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/...
Resolving the Biomarker-Clinical “Mismatch” in Alzheimer's Disease
www.linkedin.com/pulse/resolv...
www.linkedin.com/pulse/resolv...
Resolving the Biomarker-Clinical “Mismatch” in Alzheimer's Disease
A recent JAMA Neurology paper assesses the extent to which a measure of the tau protein in plasma known as p-tau217, drives the severity of Alzheimer’s disease, as measured by the Clinical Dementia Ra...
www.linkedin.com
December 20, 2025 at 9:06 PM
Resolving the Biomarker-Clinical “Mismatch” in Alzheimer's Disease
www.linkedin.com/pulse/resolv...
www.linkedin.com/pulse/resolv...
Antivirals treat active viral infections. Using HSV-1 IgG/IgM to enroll #Alzheimers patients does not mean the virus is actively driving dementia. Without viral replication, there is no target. Thus, placebo outperforming valacyclovir is unsurprising.
jamanetwork.com/journals/jam...
jamanetwork.com/journals/jam...
Valacyclovir Treatment of Early Symptomatic Alzheimer Disease
This randomized clinical trial compares the efficacy and adverse effects of valacyclovir vs placebo in patients with early symptomatic Alzheimer disease and seropositivity to herpes simplex viruses.
jamanetwork.com
December 18, 2025 at 3:40 PM
Antivirals treat active viral infections. Using HSV-1 IgG/IgM to enroll #Alzheimers patients does not mean the virus is actively driving dementia. Without viral replication, there is no target. Thus, placebo outperforming valacyclovir is unsurprising.
jamanetwork.com/journals/jam...
jamanetwork.com/journals/jam...
Can high LRRK2 kinase activity be compensatory in LRRK2-#Parkinsons? We collect evidence suggesting we may be undermining cellular restoration in ongoing kinase inhibitor trials (e.g., BIIB122) & outline precision-medicine strategies in G2019S LRRK2-PD
www.sciencedirect.com/science/arti...
www.sciencedirect.com/science/arti...
December 6, 2025 at 4:47 PM
Can high LRRK2 kinase activity be compensatory in LRRK2-#Parkinsons? We collect evidence suggesting we may be undermining cellular restoration in ongoing kinase inhibitor trials (e.g., BIIB122) & outline precision-medicine strategies in G2019S LRRK2-PD
www.sciencedirect.com/science/arti...
www.sciencedirect.com/science/arti...
On why the α-Syn SAA test cannot inform on #Parkinsons severity, biology, risk, or prognosis. In this article, I reflect on why "seeding activity" extracted from "kinetic parameters" can never reflect disease activity. linkedin.com/pulse/why-la... via @linkedin.com
Why the latest test for Parkinson’s cannot be quantitative –only binary (yes/no)
The α-Synuclein Seed Amplification Assay (α-Syn SAA) In response to many biological exposures, monomeric (normal) α-synuclein transforms into fibrillar (abnormal) aggregates, which we call Lewy pathol...
linkedin.com
November 26, 2025 at 11:15 PM
On why the α-Syn SAA test cannot inform on #Parkinsons severity, biology, risk, or prognosis. In this article, I reflect on why "seeding activity" extracted from "kinetic parameters" can never reflect disease activity. linkedin.com/pulse/why-la... via @linkedin.com
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/...
Future models will hopefully stop misleading about “timed gained” with anti-amyloid monoclonal antibodies.
October 6, 2025 at 7:17 AM
Future models will hopefully stop misleading about “timed gained” with anti-amyloid monoclonal antibodies.
Yes. The biophysical framework is better at distinguishing between normal and accelerated aging than the clinicopathologic framework. In normal aging, there is plenty of pathology 'accumulation'. Degeneration may only happen when the precipitation of monomeric peptides exceeds their replacement.
October 1, 2025 at 8:21 PM
Yes. The biophysical framework is better at distinguishing between normal and accelerated aging than the clinicopathologic framework. In normal aging, there is plenty of pathology 'accumulation'. Degeneration may only happen when the precipitation of monomeric peptides exceeds their replacement.
That's my hope, Elaine.
October 1, 2025 at 8:18 PM
That's my hope, Elaine.
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/...
I have submitted it for publication as a viewpoint, but will be thinking of other strategies too.
September 24, 2025 at 10:09 PM
I have submitted it for publication as a viewpoint, but will be thinking of other strategies too.
Thank you, Emilia. So far, the reaction is relatively subdued. I am unsure how far this view on the open-label extension has gotten.
September 22, 2025 at 4:58 PM
Thank you, Emilia. So far, the reaction is relatively subdued. I am unsure how far this view on the open-label extension has gotten.
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
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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/...
(5/5) Bottom line: The 40% ‘slower decline’ holds only if we compare the results to a historic cohort (link to earlier post below). But compared to the model, patients decline 40% faster than anticipated. We expected larger benefits, but they instead shrink rapidly.
bsky.app/profile/albe...
bsky.app/profile/albe...
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...
September 5, 2025 at 9:01 PM
(5/5) Bottom line: The 40% ‘slower decline’ holds only if we compare the results to a historic cohort (link to earlier post below). But compared to the model, patients decline 40% faster than anticipated. We expected larger benefits, but they instead shrink rapidly.
bsky.app/profile/albe...
bsky.app/profile/albe...
(4/9) Why does lecanemab look better? It is compared to a steeper-than-modeled slope from ADNI. Whereas the newly modeled decline is 0.05/mo ((1.5-0.6)/18), the observed decline is 0.07/mo ((1.8-0.5)/18), which means an actual 40% acceleration of decline ((0.07-0.05)/0.05)* 100).
September 5, 2025 at 9:01 PM
(4/9) Why does lecanemab look better? It is compared to a steeper-than-modeled slope from ADNI. Whereas the newly modeled decline is 0.05/mo ((1.5-0.6)/18), the observed decline is 0.07/mo ((1.8-0.5)/18), which means an actual 40% acceleration of decline ((0.07-0.05)/0.05)* 100).
(3/9) 2025 𝐥𝐞𝐜𝐚𝐧𝐞𝐦𝐚𝐛 𝐝𝐚𝐭𝐚: At 18 months (0.8-0.5 = 0.3) and 36 months (2.0-1.8 = 0.2), lecanemab slowed the CDR-SB decline by 37.5% vs placebo in the first period (0.3 / 0.8) \* 100). That difference narrowed to 10% in the second (0.2 / 2.0) \* 100).
September 5, 2025 at 9:01 PM
(3/9) 2025 𝐥𝐞𝐜𝐚𝐧𝐞𝐦𝐚𝐛 𝐝𝐚𝐭𝐚: At 18 months (0.8-0.5 = 0.3) and 36 months (2.0-1.8 = 0.2), lecanemab slowed the CDR-SB decline by 37.5% vs placebo in the first period (0.3 / 0.8) \* 100). That difference narrowed to 10% in the second (0.2 / 2.0) \* 100).
(2/9) 2024 𝐬𝐢𝐦𝐮𝐥𝐚𝐭𝐢𝐨𝐧: At 18 months (0.8-0.6 = 0.2) and 36 months (2.0-1.5 = 0.5), lecanemab 𝐬𝐥𝐨𝐰𝐞𝐝 𝐭𝐡𝐞 𝐂𝐃𝐑-𝐒𝐁 𝐝𝐞𝐜𝐥𝐢𝐧𝐞 by 25% vs placebo at both timepoints (0.2 / 0.8) \* 100) & (0.5 / 2.0) \* 100).
September 5, 2025 at 9:01 PM
(2/9) 2024 𝐬𝐢𝐦𝐮𝐥𝐚𝐭𝐢𝐨𝐧: At 18 months (0.8-0.6 = 0.2) and 36 months (2.0-1.5 = 0.5), lecanemab 𝐬𝐥𝐨𝐰𝐞𝐝 𝐭𝐡𝐞 𝐂𝐃𝐑-𝐒𝐁 𝐝𝐞𝐜𝐥𝐢𝐧𝐞 by 25% vs placebo at both timepoints (0.2 / 0.8) \* 100) & (0.5 / 2.0) \* 100).
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...
Those are not included, making the slope of treatment look better than it actually is.
August 30, 2025 at 8:15 PM
Those are not included, making the slope of treatment look better than it actually is.
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
(9/9) Bottom line: The illusion of ‘increasing benefit’ driven by survivor bias and historical comparisons masks the accelerated decline on treatment. Open-label extension data are incompatible with disease modification. Clinicians, patients, and policymakers beware!
August 28, 2025 at 3:10 PM
(9/9) Bottom line: The illusion of ‘increasing benefit’ driven by survivor bias and historical comparisons masks the accelerated decline on treatment. Open-label extension data are incompatible with disease modification. Clinicians, patients, and policymakers beware!
(8/9) All caveats aside, the steepening (worsening) of the slopes of decline for lecanemab and donanemab suggests that patients deteriorate more rapidly the longer they are on treatment, a pattern inconsistent with an increasing therapeutic effect.
August 28, 2025 at 3:10 PM
(8/9) All caveats aside, the steepening (worsening) of the slopes of decline for lecanemab and donanemab suggests that patients deteriorate more rapidly the longer they are on treatment, a pattern inconsistent with an increasing therapeutic effect.