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Can you escape your genetic inheritance, and do lifestyle changes actually make a difference? Daniel Cossins set out to understand what the evidence on Alzheimer’s really means for him

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.

Dorene Rentz, PsyD, Professor of Neurology at Harvard Medical School and clinical neuropsychologist at Mass General Brigham, speaks on "Detecting Risk for Cognitive Decline: Feasibility and Utility of Remote Digital Assessment Tools” September 5, 2025 episode of the Mass General McCance Center for Brain Health Seminar Series. https://www.massgeneral.org/neurology/mccance-center

Email from Don't Miss out on Our Upcoming Seminars - Register Now for CE Credits!   FROM THE DIRECTOR'S DESK Greetings! The “Dog Days of Summer” have not slowed down the team at the Henry and Allison

BackgroundPreclinical risk for Alzheimer's disease (AD), including amyloid-β (Aβ) deposition, begins 10-15 years prior to diagnosis. In addition to genetics, hypertension, type 2 diabetes, and depress...

AbstractStudy Objectives. Sleep disruptions are associated with adverse mental and physical health outcomes. Individuals with post-acute sequelae of COVID-

Giulia Menichetti, PhD, Faculty Member at Harvard Medical School, Affiliated Faculty Member at the Network Science Institute, Investigator at Brigham and Women’s Hospital, speaks on "AI for Food Processing" July 7, 2025 Episode of the Mass General McCance Center for Brain Health Seminar Series. https://www.massgeneral.org/neurology/mccance-center