P1‐137: CLINICAL DETAILS OF THE ILE213LEU PSEN1 MUTATION IN A FAMILY WITH EARLY ONSET FAMILIAL ALZHEIMER DISEASE
Bibliographic record
Abstract
The clinical manifestations of autosomal dominant Alzheimer Disease (AD) vary considerably, even within families carrying the same mutation. Factors that modulate phenotypic expression are critical for predicting disease course as well as novel therapeutic approaches. We report the first clinical description of the Ile213Leu mutation in the presenilin 1 gene (PS1) in a family with early onset familial AD (EOFAD). This variant was previously reported in a series of EOFAD cases with PS1 mutations, but without an accompanying clinical phenotype (1). The Ile213Leu mutation was validated by Sanger sequencing in the proband and two affected daughters. ApoE genotyping was performed in the affected daughters. Clinical details including age of onset (AOO) were recorded. A literature review on known modifiers of AOO in EOFAD was performed. Affected relatives had a typical amnestic presentation of AD. AOO was 43 in the proband, 39 in one daughter, and 55 in the other daughter. The affected daughter with earlier onset was homozygous for the E3 isoform of ApoE whereas her sister was heterozygous for the E2 isoform (E2/E3). This discrepancy in AOO is concordant with a recent report showing that presence of the E2 isoform delayed AOO by 12 years in carriers of the E280 PS1 mutation (2). EOFAD due to the Ile213Leu mutation in PS1 is characterized by an amnestic presentation of AD with a significantly variable AOO. While it is only speculative that the presence of the E2 isoform of ApoE led to substantial delay in AOO in one of the reported individuals, this report highlights the importance of investigating the mechanisms of E2-related neuroprotection that have been advocated recently by others (3). References: 1. Rogaeva EA, Fafel KC, Song YQ, Medeiros H, Sato C, Liang Y, et al. Screening for PS1 mutations in a referral-based series of AD cases: 21 novel mutations. Neurology. 2001;57(4):621-5. 2. Velez JI, Lopera F, Sepulveda-Falla D, Patel HR, Johar AS, Chuah A, et al. APOE*E2 allele delays age of onset in PSEN1 E280A Alzheimer's disease. Molecular psychiatry. 2016;21(7):916-24. 3. Wu L, Zhao L. ApoE2 and Alzheimer's disease: time to take a closer look. Neural regeneration research. 2016;11(3):412-3.
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.001 |
| Meta-epidemiology (narrow) | 0.001 | 0.000 |
| Meta-epidemiology (broad) | 0.001 | 0.000 |
| Bibliometrics | 0.001 | 0.001 |
| Science and technology studies | 0.001 | 0.001 |
| Scholarly communication | 0.000 | 0.001 |
| Open science | 0.001 | 0.001 |
| Research integrity | 0.002 | 0.001 |
| Insufficient payload (model declined to judge) | 0.004 | 0.001 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".