Tumor Necrosis Factor Pathway Contributes to Resilience in Alzheimer’s Disease

TNFRSF1B gene variant associated with slower progression, offering potential drug target

genetics and alzheimer's disease

A genetic variant of the tumor necrosis factor receptor 2 (TNFR2) pathway is associated with modulation of indicators of Alzheimer’s disease severity and a slower rate of functional decline over one year. These findings, from a team of Cleveland Clinic investigators, suggest that the variant (known as rs976881) could be a marker of resilience and the TNFR2 pathway a target of future therapy. The research was published online in Frontiers in Aging Neuroscience (Epub 2021 Feb 25).

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“Understanding the interplay between genetic factors and clinical patterns of Alzheimer’s disease is critical to developing precision medicine interventions,” says lead author Jagan Pillai, MD, PhD, a neurologist with Cleveland Clinic Lou Ruvo Center for Brain Health. “Our research identifies a genetic variant of the TNFR2 pathway and related TNFR2 expression levels as a promising focus.”

Genes provide clues to Alzheimer’s disease course

While it is well established that Alzheimer’s disease is characterized by amyloid beta plaques and tau neurofibrillary tangles in the brain, their amounts do not always correlate with disease course. Some patients have better than expected cognitive performance in relation to the degree of pathology, Dr. Pillai notes, a phenomenon referred to as “cognitive resilience.”

“Genetic factors likely help explain why the disease course varies cognitively and behaviorally between patients,” he says.

His team’s study focused on the products of the TNFRSF1B gene detectable in cerebrospinal fluid (CSF). The gene encodes for TNFR2 and its soluble form, sTNFR2, which is expressed primarily in immune and endothelial cells. TNF is an inflammatory marker known to play a role in synaptic plasticity and modulating responses to neural injury. TNFR2 has previously been shown to promote neuronal survival and protect against neurodegeneration.

The TNF pathway has been implicated in providing protection against certain inflammatory diseases and cancers, but whether it plays an important role in Alzheimer’s disease had not been well established. This group’s previous research found that sTNFR2 in CSF and plasma strongly correlates with t-tau and p-tau levels in the CSF, making them a good marker of Alzheimer’s disease severity (Ann Clin Trans Neurol. 2019; 6:1248-1262).

Study design

The study’s main cohort consisted of 188 participants in the Alzheimer’s Disease Neuroimaging Initiative (ADNI), a national research database. Subjects included individuals with mild cognitive impairment (MCI) and dementia.

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In addition, a replication cohort of 48 patients with MCI was drawn from a Cleveland Clinic memory clinic. Previous research from Dr. Pillai’s group indicates that these subjects tended to have more rapid progression of Alzheimer’s disease than the ADNI cohort, but they were less likely to have other significant comorbidities.

CSF samples from the cohorts were analyzed for sTNFR2 and for two related TNFRSF1B single-nucleotide polymorphisms (SNPs): rs976881 and rs1061622. In the ADNI cohort, levels of these products were evaluatedrelative to Alzheimer’s disease biomarkers (CSF t-tau, p-tau), detailed cognitive testing results, MRI brain measures and longitudinal cognitive changes over 12 months. The replication cohort data were limited to CSF levels of Alzheimer’s disease biomarkers.

Cognitive testing addressed all major domains, including verbal episodic memory, attention, executive functioning, object naming, verbal fluency and global cognition.


Significant interactions between variant rs976881 and CSF sTNFR2 were detected in both cohorts.

In the ADNI cohort, these factors significantly modulated the following:

  • CSF t-tau and p-tau levels
  • Hippocampal and whole brain volumes
  • Digit Span Forwards subtest scores
  • Clinical Dementia Rating “Sum of Boxes” scores

In the replication cohort, the CSF p-tau level was modulated, with a much larger effect size than in the ADNI cohort. The interaction to CSF t-tau observed in the ADNI cohort was also found, but it did not reach statistical significance.

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The group also investigated two alleles of rs976881 and found that the homozygous state of the minor form was associated with higher sTNFR2, lower CSF t-tau and p-tau, and slower cognitive decline over one year.

A significant interaction was also observed between rs1061622 and sTNFR2 and its effect on CSF t-tau and p-tau, but in the replication cohort only. This probably reflected baseline differences in the cohorts, according to Dr. Pillai.

Takeaways and next steps

“In summary, we found that the interaction between TNFRSF1B variant rs976881 and CSF TNFR2 levels modulates multiple severity markers and cognitive domains associated with Alzheimer’s disease,” says Dr. Pillai. “This interaction affects resilience and lends support to sTNFR2 as a promising focus for developing therapeutic interventions.”

The authors note that more work is needed to elucidate the role of TNFR2 in Alzheimer’s disease resilience. Current studies draw from predominantly white and well-educated patient groups; more diverse populations are needed to draw general conclusions.

Dr. Pillai adds that the methods of his research group — using human data rather than animal models — bolsters the clinical relevance of their findings. They will next explore what might affect TNFR2 levels, with possible factors being comorbidities, the microbiome and diet.

“Popular thinking holds that inflammation is a bad thing, but our research indicates that the reality is more complicated,” he concludes. “These findings are an important step in clarifying this picture.”