Isabel Castanho, PhD

I am honored to celebrate our publication. I work together with these future leaders in Alzheimer's research. Will AD become a controllable disease? If we can find our natural defensives and make them stronger?

Molecular hallmarks of excitatory and inhibitory neuronal resilience to Alzheimer’s disease - Molecular Neurodegeneration Background A significant proportion of individuals maintain cognition despite extensive Alzheimer’s disease (AD) pathology, known as cognitive resilience. Understanding the molecular mechanisms that protect these individuals could reveal therapeutic targets for AD. Methods This study defines molecular and cellular signatures of cognitive resilience by integrating bulk RNA and single-cell transcriptomic data with genetics across multiple brain regions. We analyzed data from the Religious Order Study and the Rush Memory and Aging Project (ROSMAP), including bulk RNA sequencing (n = 631 individuals) and multiregional single-nucleus RNA sequencing (n = 48 individuals). Subjects were categorized into AD, resilient, and control based on β-amyloid and tau pathology, and cognitive status. We identified and prioritized protected cell populations using whole-genome sequencing-derived genetic variants, transcriptomic profiling, and cellular composition. Results Transcriptomics and polygenic risk analysis position resilience as an intermediate AD state. Only GFAP and KLF4 expression distinguished resilience from controls at tissue level, whereas differential expression of genes involved in nucleic acid metabolism and signaling differentiated AD and resilient brains. At the cellular level, resilience was characterized by broad downregulation of LINGO1 expression and reorganization of chaperone pathways, specifically downregulation of Hsp90 and upregulation of Hsp40, Hsp70, and Hsp110 families in excitatory neurons. MEF2C, ATP8B1, and RELN emerged as key markers of resilient neurons. Excitatory neuronal subtypes in the entorhinal cortex (ATP8B+ and MEF2Chigh) exhibited unique resilience signaling through activation of neurotrophin (BDNF-NTRK2, modulated by LINGO1) and angiopoietin (ANGPT2-TEK) pathways. MEF2C+ inhibitory neurons were over-represented in resilient brains, and the expression of genes associated with rare genetic variants revealed vulnerable somatostatin (SST) cortical interneurons that survive in AD resilience. The maintenance of excitatory-inhibitory balance emerges as a key characteristic of resilience. Conclusions We have defined molecular and cellular hallmarks of cognitive resilience, an intermediate state in the AD continuum. Resilience mechanisms include preserved neuronal function, balanced network activity, and activation of neurotrophic survival signaling. Specific excitatory neuronal populations appear to play a central role in mediating cognitive resilience, while a subset of vulnerable interneurons likely provides compensation against AD-associated hyperexcitability. This study offers a framework to leverage natural protective mechanisms to mitigate neurodegeneration and preserve cognition in AD.

'Molecular hallmarks of excitatory and inhibitory neuronal resilience to #AlzheimersDisease'

Isabel Castanho, Pourya Naderi Yeganeh...Rudolph E. Tanzi & Winston Hide @winhide.bsky.social @harvardmed.bsky.social

#CognitiveResilience #transcriptomics #genetics

bit.ly/3VK7k5b

🧠 Key takeaway: Cognitive resilience hinges on preserving excitatory-inhibitory homeostasis. Specific “surge-protector” neurons control excess firing and shield the cortex even when plaques and tangles are abundant.

Molecular hallmarks of excitatory and inhibitory neuronal resilience to Alzheimer’s disease - Molecular Neurodegeneration Background A significant proportion of individuals maintain cognition despite extensive Alzheimer’s disease (AD) pathology, known as cognitive resilience. Understanding the molecular mechanisms that protect these individuals could reveal therapeutic targets for AD. Methods This study defines molecular and cellular signatures of cognitive resilience by integrating bulk RNA and single-cell transcriptomic data with genetics across multiple brain regions. We analyzed data from the Religious Order Study and the Rush Memory and Aging Project (ROSMAP), including bulk RNA sequencing (n = 631 individuals) and multiregional single-nucleus RNA sequencing (n = 48 individuals). Subjects were categorized into AD, resilient, and control based on β-amyloid and tau pathology, and cognitive status. We identified and prioritized protected cell populations using whole-genome sequencing-derived genetic variants, transcriptomic profiling, and cellular composition. Results Transcriptomics and polygenic risk analysis position resilience as an intermediate AD state. Only GFAP and KLF4 expression distinguished resilience from controls at tissue level, whereas differential expression of genes involved in nucleic acid metabolism and signaling differentiated AD and resilient brains. At the cellular level, resilience was characterized by broad downregulation of LINGO1 expression and reorganization of chaperone pathways, specifically downregulation of Hsp90 and upregulation of Hsp40, Hsp70, and Hsp110 families in excitatory neurons. MEF2C, ATP8B1, and RELN emerged as key markers of resilient neurons. Excitatory neuronal subtypes in the entorhinal cortex (ATP8B+ and MEF2Chigh) exhibited unique resilience signaling through activation of neurotrophin (BDNF-NTRK2, modulated by LINGO1) and angiopoietin (ANGPT2-TEK) pathways. MEF2C+ inhibitory neurons were over-represented in resilient brains, and the expression of genes associated with rare genetic variants revealed vulnerable somatostatin (SST) cortical interneurons that survive in AD resilience. The maintenance of excitatory-inhibitory balance emerges as a key characteristic of resilience. Conclusions We have defined molecular and cellular hallmarks of cognitive resilience, an intermediate state in the AD continuum. Resilience mechanisms include preserved neuronal function, balanced network activity, and activation of neurotrophic survival signaling. Specific excitatory neuronal populations appear to play a central role in mediating cognitive resilience, while a subset of vulnerable interneurons likely provides compensation against AD-associated hyperexcitability. This study offers a framework to leverage natural protective mechanisms to mitigate neurodegeneration and preserve cognition in AD.

Thrilled to share that our paper “Molecular hallmarks of excitatory and inhibitory neuronal resilience to Alzheimer’s disease” is now out in Molecular Neurodegeneration!

👉 link.springer.com/article/10.1...

#Alzheimer #Resilience #Neuroscience

Dementia Researcher Salon Debate - AI and Disparities in Research and Care Dementia Researcher Salon Debate - AI and Disparities in Research and Care

🤖 Is #AI helping close gaps in research and care, or making disparities worse?

Join @isabelscst.bsky.social & Dr Eleanor Conole for a live debate on 12 Nov at 8pm GMT.

🗳 Vote, question, decide.

communities.dementiaresearcher.nihr.ac.uk/c/events/deb...

Professor: Alzheimer’s Genetics & Genomics / Neuropathology & Neurodegeneration The Penn Neurodegeneration Genomics Center seeks an Associate or Full Prof to lead Alzheimer’s genomics research and teaching within its multidisciplinary team.

The Penn Neurodegeneration Genomics Center seeks an Associate or Full Professor to lead Alzheimer’s genomics research and teaching within its world leading multidisciplinary team. Closing date: 5th October

www.dementiaresearcher.nihr.ac.uk/job/professo...

For me what helped me the most was changing my mindset to "What's the worst that can happen? Me not getting the PhD? It's not going to happen, but if it does, I can leave with that! Not worth the price of my physical and mental health!". Still, bloody difficult, though. Keep swimming. Almost there.

Salon Debates Dementia Researcher Salon - Debates

We're looking for speakers! This October and November, our Salon Webinars will feature debates on big issues in academic careers and dementia research. Fancy taking part?

🔗 8k3qel8nuxc.typeform.com/SalonDebates

Thank you to @alzheimersresearchuk.org & @alzheimerssoc.bsky.social for supporting this work.

🔍 Main findings:

• Tau vs Aβ → pathology-specific DNA methylation remodeling
• Larger effects in the hippocampus
• Convergence with human studies: ANK1, PRDM16, SATB1
• Accelerated epigenetic age with tau accumulation

#Tau #Amyloid #Alzheimer #EndAlz #Epigenetics

Methylomic signatures of tau and amyloid-beta in transgenic mouse models of Alzheimer’s disease neuropathology Alzheimer’s disease (AD) is characterized by progressive neurodegeneration driven by tau and amyloid-β (Aβ) pathology. Emerging evidence implicates a role for epigenetic modifications, particularly al...

Proud to share my first co-last/co-corresponding manuscript (preprint): DNA methylation shifts in tau & Aβ mice 🧬🐁

This work started during my PhD at @exeter.ac.uk (outstanding mentor: Prof Jonathan Mill) & was led forward by Szi Kay Leung, now a superstar postdoc ⭐

www.biorxiv.org/content/10.1...

#AAIC25 was a blast!
🧠 Gave a talk during the Molecular Basis of Cognitive Resilience Session, followed by a great discussion
@isabelscst.bsky.social @susanrohde.bsky.social @baldassogabi.bsky.social
#TainLuquez
Feeling really energized about where this field is headed 🤓

I keep saying that scientists come in all shapes & forms! Even the other day I was telling someone that a few years ago when I was an organizer of @soapboxscience.bsky.social Exeter, I tried to bring in professors & students, of course, but also RAs, core leads, etc. I certainly see you! :)

Now that #AAIC25 - the biggest international conference on #Alzheimers & #dementia - ended, I'm still processing all that I experienced, learned, & absorbed this past week. What a week!

Looking forward to London next year, where my story as an @istaart.bsky.social ambassador began 💜

#EndAlz

US based scientists: Keep writing grants. Keep writing papers. Keep doing research.

Keep on keeping on.

Remember why you do the work you do. ✊🏼 🧪

A large group of ISTAART members in matching purple t-shirts stand and sit around large AAIC25 letters, posing for a group picture.

Exclusive offer for #AAIC25 attendees: Join @istaart.bsky.social as a new member during AAIC to receive 10% off membership dues! Stop by the Alzheimer's Association booth in the Exhibit Hall or visit alz.org/ISTAART to join.

Excited to start my bluesky journey after attending #ISTAART Skills Workshop: Amplifying Your Scientific Profile Through Social Media hosted by @isabelscst.bsky.social, @caitlynfastenau.bsky.social, and Lisa!

#AAIC25

Our second #AAIC25 special is live! Dr James Brady with @stirlandia.bsky.social, @isabelscst.bsky.social & @felixwittmann.bsky.social. Video & audio streaming now.

pod.fo/e/304afe

@mariacarrilloalz.bsky.social shares exciting #AAIC25 attendee stats:
🔬 Nearly 8,200 are in Toronto & 3,200+ are online
🔬48% of in-person attendees & 61% of virtual attendees are women
🔬 23% are under age 35
🔬 More than 22% are first-time attendees
🔬More than 70% are @istaart.bsky.social members

Dementia Researcher: AAIC Day Two 2025 Highlights In this podcast we share a few selected highlights from the Alzheimer’s Association International Conference (AAIC) first and second day of the main event in Toronto and Online, 27the - 31st July...

Our second #AAIC25 special is live! Dr James Brady with @stirlandia.bsky.social, @isabelscst.bsky.social & @felixwittmann.bsky.social. Video & audio streaming now.

pod.fo/e/304afe

@laurenfish.bsky.social
#TainLuquez
@susanrohde.bsky.social @baldassogabi.bsky.social

Proud of our session at #AAIC25 yesterday, "Molecular Basis of Cognitive Resilience". 💜

We really are trying to bring the field together, and I think we did a great job! 👏🏻

Thank you to the audience for making the Q&A so stimulating. 🤩

If you missed it, the recording is available online.

@baldassogabi.bsky.social , the youngest speaker in our session - who just started her PhD - did such a great job at #AAIC25. ⭐ I'm excited to see this superstar's science & career unfold. 🤩 Well done Gabriela 👏🏻

Adam Smith - Blog – AAIC 2025, Big, Busy and Worth It Adam Smith shares reflections and tips for navigating AAIC 2025 in Toronto – a conference that’s big, full on, and genuinely worth the effort.

“It’s okay to feel a bit lost – everyone does.” Read Adam Smith’s @betterresearch.bsky.social take on how to make the most of #AAIC25, whether attending in person or online.

www.dementiaresearcher.nihr.ac.uk/blog-aaic-20...

Have you added the session "Molecular Basis of Cognitive Resilience" to your schedule on the #AAIC25 app yet?

We have a fantastic lineup of speakers! ⭐

See you there? 🤓

That's the beauty of the virtual #AAIC25 platform 😃 I'm sure you can catch up (or even watch live) online.

And feel free to say hello if you cross paths with me or any of the speakers when you arrive + we're all a friendly bunch!

Very excited to present at the @istaart.bsky.social Skills Workshop titled Amplifying Your Scientific Profile Through Social Media at #AAIC25!

Come learn some great skills from some amazing speakers @isabelscst.bsky.social, Lisa Koen, and myself!

⏰Wednesday July 30 (12:30-1:45pm)
📍603-605

Come and check out this interesting session on #resilience on the very first morning of #AAIC25 in #Toronto or online! I will be talking about cognitive resilience in centenarians! 💯🧠

POV of commuting to work this week, ahead of #AAIC25

First pic: preparing my Sunday presentation on #cognitiveresilience to #Alzheimer on my way to work

Second pic: preparing slides for the Wednesday @istaart.bsky.social workshop on using #socialmedia to grow professionally

And have you noticed how many #womenscience will present in our session??? 😍

@baldassogabi.bsky.social
@laurenfish.bsky.social
@susanrohde.bsky.social

#AAIC25