rs744373 — BIN1

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, with the effect mediated through worse memory performance. 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.

Meta-analysis across 71,168 samples (22,395 AD cases and 48,773 controls)¹⁰¹⁰ Meta-analysis across 71,168 samples (22,395 AD cases and 48,773 controls)
confirmed the association in both Caucasian (OR=1.16) and pooled populations, though the effect appears stronger in European populations. The consistency across diverse populations and multiple independent studies has elevated BIN1 to an established risk locus with clinical validity¹¹¹¹ established risk locus with clinical validity
included in genetic risk score models for Alzheimer's prediction.

Cognitive testing in healthy individuals shows BIN1 GG homozygotes¹²¹² Cognitive testing in healthy individuals shows BIN1 GG homozygotes
perform worse on high-load working memory tasks and show larger hippocampal volumes, suggesting compensatory changes occur even before clinical symptoms. Recognition memory appears particularly vulnerable, with BIN1 genetic effects stronger predictors than APOE in some studies¹³¹³ BIN1 genetic effects stronger predictors than APOE in some studies
among cognitively healthy older men.

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 maintaining cardiovascular health through blood pressure control¹⁴¹⁴ maintaining cardiovascular health through blood pressure control
hypertension is a well-established modifiable risk factor for dementia, regular physical exercise which reduces tau pathology in animal models¹⁵¹⁵ regular physical exercise which reduces tau pathology in animal models
aerobic exercise shows protective effects in human observational studies, cognitive engagement, quality sleep (which facilitates clearance of both amyloid and tau¹⁶¹⁶ facilitates clearance of both amyloid and tau
glymphatic system function is impaired by poor sleep), and Mediterranean-style dietary patterns.

Given that BIN1 risk specifically accelerates tau accumulation in the presence of amyloid-beta, interventions that reduce amyloid burden—whether through lifestyle factors or, potentially, emerging anti-amyloid therapies—may be particularly relevant for BIN1 risk-allele carriers. However, 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

The most significant interaction is between BIN1 rs744373 and APOE genotype (determined by rs429358 and rs7412). While both are independent risk factors, studies show BIN1 risk effects are amplified in the presence of APOE ε4¹⁷¹⁷ studies show BIN1 risk effects are amplified in the presence of APOE ε4
particularly for perivascular space enlargement in APOE ε4 carriers. The combined presence of BIN1 G alleles and APOE ε4 may represent a particularly high-risk genetic profile warranting aggressive risk factor modification.

BIN1 rs744373 shows interactions with rs7561528, another BIN1 variant¹⁸¹⁸ BIN1 rs744373 shows interactions with rs7561528, another BIN1 variant
haplotype analysis suggests compound effects within the BIN1 locus. Additionally, the mechanistic link between BIN1 and tau pathology suggests potential interactions with other tau-related genetic variants, though these have been less systematically studied than APOE interactions.

Interestingly, BIN1 rs744373 risk-allele carriers show lower rates of dyslipidemia (OR=0.56)¹⁹¹⁹ 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.