by Christos Evangelou, MSc, PhD – Medical Writer and Editor

 

In a recent study, researchers at Mayo Clinic shed new light on the complex landscape of Alzheimer’s disease, revealing a spectrum of disease subtypes with distinct clinical, pathological, and cellular features. By examining over 1,300 brain samples and using innovative analytical techniques, researchers have uncovered significant associations between the distribution of abnormal tau protein in the brain, clinical symptoms, and patterns of glial cell activation.¹

According to the authors, the findings challenge our understanding of Alzheimer’s disease as a uniform condition and suggest that personalized treatment approaches may be necessary.

 

“This study introduced a novel corticolimbic index as a potential tool for personalized Alzheimer’s disease therapies, highlighting the importance of understanding the disease’s biological diversity for developing targeted treatments. By combining our knowledge from neuropathology, biostatistics, neuroscience, neuroimaging, and neurology, we’ve made significant strides in understanding how Alzheimer’s disease variably affects the brain from individual to individual,”

said Melissa E. Murray, Ph.D., the corresponding author of the study.

 

She also highlighted that this research not only deepens our understanding of Alzheimer’s disease heterogeneity but also suggests that glial reactivity may influence tangle distribution.

The report was published in JAMA Neurology.

 

The Unmet Need: Understanding Alzheimer’s Heterogeneity

Alzheimer’s disease has long been recognized as a memory disorder. However, clinicians and researchers have observed that some patients present with atypical symptoms, such as problems with language, visual perception, or executive function, rather than memory loss.¹ This variability in clinical presentation hints at underlying differences in how the disease affects the brain.

 

Dr. Murray, Professor of Neuroscience at Mayo Clinic, explains the rationale behind the study:

“Recent research revealed that the heterogeneity in how Alzheimer’s disease affects individuals is linked to neuropathologic patterns of tangle distribution. We wanted to know how corticolimbic vulnerability to abnormal tau pathology, as a continuous trait using a corticolimbic index, is associated with clinicopathologic heterogeneity and glial activation patterns in neuropathologically diagnosed Alzheimer’s disease.”

 

A Novel Approach: The Corticolimbic Index

“This study is the result of a highly collaborative Mayo Clinic environment, bringing together experts from different fields to approach Alzheimer’s disease pathophysiology from multiple angles,”

said Dr. Murray.

 

To assess the neuropathologic patterns of tangle distribution in patients with Alzheimer’s disease, the team developed an innovative metric called corticolimbic index (CLix). This index quantifies the relative distribution of tau protein aggregates — a hallmark of Alzheimer’s pathology — between the cortex (the brain’s outer layer) and limbic regions (including the hippocampus, crucial for memory). A lower CLix score indicates more tau pathology in the cortex relative to limbic areas, whereas a higher score suggests the opposite pattern.¹

The researchers examined 1,361 brain samples from the Florida Autopsied Multi-Ethnic (FLAME) cohort, representing one of the largest studies involving samples from patients with Alzheimer’s disease.¹ The cohort included individuals from various racial or ethnic backgrounds who had received care at memory disorder clinics and elected to participate in brain donation.

The team also incorporated neuroimaging data from 93 participants who had undergone magnetic resonance imaging (MRI) or tau-positron emission tomography (PET) scans before death, allowing them to validate their findings with in vivo measures.

 

“We applied the CLix methodology to evaluate the relationship with neuroimaging and found strong correlations with structural MRI and tau-PET measures,”

said Dr. Murray.

 

A Spectrum of Alzheimer’s Subtypes

Dr. Murray explained that CLix classified Alzheimer’s disease cases into three subtypes based on where brain changes occur, scoring the location of aggregated thioflavin-S tangle distribution in the brain: lower CLix scores reflected a relative cortical predominance/hippocampal-sparing disease, median CLix score a typical Alzheimer’s disease distribution, and higher CLix scores reflected relative cortical sparing/limbic predominant disease.

The study also revealed several important associations between CLix scores and clinical, demographic, and neuropathologic features. Lower CLix scores (indicating more cortical tau) were strongly associated with younger age at symptom onset, suggesting that young-onset Alzheimer’s disease may have a distinct neuropathologic profile.¹ Moreover, patients with atypical, non-memory symptoms were more likely to have lower CLix scores, providing a biological basis for the clinical heterogeneity observed in Alzheimer’s disease.

Furthermore, lower CLix scores correlated with faster cognitive decline, highlighting the aggressive nature of cortical-predominant Alzheimer’s disease subtypes. Interestingly, carriers of the APOE ε4 allele (a known risk factor for Alzheimer’s disease) tended to have higher CLix scores. In contrast, carriers of a rare variant in the TREM2 gene had lower scores.¹ These findings suggest that different genetic risk factors may influence the pattern of disease spread in the brain.

In the subset of patients with available neuroimaging, lower CLix scores were associated with greater tau-PET uptake in cortical regions and larger hippocampal volumes on MRI.¹

 

Glial Activation Patterns

The team also used digital pathology approaches to analyze glial cell activation patterns in a subset of 60 brains. Glial cells, including astrocytes and microglia, play crucial roles in brain health and disease.¹

 

“Using digital pathology techniques in a subgroup of participants, we discovered a continuum of regional brain changes characterized by unique clinical features and brain immune cell phenotypes, including a group of hippocampal sparing Alzheimer’s disease cases with unusual microglial patterns,”

noted Dr. Murray.

 

In cases with low CLix scores (those with more cortical tau pathology), there were lower levels of activated microglia in the cortex despite the high tau burden. Dr. Murray explained that this finding was surprising, as more microglial activation would be expected in areas with more pathology. She added that this finding suggests that there may be a dysfunction in the microglial response in certain Alzheimer’s disease subtypes, potentially contributing to the aggressive nature of cortical-predominant cases.

 

Potential Implications and Future Work

According to Dr. Murray, the CLix score will encourage a paradigm shift toward understanding the individuality of Alzheimer’s disease to broaden our perspective on this complex disease.

 

“We believe that our findings have the potential to significantly impact clinical practice in neurology and inspire further investigations into personalized treatment approaches for Alzheimer’s disease,”

she said.

 

She acknowledged, however, that several questions remain unanswered. The team used GFAP and CD68 to study glial activation patterns, but these markers might not capture the full spectrum of glial activity in Alzheimer’s disease.

 

“Although we detected decreased CD68 immunoreactivity in the cortex of hippocampal sparing Alzheimer’s disease cases, additional microglial markers could provide important information to explain why the tau pathology in these patients’ cortices is so pervasive,”

she said.

 

Future studies are also required to explore whether analysis of the occipital cortex might better characterize Alzheimer’s cases with posterior cortical atrophy. Moreover, Dr. Murray highlighted the need for more robust methods to recognize extracellular ghost tangles.

 

“Although our corticolimbic index showed promise for clinical translation, additional research is necessary to validate its effectiveness across different stages of the disease. Future studies should address these areas to enhance our understanding and improve diagnostic tools,”

Dr. Murray concluded.

 

 

The study received financial support from the National Institute on Aging, the National Institute of Neurological Disorders and Stroke, the Department of Defense, the Florida Department of Health, the Ed and Ethel Moore Alzheimer’s Disease Research Program, Alzheimer’s Association, a kind gift from David and Frances Strawn, the Gerstner Family Career Development Award, the Elsie and Marvin Dekelboum Family Foundation, the Alexander Family Alzheimer’s Disease Research Professorship of the Mayo Clinic, the Liston Award, the Schuler Foundation, the GHR Foundation, the Mayo Foundation for Medical Education and Research, the Mayo Clinic Dorothy and Harry T. Mangurian Jr Lewy Body Dementia Program, and the Robert E. Jacoby Professorship.

References

1. Kouri N, Frankenhauser I, Peng Z, et al. Clinicopathologic Heterogeneity and Glial Activation Patterns in Alzheimer Disease. JAMA Neurol. 2024;81(6):619-629. doi:10.1001/jamaneurol.2024.0784