Variability of age at onset in siblings with familial Alzheimer disease
Abstract
BACKGROUND: Variability of age at onset (AO) of Alzheimer disease (AD) among members of the same family is important as a biological clue and because of its clinical effects. OBJECTIVE: To evaluate which clinical variables influence the discrepancy in AO among affected relatives with familial AD. SETTING: Clinical genetic project of Spanish kindred with AD conducted by 4 academic hospitals in Madrid, Spain. METHODS: Age at onset of AD in 162 families and discrepancy in AO in intragenerational and intergenerational affected pairs were analyzed in relation to age, sex, maternal or paternal transmission, pattern of inheritance, and apolipoprotein E genotype. RESULTS: Maternal transmission of AD was significantly more frequent than paternal transmission (P < .001). In 27% of the affected individuals, AO occurred before the patient was 65 years old. Discrepancy in AO among siblings was within 5 years in 44% of the families, 6 to 10 years in 29%, and more than 10 years in 27% (range, 0-22). This discrepancy was independent of the sex of the sibling pairs and was significantly lower with maternal transmission of AD (P = .02). Segregation analysis showed no differences in the inheritance pattern between families with low (< or =5 years) or high (>5 years) AO discrepancy. Age at onset in carriers of the apolipoprotein E epsilon4 allele was slightly younger. However, among siblings, an extra apolipoprotein E epsilon4 allele was not consistently associated with earlier onset of AD. Eighty percent of patients, independent of sex or mode of transmission, were already affected at their parents' reported AO. CONCLUSIONS: There is a wide discrepancy in AO in affected siblings that is not clearly explained by a single clinical variable or apolipoprotein E genotype. The interaction of many factors probably determines AO in each affected individual. However, maternal transmission of AD seems to result in a similar AO in offspring, and the risk of developing dementia after the parent's reported AO decreases significantly.
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Both mothers and fathers contribute to their offspring's AD risk, but mothers contribute more because mtDNA is maternally inherited.
“In this respect, both mothers and fathers contribute to their offspring's AD risk, but because mitochondrial DNA (mtDNA) is maternally inherited mothers contribute more.”
From The Alzheimer’s disease mitochondrial cascade hypothesis: progress and perspectives (2014) · cites this paper as [116]
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- Authors
- Gómez-Tortosa, E., Barquero, M. S., Barón, M., Sainz, M. J., Manzano, S., Payno, M., Ros, R., Almaraz, C., Gómez-Garré, P., & Jiménez-Escrig, A.
- ORCID
- Manzano, Sagrario
- Venue
- Archives of Neurology
- Publisher
- American Medical Association (AMA)
- Published
- 2007-12-01
- Volume
- 64
- Issue
- 12
- Pages
- 1743
- ISSN
- 0003-9942 (ISSN-L)
- OpenAlex
- W1974885793
- Cited by
- 47
- References
- 22
- Citations by year
- 2026: 3 · 2025: 1 · 2024: 5 · 2023: 1 · 2021: 2 · 2020: 2 · 2019: 3 · 2018: 3 · 2016: 1 · 2015: 1 · 2014: 2 · 2013: 4 · 2012: 3
- FWCI
- 1.78
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Archives of Neurology (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
- Health Sciences › Medicine › Neurology › Amyotrophic Lateral Sclerosis Research
- Keywords
- familial Alzheimer's disease, age of onset, siblings, mother-to-child transmission, paternal transmission, APOE ε4, mode of inheritance, segregation analysis, dementia risk
- MeSH terms
- Adult, Aged, Aged, 80 and over, Alzheimer Disease, Apolipoproteins E, Female, Genotype, Humans, Male, Middle Aged, Spain, Age of Onset, Siblings
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