#alzheimers #tau | Alberto Espay | 23 comments 𝐀𝐥𝐳𝐡𝐞𝐢𝐦𝐞𝐫'𝐬 𝐭𝐚𝐮 𝐛𝐢𝐨𝐦𝐚𝐫𝐤𝐞𝐫𝐬 𝐜𝐨𝐫𝐫𝐞𝐜𝐭𝐞𝐝. 𝐀𝐥𝐳𝐡𝐞𝐢𝐦𝐞𝐫'𝐬 𝐝𝐢𝐬𝐞𝐚𝐬𝐞 𝐮𝐧𝐜𝐡𝐚𝐧𝐠𝐞𝐝. Over the past decade in Alzheimer’s disease, ~10–12 anti-tau monoclonal antibodies have been tested across ~6–8 Phase 2 programs, ...

𝐀𝐥𝐳𝐡𝐞𝐢𝐦𝐞𝐫'𝐬 𝐭𝐚𝐮 𝐛𝐢𝐨𝐦𝐚𝐫𝐤𝐞𝐫𝐬 𝐜𝐨𝐫𝐫𝐞𝐜𝐭𝐞𝐝. 𝐀𝐥𝐳𝐡𝐞𝐢𝐦𝐞𝐫'𝐬 𝐝𝐢𝐬𝐞𝐚𝐬𝐞 𝐮𝐧𝐜𝐡𝐚𝐧𝐠𝐞𝐝.
~10 anti-tau monoclonal antibodies tested to date in #Alzheimers. They change tau, not the disease.
www.linkedin.com/posts/albert...

I now understand why we can look at the same data on tests of pathology and come to very different conclusions. Some see blood-based biomarkers like high pTau217 and conclude: “We can now detect… | A... I now understand why we can look at the same data on tests of pathology and come to very different conclusions. Some see blood-based biomarkers like high pTau217 and conclude: “We can now detect Alzh...

I now understand why we can look at the same data on studies of tests of pathology and come to very different conclusions. My thoughts here. www.linkedin.com/posts/albert...

A 56-year-old man presents with parkinsonism. Brain imaging reveals basal ganglia calcifications. His clinician, concluding that the calcifications triggered his symptoms, prescribes calcium… | Albert... A 56-year-old man presents with parkinsonism. Brain imaging reveals basal ganglia calcifications. His clinician, concluding that the calcifications triggered his symptoms, prescribes calcium chelation...

A faux vignette illustrates a flawed causal inference in Parkinson's research: pathology ('calcification') is mistaken for a pathogenic mechanism ('toxicity') rather than a marker of protein dyshomeostasis ('calcium metabolism').
@ajlees.bsky.social
www.linkedin.com/posts/albert...

Statins for primary cardiovascular prevention in Parkinson’s disease: is it time to rethink the balance of risk and benefit? A new study adds to the concern that statins may not be benign in PD. In… ... Statins for primary cardiovascular prevention in Parkinson’s disease: is it time to rethink the balance of risk and benefit? A new study adds to the concern that statins may not be benign in PD. In 3...

Time to reconsider use of statins for primary cardiovascular prophylaxis in Parkinson's disease? www.linkedin.com/posts/albert...

If Parkinson’s is “biologically defined” by a positive α-synuclein test, what do we do with the 10% who are negative? The α-synuclein seed amplification assay (αsyn-SAA) sensitively detects… | Alberto... If Parkinson’s is “biologically defined” by a positive α-synuclein test, what do we do with the 10% who are negative? The α-synuclein seed amplification assay (αsyn-SAA) sensitively detects aggregated...

If Parkinson’s is “biologically defined” by a positive α-synuclein test, what do we do with the 10% who are negative? Can we distinguish between detecting pathology and defining disease?
www.linkedin.com/posts/albert...

Science For Sale: How Drugmakers Captured The FDA | Alberto Espay 𝐓𝐡𝐢𝐬 𝐭𝐫𝐞𝐚𝐭𝐦𝐞𝐧𝐭 𝐜𝐚𝐧 𝐤𝐢𝐥𝐥. 𝐂𝐨𝐮𝐧𝐭𝐢𝐧𝐠 𝐢𝐬 𝐥𝐞𝐠𝐚𝐥𝐥𝐲 𝐩𝐫𝐨𝐡𝐢𝐛𝐢𝐭𝐞𝐝.* (*until 2036–2037) 𝐃𝐞𝐚𝐭𝐡𝐬 𝐚𝐬 𝐩𝐫𝐨𝐩𝐫𝐢𝐞𝐭𝐚𝐫𝐲 𝐝𝐚𝐭𝐚. It has now been 15 months since I retracted my first and only paper, which sought to estimate ...

𝐓𝐡𝐢𝐬 𝐭𝐫𝐞𝐚𝐭𝐦𝐞𝐧𝐭 𝐜𝐚𝐧 𝐤𝐢𝐥𝐥. 𝐂𝐨𝐮𝐧𝐭𝐢𝐧𝐠 𝐢𝐬 𝐥𝐞𝐠𝐚𝐥𝐥𝐲 𝐩𝐫𝐨𝐡𝐢𝐛𝐢𝐭𝐞𝐝
(*until 2036–2037).
Deaths occur with lecanemab & donanemab, but excess mortality can’t be estimated: it is proprietary data and can be withheld for a decade. www.linkedin.com/posts/albert...

𝐓𝐡𝐢𝐬 𝐭𝐫𝐞𝐚𝐭𝐦𝐞𝐧𝐭 𝐰𝐢𝐥𝐥 𝐬𝐡𝐫𝐢𝐧𝐤 𝐲𝐨𝐮𝐫 𝐛𝐫𝐚𝐢𝐧. 𝐘𝐨𝐮'𝐫𝐞 𝐰𝐞𝐥𝐜𝐨𝐦𝐞. That statement is not rhetorical. We are told that reduced brain volume is the mechanism by which… | Alberto Espay 𝐓𝐡𝐢𝐬 𝐭𝐫𝐞𝐚𝐭𝐦𝐞𝐧𝐭 𝐰𝐢𝐥𝐥 𝐬𝐡𝐫𝐢𝐧𝐤 𝐲𝐨𝐮𝐫 𝐛𝐫𝐚𝐢𝐧. 𝐘𝐨𝐮'𝐫𝐞 𝐰𝐞𝐥𝐜𝐨𝐦𝐞. That statement is not rhetorical. We are told that reduced brain volume is the mechanism by which anti-amyloid (Aβ) monoclonal antibodies benefi...

𝐘𝐨𝐮𝐫 𝐛𝐫𝐚𝐢𝐧 𝐰𝐢𝐥𝐥 𝐬𝐡𝐫𝐢𝐧𝐤 𝐛𝐮𝐭 𝐭𝐡𝐢𝐬 𝐢𝐬 “𝐩𝐬𝐞𝐮𝐝𝐨-𝐚𝐭𝐫𝐨𝐩𝐡𝐲,” 𝐭𝐫𝐮𝐬𝐭 𝐮𝐬. We need independent analysis, not trust. The dry weight of Aβ accounts for <1/1,000 of the observed volume change in #Alzheimers with treatment. www.linkedin.com/posts/albert...

Parkinson’s disease is often framed as a disorder of &#39;toxic accumulation&#39; of pathological α-synuclein. Yet the reciprocal process, the depletion of soluble, functional α-synuclein, has receive... Parkinson’s disease is often framed as a disorder of 'toxic accumulation' of pathological α-synuclein. Yet the reciprocal process, the depletion of soluble, functional α-synuclein, has received far le...

In Parkinson’s, we obsess over what α-synuclein becomes when aggregated, and ignore what neurons lose when its normal form disappears. New data in α-syn KO mice: hyposmia, apoptosis, impaired autophagy. Depletion may matter more than we think. www.linkedin.com/posts/albert...

Alzheimer’s Isn’t Inevitable - What Top Harvard Scientist Now Knows About Prevention YouTube video by The HumanWare Project

“Alzheimer’s is caused by pathology decades before symptoms.” If so, removing pathology in preclinical AD should prevent decline. It didn't—most preclinical AD trials (4/6) worsened outcomes in treated vs placebo. Pathology ≠ disease.
www.youtube.com/watch?v=_Z_Z...

Detecting Alzheimer’s — or Detecting Age? A blood-based biomarker of Alzheimer’s quintuples the population prevalence of Alzheimer’s. This is in the newly created world, where a pathology test trumps clinical symptoms.

Detecting Alzheimer’s, or Detecting Age?
A new @Nature study shows the wide gap between #Alzheimers pathology (Tau217) and disease. Pathology and disease prevalence diverge across adulthood. Is pathology a marker of successful aging?
www.linkedin.com/pulse/detect... via @LinkedIn

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...

Resolving the Biomarker-Clinical “Mismatch” in Alzheimer's Disease
www.linkedin.com/pulse/resolv...

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.

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...

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...

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...

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

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

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...

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...

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/...

Beyond Pathology: α‐Synuclein Homeostasis and Three Principles to Guide Research Click on the article title to read more.

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/...

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.

That's my hope, Elaine.

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....

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/...

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.

‘Pathology is disease’ Parkinson's mythology: The ‘brain-first-body-first’ case study - Alberto J. Espay, Andrew J. Lees, 2025

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/...

Sage Journals: Discover world-class research Subscription and open access journals from Sage, the world's leading independent academic publisher.

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/...

(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...

(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).

(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).