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).

Here is a handful of thoughts on the idea of #Alzheimers being repackaged as an autoimmune disease. via @LinkedIn.

Introducing Grok Imagine.

PS. Con my gratitud a los organizadores y líderes de la Asociación Colombiana de Neurología (@ACNeurologia) por todas las atenciones. Gracias Gabriel, Juan Diego, y el resto del buen equipo.

The XV Colombian Symposium of Movement Disorders just concluded in Santa Marta was nurturing to the soul. A vibrant, talented group of 175 seasoned clinicians and neurologists in training injected me with optimism. This is a premier ⁦@movedisorder⁩ meeting in South America.

(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.

(7/9) Add the survivor bias: By the end of the OLE, only 56% of patients remained on lecanemab, 53% on donanemab. The disproportionate influence of better-tolerating, slower-progressing participants enriching the open-label extension skews the mean CDR-SB changes.

(6/9) Comparing the extrapolated slope of the placebo arm vs the observed donanemab arm, the CDR-SB difference favoring donanemab shrinks from 0.6 at 18 months to 0.3 at 36 months. Versus the ADNI slope used for lecanemab there would be no difference. This ADNI slope is steeper.

(5/9) Comparing the extrapolated slope of the placebo arm vs the observed lecanemab arm, the CDR-SB difference favoring lecanemab does not expand but shrinks: from 0.5 at the end of the double-blind period to 0.2 at month 48 of the open-label extension.

(4/9) So why do the curves shown at AAIC look like the gap widens over time? Because instead of a concurrent placebo group, results were compared to an 𝗲𝘅𝘁𝗲𝗿𝗻𝗮𝗹 𝗵𝗶𝘀𝘁𝗼𝗿𝗶𝗰𝗮𝗹 𝗰𝗼𝗵𝗼𝗿𝘁 (ADNI)—a method riddled with bias (inclusion criteria, dropout rates, etc.).

(3/9) Donanemab: In the 18 double-blind months, the CDR-SB score lowers by 1.6 (vs. 2.2 in placebo); in the subsequent 18 open-label months, the CDR-SB lowers 2.5 (4.1-1.6) –a 𝟱𝟲% 𝗳𝗮𝘀𝘁𝗲𝗿 𝗱𝗲𝗰𝗹𝗶𝗻𝗲 (2.5 -1.6 /1.6 * 100).

(2/9) Lecanemab: In the 18 double-blind months, the CDR-SB score lowers (worsens) by 1.2 (vs. 1.7 in placebo); in the subsequent 18 open-label months, the CDR-SB lowers by 1.8 (3 -1.2) –a 𝟱𝟬% 𝗳𝗮𝘀𝘁𝗲𝗿 𝗱𝗲𝗰𝗹𝗶𝗻𝗲 (1.8 -1.2 /1.2 * 100).

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).

RT @ScienceofPD: "These findings suggest that restoring, not reducing, γ-secretase activity & monomeric Aβ42 levels above a compensation th….

RT @Brain1878: Espay et al. challenge the view that AD results from increased gamma-secretase activity and Aβ42 overproduction. Instead, th….

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)?.

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 .

7/7 But the correlation was with the 𝗿𝗮𝘁𝗲 𝗼𝗳 𝗠𝗠𝗦𝗘 𝗰𝗵𝗮𝗻𝗴𝗲, not raw MMSE scores. Lower C-α-syn → faster cognitive decline → worse outcomes, which suggests a protective, not toxic, role of C-α-syn. Even if that doesn’t fit the "toxic proteins" dogma.

6/7 The authors’ interpretation differs:.“The inverse correlation between C-α-syn and MMSE, supports the hypothesis that soluble α-syn species in CSF, including pS129 α-syn, may reflect synaptic degeneration rather than α-syn aggregation”.

5/7 The most interesting finding:.Higher CSF C-α-syn was linked to slower MMSE decline in AD. The higher the CSF C-α-syn, the lower the rate of MMSE change (dMMSE/dT) in AD patients; therefore, the more stable the MMSE is. This is good!

4/7 The results?.pS129 α-syn was tiny in PD (1% of total α-syn).Same levels in PD and controls.No link to α-syn-SAA 'kinetic' measures.No correlation with α-syn-SAA positivity.Higher in Alzheimer’s — a non-synucleinopathy!.