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Clinical Features of Early-Onset Alzheimer Disease in a Large Kindred With an E280A Presenilin-1 Mutation
Abstract
OBJECTIVES: To characterize clinical features of a very large pedigree with early-onset Alzheimer disease (AD) in which all affected individuals carry the identical glutamic acid-to-alanine mutation at codon 280 in the presenilin-1 gene. DESIGN: Clinical histories were obtained by patient and family interviews and through medical or civil records. Using standard diagnostic criteria, a case series of 128 individuals was identified, of which 6 have definitive (autopsy-proven) early-onset AD, 93 have probable early-onset AD, and 29 have possible early-onset AD. SETTING: Community based in Antioquia, Colombia. PATIENTS: A population-based sample in which all members of 5 extended families (nearly 3000 individuals) were surveyed. Criteria for inclusion required obtaining sufficient information to categorize the individual as affected. MAIN OUTCOME MEASURES: Age at onset, neuropsychological profile, neurologic history, and examination. RESULTS: The patients had a mean age at onset of 46.8 years (range, 34-62 years). The average interval until death was 8 years. Headache was noted in affected individuals significantly more frequently than in those not affected. The most frequent presentation was memory loss followed by behavior and personality changes and progressive loss of language ability. In the final stages, gait disturbances, seizures, and myoclonus were frequent. CONCLUSIONS: Other than the early onset, this clinical phenotype is indistinguishable from sporadic AD except that affected individuals frequently complained of headache preceding and during the disease. Despite the uniform genetic basis for the disease, there was significant variability in the age at onset, suggesting an important role for environmental factors or genetic modifiers in determining the age at onset.
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In the citing paper
“Large ADAD families such as the kindred harboring the Colombian PSEN1 NM_000021:c.839A>C,p. (Glu280Ala) (canonically known as PSEN1 E280A) mutation, the world's largest ADAD founder population with a comprehensive family tree of thousands of individuals [3], provide an opportunity to assess the contribution of genetic variation to unexplained variability in age of dementia onset.”
From Genetic associations with age at dementia onset in the PSEN1 E280A Colombian kindred (2023) · cites this paper as [3]
In the citing paper
“This study addresses these limitations by employing a well-described phenotype in a geographically isolated population with a monogenic form of AD [3].”
From Genetic associations with age at dementia onset in the PSEN1 E280A Colombian kindred (2023) · cites this paper as [3]
In the citing paper
“For the past three decades, we have studied the world's largest known pedigree in which a presenilin-1 (PSEN1) mutation (p.Glu280Ala, E280A), often referred as the Paisa mutation, dominantly cosegregates with early-onset of Alzheimer's disease (AD).1”
From APOE*E2 allele delays age of onset in PSEN1 E280A Alzheimer’s disease (2016) · cites this paper as [1]
In the citing paper
“Our present study mitigates most of these confounders by using an expertly phenotyped, geographically isolated founder population affected with a monogenic early-onset form of AD.8”
From Whole-genome sequencing suggests a chemokine gene cluster that modifies age at onset in familial Alzheimer's disease (2015) · cites this paper as [8]
In the citing paper
“The age at clinical onset of autosomal dominant Alzheimer’s disease is similar between generations14 and is affected mostly by the mutation type and background family genetics.15”
From Clinical and biomarker changes in dominantly inherited Alzheimer's disease (2012) · cites this paper as [14]
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Metadata
- Authors
- Lopera, F.
- Affiliations
- Universidad de Antioquia (CO)
- Corresponding author
- Lopera, Francisco
- ORCID
- Lopera, Francisco
- Venue
- JAMA: The Journal of the American Medical Association
- Publisher
- American Medical Association (AMA)
- Published
- 1997-03-12
- Volume
- 277
- Issue
- 10
- Pages
- 793
- ISSN
- 0002-9955 (ISSN-L)
- 0098-7484
- OpenAlex
- W2110985141
- Cited by
- 351
- References
- 52
- Citations by year
- 2026: 5 · 2025: 13 · 2024: 19 · 2023: 17 · 2022: 8 · 2021: 14 · 2020: 16 · 2019: 16 · 2018: 13 · 2017: 13 · 2016: 19 · 2015: 22 · 2014: 21 · 2013: 14 · 2012: 23
- FWCI
- 6.03
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- JAMA (publishedVersion)
- PubMed (publishedVersion)
- UCL Discovery (University College London) (submittedVersion)
- Topics
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Alzheimer's disease research and treatments
- Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
- Health Sciences › Medicine › Clinical Neurology › Amyotrophic Lateral Sclerosis Research
- Keywords
- early-onset Alzheimer's disease, presenilin 1, PSEN1 E280A mutation, familial Alzheimer's disease, clinical phenotype, age of onset, headache, memory loss, behavioral and personality changes, language loss, gait disturbance, seizures, myoclonus, genetic modifiers, extended family
- MeSH terms
- Adult, Alanine, Alzheimer Disease, Autopsy, Brain, Codon, Female, Headache, Humans, Male, Membrane Proteins, Middle Aged, Neuropsychological Tests, Pedigree, Phenotype, Point Mutation, Age of Onset, Glutamic Acid, Presenilin-1
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