rs63749891 — PSEN1 R278I / R278T

PSEN1 R278I / R278T — A Founder Mutation Driving Early-Onset Familial Alzheimer's Disease

PSEN1¹¹ PSEN1
Presenilin-1, encoded by PSEN1 on chromosome 14q24.2, is the catalytic subunit of the gamma-secretase complex. Gamma-secretase cleaves the transmembrane domain of the amyloid precursor protein (APP), determining the C-terminal length of the amyloid-beta (Aβ) peptide produced. The relative amounts of longer Aβ42 and Aβ43 versus shorter Aβ40 are central to the amyloid cascade hypothesis of Alzheimer's disease is the most mutation-rich gene in all of medicine, with over 300 pathogenic variants documented in the PSEN1 mutation database. Among these, the Arg278 codon is a hotspot: two independent single-nucleotide substitutions — R278I (c.833G>T, rs63749891 T allele) and R278T (c.833G>C, rs63749891 C allele) — both cause autosomal dominant early-onset Alzheimer's disease. This entry covers both mutations.

Arginine at position 278 lies within transmembrane domain 7 of presenilin-1, a critical structural region for maintaining proper gamma-secretase geometry. The R278I substitution in particular has been used as a reference mutation in mechanistic studies because it produces an unusually severe disruption of enzyme–substrate interactions, making it one of the most thoroughly characterised PSEN1 pathogenic variants at the molecular level.

The Mechanism

Szaruga et al. 2017²² Szaruga et al. 2017
Pathogenic PSEN mutations destabilize the enzyme–substrate complex during gamma-secretase processing of APP, shifting the Aβ peptide length distribution toward longer, more amyloidogenic species. Cell 170:443–456 established the unifying mechanistic framework: normal PSEN1 processively trims Aβ peptides from ~48 amino acids down to predominantly Aβ40, with small amounts of Aβ42 as a byproduct. FAD-causing mutations destabilise the enzyme–substrate complex, causing premature product release at longer lengths and generating disproportionately large quantities of Aβ42 and Aβ43.

Saito et al. 2011³³ Saito et al. 2011
PSEN1 R278I knock-in mice show elevated Aβ43, impaired short-term memory, and accelerated amyloid pathology; Aβ43 aggregates faster and is more neurotoxic than Aβ42; Aβ43 production by other PSEN1 mutations correlates inversely with age of disease onset. Nat Neurosci 14:1023–32 specifically identified Aβ43 — previously understudied — as a potent contributor to pathology in R278I carriers. Heilig et al. 2013⁴⁴ Heilig et al. 2013
Mutant PS1 (R278I) physically interacts with wild-type PS1 to cause dominant-negative inhibition, stimulating Aβ42 and reducing Aβ40 from wild-type presenilin, explaining why a single heterozygous mutation is sufficient for disease. J Neurosci 33:10314–26 extended this model by showing that the mutant allele does not act passively — it actively corrupts the wild-type protein, dramatically amplifying the Aβ42:Aβ40 ratio beyond what the mutant allele alone could produce.

The Evidence

Genotype-phenotype data from large FAD case series converge on a mean age of onset for PSEN1 mutations of approximately 43–45 years (SD ~7 years), with individual mutations accounting for 72% of onset variance, meaning the specific mutation matters more than other genetic background. Ryan et al. 2016⁵⁵ Ryan et al. 2016
Lancet Neurology case series of autosomal dominant FAD; PSEN1 carriers mean onset 43.6 years (SD 7.2); myoclonus in 47%; seizures in ~25%. Lancet Neurol 15:1326–35 documented neurological co-features — myoclonus, seizures — that distinguish PSEN1 carriers from late-onset sporadic Alzheimer's disease.

The R278I variant has a distinctive clinical phenotype first described by Godbolt et al. 2004⁶⁶ Godbolt et al. 2004
Two family members with PSEN1 R278I presenting with progressive language impairment (aphasia) as the initial and dominant symptom, with relative memory preservation; screening for PSEN1 mutations is warranted even in atypical dementia presentations. Neurology 63:1774–5 — a logopenic or frontal-language variant rather than the typical amnestic presentation. A Korean family with the same mutation confirmed the familial segregation pattern (PMID 32174048). The R278T mutation, originally described by Kwok et al. 1997⁷⁷ Kwok et al. 1997
Two novel PSEN1 mutations including R278T in early-onset AD families; R278T associated with co-presenting spastic paraparesis and distinctive large eosinophilic plaques (cotton wool plaques) on neuropathology. Neuroreport 8:1537–40 adds spastic paraparesis as a notable phenotypic feature in some pedigrees.

These pathogenic alleles are essentially absent from population databases — gnomAD v4 shows 0 of 660 alleles in population studies, confirming that virtually no carrier survives to reproductive age without disease manifesting.

Practical Actions

Carriers of one R278I or R278T allele will develop Alzheimer's disease; the principal decisions involve monitoring for early symptom onset, enrolling in prevention and trial registries, and informing first-degree relatives of their 50% inheritance risk. The window for disease-modifying intervention is presymptomatic, making early enrolment in longitudinal studies such as the DIAN (Dominantly Inherited Alzheimer Network)⁸⁸ DIAN (Dominantly Inherited Alzheimer Network)
Multi-site longitudinal study of FAD mutation carriers tracking biomarkers, imaging, and cognition from 20 years before expected symptom onset; mutation carriers are eligible for the DIAN-TU prevention trial the most impactful clinical action available. Tau PET and amyloid PET imaging become abnormal 10–15 years before symptom onset in PSEN1 mutation carriers, providing an observable biomarker window for intervention.

Anti-amyloid immunotherapy (lecanemab, donanemab) approved for early symptomatic sporadic Alzheimer's disease has been tested in DIAN-TU participants; data on PSEN1 mutation carriers specifically continue to evolve. Individuals should discuss eligibility for prevention or treatment trials with a specialist in familial Alzheimer's disease.

Interactions

PSEN1 R278I/R278T acts purely through autosomal dominant haploinsufficiency, so second-allele status at APOE (rs429358 / rs7412) modifies risk trajectory. APOE ε4 carriage accelerates amyloid accumulation and may shift symptom onset earlier even within a PSEN1-mutation background. PSEN2 mutations (e.g. rs63750847 N141I) and APP mutations (rs63750264 V717I) cause the same FAD syndrome but with generally later and earlier onset respectively; compound occurrence of two FAD mutations in one individual is exceedingly rare.