Segregation of a missense mutation in the amyloid precursor protein gene with familial Alzheimer's disease
Abstract
A locus segregating with familial Alzheimer's disease (AD) has been mapped to chromosome 21, close to the amyloid precursor protein (APP) gene. Recombinants between the APP gene and the AD locus have been reported which seemed to exclude it as the site of the mutation causing familial AD. But recent genetic analysis of a large number of AD families has demonstrated that the disease is heterogeneous. Families with late-onset AD do not show linkage to chromosome 21 markers. Some families with early-onset AD show linkage to chromosome 21 markers, but some do not. This has led to the suggestion that there is non-allelic genetic heterogeneity even within early onset familial AD. To avoid the problems that heterogeneity poses for genetic analysis, we have examined the cosegregation of AD and markers along the long arm of chromosome 21 in a single family with AD confirmed by autopsy. Here we demonstrate that in this kindred, which shows linkage to chromosome 21 markers, there is a point mutation in the APP gene. This mutation causes an amino-acid substitution (Val----Ile) close to the carboxy terminus of the beta-amyloid peptide. Screening other cases of familial AD revealed a second unrelated family in which this variant occurs. This suggests that some cases of AD could be caused by mutations in the APP gene.
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FAD mutations in APP near the β- and γ-secretase cleavage sites either elevate total Aβ production (Swedish K670N/M671L) or increase Aβ42 generation specifically (Florida I716V and London V717I).
“FAD mutations in APP that cluster near the 𝛃 - and 𝛄 -secretase cleavage sites either elevate the production of total A 𝛃 , as is the case with the K670N/ M671L substitution [Swedish mutation (Mullan et al., 1992a)], or increase the generation of A 𝛃 42 specifically, as occurs with the I716V [Florida mutation (Eckman et al., 1997)] and V717I [London mutation (Goate et al., 1991)] substitutions.”
From Intraneuronal β-Amyloid Aggregates, Neurodegeneration, and Neuron Loss in Transgenic Mice with Five Familial Alzheimer's Disease Mutations: Potential Factors in Amyloid Plaque Formation (2006) · cites this paper as Goate et al., 1991
The 5XFAD mouse is one of a few known mouse models that exhibits significant neuron loss in addition to displaying other AD hallmarks such as amyloid plaques.
“The 5XFAD mouse, along with the APPSLPS1KI, is one of a few known mouse models that exhibits significant neuron loss in addition to displaying other AD hallmarks such as amyloid plaques [10,11,16].”
From Neuron loss in the 5XFAD mouse model of Alzheimer’s disease correlates with intraneuronal Aβ42 accumulation and Caspase-3 activation (2013) · cites this paper as [10]
Frank neuron loss has been observed in 5XFAD and APPSLPS1KI transgenic mouse models that also exhibit intraneuronal Aβ42 prior to plaque formation.
“Frank neuron loss has been observed in two aggressive amyloid plaque transgenic mouse models that also exhibit accumulation of intraneuronal Aβ42 prior to plaque formation: the 5XFAD and APPSLPS1K1 lines [10,11].”
From Neuron loss in the 5XFAD mouse model of Alzheimer’s disease correlates with intraneuronal Aβ42 accumulation and Caspase-3 activation (2013) · cites this paper as [10]
Early onset Alzheimer's disease can be caused by mutations in the APP, presenilin 1, and presenilin 2 genes.
“Early onset Alzheimer's disease can be caused by mutations in the APP (Chartier-Harlin et al., 1991;Goate et al., 1991;Murrell et al., 1991;Mullan et al., 1992), presenilin 1 (PS1) (Sherrington et al., 1995), and presenilin 2 (PS2) (Levy-Lahad et al., 1995) genes.”
From Age-Dependent Changes in Brain, CSF, and Plasma Amyloid β Protein in the Tg2576 Transgenic Mouse Model of Alzheimer's Disease (2001) · cites this paper as Goate et al., 1991
The amyloid cascade hypothesis is strongly supported by neuropathological and human genetic evidence.
“The amyloid cascade hypothesis of Alzheimer disease (AD), which proposes that deposition of the amyloid-β (Aβ) peptide in the brain is a central event in disease pathology (Figure 1), is strongly supported by neuropathological and human genetic evidence”
From The amyloid hypothesis in Alzheimer disease: new insights from new therapeutics (2022) · cites this paper as [2]
Mutations in APP, PSEN1 and PSEN2 that increase Aβ production, elevate Aβ42/Aβ40 ratio and promote plaque formation cause autosomal dominant early-onset familial AD.
“Mutations in APP, presenilin 1 (PSEN1) and PSEN2 genes that increase Aβ production, elevate Aβ42/Aβ40 ratio and promote plaque formation cause autosomal dominant early-onset familial AD (FAD)”
From Amyloid β-based therapy for Alzheimer’s disease: Challenges, successes and future (2023) · cites this paper as [38]
Less than 1% of all AD cases are early-onset with symptoms at age 50s and earlier, caused by gene mutations in APP, PSEN1 or PSEN2.
“Less than 1% of all AD cases are early-onset with symptoms developed at an age of 50 s and earlier, and caused by gene mutations in APP, PSEN1 or PSEN2.7,38,39”
From Amyloid β-based therapy for Alzheimer’s disease: Challenges, successes and future (2023) · cites this paper as [38]
Gene mutations directly responsible for aberrant Aβ accumulation (APP, PSEN1, PSEN2) underlie rare familial forms of early-onset AD.
“This hypothesis gained favor in the 1990s after several gene mutations directly responsible for aberrant Aβ accumulation (APP, PSEN1, PSEN2) were found to underlie rare familial forms of early-onset AD [20–22].”
From Systems-based proteomics to resolve the biology of Alzheimer’s disease beyond amyloid and tau (2021) · cites this paper as [21]
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“Early onset Alzheimer’s disease can be caused by mutations in the APP (Chartier-Harlin et al., 1991; Goate et al., 1991; Murrell et al., 1991; Mullan et al., 1992), presenilin 1 (PS1) (Sherrington et al., 1995), and presenilin 2 (PS2) (Levy-Lahad et al., 1995) genes.”
BackgroundAmyloid β-Protein Fibrillogenesis
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Network abnormalities and interneuron dysfunction in Alzheimer disease
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Amyloid β-based therapy for Alzheimer’s disease: Challenges, successes and future
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“Mutations in APP, presenilin 1 (PSEN1) and PSEN2 genes that increase Aβ production, elevate Aβ42/Aβ40 ratio and promote plaque formation cause autosomal dominant early-onset familial AD (FAD), implicating a role of altering APP processing in AD pathogenesis.(7,38,39) In contrast, an APP mutation identified in the Icel…”
BackgroundInfluentialImpaired synaptic plasticity and learning in aged amyloid precursor protein transgenic mice
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Microglia in Alzheimer's disease
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The genetic landscape of Alzheimer disease: clinical implications and perspectives
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Cell biology of protein misfolding: the examples of Alzheimer's and Parkinson's diseases
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APP mouse models for Alzheimer’s disease preclinical studies.
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Self-citationThe Alzheimer’s disease mitochondrial cascade hypothesis: progress and perspectives
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“Sequence analysis of a candidate gene, the APP gene, in a handful of these familial AD (FAD) kindreds revealed APP mutations [10].”
BackgroundDoes neuroinflammation fan the flame in neurodegenerative diseases?
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The genetics of Alzheimer disease
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The amyloid hypothesis in Alzheimer disease: new insights from new therapeutics
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TREM2 — a key player in microglial biology and Alzheimer disease
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History and progress of hypotheses and clinical trials for Alzheimer’s disease
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Neurodegenerative diseases: a decade of discoveries paves the way for therapeutic breakthroughs
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The role of microglia in amyloid clearance from the AD brain
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The genetic epidemiology of neurodegenerative disease
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Neuropathology and Cognitive Impairment in Alzheimer Disease: A Complex but Coherent Relationship
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Self-citationMolecular genetics of early-onset Alzheimer’s disease revisited
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The road to restoring neural circuits for the treatment of Alzheimer's disease
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Amyloid cascade hypothesis: Pathogenesis and therapeutic strategies in Alzheimer's disease
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Microglia in Neuroinflammation and Neurodegeneration: From Understanding to Therapy
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The Alzheimer’s Disease Mitochondrial Cascade Hypothesis
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“The amyloid cascade hypothesis was formulated after an AβPP mutation was reported in a family with autosomal dominant amyloid angiopathy, dementia, and AD-typical histology [4].”
BackgroundThe Alzheimer's disease Beta-secretase enzyme, BACE1
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Linking Aβ and Tau in Late-Onset Alzheimer's Disease: A Dual Pathway Hypothesis
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Synaptic degeneration in Alzheimer's disease
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REVIEW: Curcumin and Alzheimer’s disease
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- Authors
- Goate, A., Chartier-Harlin, M.-C., Mullan, M., Brown, J., Crawford, F., Fidani, L., Giuffra, L., Haynes, A., Irving, N., James, L., Mant, R., Newton, P., Rooke, K., Roques, P., Talbot, C., Pericak-Vance, M., Roses, A., Williamson, R., Rossor, M., Owen, M., & Hardy, J.
- Affiliations
- St Mary's Hospital (GB)
- Yale University (US)
- University of Wales (GB)
- Duke Medical Center (US)
- Venue
- Nature
- Published
- 1991-02-21
- Volume
- 349
- Issue
- 6311
- Pages
- 704-706
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- OpenAlex
- W2058723245
- Cited by
- 4,659
- References
- 30
- Citations by year
- 2026: 62 · 2025: 85 · 2024: 111 · 2023: 88 · 2022: 112 · 2021: 130 · 2020: 149 · 2019: 115 · 2018: 112 · 2017: 130 · 2016: 160 · 2015: 131 · 2014: 129 · 2013: 166 · 2012: 135
- FWCI
- 153.93
- Type
- journal article
- Language
- en
- Open access
- closed
- Licence
- Locations
- Nature (publishedVersion)
- PubMed (publishedVersion)
- UCL Discovery (University College London) (submittedVersion)
- ORCA Online Research @Cardiff (Cardiff University) (submittedVersion)
- Funders
- Wellcome Trust
- National Institute on Aging (AG05 128, P50AG005128)
- Topics
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Associations and Epidemiology
- Keywords
- familial Alzheimer's disease, amyloid precursor protein gene, APP gene mutations, missense mutations, genetic heterogeneity, co-segregation, early-onset Alzheimer's disease, late-onset Alzheimer's disease, beta-amyloid peptide
- MeSH terms
- Alzheimer Disease, Amino Acid Sequence, Base Sequence, Chromosomes, Human, Pair 21, Exons, Genetic Testing, Genotype, Humans, Genetic Linkage, Molecular Sequence Data, Mutation, Pedigree, Protein Precursors, Polymorphism, Restriction Fragment Length, Polymerase Chain Reaction, Amyloid beta-Peptides, Amyloid beta-Protein Precursor
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