Phenotypic Profile of Early-Onset Familial Alzheimer's Disease Caused by Presenilin-1 E280A Mutation
Abstract
Presenilin 1 (PS1) mutations are the most common cause of early-onset familial Alzheimer's disease (EOFAD). They show a common phenotypic profile characterized by early age of onset, severe dementia and distinct neurodegeneration. The largest population of EOFAD carries the E280A mutation in PS1 and resides in Antioquia, Colombia, currently comprising around 5,000 individuals. Carriers start showing memory impairment in the third decade of life, followed by progressive impairment of language and other cognitive processes. They reach mild cognitive impairment around 45 and dementia around 50 years of age. There is some phenotypic variability among the carriers of this single PS1 mutation. Some patients present with epilepsy, verbal impairment, and cerebellar ataxia. Neuropathologically, PS1 E280A cases show pronounced brain atrophy, severe amyloid-β pathology, distinct hyperphosphorylated tau-related pathology, and cerebellar damage. The earliest event identified by functional magnetic imaging resonance is hyperactivation within the right anterior hippocampus around 33 years of age. This well-studied population with a clear pre-clinical profile and wide phenotypic variability in age of onset and clinical presentation is ideally suited for clinical trials and to study molecular mechanisms of Alzheimer's disease.
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The E280A mutation generally produces a more aggressive course of pathology than SAD.
“which generally produces a more aggressive course of pathology than SAD [55, 56].”
From Gliovascular alterations in sporadic and familial Alzheimer's disease: <scp><i>APOE3</i></scp> Christchurch homozygote glioprotection (2023) · cites this paper as [56]
Previous studies of our group have identified molecular differences between SAD and FAD in addition to divergences in clinical manifestations.
“Previous studies of our group have identified molecular differences between SAD and FAD [55, 56, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79] in addition to divergences in the clinical manifestations [55, 56].”
From Gliovascular alterations in sporadic and familial Alzheimer's disease: <scp><i>APOE3</i></scp> Christchurch homozygote glioprotection (2023) · cites this paper as [56]
Approximately 0.6% of AD cases present a hereditary form (FAD) caused by mutations in APP, PSEN1, or PSEN2 that lead to aberrant Aβ overproduction and aggregation.
“However, approximately 0.6% of cases present a hereditary form (familial AD or FAD) caused by mutations in APP, PSEN1, or PSEN2 that lead to aberrant Aβ overproduction and aggregation [55, 56].”
From Gliovascular alterations in sporadic and familial Alzheimer's disease: <scp><i>APOE3</i></scp> Christchurch homozygote glioprotection (2023) · cites this paper as [56]
The duration of disease was similar between SAD and FAD.
“In accordance with what is known for late‐ and early‐onset AD [56], the duration of the disease was similar between SAD and FAD (Table 1 and Table S1).”
From Gliovascular alterations in sporadic and familial Alzheimer's disease: <scp><i>APOE3</i></scp> Christchurch homozygote glioprotection (2023) · cites this paper as [56]
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- Authors
- Sepulveda-Falla, D., Glatzel, M., & Lopera, F.
- Affiliations
- Institute of Neuropathology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
- University Medical Center Hamburg-Eppendorf (DE)
- Universidad de Antioquia (CO)
- Corresponding author
- Lopera, Francisco
- Venue
- Journal of Alzheimer's Disease
- Publisher
- SAGE Publications
- Published
- 2012-09-25
- Volume
- 32
- Issue
- 1
- Pages
- 1-12
- ISSN
- 1387-2877 (ISSN-L)
- 1875-8908
- OpenAlex
- W1634661592
- Cited by
- 75
- References
- 8
- Citations by year
- 2026: 4 · 2025: 5 · 2024: 10 · 2023: 6 · 2022: 4 · 2021: 6 · 2020: 11 · 2019: 4 · 2018: 4 · 2017: 2 · 2016: 2 · 2015: 4 · 2014: 5 · 2013: 6 · 2012: 2
- FWCI
- 3.65
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Journal of Alzheimer s Disease (publishedVersion)
- PubMed (publishedVersion)
- Repositorio Digital - Academia Colombiana de Ciencias Exactas, Fisicas y Naturales (submittedVersion)
- 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
- early-onset familial Alzheimer's disease, presenilin 1
- MeSH terms
- Adult, Aged, Alzheimer Disease, Brain, Cognition, Colombia, Heterozygote, Humans, Middle Aged, Mutation, Phenotype, Amyloid beta-Protein Precursor, Age of Onset, Presenilin-1, Presenilin-2
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