How BIN1 Gene Powers Tau Pathology
Imagine your brain as a bustling city, with billions of neurons communicating in a complex network that allows you to think, remember, and feel. Now picture tiny workers within each neuron, diligently managing traffic, maintaining structures, and ensuring efficient communication.
BIN1 is the second most important genetic risk factor for late-onset Alzheimer's disease, right after the well-known APOE gene.
For those carrying this genetic variant, the odds of developing Alzheimer's disease increase by 17-19% 3 . What makes this discovery particularly exciting is that BIN1-associated risk appears to be specifically driven by tau pathology rather than amyloid processes.
A pivotal 2019 study published in Nature Communications broke new ground by investigating whether the BIN1 rs744373 SNP was associated with increased tau pathology in living subjects 8 .
89 older adults without dementia—49 cognitively normal individuals and 40 with mild cognitive impairment (MCI)—from the Alzheimer's Disease Neuroimaging Initiative (ADNI) database 8 .
Researchers determined each participant's BIN1 rs744373 status through genetic testing, classifying them as either risk-allele carriers or normal-allele carriers.
All subjects underwent AV1451 tau-PET scanning, a specialized imaging technique that visualizes and quantifies tau tangles in specific brain regions.
Participants also received AV45 amyloid-PET scans to measure amyloid plaque deposition.
BIN1 rs744373 risk-allele carriers showed significantly higher levels of tau across multiple brain regions 8 .
The BIN1 risk variant was not associated with increased amyloid beta deposition, highlighting its specific connection to tau 8 .
Risk-allele carriers performed worse on memory tests, with tau pathology as the mechanism linking BIN1 to cognitive impairment 8 .
| Characteristic | CN BIN1 Normal (n=27) | CN BIN1 Risk (n=22) | MCI BIN1 Normal (n=22) | MCI BIN1 Risk (n=18) | p-value |
|---|---|---|---|---|---|
| Age | 80.3 (6.09) | 80.25 (5.55) | 76.48 (8.13) | 77.03 (6.35) | 0.118 |
| Gender (m/f) | 14/13 | 11/11 | 11/11 | 10/8 | 0.984 |
| Education | 17.07 (2.38) | 16.64 (2.94) | 15.45 (3.47) | 15.78 (2.67) | 0.349 |
| ADNI-MEM | 0.93 (0.51) | 0.79 (0.43) | 0.43 (0.75) | 0.09 (0.43) | <0.001 |
| AV1451 global SUVR | 1.05 (0.12) | 1.09 (0.07) | 1.08 (0.10) | 1.18 (0.15) | 0.002 |
Table shows the baseline characteristics of participants across different BIN1 genotype and cognitive status groups. Note the significantly lower ADNI-MEM scores (a measure of memory performance) and higher AV1451 global SUVR (indicating more tau) in MCI risk-allele carriers. Adapted from 8 .
Understanding how BIN1 influences tau pathology requires sophisticated tools that allow researchers to visualize and measure biological processes in the brain.
Visualizes and quantifies tau protein aggregates in living brains. Used to measure tau accumulation across different brain regions in BIN1 risk-allele carriers 8 .
Identifies genetic variants associated with disease risk. Used to discover BIN1 rs744373 as the second most significant Alzheimer's risk gene 3 .
Measures protein levels in spinal fluid. Earlier studies found BIN1 risk allele associated with higher CSF tau and phospho-tau 3 .
Provides detailed images of brain anatomy. Previous research linked BIN1 risk variants to reduced cortical thickness in memory regions 8 .
Understanding how BIN1 influences tau pathology could lead to novel treatment approaches targeting tau spreading, clearance, or aggregation mechanisms.
Individuals with BIN1 risk variants might benefit from early monitoring with tau-PET imaging and lifestyle interventions specifically targeting tau pathology.
The discovery that BIN1 rs744373 drives tau pathology independent of amyloid represents a significant advancement in our understanding of Alzheimer's disease. It moves us beyond the narrow focus on amyloid-centric models toward a more nuanced appreciation of the disease's complex genetic architecture. While much work remains, each discovery like this brings us closer to effective therapies that might one day prevent or reverse the devastating effects of Alzheimer's disease and other tauopathies.