Resistance is NOT futile: The brain cells that confer resilience to Alzheimer’s disease

 An estimated $42.5 billion has been invested in Alzheimer's disease (AD) research and development, with over 100 failed clinical trials, the majority targeting the amyloid beta cascade hypothesis, first proposed in 1992. More than three decades of intense focus on amyloid beta have yielded limited therapeutic success. However, one compelling observation about AD remains: certain populations around the world appear to have naturally low rates of the disease.

Insights from Blue Zones: A Model for Alzheimer’s Resilience

Blue Zones are geographically defined regions where individuals live exceptionally long and healthy lives, with a high concentration of centenarians and markedly reduced rates of age-related diseases, including Alzheimer’s disease. These regions—Okinawa (Japan), Sardinia (Italy), Nicoya (Costa Rica), Ikaria (Greece), and Loma Linda (California)—have been extensively studied for their shared lifestyle characteristics, which may contribute to cognitive longevity and resilience against neurodegenerative diseases.

The common factors among Blue Zone populations include:

• Predominantly plant-based, anti-inflammatory diets, rich in whole foods and low in processed ingredients

• Consistent physical activity and movement, embedded in daily life rather than structured exercise

• Strong social bonds, reducing chronic stress and promoting emotional well-being

• A defined sense of purpose ("Ikigai" or "Plan de Vida"), linked to lower dementia risk

• Effective stress management practices, such as meditation, naps, or religious involvement

• Lifelong learning and cognitive engagement, fostering neural plasticity

• Intergenerational and community-based living, enhancing emotional support

• Moderate wine consumption, particularly in regions where red wine is rich in polyphenols with potential neuroprotective properties

The study of these populations provides compelling epidemiological evidence that lifestyle factors can significantly impact neurodegenerative disease risk. However, translating these observations into molecular mechanisms of Alzheimer’s resilience remains a critical challenge. In this context, a recent preprint from Winston Hide’s lab at the BIDMC Stem Cell Institute at Harvard provides valuable new insights into the cellular and molecular underpinnings of resilience to AD.

Cell types that confer resilience to Alzheimer’s disease

To set some background on what we know about cell types in the progression from presymptomatic ALZ to ALZ with cognitive impairment, my brother’s paper (Webster…Masliah, 2006) looked at activation of the MAPK pathway, an indicator of an inflammatory reactive phenotype, in various cell types in brain tissue from donors with cognitive impairment and concomitant hallmarks of ALZ, compared to those donors with mild cognitive impairment, or pre-symptomatic, ALZ. He found that inflammatory activation of astrocytes, or astrogliosis, precedes neuron damage and neurodegeneration, and represents an early, perhaps presymptomatic stage, represented by mild cognitive impairment. Whereas, progression to full ALZ with cognitive impairment was characterized by MAPK activation in neurons, but not astrocytes. Inflammatory activation may be seeded in astrocytes and then move into neurons in later stages of the disease.

The Castanho et al., (Biorxiv, January 15, 2025) paper is very compelling because they show, using integrated bulk RNAseq and single nucleus RNA sequencing (snRNAseq), extremely high fidelity methods that capture the entire transcriptome of each individual cell in the human ALZ brain, that indeed, reactive astrocytes represent a ‘resilience,’ or perhaps, prolonged intermediate phase, to ALZ. 

‘Resilient’ individuals were defined by the presence of amyloid beta plaque and tau formation, characteristic of ALZ, but lacking the cognitive deficits. Castanho et al. identified two genes that are differentially expressed between the ‘resilient’ cohort and healthy age matched controls. Glial fibrillary acid protein, or GFAP, is often a marker for inflammatory astrocytes, but could also be an indicator of healthy but activated astrocytes. GFAP was one of the differentially expressed genes that the paper identified between RES and CTL brains, suggesting, as my brother saw nearly twenty years ago, that activated astrocytes represent an intermediate transition between healthy and ALZ brain. It is possible that this phase characterized by astrogliosis can remain static indefinitely, though more work needs to be done to establish the determinants of progression to ALZ. 

The other gene that Castaho et al identified as differential was downregulated KLF4 in RES compared to CTL. Kruppel-like factor is a zinc finger transcription factor that is highly expressed in microglia in the human brain (Brain RNA-seq Database, Barres lab). In microglia, the brains resident immune cells that are responsible for much of the neuroinflammation in the case of disease, KLF4 is an inflammatory transcription factor that activates the microglia inflammasome via NF-kB. Castanho et al show that KLF4 is actually downregulated in RES individuals compared to CTL brains, suggesting that this critical transcription factor may be shifting the microglial phenotype from one that would generally be inflamed in an ALZ pathological context, to one that displays downregulated inflammation, even when bombarded with toxic ALZ plaques. 

Taken together, ‘Resilience’ to ALZ may require activated astrocyte phenotypes, though it’s unknown whether the increased GFAP represents an A1 or A2 morphology, an inflamed astrogliosis morphology or an anti-inflammatory, supportive morphology, respectively. The case has been demonstrated that astrocytes play a major role in ‘Resilience.’ Better understanding the nature of these reactive astrocytes will pave the way for an improved understanding of the cellular underpinnings of ALZ. Additionally, if the downregulated KLF4 in microglia represents a phenotype switch from inflammatory activated microglia to a resting, anti-inflammatory morphology, and this prevents neuroinflammation in the case of ALZ pathology, it would be pertinent to better understand how this phenotype switch could occur. Whether the downregulated KLF4 in microglia occurs in a cell autonomous fashion, or requires the phenotype represented by GFAP positive astrocytes also seen is a question that should be addressed. The phenotypic information about astrocytes and microglia afforded by the Castaho et al. paper in the context of ‘Resilience’ to ALZ not only validates earlier findings that astrogliosis represents an intermediate stage in disease progression, but also is an invaluable discovery likely to fuel much research going forward.