期刊
出版社
WILEY
DOI: 10.1002/dad2.12155
关键词
Alzheimer' s disease; biological pathways of disease; familial AD; genetic etiology; rare variants; sporadic AD
资金
- Flemish Government-initiated Flanders Impulse Program on Networks for Dementia Research
- Flemish Government-initiated Methusalem Excellence Program
- Research Foundation Flanders (FWO)
- University of Antwerp Research Fund, Belgium
- FWO
Early-onset Alzheimer's disease (EOAD) is often linked to dominant disease-causing mutations, but they only account for a small fraction of patients, and familial EOAD does not always show clear autosomal dominant inheritance. Studies suggest that factors beyond the amyloid beta pathway are also crucial in AD pathophysiology.
Early-onset Alzheimer's disease (EOAD) is generally known as a dominant disease due to highly penetrant pathogenic mutations in the amyloid precursor protein, presenilin 1 and 2. However, they explain only a fraction of EOAD patients (5% to 10%). Furthermore, only 10% to 15% of EOAD families present with clear autosomal dominant inheritance. Studies showed that only 35% to 60% of EOAD patients have at least one affected first-degree relative. Parent-offspring concordance in EOAD was estimated to be <10%, indicating that full penetrant dominant alleles are not the sole players in EOAD. We aim to summarize current knowledge of rare variants underlying familial and seemingly sporadic Alzheimer's disease (AD) patients. Genetic findings indicate that in addition to the amyloid beta pathway, other pathways are of importance in AD pathophysiology. We discuss the difficulties in interpreting the influence of rare variants on disease onset and we underline the value of carefully selected ethnicity-matched cohorts in AD genetic research.
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