rs113809142 — ABCA7 ABCA7 splice donor variant (c.4416+2T>G)

ABCA7 c.4416+2T>G — A Splice Defect That Silences the Brain's Amyloid Disposal Team

ABCA7 (ATP-binding cassette sub-family A member 7) is a membrane-spanning lipid transporter expressed at its highest levels in neurons and microglia — exactly the cells responsible for managing amyloid-beta (Aβ) accumulation in the aging brain. The protein ferries phospholipids and cholesterol across cell membranes, a function that turns out to be central to Aβ clearance, lipid raft organisation, and amyloid precursor protein (APP) processing. Loss-of-function variants in ABCA7 consistently rank as the strongest non-APOE genetic risk factors for late-onset Alzheimer's disease (LOAD) in people of European ancestry, and carry even larger effect sizes in African American cohorts.

rs113809142 is the c.4416+2T>G variant, a single nucleotide change at the splice donor site of intron 32 in ABCA7 (also annotated as IVS32+2T>G). This position — immediately adjacent to the GU dinucleotide that marks the boundary between exon and intron — is a canonical splice signal. The G allele disrupts the splice donor consensus sequence, causing intron retention or exon skipping and generating a premature termination codon. RNAseq data from carriers confirm that the mutant allele extends into intronic sequence rather than splicing correctly.

The Mechanism

When ABCA7 is haploinsufficient, neurons and microglia operate with roughly half the normal transporter capacity. Three downstream consequences compound in the direction of Aβ accumulation:

1. Impaired microglial phagocytosis. Fu et al. 2016¹¹ Fu et al. 2016
   ABCA7-null mice showed substantially reduced clearance of Aβ oligomers by microglia and macrophages; ABCA7 transcription was simultaneously up-regulated in AD brains, suggesting attempted compensation. Without adequate ABCA7, the phosphatidylserine flip that signals apoptotic cells and protein aggregates for phagocytosis is impaired, and phagosomes form less efficiently.

2. SREBP2-BACE1 pathway activation. ABCA7 deficiency elevates SREBP2 (sterol regulatory element-binding protein 2), which up-regulates BACE1 — the β-secretase enzyme that cleaves APP into Aβ. Simultaneously, altered phospholipid composition of lipid rafts may increase the probability of BACE1 encountering APP in the membrane, further accelerating Aβ production.

3. Mitochondrial lipid dysregulation. Kawatani et al. 2023²² Kawatani et al. 2023
   iPSC-derived neuron and organoid models; electron microscopy confirmed enlarged dysmorphic mitochondria; phosphatidylglycerol and cardiolipin levels specifically reduced in ABCA7-deficient cells demonstrated that ABCA7 loss disrupts transport of phosphatidic acid from the endoplasmic reticulum to mitochondria, depleting the cardiolipin precursors that mitochondria require for normal respiration. Reduced ATP production and increased oxidative stress follow.

More recently, von Maydell et al. 2025³³ von Maydell et al. 2025
iPSC-derived neurons; ABCA7 LOF variants from the ROSMAP cohort; transcriptomics and lipidomics identified elevated saturated phosphatidylcholine as a key metabolic signature of ABCA7 dysfunction, with downstream mitochondrial uncoupling and neuronal hyperexcitability. Critically, this phenotype was fully rescued by CDP-choline supplementation in neurons, pointing to a potentially targetable metabolic bottleneck.

The Evidence

The c.4416+2T>G variant was among the splice-site LOF alleles discovered in the landmark Steinberg et al. 2015 Nature Genetics study⁴⁴ Steinberg et al. 2015 Nature Genetics study
whole-genome sequencing of ~2,636 Icelanders; 3,419 cases and >151,000 controls; individual LOF variants aggregated to OR 2.12 in Icelanders, OR 2.03 combined across European and US cohorts. This established ABCA7 LOF haploinsufficiency as a LOAD risk mechanism of genome-wide significance.

In a European American replication cohort, Del-Aguila et al. 2015⁵⁵ Del-Aguila et al. 2015
3,476 European Americans; gene-level burden test found the c.4416+2T>G MAF was 0.002 in cases versus 0.0012 in controls, with the aggregate LOF variant burden significant at P=0.039 (OR 1.54). Individual variant power was limited by the rarity of c.4416+2T>G in non-Icelandic populations; the combined Icelandic OR of 4.42 for this specific variant likely reflects founder-effect enrichment.

Allen et al. 2017 Neurology: Genetics⁶⁶ Allen et al. 2017 Neurology: Genetics
Mayo Clinic ROSMAP cohort; six ABCA7 LOF variants including rs113809142; brain expression analysis; autopsy-confirmed diagnoses reported OR 2.97 for LOAD and OR 3.05 for non-AD neuropathologies, underscoring that ABCA7 haploinsufficiency raises risk broadly across late-life neurodegenerative pathology — not exclusively Alzheimer's.

Campbell et al. 2022⁷⁷ Campbell et al. 2022
clinical deep phenotyping of 67 ABCA7 LOF carriers; mean age at onset 75.6 years; 76% amnestic presentation; 10/11 autopsy cases confirmed Alzheimer neuropathology confirmed a predominantly late-onset amnestic syndrome in ABCA7 LOF carriers, phenotypically similar to sporadic LOAD but with somewhat younger onset and higher family history burden.

Practical Actions

No current therapy reverses haploinsufficiency in a living carrier. The actionable levers are those that support the biological processes ABCA7 normally facilitates: phospholipid metabolism, amyloid-β clearance capacity, and mitochondrial function. CDP-choline (citicoline) normalises the phosphatidylcholine deficit in ABCA7-deficient neurons in vitro and is safe for long-term use; while definitive human trials in ABCA7 carriers are still pending, the mechanistic evidence and its established safety profile make it the highest-priority supplement recommendation here. NMN or NR (NAD+ precursors) similarly rescued mitochondrial function in cell models.

Proactive cognitive monitoring — baseline neuropsychological testing in mid-life, annual self-monitoring, and follow-up if any cognitive concerns arise — is warranted for carriers given the substantial increase in LOAD risk. Earlier detection of cognitive decline enables timely access to emerging disease-modifying therapies (e.g., anti-amyloid antibodies) that are most effective before extensive Alzheimer pathology accumulates.

Interactions

ABCA7 haploinsufficiency interacts with APOE genotype: APOE ε4 carriers with concurrent ABCA7 LOF variants face compounding impairments across both the lipid transport (ABCA7) and lipid clearance/APOE-receptor axis, with observational data suggesting substantially earlier age at onset when both risk alleles are present. The ABCA7–APOE interaction has not yet been characterised for this specific splice variant but is biologically plausible given shared lipid-transport pathway involvement.

ABCA7 LOF variants have also been reported at modestly elevated frequency in Parkinson's disease with dementia (OR ~4.94 for the LOF variant aggregate in one cohort; PMID 27066581), consistent with the Allen et al. finding of elevated risk for Lewy body pathology.