Atypical early-onset Alzheimer's disease caused by the Iranian APP mutation

doi:10.1016/j.jns.2007.11.021

Journal of the Neurological Sciences

Volume 268, Issues 1–2, 15 May 2008, Pages 124-130

https://doi.org/10.1016/j.jns.2007.11.021 Get rights and content

Abstract

Background

Approximately 1% of all cases of Alzheimer's disease are inherited autosomal dominantly, and to date, three causative genes have been found, the Presenilin 1 (PSEN1) gene, the Presenilin 2 (PSEN2) gene and the Amyloid precursor protein (APP) gene. We describe atypical phenotypic features in a family with a pathogenic APP gene mutation and discuss possible explanations for these atypical features.

Methods and results

We report a family with a history of dementia compatible with autosomal dominant transmission. The disease course in the proband was not typical for Alzheimer's disease as the diagnosis was preceded by 8 years of an isolated amnesia. Further, the proband had epilepsy with complex partial seizures and central degenerative autonomic failure as determined by clinical physiology. Sequencing the three known causative Alzheimer genes revealed a pathogenic missense mutation, APP Thr714Ala (the Iranian mutation).

Conclusions

The atypical clinical phenotype with long prodromal phase, autonomic failure and seizures in this new proband with the APP Thr714Ala mutation illustrates the clinical heterogeneity in families with identical pathogenic mutations.

Introduction

The first APP missense mutations in patients with early-onset autosomal dominant Alzheimer's disease (ADAD) were identified in 1991 [1], and to date 27 different mutations in only 75 families with mutations in the APP gene have been described (http://www.molgen.ua.ac.be/ADMutations/) [2].

Generally the phenotype in families with ADAD is indistinguishable from the phenotype in sporadic AD. The age at onset is usually earlier and the disease course shorter in ADAD; and, unique features have been described for a few individual mutations; i.e. the “delta9” mutations in the presenilin 1 gene (PSEN1) [3], [4]. The unique phenotypic features of individual missense mutations enable us to study molecular mechanisms, potentially explaining phenotypic differences and providing useful knowledge for the development of new therapeutic agents.

Presymptomatic testning in families with early-onset ADAD has been possible for some years but at present there are no preventive measures to offer mutation carriers.

Here we present the unique phenotypic features of a patient with early-onset ADAD and a rare mutation in the APP gene, in whom the AD diagnosis was made after an unusually long prodromal phase with unexplained amnesia as described in a previous report [5].

Section snippets

Clinical case description

In 1995, a 49-year old male, married engineer, was referred to our memory clinic because of subjective memory problems for approximately two years.

Discussion

The presented case is atypical in several ways. Although the duration of the prodromal phase with amnesia varies significantly among AD patients, a period of 2–3 years is probably typical, and during these years, the symptoms are mostly mild. A prodromal phase of eight years is very unusual, also among sporadic cases. If the initial symptoms had been very mild, the high premorbid education level and a demanding job in which deficits would be revealed at an early stage might be part of a

Acknowledgements

The authors thank the patient and his family for their participation in this study. Research nurse Oda Jakobsen is acknowledged for assistance in the long-term follow-up of this patient. This study was supported by the Research Council at Copenhagen University Hospital Rigshospitalet, the Danish Alzheimer Research Foundation and the Novo Nordisk Foundation.

References (18)

C. Zekanowski et al.
Mutations in presenilin 1, presenilin 2 and amyloid precursor protein genes in patients with early-onset Alzheimer's disease in Poland
Exp Neurol
(2003)
D.R. Royall et al.
Insular Alzheimer's disease pathology as a cause of “age-related” autonomic dysfunction and mortality in the non-demented elderly
Med Hypotheses
(2006)
A. Goate et al.
Segregation of a missense mutation in the amyloid precursor protein gene with familial Alzheimer's disease
Nature
(1991)
...
R. Crook et al.
A variant of Alzheimer's disease with spastic paraparesis and unusual plaques due to deletion of exon 9 of presenilin 1
Nat Med
(1998)
A. Rovelet-Lecrux et al.
APP locus duplication causes autosomal dominant early-onset Alzheimer disease with cerebral amyloid angiopathy
Nat Genet
(2006)
J. Stokholm et al.
Years of severe and isolated amnesia can precede the development of dementia in early-onset Alzheimer's disease
Neurocase
(2005)
W. Wieling et al.
M. Mendez et al.
Seizures in elderly patients with dementia: epidemiology and management
Drugs Aging
(2003)

There are more references available in the full text version of this article.

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Citation Excerpt :
The p.Thr714Ile APP mutation has been described in a large American family affected by AD with an unusual age of onset at 30 years, in which patients developed seizures and myoclonus in the early stages of the disease [24]. On the other hand, the p.Thr714Ala APP mutation caused different types of seizures: generalized tonic-clonic or complex partial seizures [25]. Individuals with extra copies of APP showed a higher risk for convulsive seizures [26].
Alzheimer’s disease (AD) is a heterogeneous neurodegenerative disorder and represents the most common form of dementia in the elderly. Mutations in genes encoding presenilin 1 (PSEN1), presenilin 2 (PSEN2) and amyloid precursor protein (APP) are responsible for early-onset familial AD (EOFAD).
Several pieces of evidence report that patients with rare autosomal dominant forms of AD carry a significant risk to develop seizures. However, the molecular mechanisms linking epilepsy and AD are needed to be clarified: the pathophysiology of seizures in AD may be related to an increased production of amyloid-β (Aβ) peptide or structural alterations in neurons probably due to cerebrovascular changes, neurotransmitter or cytoskeletal dysfunctions. Seizures have traditionally been related to neuronal loss in the late stages of AD as a consequence of neurodegeneration, however, recent studies indicated that seizures may contribute to the emergence of AD symptoms in early stages of the disease, mainly in familial AD. So, a better understanding of possible common neural mechanisms might help to improve the clinical management of both conditions.
This review aims to give a comprehensive overview and to analyze the association between epilepsy and EOFAD, focusing on possible overlapping pathological mechanisms.
Seizures in Alzheimer's disease
2015, Neuroscience
Citation Excerpt :
Both of the T714A patients examined by Lindquist et al. experienced recurrent seizures starting roughly a decade after onset of cognitive impairment (2008). One T714A patient displayed generalized tonic–clonic epileptic seizures and the other experienced short complex partial seizures followed by a short loss of consciousness (Lindquist et al., 2008). Seizures and myoclonus were also common in a kindred with a missense mutation in APP at V7171G (Kennedy et al., 1993; Rossor et al., 1993).
Alzheimer’s disease (AD) increases the risk for late-onset seizures and neuronal network abnormalities. An elevated co-occurrence of AD and seizures has been established in the more prevalent sporadic form of AD. Recent evidence suggests that nonconvulsive network abnormalities, including seizures and other electroencephalographic abnormalities, may be more commonly found in patients than previously thought. Patients with familial AD are at an even greater risk for seizures, which have been found in patients with mutations in PSEN1, PSEN2, or APP, as well as with APP duplication. This review also provides an overview of seizure and electroencephalography studies in AD mouse models. The amyloid-β (Aβ) peptide has been identified as a possible link between AD and seizures, and while Aβ is known to affect neuronal activity, the full-length amyloid precursor protein (APP) and other APP cleavage products may be important for the development and maintenance of cortical network hyperexcitability. Nonconvulsive epileptiform activity, such as seizures or network abnormalities that are shorter in duration but may occur with higher frequency, may contribute to cognitive impairments characteristic of AD, such as amnestic wandering. Finally, the review discusses recent studies using antiepileptic drugs to rescue cognitive deficits in AD mouse models and human patients. Understanding the mechanistic link between epileptiform activity and AD is a research area of growing interest. Further understanding of the connection between neuronal hyperexcitability and Alzheimer’s as well as the potential role of epileptiform activity in the progression of AD will be beneficial for improving treatment strategies.
Seizures and dementia in the elderly: Nationwide inpatient sample 1999-2008
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Human studies have also revealed a genetic association between epilepsy and AD. Multiple studies have found mutations in the amyloid precursor protein (APP) and the gamma-secretase modulatory genes — presenilin 1 (PS1) and presenilin 2 (PS2) in elderly subjects presenting with complex partial seizures [10–12]. These genes have also been identified as being highly correlated with early-onset AD [13,14].
This study aimed to examine the association between incidence of admission for a primary diagnosis of “seizure” or “epilepsy” and dementia in a nationally representative database, the Nationwide Inpatient Sample, among the elderly population (55 years of age and above) and to determine whether this relationship is different in individuals with Alzheimer's dementia versus those with non-Alzheimer's dementia.
Data were obtained from the Nationwide Inpatient Sample using appropriate ICD-9 codes. Frequencies and descriptive analysis adjusting for influence of comorbidities and confounders were utilized. A multivariate logistic regression model adjusted for age, gender, and race was used to further explore the relationship.
Those with AD had a higher risk of developing seizures or epilepsy (OR = 3.07, 95% CI = 2.98–3.16) as compared with cases with NAD (OR = 2.20, 95% CI = 2.14–2.27). After adjusting for age, the association increased for patients with AD (OR = 4.065, 95% CI = 3.95–4.17) but not appreciably for patients with NAD (OR = 2.68, 95% CI = 2.60–2.75). Adding gender and race to the model did not change the relationship for either AD or NAD. Further adjustment for African-American race did not further change the relationship for AD and seizure (OR = 3.96, 95% CI = 3.854–4.077) as well as for NAD and seizure (OR = 2.652, 95% CI = 2.575–2.731). Similarly, Hispanic race did not change the relationship significantly for AD (OR = 4.1, 95% CI = 4.01–4.25) and NAD (OR = 2.65, 95% CI = 2.56–2.74).
Patients with AD have a higher prevalence of a seizure compared with patients with NAD. Younger patients with AD were more likely to have seizures. Race, when analyzed as a whole and separately as African-American and Hispanic race, did not alter this relationship.
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Clinical characteristics and genotype-phenotype correlation analysis of familial Alzheimer’s disease patients with pathogenic/likely pathogenic amyloid protein precursor mutations
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View full text

Atypical early-onset Alzheimer's disease caused by the Iranian APP mutation

Abstract

Background

Methods and results

Conclusions

Introduction

Section snippets

Clinical case description

Discussion

Acknowledgements

Exp Neurol

Med Hypotheses

Segregation of a missense mutation in the amyloid precursor protein gene with familial Alzheimer's disease

Nature

A variant of Alzheimer's disease with spastic paraparesis and unusual plaques due to deletion of exon 9 of presenilin 1

Nat Med

APP locus duplication causes autosomal dominant early-onset Alzheimer disease with cerebral amyloid angiopathy

Nat Genet

Years of severe and isolated amnesia can precede the development of dementia in early-onset Alzheimer's disease

Neurocase

Seizures in elderly patients with dementia: epidemiology and management

Drugs Aging