker with maker, we could just conclude that high p-tau217 is a homeostatic response.
neurosciencenews.com/newborn-alzh...
High p-tau217 in premature infants? It's protective.
Same protein change, different stories.
If we didn't conflate marker with maker, we could just conclude that high p-tau217 is a homeostatic response.
neurosciencenews.com/newborn-alzh...
Newborns and Alzheimer’s Patients Share a Brain Protein Spike - Neuroscience News
A new study has revealed that newborn babies and Alzheimer’s patients both have elevated levels of the same protein, p-tau217, in their blood.
neurosciencenews.com
June 28, 2025 at 1:23 PM
High p-tau217 in #Alzheimers? It's a cause.
High p-tau217 in premature infants? It's protective.
Same protein change, different stories.
If we didn't conflate marker with maker, we could just conclude that high p-tau217 is a homeostatic response.
neurosciencenews.com/newborn-alzh...
High p-tau217 in premature infants? It's protective.
Same protein change, different stories.
If we didn't conflate marker with maker, we could just conclude that high p-tau217 is a homeostatic response.
neurosciencenews.com/newborn-alzh...
How does physics inform neurodegeneration? Supersaturation lowers the nucleation barrier for the precipitation of monomeric proteins into their pathological state. In normal aging, replacement matches loss; in accelerated aging, it does not. (1/4)
onlinelibrary.wiley.com/doi/10.1002/...
onlinelibrary.wiley.com/doi/10.1002/...
Physics of Protein Aggregation in Normal and Accelerated Brain Aging
Soluble monomeric proteins precipitate via nucleation into insoluble amyloids in response to age-related exposures (e.g., microbes, nanoparticles). Persistent soluble-to-insoluble phase transition de....
onlinelibrary.wiley.com
June 27, 2025 at 9:50 PM
How does physics inform neurodegeneration? Supersaturation lowers the nucleation barrier for the precipitation of monomeric proteins into their pathological state. In normal aging, replacement matches loss; in accelerated aging, it does not. (1/4)
onlinelibrary.wiley.com/doi/10.1002/...
onlinelibrary.wiley.com/doi/10.1002/...
Brain pathologies are markers of brain reactivity, not makers of disease. Yet the century-old 'pathology is disease' fixation leads to the false dichotomy between "primary" pathology and "co-pathology." It also leads to confusing articles like this one.
jamanetwork.com/journals/jam...
jamanetwork.com/journals/jam...
Copathology in Atypical Parkinsonism
This Viewpoint reports on the potential of multimodal approaches that include validation, standardization, and ethical considerations in diagnosing neurodegenerative diseases, many of which have overl...
jamanetwork.com
June 14, 2025 at 4:08 PM
Brain pathologies are markers of brain reactivity, not makers of disease. Yet the century-old 'pathology is disease' fixation leads to the false dichotomy between "primary" pathology and "co-pathology." It also leads to confusing articles like this one.
jamanetwork.com/journals/jam...
jamanetwork.com/journals/jam...