Investigation of an amyloid precursor protein protective mutation (A673T) in a North American case-control sample of late-onset Alzheimer's disease

doi:10.1016/j.neurobiolaging.2014.01.020

Neurobiology of Aging

Volume 35, Issue 7, July 2014, Pages 1779.e15-1779.e16

https://doi.org/10.1016/j.neurobiolaging.2014.01.020 Get rights and content

Abstract

A rare amyloid precursor protein gene variant, A673T (rs63750847) was recently reported to protect against Alzheimer's disease and age-related cognitive decline among Icelanders and the same rare variant was observed also in Finnish, Norwegian, and Swedish populations. We investigated this variant in 1674 late-onset Alzheimer's disease cases and 2644 elderly control subjects, all North American Whites (US Whites). We did not observe any example of the A673T variant in our large sample. Our findings suggest that this rare variant could be specific to the individuals of the origin from the Nordic countries.

Introduction

Recently, Jonsson et al. (2012) have reported that an amyloid precursor protein (APP) rare missense variant, A673T (rs63750847), is protective against late-onset Alzheimer's disease (AD) and cognitive impairment in non-AD elderly individuals among the Icelanders and they observed the same variant also in the Finnish, Norwegian, and Swedish populations. The A673T variant is adjacent to the β–site APP cleaving enzyme 1 cleavage site and thus may affect the production of amyloid-β, as supported by in vitro findings (Jonsson et al., 2012). In fact, this variant was recently detected also in a 104.8-year-old Finnish demented subject who showed little β-amyloid pathology (Kero et al., 2013), further supporting the possibility that this mutation might protect against amyloid-β accumulation. Recent studies conducted in Asians, however, have found no example of this rare variant among Chinese individuals (Liu et al., 2013, Ting et al., 2013).

In this study, we genotyped 4318 late-onset AD cases and older control subjects to determine the frequency of this variant among US Whites and its effect on modulating AD risk in this population.

Section snippets

Methods

The 4318 subjects included in this study were derived from 2 cohorts. The first cohort from the University of Pittsburgh Alzheimer Disease Research Center (Kamboh et al., 2012) consisted of 1390 late-onset AD cases (mean age = 73.8 ± 6.9 [standard deviation] years; age-at-onset = 72.9 ± 6.4 years) and 1031 control subjects (mean age = 80.7 ± 6.4 years). Diagnosis of AD was based on established criteria (DSM-IV) via multidisciplinary consensus conference as described in Lopez et al. (2000). The

Results and discussion

We genotyped a total of 4318 subjects consisting of 1674 late-onset AD cases and 2644 elderly control subjects to determine the frequency of the A673T variant in US Whites. All our genotyped samples demonstrated the absence of the A673T variant, except for the positive control included for assay verification. It should be noted that the previous positive reports about the identification of this variant were primarily in subjects from the Nordic countries but it seems to be extremely rare in

Disclosure statement

The authors declare that they have no conflicts of interest in regard to this work.

Acknowledgements

This study was supported by the National Institute on Aging grants AG041718, AG030653, and AG005133 and by U01 AT000162 from the National Center for Complementary and Alternative Medicine.

References (7)

M. Kero et al.
Amyloid precursor protein (APP) A673T mutation in the elderly Finnish population
Neurobiol. Aging
(2013)
S.K. Ting et al.
Absence of A673T amyloid-β precursor protein variant in Alzheimer's disease and other neurological diseases
Neurobiol. Aging
(2013)
T. Jonsson et al.
A mutation in APP protects against Alzheimer's disease and age-related cognitive decline
Nature
(2012)

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

Cited by (27)

Genomics and Functional Genomics of Alzheimer’s Disease
2022, Neurotherapeutics
Alzheimer's disease (AD) is a complex and multifactorial neurodegenerative disease. Due to its long clinical course and lack of an effective treatment, AD has become a major public health problem in the USA and worldwide. Due to variation in age-at-onset, AD is classified into early-onset (< 60 years) and late-onset (≥ 60 years) forms with early-onset accounting for only 5–10% of all cases. With the exception of a small number of early-onset cases that are afflicted because of high penetrant single gene mutations in APP, PSEN1, and PSEN2 genes, AD is genetically heterogeneous, especially the late-onset form having a polygenic or oligogenic risk inheritance. Since the identification of APOE as the most significant risk factor for late-onset AD in 1993, the path to the discovery of additional AD risk genes had been arduous until 2009 when the use of large genome-wide association studies opened up the discovery gateways that led the identification of ~ 95 additional risk loci from 2009 to early 2022. This article reviews the history of AD genetics followed by the potential molecular pathways and recent application of functional genomics methods to identify the causal AD gene(s) among the many genes that reside within a single locus. The ultimate goal of integrating genomics and functional genomics is to discover novel pathways underlying the AD pathobiology in order to identify drug targets for the therapeutic treatment of this heterogeneous disorder.
Alzheimer's disease beyond amyloid: Can the repetitive failures of amyloid-targeted therapeutics inform future approaches to dementia drug discovery?
2020, Biochemical Pharmacology
Alzheimer’s Disease (AD) therapeutics based on the amyloid hypothesis have repeatedly failed in clinical trials. Together with numerous reports that amyloid is present in brains from aged individuals without cognitive dysfunction, this suggests that the association of amyloid with AD is collateral rather than causal. However, the preeminence of the amyloid hypothesis has resulted in the ‘systematic …thwart[ing of] alternative approaches’ to AD/dementia driven by a ‘cabal’ of amyloid acolytes who have effectively controlled the ideas funded and published, which startups received venture investment and which programs were advanced in biopharmaceutical companies where they consulted. As a result, dementia research is estimated to be 15–30 years behind where it could be with conflicting data ignored in favor of the amyloid dogma and clinical trial failures being ascribed to faulty design or inadequacies in the compound selection process including flawed animal models. Major concerns regarding the precise diagnosis of AD/dementia and conflicting views on the validated status of fluid biomarker assays have resulted in trials that included patients with unknown amyloid pathologies. With the failure of the amyloid approach, emerging data on the role(s) of vascular, mitochondrial and synaptic network dysfunction, infection, diabetes, sleep, hearing loss, the gut microbiome and neuroinflammation/ innate immune function as dementia targets are driving research in new directions bolstered by recent findings on the genetic, omics and systems biology associated with AD/dementia. In moving forward, lessons learnt from the amyloid debacle should be used to enhance the objective identification of AD/dementia therapeutics as a multifactorial disease syndrome.
Dementia: Paradigm shifting into high gear
2019, Alzheimer's and Dementia
Citation Excerpt :
Resilience is being used here in a restricted sense: biological, psychological, social, and environmental factors leading to increased resistance to brain pathologies. Apart from a rare amyloid precursor protein variant (A673T rs 63 750347) gene identified in Nordic populations, but not white North Americans [28], most of the associations with resilience have been psychological and social such as a personality, social connectedness, and psychological wellbeing [29]. One difficulty in interpreting these associations is reverse causality, that is, those who are healthier, are more likely to have better outlooks, and be socially and physically engaged.
Redressing the rising threat of dementia demands not only an increase, but a diversification of efforts. We need new approaches, trials, and partners. We cannot afford to continue to only round up the usual suspects, β amyloid, and tau and try to stop them with a single drug “silver bullet”. Dementia of late onset is not a disease, but an amalgam of interactive pathologies on the shifting background of aging, requiring multimodal targeting. Cerebrovascular diseases coexist and coact with all major neurodegenerative pathologies, increasing two-fold the likelihood that they will manifest clinically. Cerebrovascular diseases need to be controlled, to give antidegenerative drugs a chance to succeed. This calls for new types of trials and designs. Stroke doubles the chances of developing dementia and decreases in stroke incidence correlate with decreases in dementia. Ninety percent of strokes are potentially preventable and so are a proportion of dementias. The stroke and dementia communities need to partner and complement the search for silver bullets with the golden opportunity of doing something now.
Genetics of Alzheimer's disease: From pathogenesis to clinical usage
2017, Journal of Clinical Neuroscience
Citation Excerpt :
This protective effect of A673T variant against AD and cognitive decline in the elderly might be induced by modulating the β-secretase cleavage of APP. However, this effect was failed to be replicated in several other populations [123–125]. Identification of genetic risk factors can not only be beneficial to the exploration of AD pathogenesis, but also be helpful for the diagnosis and prognosis of the disease.
Alzheimer’s disease (AD) is the most common type of dementia and has caused a major global health concern. Understanding the etiology of AD can be beneficial for the diagnosis and intervention of this disease. Genetics plays a vital role in the pathogenesis of AD. Research methods in genetics such as the linkage analysis, study of candidate genes, genome-wide association study (GWAS), and next-generation sequencing (NGS) technology help us map the genetic information in AD, which can not only provide a new insight into the pathogenesis of AD but also be beneficial for early targeted intervention of AD. This review summarizes the pathogenesis as well as the diagnostic and therapeutic value of genetics in AD.
Systems biology approach to late-onset Alzheimer's disease genome-wide association study identifies novel candidate genes validated using brain expression data and Caenorhabditis elegans experiments
2017, Alzheimer's and Dementia
We sought to determine whether a systems biology approach may identify novel late-onset Alzheimer's disease (LOAD) loci.
We performed gene-wide association analyses and integrated results with human protein-protein interaction data using network analyses. We performed functional validation on novel genes using a transgenic Caenorhabditis elegans Aβ proteotoxicity model and evaluated novel genes using brain expression data from people with LOAD and other neurodegenerative conditions.
We identified 13 novel candidate LOAD genes outside chromosome 19. Of those, RNA interference knockdowns of the C. elegans orthologs of UBC, NDUFS3, EGR1, and ATP5H were associated with Aβ toxicity, and NDUFS3, SLC25A11, ATP5H, and APP were differentially expressed in the temporal cortex.
Network analyses identified novel LOAD candidate genes. We demonstrated a functional role for four of these in a C. elegans model and found enrichment of differentially expressed genes in the temporal cortex.
Genomics of Alzheimer's disease: Value of high-throughput genomic technologies to dissect its etiology
2016, Molecular and Cellular Probes
Citation Excerpt :
This variant decreases β-secretase processing of APP, leading to lower Aβ burden; clinically, it seems to protect elderly without cognitive impairment against cognitive decline and AD. Follow up studies in elderly from the United States suggested that this variant is extremely rare and might be primarily present in Icelandic and Scandinavian populations [49–52]. Several independent studies identified rare disease-associated variants at loci identified by GWAS (Table 1).
Late-onset Alzheimer's disease (AD), the most common neurodegenerative disorder in western countries, is clinically defined by progressive worsening in cognitive functions along with function and behavioral impairment. This ultimately results in complete incapacity and death. AD is a clinically and pathologically heterogeneous disease, and this is reflected by the numerous genetic findings that point to several diverse molecular mechanisms and pathways. Linkage, genome-wide association and next-generation sequencing studies have led to the identification of more than 20 novel susceptibility loci for AD. While these observations have significantly increased the knowledge of pathogenic mechanisms and potential therapeutic targets, a large part of the genetic component underlying AD is still unexplained. This review will summarize and discuss the major genetic findings and their potential impact on AD diagnosis and prediction of prognosis.

View all citing articles on Scopus

View full text

Genetic report abstractNegative resultsInvestigation of an amyloid precursor protein protective mutation (A673T) in a North American case-control sample of late-onset Alzheimer's disease

Abstract

Introduction

Section snippets

Methods

Results and discussion

Disclosure statement

Acknowledgements

Neurobiol. Aging

Neurobiol. Aging

A mutation in APP protects against Alzheimer's disease and age-related cognitive decline

Nature

Genetic report abstract
Negative results
Investigation of an amyloid precursor protein protective mutation (A673T) in a North American case-control sample of late-onset Alzheimer's disease