rs3851179 — PICALM

PICALM and Alzheimer's Disease Risk — A Blood-Brain Barrier Story

The PICALM gene¹¹ The PICALM gene
PICALM (Phosphatidylinositol binding clathrin assembly protein) orchestrates clathrin-mediated endocytosis, a cellular process critical for transporting molecules across cell membranes. Located on chromosome 11q14.2, PICALM is expressed most abundantly in brain microvessels—the endothelial cells forming the blood-brain barrier—where it plays a central role in clearing toxic amyloid-beta (Aβ) peptides from the brain. The rs3851179 variant, situated approximately 88 kb upstream of the PICALM gene, has emerged as one of the most consistently replicated genetic risk factors for late-onset Alzheimer's disease after APOE and BIN1.

The Mechanism

PICALM regulates the blood-brain barrier's ability to clear amyloid-beta from the brain into the bloodstream²² PICALM regulates the blood-brain barrier's ability to clear amyloid-beta from the brain into the bloodstream
The protein facilitates clathrin-dependent internalization of Aβ bound to LRP1 (low density lipoprotein receptor-related protein-1), a key clearance receptor, and guides the Aβ-LRP1 complex to endosomes for transcytosis—transport across the endothelial cell wall. The rs3851179 A allele, which is protective against Alzheimer's, correlates with increased PICALM expression in brain endothelium³³ The rs3851179 A allele, which is protective against Alzheimer's, correlates with increased PICALM expression in brain endothelium
In contrast, reduced PICALM expression—associated with the G allele—impairs Aβ clearance, accelerates Aβ accumulation in the brain, and correlates with cognitive impairment.

The variant is intergenic, located in a regulatory region between PICALM and the EED gene⁴⁴ The variant is intergenic, located in a regulatory region between PICALM and the EED gene
It does not change the PICALM protein sequence but appears to affect gene expression levels. PICALM is also linked functionally to ABCB1/P-glycoprotein, another Aβ clearance protein, suggesting a coordinated transcytosis system for removing brain-derived amyloid⁵⁵ PICALM is also linked functionally to ABCB1/P-glycoprotein, another Aβ clearance protein, suggesting a coordinated transcytosis system for removing brain-derived amyloid.

The Evidence

The initial discovery came from a genome-wide association study of over 5,000 Alzheimer's patients and 10,000 controls⁶⁶ The initial discovery came from a genome-wide association study of over 5,000 Alzheimer's patients and 10,000 controls
Carriers of the A allele showed a 15% reduced risk of Alzheimer's disease (OR 0.85, p=1.9×10⁻⁸). This association has been replicated across multiple ethnicities⁷⁷ This association has been replicated across multiple ethnicities
A 2016 meta-analysis of 9,435 samples confirmed the association in Chinese populations, and a 2018 systematic review of 16 case-control studies across Caucasian and Asian populations found significant associations in all genetic models examined⁸⁸ a 2018 systematic review of 16 case-control studies across Caucasian and Asian populations found significant associations in all genetic models examined.

The protective effect of the A allele remains evident even in APOE ε4 non-carriers⁹⁹ The protective effect of the A allele remains evident even in APOE ε4 non-carriers
suggesting PICALM acts through a mechanism independent of APOE. Interestingly, the A allele shows protective effects not only for Alzheimer's but also for Parkinson's disease in some populations¹⁰¹⁰ Interestingly, the A allele shows protective effects not only for Alzheimer's but also for Parkinson's disease in some populations, highlighting PICALM's broader role in neurodegeneration.

Functional studies demonstrate that the A allele is associated with increased PICALM mRNA expression in brain tissue¹¹¹¹ Functional studies demonstrate that the A allele is associated with increased PICALM mRNA expression in brain tissue
particularly in microvessels, and that this increase correlates with greater amyloid-beta clearance capacity. Mouse models with reduced Picalm expression show accelerated Aβ pathology and cognitive deficits, which can be reversed by restoring endothelial PICALM expression¹²¹² Mouse models with reduced Picalm expression show accelerated Aβ pathology and cognitive deficits, which can be reversed by restoring endothelial PICALM expression.

Practical Implications

While you cannot change your PICALM genotype, understanding your genetic risk profile can inform proactive strategies. The GG genotype confers modestly increased Alzheimer's risk, but this is just one piece of a multifactorial puzzle. Lifestyle factors—cardiovascular health, cognitive engagement, exercise, and sleep quality—significantly influence Alzheimer's risk regardless of genetics.

PICALM's role in vascular amyloid clearance underscores the importance of maintaining blood-brain barrier integrity¹³¹³ PICALM's role in vascular amyloid clearance underscores the importance of maintaining blood-brain barrier integrity
Cardiovascular risk factors (hypertension, diabetes, high cholesterol) damage the blood-brain barrier and impair its clearance function. Managing these factors may help compensate for genetic vulnerabilities in the PICALM pathway.

Interactions

The PICALM rs3851179 variant does not operate in isolation. While the protective effect of the A allele is independent of APOE ε4 status, individuals carrying both APOE ε4 and the PICALM GG genotype face compounded Alzheimer's risk through different mechanisms—APOE affects amyloid aggregation and clearance through lipoprotein pathways, while PICALM regulates transcytosis across the blood-brain barrier. Other Alzheimer's risk genes including BIN1, CLU (clusterin), and CR1 (complement receptor 1) may also interact with PICALM in the broader context of brain amyloid homeostasis. The rs3851179 variant is in high linkage disequilibrium with other PICALM-region SNPs including rs10792832, rs561655, and rs541458, all of which show genome-wide significant associations with Alzheimer's disease.