BIN1 — The Second Strongest Alzheimer's Risk Gene
After APOE ε411 APOE ε4
the strongest genetic risk factor for late-onset Alzheimer's disease, variants in the BIN1 (bridging integrator 1) gene represent the second most significant genetic influence on Alzheimer's disease risk. The rs744373 variant sits in a regulatory region upstream of BIN1 and is associated with an odds ratio of 1.17–1.19 for developing Alzheimer's disease22 odds ratio of 1.17–1.19 for developing Alzheimer's disease
replicated across multiple large genome-wide association studies, meaning G-allele carriers have roughly 17–19% increased risk compared to non-carriers. With a global allele frequency near 40%33 global allele frequency near 40%
making it one of the most common Alzheimer's risk variants, this variant affects a substantial portion of the population.
The Mechanism
BIN1 encodes a protein involved in clathrin-mediated endocytosis44 clathrin-mediated endocytosis
the cellular process of internalizing material from outside the cell, membrane remodeling, and regulation of the actin cytoskeleton. The rs744373 variant lies in an enhancer region that affects BIN1 expression levels in brain tissue55 enhancer region that affects BIN1 expression levels in brain tissue
expression quantitative trait loci analysis shows strong association, with the G risk allele associated with altered gene expression. In the brain, BIN1 plays critical roles in synaptic vesicle endocytosis and, crucially, in tau protein metabolism and the spread of tau pathology between neurons66 tau protein metabolism and the spread of tau pathology between neurons
BIN1 is found in tau-containing exosomes in cerebrospinal fluid.
The protein interacts directly with tau and influences its secretion and uptake via vesicle-mediated mechanisms77 vesicle-mediated mechanisms
preclinical studies show BIN1 modulates trans-neuronal tau spreading. Unlike APOE, which primarily affects amyloid-beta accumulation, BIN1 variants specifically influence tau pathology—the neurofibrillary tangles that are more directly correlated with neurodegeneration and cognitive decline in Alzheimer's disease.
The Evidence
Franzmeier et al. (2019) used tau-PET imaging to demonstrate that rs744373 risk-allele carriers88 Franzmeier et al. (2019) used tau-PET imaging to demonstrate that rs744373 risk-allele carriers
89 older individuals without dementia showed higher tau accumulation across brain regions corresponding to Braak stages II–VI. Critically, BIN1 genotype was not associated with amyloid-PET uptake, confirming its specific role in tau pathology rather than amyloid accumulation.
A follow-up longitudinal study in two independent cohorts (ADNI n=153, BioFINDER n=63)99 A follow-up longitudinal study in two independent cohorts (ADNI n=153, BioFINDER n=63)
demonstrated BIN1 rs744373 risk-allele carriers show faster tau accumulation over time, particularly in the presence of elevated amyloid-beta. This interaction between BIN1 and amyloid suggests that BIN1 risk accelerates tau spread once the initial amyloid trigger is present, potentially explaining how these two pathologies converge to drive neurodegeneration.
Practical Implications
Unlike pharmacogenomic variants with clear medication adjustments, genetic Alzheimer's risk factors like BIN1 primarily inform risk assessment and motivate preventive strategies. Knowing your BIN1 genotype becomes most actionable when combined with other risk factors—particularly APOE status, family history, and cardiovascular health markers.
For individuals carrying one or two G alleles, the focus shifts to modifiable risk factors that reduce Alzheimer's risk across all genetic backgrounds. These include cognitive engagement, quality sleep (which facilitates clearance of both amyloid and tau1010 facilitates clearance of both amyloid and tau
glymphatic system function is impaired by poor sleep), and Mediterranean-style dietary patterns.
Genetic testing for BIN1 is not currently part of routine clinical practice, as the effect size is modest and there are no genotype-specific interventions.
Interactions
Interestingly, BIN1 rs744373 risk-allele carriers show lower rates of dyslipidemia (OR=0.56)1111 BIN1 rs744373 risk-allele carriers show lower rates of dyslipidemia (OR=0.56)
opposite to the increased dyslipidemia seen with APOE ε4, highlighting that these two major Alzheimer's risk genes may have distinct metabolic profiles. This could have implications for cardiovascular risk management strategies in individuals with different genetic risk profiles.