American Journal of Alzheimer's Disease and Other Dementias http://aja.sagepub.com/
The Patterns of Inheritance in Early-Onset Dementia: Alzheimer's Disease and Frontotemporal Dementia Anna I. Jarmolowicz, Huei-Yang Chen and Peter K. Panegyres AM J ALZHEIMERS DIS OTHER DEMEN published online 21 August 2014 DOI: 10.1177/1533317514545825 The online version of this article can be found at: http://aja.sagepub.com/content/early/2014/08/20/1533317514545825
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Current Topics in Research
The Patterns of Inheritance in Early-Onset Dementia: Alzheimer’s Disease and Frontotemporal Dementia
American Journal of Alzheimer’s Disease & Other Dementias® 1-8 ª The Author(s) 2014 Reprints and permission: sagepub.com/journalsPermissions.nav DOI: 10.1177/1533317514545825 aja.sagepub.com
Anna I. Jarmolowicz, B. HealthSci1, Huei-Yang Chen, PhD1, and Peter K. Panegyres, MD, PhD1
Abstract Aim: To investigate the patterns of inheritance and gene mutation status in early-onset dementia (EOD). Methods: Data were collected on 202 consecutive patients presenting to an EOD clinic. Early-onset Alzheimer’s disease (EOAD, n ¼ 120) and earlyonset frontotemporal dementia (EOFTD, n ¼ 82) were studied. Results: The majority of participants, 72.5% with EOAD and 74.4% with EOFTD, did not have a positive family history of dementia. An autosomal dominant pattern of inheritance was observed in 14.2% of patients with EOAD and 13.4% of patients with FTD. Of those with an autosomal dominant pattern of inheritance, 11.8% of EOAD and 45.5% of FTD probands had known pathogenic mutations. Only 1.6% of the total population of EOAD and 7.3% of EOFTD possessed known gene mutations. Conclusion: Early-onset dementia does not appear to be a strongly inherited autosomal dominant condition. The majority of patients were sporadic. Known mutations were uncommon and do not explain the total autosomal dominant burden. Keywords early onset dementia, family history, genes and dementia, Alzheimer’s disease, frontotemporal dementia
Introduction Early-onset dementia (EOD) affects 67 to 81 per 100 000 individuals aged between 45 and 65 years1 with this figure expected to grow to 81.1 million people in 2040.2 Earlyonset Alzheimer’s disease (EOAD) and early-onset frontotemporal dementia (EOFTD) are historically defined by age of onset prior to 65 years of age, with symptoms similar to later onset Alzheimer’s disease (AD) and frontotemporal dementia (FTD); however, EOD is usually more severe and follows a natural history of rapid decline.3,4 Furthermore, patients with EOAD might have more executive functions and more impaired hypometabolism in the parietal regions, in comparison with late-onset patients who might have more impaired confrontational naming and verbal recognition memory and greater hypometabolism in the interior frontemporal regions.5 Early-onset dementia is often underdiagnosed, and management tends to be poor as limited resources are available for this specific group.6,7 Additionally, caregiver burden can differ from late-onset conditions, as patients still carry many economic and social responsibilities.8 There have been major advances in the understanding of the genetics of neurodegenerative disorders in the recent years. In AD, there is a risk spectrum that is composed of Mendelian genetic traits, genetic population risk factors, and nongenetic risk factors such as cognitive reserve, education, and head trauma.9 The apolipoprotein E (APOE) e4 allele
on chromosome 19 is an important population risk factor, the presence of 1 allele increasing risk by 3% and 2 alleles to 15X.10 Since then, over 550 genes have been suspected as enforcing risk of AD, but their risk is much less than APOE.11 Three causal genes have been identified so far for AD: these include the amyloid precursor protein (APP) gene on chromosome 21, the presenilin 1 (PSEN1) gene on chromosome 14, and presenilin 2 (PSEN2) on chromosome 1.12,13 Frontotemporal dementia is one of the most common forms of dementia in adults aged younger than 65 years. Frontotemporal dementia most commonly presents with personality or behavioral disorder or a linguistic syndrome. Frontotemporal dementia might overlap with motor neuron disease (MND), extrapyramidal syndrome, corticobasal disorders, and progressive supranuclear palsy. At least 7 Mendelian inherited, autosomal dominant genetic traits have been associated with FTD: mutations in microtubule-associated protein t (MAPT), progranulin (PGRN), and the hexanucleotide repeat expansion C9orf72
1
Neurodegenerative Disorders Research Pty Ltd, Subiaco, West Perth, Australia Corresponding Author: Peter K Panegyres, MD, PhD, Neurodegenerative Disorders Research Pty Ltd, 4 Lawrence Avenue, West Perth, Australia 6005. Email: [email protected]
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ARTEMIS Project n=228
Age at Onset >65 n=21
Inconclusive Diagnosis n=4
Undetermined Family History n=1
FADS Population n=202 (EOAD n=120, EOFTD=82)
Figure 1. Project design: Familial Dementia Study (FADS).
are the most common. Mutations in valosin-containing protein (VCP), charged multivesicular body protein 2B (CHMP28), TAR DNA-binding protein 43 (TARDP), and sigma nonopioid intracellular receptor 1 (SIGMAR1) are rarer causes.14,15 These genes, however, might only explain half of the total genetic load for EOD.16,17 This is contrary to several review articles, which report significant autosomal dominant pattern of inheritance in EOD.18,19 This is a larger proportion than we believe is seen in clinical practice and may indicate a bias toward selecting patients who are concerned about their genetic risk in centers which specialize in genetic testing. This study seeks to examine the proportion of patients with a family history of EOD and compare this to their mutation status. We analyzed an unselected consecutive population, coming forward with the question of EOD and without selection bias; that is, all patients with EOD were incorporated into the study irrespective of family history or other variables. We wished to investigate the patterns of inheritance and their genetic predisposition (the population used is part of the Artemis Project, a prospective analysis of patients with EOD).
Methods A cross-sectional analysis of the pattern of inheritance in a consecutive series of 228 patients collected over a 10-year period from January 1, 2001, and referred to a Neurodegenerative Disorders Research Clinic for the possibility of EOD. The patients were a subset group from a larger study (The Artemis Project)
which has been in progress for more than 10 years—a prospective evaluation of patients with the suspicion of dementia. Patients in this study are diagnosed using published criteria.20-25 The patients are referred from the Perth metropolitan area and regional Western Australia. Neurodegenerative Disorders Research Pty Ltd is the major referral center for EOD. The Artemis cohort consists of approximately 400 patients: AD (20%) and FTD (20%) are the most common diagnoses; patients with a primary psychiatric diagnosis (12.5%); cognitive abnormality without diagnosis (7.5%); and the remainder being a miscellaneous combination of vascular cognitive impairment, the sequelae of head injury, mild cognitive impairment, alcoholism, and individuals with symptomatic memory impairment for which no diagnosis was established. As AD and FTD are the most common diagnoses in the population of EOD, these 2 diagnoses were the basis of this investigation. Patients with FTD described in this study had the behavioral variant (75%), primary progressive aphasia (25%), and patients with AD had the amnestic form (95%) and the posterior cortical atrophy variant (5%). Twenty-six patients were excluded on the basis of age at onset >65 (n ¼ 21), undetermined diagnosis (n ¼ 4), and inadequate information regarding family history (n ¼ 1). A total of 202 patients (AD ¼ 120, FTD ¼ 82) met the selection criteria and were included (Figure 1). This data set consists of 201 different families, with 2 participants originating from the same family (Familial Dementia Study [FADS]). Information was collected on gender, diagnosis, age at onset, comorbid medical conditions and psychiatric history, mutation status, family history of dementia, and MND. Family history data were obtained from the participant and family members, with medical records of relatives consulted where possible. A family history of early- or late-onset Alzheimer’s disease (AD), early- or late-onset FTD, MND, and vascular dementia was accepted. Patient data were deidentified and coded. Family history was classified in 2 ways: a family member affected by dementia or according to a Modified Goldman classification.26,27 A Goldman score was obtained through analysis of family history data and separated into 5 categories based on the number of affected relatives: (1) autosomal dominant—3 affected individuals over 2 generations with 1 person being a first-degree relative of the other 2; (2) familial aggregation—3 relatives affected without satisfying the criteria for autosomal dominant inheritance; (3) single affected firstdegree relative younger than the age of 65 years, (3.5) single affected first-degree relative older than the age of 65 years old; and (4) a family history that does not satisfy the previous classifications or no family history. Each participant with an autosomal dominant family history had been offered genetic screening to determine their mutation status for the following common genes associated with dementia: APP, PSEN1, PSEN2, MAPT, PGRN, SIGMAR1, and C9orf72. In all, 17 patients with autosomal dominant AD and 11 patients with FTD had genetic testing. Screening was conducted by Neuroscience Research Australia by direct sequencing of polymerase chain reaction (PCR) products derived
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Table 1. Descriptive Data and Goldman Classification. Early-Onset Alzheimer’s Disease (N ¼ 120)
Male Family history
Age at onset Goldman classification 1 2 3 3.5 4 Mother Father Grandparents Sibling Aunt Other relatives Mutationsa
N
%
56 42
46.7 35.0
Mean
Std
Min
56.1
6.15
37
17 2 6 8 87 18 15 10 6 12 7 2
Max 65
14.2 1.7 5.0 6.7 72.5 15.0 12.5 8.3 5.0 10.0 5.8 1.6
Early-onset frontotemporal dementia (n ¼ 82)
Male Family history
Age at onset Goldman classification 1 2 3 3.5 4 Mother Father Grandparents Sibling Aunt Other relatives Mutationsb
N
%
53 25
64.6 30.5
Mean
Std
Min
56.1
6.12
38
11 3 5 2 61 12 8 5 8 11 6 7c
Max 64
13.4 3.7 6.1 2.4 74.4 14.6 9.8 6.1 9.8 13.4 7.3 7.3
Abbreviations: max, maximum; min, minimum; std, standard. a Known pathogenic mutations in PSEN1. b Known pathogenic mutations in PGRN, SIGMAR1 and C9orf72. c One participant had both C9orf72 and SIGMAR1 mutations.
from genomic DNA. The sequencing team were blinded as to diagnosis. Hexanucleotide repeat expansions in C9orf72 were determined by repeat-primed PCR. Southern blotting was performed on peripheral blood lymphocyte genomic DNA. DNA (10 mg) was digested with Hind III and Xba I and separated on a 0.9% agarose gel. Fragments were transferred to alkali blotting onto (Amersham Hyland NTM-XL, GE Healthcare Australia Pty Ltd. Building 4B Parklands Estate, 21
South Street, Rydalmere, NSW Australia, 2116) and hybridized to a 32P-labeled probe at 70 C overnight. The filters were masked with Church’s wash buffer (0.5 mol/L sodium phosphate, 1% sodium dodecyl sulphate). Autoradiography was for 4 to 6 days at –80 C. BstE II-digested l DNA was used as a size marker. Mean repeat size was measured by eye by laboratory staff blinded to the diagnosis. Nucleotide changes in the coding sequences of APP gene, PGRN gene, the PSEN1 and PSEN2 genes, and the t gene were determined by direct sequencing of PCR products derived from genomic DNA. Nucleotide sequence information from each PCR product was obtained from a single strand except where possible mutations or polymorphisms were detected, in which case the substitutions were verified by an independent amplification of the PCR product and sequence information from the opposite strand. Exons 16 and 17 (which code for the b-amyloid peptide) were screened for by PCR of genomic DNA of APP. The entire coding region of the PGRN was screened as were the entire coding regions of PSEN1 and PSEN2. Only exons expressed in the adult brain isoforms of t were screened by PCR of genomic DNAs (exons 1, 2, 3, 4, 8, 9, 10, 11, 12, 13, and 14). The SIGMAR1 intronic PCR primers were designed to amplify each coding and noncoding exons and flanking intronic sequences using the Exon Primer program (Institute of Human Genetics, Helmholtz Zentrum Munchen, www.ihg. helmholtzmunchen.de). The PCR products amplified from genomic templates were sequenced using Big Dye chemistry and a 3730 Analyzer (Applied Biosystems, Foster City, California). Nucleotide sequence information from each PCR product was obtained from each allele. Mutation status was verified by an independent amplification of the PCR products and resequencing. All patients gave written informed consent to participant in this study, which has institutional review board approval.
Results The demographics of the study population are presented in Tables 1 and 2. There were approximately equal number of males and females in the EOAD subgroup (n ¼ 120). Males accounted for 64.6% of the EOFTD subgroup (n ¼ 82). The age at onset for EOAD ranged from 37 to 65 years (mean 56.1 + 6.15) and from 38 to 64 years (mean 56.1 + 6.12) in patients with EOFTD. Patients with genetic EOAD had a significantly earlier age of onset (P < .0001) in comparison to sporadic AD, whereas there was no significant difference in age of onset in familial and genetic FTD. There was no significant difference in age of onset between genetic AD and FTD. Patients with AD, be it genetic or sporadic, mostly had an amnestic presentation, whereas patients with FTD mostly had the behavioral variant (Table 2). In all, 35.0% and 30.5% of patients with EOAD and EOFTD, respectively, had a history of at least 1 family member who had been diagnosed with any form of dementia. The Modified Goldman score was used to categorize the sample (Table 1). The majority of patients did not have firstdegree relatives with dementia (EOAD 72.5%, EOFTD
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American Journal of Alzheimer’s Disease & Other Dementias®
4 Table 2. Demographic Features: Genetic and Sporadic AD and FTD. EOAD (Genetic) Patient/Sex
EOFTD (Genetic)
Age at Onset
1. M 2. M
Presenting Clinical Feature
37 45
Amnestic syndrome Amnestic syndrome
41 + 5.7 (95% lower CI 10.2; upper CI 92.2)
Mean age at onset
Patient/Sex
Age at Onset
3. F 4. M 5. M 6. F 7. M 8. M
43 48 56 62 58 58
Frontal lobe syndrome Memory loss Psychosis Frontal lobe syndrome Frontal lobe syndrome Frontal lobe syndrome
Mean age at onset
EOAD (Sporadic)
Presenting Clinical Feature
54.17 (95% lower CI 46.6; upper CI 66.69)a
EOFTD (Sporadic) 59.38 + 5.23 (95% lower CI 58.4; upper CI 60.3); predominantly amnestic form 2-tailed unpaired t, P < .0001 ! EXT SIG (sporadic vs genetic AD)
Mean age at onset (N ¼ 118)
Mean age at onset (N ¼ 76)
58.70 + 8.1 (95% lower CI 58.8; upper CI 60.5); predominantly behavioral variant 2-tailed unpaired t, P < .1881 ! NS (Sporadic vs genetic FTD)
Abbreviations: AD, Alzheimer’s disease; CI, confidence interval; EOAD, early-onset Alzheimer’s disease; EOFTD, early-onset frontotemporal dementia; EXT SIG, extensively significant; F, female; FTD, frontotemporal dementia; M, male; NS, not significant. a Mann-Whitney U test, 2-tailed P ¼ .1314 (NS, mean age onset, genetic AD vs FTD).
Table 3. Mutation Status of Individuals With Autosomal Dominant Patterns of Inheritance. EOAD (n ¼ 17)
Mutationa positive Mutationa negative
EOFTD (n ¼ 11)
n
%
n
%
2 15
11.8 88.2
5b 6
45.5c 54.5
Abbreviations: EOAD, early-onset Alzheimer’s disease; EOFTD, early-onset frontotemporal dementia. a Known pathogenic mutations in PSEN1, PGRN, SIGMAR1, and C9orf72. b One participant had both C9orf72 and SIGMAR1 mutations. c Only probands included, brother of patient 4 not included (see Table 4).
74.4%). An autosomal dominant pattern of inheritance was found in 14.2% of patients with EOAD and 13.4% patients with EOFTD (Table 1). There was roughly an equal proportion of a single affected first-degree relative below or greater than 65 years. Twenty-eight individuals with an autosomal dominant family history had been offered gene testing to determine the presence of mutations known to cause EOAD and EOFTD (Table 3). Nine (AD ¼ 2, FTD ¼ 7) mutation carriers were identified within our study sample. The characteristics of the mutations are presented in Table 4. Of those sequenced with an autosomal dominant pattern of inheritance, 88.24% of those sequenced with AD and 45.56% with FTD did not harbor a mutation. One individual carried 2 FTD mutations (SIGMAR1 and C9orf72). An autosomal dominant pattern of inheritance was observed in 14.2% of individuals with EOAD and 13.4% of individuals with EOFTD according to the modified Goldman classification (Table 1). In all, 2 EOAD and 5 EOFTD probands had
gene mutations with 1 brother sharing the PGRN mutation (Table 3). Of the autosomal dominant EOAD and EOFTD probands,11.8% and 45.5% carried a known mutation. There were 67 individuals with at least 1 relative who had been diagnosed with dementia. Some people may have had more than 1 family member affected, for example, a mother, maternal aunt, and sibling. The most common affected relative was the mother (30 families), father (23 families), and aunt (23 families) for both diagnoses (Table 5). A chi-square analysis was performed and confirmed that there were no significant differences in the proportions of the types of family history between EOAD and EOFTD, suggesting that the family history pattern is similar for both the groups. Pedigrees were constructed for all families with an affected family member and grouped by apparent pattern. The most common affected relative was mother, father, and aunt as shown in Figure 2.
Discussion The majority of participants studied using a Goldman analysis did not show a positive family history of dementia. Autosomal dominant inheritance patterns were seen in only 14.2% and 13.4% of families with EOAD and EOFTD. This is consistent with other studies reporting the majority of EOD is not inherited through autosomal dominant transmission and only accounts for 10% to 15% of inheritance patterns.26,28,29 Reviews on this topic, however, report a significant autosomal dominant pattern of inheritance in EOD.18,19 This controversy may be explained by an historic recruiting bias resulting in the selection of individuals with genetic susceptibility. An advantage of this study is the longitudinal, consecutively
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Table 4. The Nature of the Mutations in Early-Onset AD and FTD. Patient/Sex
Age at onset
Presentation
Mutation
EOAD 1. M 2. M
37 45
Amnesia Amnesia
Presenilin M233T Presenilin Q222H
EOFTD 3. F
43
Frontal lobe syndrome (FLS)
PGRN Exon 8 T272 fs
4. M
48
Memory loss
PGRN
5. M
56
Psychosis
6. F
62
FLS
7. M 8. M
58 58
FLS FLS
p.R493X c. 1477 C>T C9orf72 4G2C expansion ¼ 1250 SIGMAR1 c. 672*51G>T SIGMAR1 c. 672*26 C>T C9orf72 4G2C expansion ¼ 1200 PGRN P R493X C 1477 C>T
Comment
Tetranucleotide deletion in coding region causing frameshift and premature translation termination ! nonsense-mediated RNA decay Stop codon Developed motor neuron disease (MND) No MND in proband and 3 affected family members MND in brother Brother of patient 4
Abbreviations: AD, Alzheimer’s disease; CI, confidence interval; EOAD, early-onset Alzheimer’s disease; EOFTD, early-onset frontotemporal dementia; F, female; FTD, frontotemporal dementia; M, male; PGRN, progranulin; SIGMAR1, sigma nonopioid intracellular receptor 1.
Table 5. Positive Family History of Early Onset Dementia.a EOAD (n ¼ 42)
Mother Father Grandparents Siblings Aunt Others
n
%
18 15 10 6 12 7
42.9 35.7 23.8 14.3 28.6 16.7
95% CI
EOFTD (n ¼ 25) n
%
95% CI
w2
27.9-57.8 12 48.0 28.4-67.6 0.17 21.2-50.2 8 32.0 13.7-50.3 0.1 10.9-36.7 5 20.0 4.3-35.7 0.13 3.7-24.9 8 32.0 13.7-50.3 1.65 14.9-42.2 11 44.0 24.5-63.5 2.98 5.4-27.9 6 24.0 7.3-40.7 0.54
P Value .68 .76 .72 .2 .08 .46
Abbreviations: CI, confidence interval; EOAD, early-onset Alzheimer’s disease; EOFTD, early-onset frontotemporal dementia. a 2 w ¼ no significant differences in the pattern of inheritance.
collected data set where the majority of patients with EOD in the catchment area of Perth and Western Australia have been referred to a single center with a special interest and without bias as to the genetic or other etiology of their dementia, thereby limiting referral bias. Results obtained from this data set are probably more representative of the wider population of susceptible individuals, as participants were recruited on the basis of diagnosis and treatment for the possibility of dementia and not for genetic predisposition. Participants were seen on a regular basis (minimum biyearly). Family history information was collected and clarified over the course of their management. Both a Goldman score and a family history score were used to categorize the data set. The Modified Goldman score provided a conservative estimate of 27.5% of participants with EOAD and 25.6% of those with EOFTD showing a family history of some description. This is lower than the findings of Rohrer et al29 who used a Modified Goldman score to determine 41.8% of their EOFTD
sample showed a familial component. A family history score was also used to categorize the sample, considering any relative affected with AD, FTD, and MND to determine the full scope of familial contribution, beyond the typical first-degree family members. On the basis of this score, 35% of the EOAD population and 30.5% of the EOFTD population sample did have some degree of family history; however, the nature of this differed from that of an autosomal dominant pattern to that of a single affected relative. It should be borne in mind that family size will impact upon the Goldman classification, with individuals coming from larger families having more people in categories 2, 3, and 4—probably due to the fact that larger families will have a high probability of someone developing a neurodegenerative disorder. All patients within the study were regularly offered and tested for common mutations causing EOD. This was repeated with the availability of novel screening technology or with the discovery of new mutations. Despite continued testing, only 1.6% of the total population with EOAD and 7.3% of the total population with EOFTD were found to possess a known mutation. Within autosomal dominant inheritance patterns, 11.8% of EOAD and 54.5% of EOFTD were explained by known mutations. The small number of mutations found is possibly explained by differences in populations studied and study design; however, screening procedures allowed for the detection of rare mutations.30 Other studies have reported an inability to determine genetic factors for a major proportion of patients with AD—approximately 23% to 25%.31,32 Similarly, Janssen et al33 were unable to find pathogenic mutations in 32% of their EOAD sample. It is possible that the clinical heterogeneity of EOAD might explain the differences in genetic load; however, over 90% of our patients with EOD had an
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AD
FTD
Mother
Mother
n = 18
n = 12
Father
Father
n = 15
n=8
Aunt
Aunt
n = 12
n = 11
n = number of families
Figure 2. The patterns of inheritance in early-onset dementia.
amnestic presentation (remainder posterior cortical atrophy and apraxic variants). It is likely that there are susceptibility genes yet to be discovered and rare variants that have not been identified. It is also possible that the genetic risk of autosomal dominant inheritance for AD is influenced by age where younger patients with age of onset less than 40 years are more likely to possess mutations. Genome-wide association studies may be able to explain this genetic heritability in the future.34 Furthermore, cerebrospinal fluid (CSF) analysis of cognitively normal individuals with a family history of AD showed, independent of APOE4, changes to CSF biomarkers.35 This further suggests that there may be other susceptibility genes that can influence disease progression. Affected mothers, fathers, and, surprisingly, aunts featured in patterns of inheritance within this sample. A mitochondrial association might be inferred from this pattern, supported by approximately equal numbers of male and female probands.36 Maternal patterns of inheritance have been considered in AD37 and documented in other neurological disorders such as multiple sclerosis.38 The preponderance of mothers being the most commonly affected relative might also relate to the more detailed family history obtained from mothers and the prevalence of AD greater in women. We acknowledge that there are difficulties comparing families of different sizes with members
having different ages of death; when considering differences in family history in siblings and aunts, however, the data set is as complete as possible, given the 6 monthly follow-up over at least 10 years in some families—this minimizes any possibility of missing data. Mitochondrial mechanisms might relate to chronic oxidative stress leading to synaptic abnormalities and degeneration.39 Recently discovered genotypic features such as TOMM40 demonstrate possible biological pathways for mitochondrial DNA to impact upon dementia disease progression.40 These factors may hint at yet to be discovered genetic susceptibility in the mitochondrial genome. Oligogenetic inheritance patterns have been recently discovered for some neurological diseases, including FTD. Van Blitterswijk et al41 found a co-occurrence of C9orf72 and either PGRN or MAPT in 1.8% of the North American and Italian families studied. Within our sample, 1 patient was identified carrying 2 genes known to increase the risk of EOFTD, SIGMAR1 and C9orf72. Recombination and coinheritance of these genes may or may not occur as they are located 7Mbases apart within the genome; it is possible that the SIGMAR1 mutation is not pathogenic and may be a rare, normal variant. Heterogeneity of genes within a single pathway has also complicated determining causative genes for EOAD.42 These genetic processes have implications for genetic counseling of dominantly inherited disorders and the penetrance within families as each genetic mutation may present a different relative risk. The National Society of Genetic Counsellors recommends that first-degree relatives of an affected individual should be advised that they have an estimated 15% to 39% lifetime risk of developing AD.43 This is increased compared to the general population by 2 to 4. This, however, does not distinguish familial from sporadic cases, which can be a clinically difficult and ambiguous process.44 The family of a sporadic case may have a risk more akin to population level while within a family with a strong autosomal genetic risk factor could have a risk of 50% or greater. Loy et al45 also highlights the distinction between a relative of an individual with dementia possessing a lower risk (20% lifetime risk) when compared to a relative with a Mendelian form (up to 95% lifetime risk). These issues bring into question the meaning of family history in terms of EOD diagnosis. More than 70% of our patients are seemingly sporadic with small percentages possessing a known mutation. Within autosomal dominant patterns, the chance of finding a mutation is greater (11.8% and 54.5% in EOAD and EOFTD, respectively). From these results it appears there is little benefit from gene testing of relatives, unless a known mutation has been verified within an individual family.
Conclusion A major limitation of this study was that medical records were not available to confirm relative’s diagnosis for all cases; despite this, EOD does not appear to be a dominantly inherited condition within our sample, with more than 70% of patients being sporadic in nature. Furthermore, known mutations were found in only 1.6% of the total population with EOAD and
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7.3% of the total population with EOFTD. Future research involving whole genome sequencing might uncover novel and potentially rare variants46 of EOD predisposing genes possibly involving mitochondrial and oligogenic inheritance pathways but only if these are frequent causes of EOAD or EOFTD. There is a need to combine this new technology with larger sample sizes as well as careful meta-analysis to bring together the variability between countries and studies with small numbers. Declaration of Conflicting Interests The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.
Funding The authors disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This research was funded by Neurodegenerative Disorders Research Pty Ltd. No editorial service was provided.
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13. Weggen S, Beher D. Molecular consequences of amyloid precursor protein and presenilin mutations causing autosomaldominant Alzheimer’s disease. Alzheimers Res Ther. 2012; 4(2):9. 14. Galimberti D, Scarpini E. Genetics of frontotemporal lobar degeneration. Front Neurol. 2012;3:52. 15. Luty AA, Kwok JB, Dobson-Stone C, et al. Sigma nonopioid intracellular receptor 1 mutations cause frontotemporal lobar degeneration-motor neuron disease. Ann Neurol. 2010;68(5): 639-649. 16. Campion D, Dumanchin C, Hannequin D, et al. Early-onset autosomal dominant Alzheimer disease: prevalence, genetic heterogeneity, and mutation spectrum. Am J Hum Genet. 1999; 65(3):664-670. 17. Goldman JS, Rademakers R, Huey ED, et al. An algorithm for genetic testing of frontotemporal lobar degeneration. Neurology. 2011;76(5):475-483. 18. Paulson H, Igo I. Genetics of dementia. Semin Neurol. 2011; 31(5):449-460. 19. Lill CM, Bertram L. Towards unveiling the genetics of neurodegenerative diseases. Semin Neurol. 2011;31(5):531-541. 20. Neary D, Snowden JS, Gustafson L, et al. Frontotemporal lobar degeneration: a consensus on clinical diagnostic criteria. Neurology. 1998;51(6):1546-1554. 21. McKhann G, Drachman D, Folstein M, et al. Clinical diagnosis of Alzheimer’s disease: report of the NINCDS-ADRDA Work Group under the auspices of the Department of Health and Human Services Task Force on Alzheimer’s Disease. Neurology. 1984; 34(7):939-944. 22. American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders, 4th ed. Washington, DC: American Psychiatric Association; 1994. 23. McKeith IG, Galasko D, Kosaka K, et al. Consensus guidelines for the clinical and pathologic diagnosis of dementia with Lewy bodies (DLB): report of the consortium on DLB international workshop. Neurology. 1996;47(5):1113-1124. 24. Roman GC, Tatemichi TK, Erkinjuntti T, et al. Vascular dementia: diagnostic criteria for research studies. Report of the NINDS-AIREN International workshop. Neurology. 1993; 43(2):250-260. 25. Ritchie K, Artero S, Touchon J. Classification criteria for mild cognitive impairment: a population-based validation study. Neurology. 2001;56(1):37-42. 26. Goldman JS, Farmer JM, Wood EM, et al. Comparison of family historiesin FTLD subtypes and related tauopathies. Neurology. 2005;65(11):1817-1819. 27. Beck J, Rohrer JD, Campbell T, et al. A distinct clinical, neuropsychological and radiological phenotype is associated with progranulin gene mutations in a large UK series. Brain. 2008; 131(pt 3):706-720 28. Wingo TS, Lah JJ, Levey AI, Cutler DJ. Autosomal recessive causes likely in early-onset Alzheimer disease. Arch Neurol. 2012;69(1):59-64. 29. Rohrer JD, Guerreiro R, Vandrovcova J, et al. The heritability and genetics of frontotemporal lobar degeneration. Neurology. 2009; 73(18):1451-1456.
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8 30. Hooli BV, Mohapatra G, Mattheisen M, et al. Role of common and rare APP DNA sequence variants in Alzheimer disease. Neurology. 2012;78(16):1250-1257. 31. Wallon D, Rousseau S, Rovelet-Lecrux A, et al. The French series of autosomal dominant early onset Alzheimer’s disease cases: mutation spectrum and cerebrospinal fluid biomarkers. J Alzheimers Dis. 2012;30(4):847-856. 32. Brickell KL, Steinbart EJ, Rumbaugh M, et al. Early-onset Alzheimer disease in families with late-onset Alzheimer disease: a potential important subtype of familial Alzheimer disease. Arch Neurol. 2006;63(9):1307-1311. 33. Janssen JC, Beck JA, Campbell TA, et al. Early onset familial Alzheimer’s disease: mutation frequency in 31 families. Neurology. 2003;60(2):235-239. 34. Cruchaga C, Haller G, Chakraverty S, et al. Rare variants in APP, PSEN1 and PSEN2 increase risk for AD in late-onset Alzheimer’s disease families. PLoS One. 2012;7(2):e31039. 35. Xiong C, Roe CM, Buckles V, et al. Role of family history for Alzheimer biomarker abnormalities in the adult children study. Arch Neurol. 2011;68(10):1313-1319. 36. Mili F, Flanders WD, Sherman SL, et al. Genetic epidemiologic methods to screen for matrilineal inheritance in mitochondrial disorders. Genet Epidemiol. 1996;13(6):605-614. 37. Honea RA, Swerdlow RH, Vidoni ED, Burns JM. Progressive regional atrophy in normal adults with a maternal history of Alzheimer disease. Neurology. 2011;76(9):822-829.
38. Herrera BM, Ramagopalan SV, Lincoln MR, et al. Parent-oforigin effects in MS: observations from avuncular pairs. Neurology. 2008;71(11):799-803. 39. Eckert A, Schmitt K, Go¨tz J. Mitochondrial dysfunction: the beginning of the end in Alzheimer’s disease? Separate and synergistic modes of tau and amyloid-b toxicity. Alzheimers Res Ther. 2011;3(2):15. 40. Caselli RJ, Dueck AC, Huentelman MJ, et al. Longitudinal modeling of cognitive aging and the TOMM40 effect. Alzheimers Dement. 2012;8(6):490-495. 41. Van Blitterswijk M, Baker MC, Dejesus-Hernandez M, et al. C9orf72 repeat expansions in cases with previously identified pathogenic mutations. Neurology. 2013;81(15):1332-1341. 42. Pottier C, Hannequin D, Coutant S, et al. High frequency of potentially pathogenic SORL1 mutations in autosomal dominant earlyonset Alzheimer disease. Mol Psychiatry. 2012;17(9):875-879. 43. Goldman JS, Hahn SE, Catania JW, et al. Genetic counseling and testing for Alzheimer disease: joint practice guidelines of the American College of Medical Genetics and the National Society of Genetic Counselors. Genet Med. 2011;13(6):597-605 44. Byrne S, Elamin M, Bede P, Hardiman O. Absence of consensus in diagnostic criteria for familial neurodegenerative diseases. J Neurol Neurosurg Psych. 2012;83(4):365-367. 45. Loy CT, Schofield PR, Turner AM, Kwok JB. Genetics of dementia. Lancet. 2014; 383(9919):828-840. 46. Bettens K, Sleegers K, Van Broeckhoven C. Genetic insights in Alzheimer’s disease. Lancet Neurol. 2013;12(1):92-104.
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The Patterns of Inheritance in Early-Onset Dementia: Alzheimer's Disease and Frontotemporal Dementia Anna I. Jarmolowicz, Huei-Yang Chen and Peter K. Panegyres AM J ALZHEIMERS DIS OTHER DEMEN published online 21 August 2014 DOI: 10.1177/1533317514545825 The online version of this article can be found at: http://aja.sagepub.com/content/early/2014/08/20/1533317514545825
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Current Topics in Research
The Patterns of Inheritance in Early-Onset Dementia: Alzheimer’s Disease and Frontotemporal Dementia
American Journal of Alzheimer’s Disease & Other Dementias® 1-8 ª The Author(s) 2014 Reprints and permission: sagepub.com/journalsPermissions.nav DOI: 10.1177/1533317514545825 aja.sagepub.com
Anna I. Jarmolowicz, B. HealthSci1, Huei-Yang Chen, PhD1, and Peter K. Panegyres, MD, PhD1
Abstract Aim: To investigate the patterns of inheritance and gene mutation status in early-onset dementia (EOD). Methods: Data were collected on 202 consecutive patients presenting to an EOD clinic. Early-onset Alzheimer’s disease (EOAD, n ¼ 120) and earlyonset frontotemporal dementia (EOFTD, n ¼ 82) were studied. Results: The majority of participants, 72.5% with EOAD and 74.4% with EOFTD, did not have a positive family history of dementia. An autosomal dominant pattern of inheritance was observed in 14.2% of patients with EOAD and 13.4% of patients with FTD. Of those with an autosomal dominant pattern of inheritance, 11.8% of EOAD and 45.5% of FTD probands had known pathogenic mutations. Only 1.6% of the total population of EOAD and 7.3% of EOFTD possessed known gene mutations. Conclusion: Early-onset dementia does not appear to be a strongly inherited autosomal dominant condition. The majority of patients were sporadic. Known mutations were uncommon and do not explain the total autosomal dominant burden. Keywords early onset dementia, family history, genes and dementia, Alzheimer’s disease, frontotemporal dementia
Introduction Early-onset dementia (EOD) affects 67 to 81 per 100 000 individuals aged between 45 and 65 years1 with this figure expected to grow to 81.1 million people in 2040.2 Earlyonset Alzheimer’s disease (EOAD) and early-onset frontotemporal dementia (EOFTD) are historically defined by age of onset prior to 65 years of age, with symptoms similar to later onset Alzheimer’s disease (AD) and frontotemporal dementia (FTD); however, EOD is usually more severe and follows a natural history of rapid decline.3,4 Furthermore, patients with EOAD might have more executive functions and more impaired hypometabolism in the parietal regions, in comparison with late-onset patients who might have more impaired confrontational naming and verbal recognition memory and greater hypometabolism in the interior frontemporal regions.5 Early-onset dementia is often underdiagnosed, and management tends to be poor as limited resources are available for this specific group.6,7 Additionally, caregiver burden can differ from late-onset conditions, as patients still carry many economic and social responsibilities.8 There have been major advances in the understanding of the genetics of neurodegenerative disorders in the recent years. In AD, there is a risk spectrum that is composed of Mendelian genetic traits, genetic population risk factors, and nongenetic risk factors such as cognitive reserve, education, and head trauma.9 The apolipoprotein E (APOE) e4 allele
on chromosome 19 is an important population risk factor, the presence of 1 allele increasing risk by 3% and 2 alleles to 15X.10 Since then, over 550 genes have been suspected as enforcing risk of AD, but their risk is much less than APOE.11 Three causal genes have been identified so far for AD: these include the amyloid precursor protein (APP) gene on chromosome 21, the presenilin 1 (PSEN1) gene on chromosome 14, and presenilin 2 (PSEN2) on chromosome 1.12,13 Frontotemporal dementia is one of the most common forms of dementia in adults aged younger than 65 years. Frontotemporal dementia most commonly presents with personality or behavioral disorder or a linguistic syndrome. Frontotemporal dementia might overlap with motor neuron disease (MND), extrapyramidal syndrome, corticobasal disorders, and progressive supranuclear palsy. At least 7 Mendelian inherited, autosomal dominant genetic traits have been associated with FTD: mutations in microtubule-associated protein t (MAPT), progranulin (PGRN), and the hexanucleotide repeat expansion C9orf72
1
Neurodegenerative Disorders Research Pty Ltd, Subiaco, West Perth, Australia Corresponding Author: Peter K Panegyres, MD, PhD, Neurodegenerative Disorders Research Pty Ltd, 4 Lawrence Avenue, West Perth, Australia 6005. Email: [email protected]
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2
ARTEMIS Project n=228
Age at Onset >65 n=21
Inconclusive Diagnosis n=4
Undetermined Family History n=1
FADS Population n=202 (EOAD n=120, EOFTD=82)
Figure 1. Project design: Familial Dementia Study (FADS).
are the most common. Mutations in valosin-containing protein (VCP), charged multivesicular body protein 2B (CHMP28), TAR DNA-binding protein 43 (TARDP), and sigma nonopioid intracellular receptor 1 (SIGMAR1) are rarer causes.14,15 These genes, however, might only explain half of the total genetic load for EOD.16,17 This is contrary to several review articles, which report significant autosomal dominant pattern of inheritance in EOD.18,19 This is a larger proportion than we believe is seen in clinical practice and may indicate a bias toward selecting patients who are concerned about their genetic risk in centers which specialize in genetic testing. This study seeks to examine the proportion of patients with a family history of EOD and compare this to their mutation status. We analyzed an unselected consecutive population, coming forward with the question of EOD and without selection bias; that is, all patients with EOD were incorporated into the study irrespective of family history or other variables. We wished to investigate the patterns of inheritance and their genetic predisposition (the population used is part of the Artemis Project, a prospective analysis of patients with EOD).
Methods A cross-sectional analysis of the pattern of inheritance in a consecutive series of 228 patients collected over a 10-year period from January 1, 2001, and referred to a Neurodegenerative Disorders Research Clinic for the possibility of EOD. The patients were a subset group from a larger study (The Artemis Project)
which has been in progress for more than 10 years—a prospective evaluation of patients with the suspicion of dementia. Patients in this study are diagnosed using published criteria.20-25 The patients are referred from the Perth metropolitan area and regional Western Australia. Neurodegenerative Disorders Research Pty Ltd is the major referral center for EOD. The Artemis cohort consists of approximately 400 patients: AD (20%) and FTD (20%) are the most common diagnoses; patients with a primary psychiatric diagnosis (12.5%); cognitive abnormality without diagnosis (7.5%); and the remainder being a miscellaneous combination of vascular cognitive impairment, the sequelae of head injury, mild cognitive impairment, alcoholism, and individuals with symptomatic memory impairment for which no diagnosis was established. As AD and FTD are the most common diagnoses in the population of EOD, these 2 diagnoses were the basis of this investigation. Patients with FTD described in this study had the behavioral variant (75%), primary progressive aphasia (25%), and patients with AD had the amnestic form (95%) and the posterior cortical atrophy variant (5%). Twenty-six patients were excluded on the basis of age at onset >65 (n ¼ 21), undetermined diagnosis (n ¼ 4), and inadequate information regarding family history (n ¼ 1). A total of 202 patients (AD ¼ 120, FTD ¼ 82) met the selection criteria and were included (Figure 1). This data set consists of 201 different families, with 2 participants originating from the same family (Familial Dementia Study [FADS]). Information was collected on gender, diagnosis, age at onset, comorbid medical conditions and psychiatric history, mutation status, family history of dementia, and MND. Family history data were obtained from the participant and family members, with medical records of relatives consulted where possible. A family history of early- or late-onset Alzheimer’s disease (AD), early- or late-onset FTD, MND, and vascular dementia was accepted. Patient data were deidentified and coded. Family history was classified in 2 ways: a family member affected by dementia or according to a Modified Goldman classification.26,27 A Goldman score was obtained through analysis of family history data and separated into 5 categories based on the number of affected relatives: (1) autosomal dominant—3 affected individuals over 2 generations with 1 person being a first-degree relative of the other 2; (2) familial aggregation—3 relatives affected without satisfying the criteria for autosomal dominant inheritance; (3) single affected firstdegree relative younger than the age of 65 years, (3.5) single affected first-degree relative older than the age of 65 years old; and (4) a family history that does not satisfy the previous classifications or no family history. Each participant with an autosomal dominant family history had been offered genetic screening to determine their mutation status for the following common genes associated with dementia: APP, PSEN1, PSEN2, MAPT, PGRN, SIGMAR1, and C9orf72. In all, 17 patients with autosomal dominant AD and 11 patients with FTD had genetic testing. Screening was conducted by Neuroscience Research Australia by direct sequencing of polymerase chain reaction (PCR) products derived
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Table 1. Descriptive Data and Goldman Classification. Early-Onset Alzheimer’s Disease (N ¼ 120)
Male Family history
Age at onset Goldman classification 1 2 3 3.5 4 Mother Father Grandparents Sibling Aunt Other relatives Mutationsa
N
%
56 42
46.7 35.0
Mean
Std
Min
56.1
6.15
37
17 2 6 8 87 18 15 10 6 12 7 2
Max 65
14.2 1.7 5.0 6.7 72.5 15.0 12.5 8.3 5.0 10.0 5.8 1.6
Early-onset frontotemporal dementia (n ¼ 82)
Male Family history
Age at onset Goldman classification 1 2 3 3.5 4 Mother Father Grandparents Sibling Aunt Other relatives Mutationsb
N
%
53 25
64.6 30.5
Mean
Std
Min
56.1
6.12
38
11 3 5 2 61 12 8 5 8 11 6 7c
Max 64
13.4 3.7 6.1 2.4 74.4 14.6 9.8 6.1 9.8 13.4 7.3 7.3
Abbreviations: max, maximum; min, minimum; std, standard. a Known pathogenic mutations in PSEN1. b Known pathogenic mutations in PGRN, SIGMAR1 and C9orf72. c One participant had both C9orf72 and SIGMAR1 mutations.
from genomic DNA. The sequencing team were blinded as to diagnosis. Hexanucleotide repeat expansions in C9orf72 were determined by repeat-primed PCR. Southern blotting was performed on peripheral blood lymphocyte genomic DNA. DNA (10 mg) was digested with Hind III and Xba I and separated on a 0.9% agarose gel. Fragments were transferred to alkali blotting onto (Amersham Hyland NTM-XL, GE Healthcare Australia Pty Ltd. Building 4B Parklands Estate, 21
South Street, Rydalmere, NSW Australia, 2116) and hybridized to a 32P-labeled probe at 70 C overnight. The filters were masked with Church’s wash buffer (0.5 mol/L sodium phosphate, 1% sodium dodecyl sulphate). Autoradiography was for 4 to 6 days at –80 C. BstE II-digested l DNA was used as a size marker. Mean repeat size was measured by eye by laboratory staff blinded to the diagnosis. Nucleotide changes in the coding sequences of APP gene, PGRN gene, the PSEN1 and PSEN2 genes, and the t gene were determined by direct sequencing of PCR products derived from genomic DNA. Nucleotide sequence information from each PCR product was obtained from a single strand except where possible mutations or polymorphisms were detected, in which case the substitutions were verified by an independent amplification of the PCR product and sequence information from the opposite strand. Exons 16 and 17 (which code for the b-amyloid peptide) were screened for by PCR of genomic DNA of APP. The entire coding region of the PGRN was screened as were the entire coding regions of PSEN1 and PSEN2. Only exons expressed in the adult brain isoforms of t were screened by PCR of genomic DNAs (exons 1, 2, 3, 4, 8, 9, 10, 11, 12, 13, and 14). The SIGMAR1 intronic PCR primers were designed to amplify each coding and noncoding exons and flanking intronic sequences using the Exon Primer program (Institute of Human Genetics, Helmholtz Zentrum Munchen, www.ihg. helmholtzmunchen.de). The PCR products amplified from genomic templates were sequenced using Big Dye chemistry and a 3730 Analyzer (Applied Biosystems, Foster City, California). Nucleotide sequence information from each PCR product was obtained from each allele. Mutation status was verified by an independent amplification of the PCR products and resequencing. All patients gave written informed consent to participant in this study, which has institutional review board approval.
Results The demographics of the study population are presented in Tables 1 and 2. There were approximately equal number of males and females in the EOAD subgroup (n ¼ 120). Males accounted for 64.6% of the EOFTD subgroup (n ¼ 82). The age at onset for EOAD ranged from 37 to 65 years (mean 56.1 + 6.15) and from 38 to 64 years (mean 56.1 + 6.12) in patients with EOFTD. Patients with genetic EOAD had a significantly earlier age of onset (P < .0001) in comparison to sporadic AD, whereas there was no significant difference in age of onset in familial and genetic FTD. There was no significant difference in age of onset between genetic AD and FTD. Patients with AD, be it genetic or sporadic, mostly had an amnestic presentation, whereas patients with FTD mostly had the behavioral variant (Table 2). In all, 35.0% and 30.5% of patients with EOAD and EOFTD, respectively, had a history of at least 1 family member who had been diagnosed with any form of dementia. The Modified Goldman score was used to categorize the sample (Table 1). The majority of patients did not have firstdegree relatives with dementia (EOAD 72.5%, EOFTD
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4 Table 2. Demographic Features: Genetic and Sporadic AD and FTD. EOAD (Genetic) Patient/Sex
EOFTD (Genetic)
Age at Onset
1. M 2. M
Presenting Clinical Feature
37 45
Amnestic syndrome Amnestic syndrome
41 + 5.7 (95% lower CI 10.2; upper CI 92.2)
Mean age at onset
Patient/Sex
Age at Onset
3. F 4. M 5. M 6. F 7. M 8. M
43 48 56 62 58 58
Frontal lobe syndrome Memory loss Psychosis Frontal lobe syndrome Frontal lobe syndrome Frontal lobe syndrome
Mean age at onset
EOAD (Sporadic)
Presenting Clinical Feature
54.17 (95% lower CI 46.6; upper CI 66.69)a
EOFTD (Sporadic) 59.38 + 5.23 (95% lower CI 58.4; upper CI 60.3); predominantly amnestic form 2-tailed unpaired t, P < .0001 ! EXT SIG (sporadic vs genetic AD)
Mean age at onset (N ¼ 118)
Mean age at onset (N ¼ 76)
58.70 + 8.1 (95% lower CI 58.8; upper CI 60.5); predominantly behavioral variant 2-tailed unpaired t, P < .1881 ! NS (Sporadic vs genetic FTD)
Abbreviations: AD, Alzheimer’s disease; CI, confidence interval; EOAD, early-onset Alzheimer’s disease; EOFTD, early-onset frontotemporal dementia; EXT SIG, extensively significant; F, female; FTD, frontotemporal dementia; M, male; NS, not significant. a Mann-Whitney U test, 2-tailed P ¼ .1314 (NS, mean age onset, genetic AD vs FTD).
Table 3. Mutation Status of Individuals With Autosomal Dominant Patterns of Inheritance. EOAD (n ¼ 17)
Mutationa positive Mutationa negative
EOFTD (n ¼ 11)
n
%
n
%
2 15
11.8 88.2
5b 6
45.5c 54.5
Abbreviations: EOAD, early-onset Alzheimer’s disease; EOFTD, early-onset frontotemporal dementia. a Known pathogenic mutations in PSEN1, PGRN, SIGMAR1, and C9orf72. b One participant had both C9orf72 and SIGMAR1 mutations. c Only probands included, brother of patient 4 not included (see Table 4).
74.4%). An autosomal dominant pattern of inheritance was found in 14.2% of patients with EOAD and 13.4% patients with EOFTD (Table 1). There was roughly an equal proportion of a single affected first-degree relative below or greater than 65 years. Twenty-eight individuals with an autosomal dominant family history had been offered gene testing to determine the presence of mutations known to cause EOAD and EOFTD (Table 3). Nine (AD ¼ 2, FTD ¼ 7) mutation carriers were identified within our study sample. The characteristics of the mutations are presented in Table 4. Of those sequenced with an autosomal dominant pattern of inheritance, 88.24% of those sequenced with AD and 45.56% with FTD did not harbor a mutation. One individual carried 2 FTD mutations (SIGMAR1 and C9orf72). An autosomal dominant pattern of inheritance was observed in 14.2% of individuals with EOAD and 13.4% of individuals with EOFTD according to the modified Goldman classification (Table 1). In all, 2 EOAD and 5 EOFTD probands had
gene mutations with 1 brother sharing the PGRN mutation (Table 3). Of the autosomal dominant EOAD and EOFTD probands,11.8% and 45.5% carried a known mutation. There were 67 individuals with at least 1 relative who had been diagnosed with dementia. Some people may have had more than 1 family member affected, for example, a mother, maternal aunt, and sibling. The most common affected relative was the mother (30 families), father (23 families), and aunt (23 families) for both diagnoses (Table 5). A chi-square analysis was performed and confirmed that there were no significant differences in the proportions of the types of family history between EOAD and EOFTD, suggesting that the family history pattern is similar for both the groups. Pedigrees were constructed for all families with an affected family member and grouped by apparent pattern. The most common affected relative was mother, father, and aunt as shown in Figure 2.
Discussion The majority of participants studied using a Goldman analysis did not show a positive family history of dementia. Autosomal dominant inheritance patterns were seen in only 14.2% and 13.4% of families with EOAD and EOFTD. This is consistent with other studies reporting the majority of EOD is not inherited through autosomal dominant transmission and only accounts for 10% to 15% of inheritance patterns.26,28,29 Reviews on this topic, however, report a significant autosomal dominant pattern of inheritance in EOD.18,19 This controversy may be explained by an historic recruiting bias resulting in the selection of individuals with genetic susceptibility. An advantage of this study is the longitudinal, consecutively
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Table 4. The Nature of the Mutations in Early-Onset AD and FTD. Patient/Sex
Age at onset
Presentation
Mutation
EOAD 1. M 2. M
37 45
Amnesia Amnesia
Presenilin M233T Presenilin Q222H
EOFTD 3. F
43
Frontal lobe syndrome (FLS)
PGRN Exon 8 T272 fs
4. M
48
Memory loss
PGRN
5. M
56
Psychosis
6. F
62
FLS
7. M 8. M
58 58
FLS FLS
p.R493X c. 1477 C>T C9orf72 4G2C expansion ¼ 1250 SIGMAR1 c. 672*51G>T SIGMAR1 c. 672*26 C>T C9orf72 4G2C expansion ¼ 1200 PGRN P R493X C 1477 C>T
Comment
Tetranucleotide deletion in coding region causing frameshift and premature translation termination ! nonsense-mediated RNA decay Stop codon Developed motor neuron disease (MND) No MND in proband and 3 affected family members MND in brother Brother of patient 4
Abbreviations: AD, Alzheimer’s disease; CI, confidence interval; EOAD, early-onset Alzheimer’s disease; EOFTD, early-onset frontotemporal dementia; F, female; FTD, frontotemporal dementia; M, male; PGRN, progranulin; SIGMAR1, sigma nonopioid intracellular receptor 1.
Table 5. Positive Family History of Early Onset Dementia.a EOAD (n ¼ 42)
Mother Father Grandparents Siblings Aunt Others
n
%
18 15 10 6 12 7
42.9 35.7 23.8 14.3 28.6 16.7
95% CI
EOFTD (n ¼ 25) n
%
95% CI
w2
27.9-57.8 12 48.0 28.4-67.6 0.17 21.2-50.2 8 32.0 13.7-50.3 0.1 10.9-36.7 5 20.0 4.3-35.7 0.13 3.7-24.9 8 32.0 13.7-50.3 1.65 14.9-42.2 11 44.0 24.5-63.5 2.98 5.4-27.9 6 24.0 7.3-40.7 0.54
P Value .68 .76 .72 .2 .08 .46
Abbreviations: CI, confidence interval; EOAD, early-onset Alzheimer’s disease; EOFTD, early-onset frontotemporal dementia. a 2 w ¼ no significant differences in the pattern of inheritance.
collected data set where the majority of patients with EOD in the catchment area of Perth and Western Australia have been referred to a single center with a special interest and without bias as to the genetic or other etiology of their dementia, thereby limiting referral bias. Results obtained from this data set are probably more representative of the wider population of susceptible individuals, as participants were recruited on the basis of diagnosis and treatment for the possibility of dementia and not for genetic predisposition. Participants were seen on a regular basis (minimum biyearly). Family history information was collected and clarified over the course of their management. Both a Goldman score and a family history score were used to categorize the data set. The Modified Goldman score provided a conservative estimate of 27.5% of participants with EOAD and 25.6% of those with EOFTD showing a family history of some description. This is lower than the findings of Rohrer et al29 who used a Modified Goldman score to determine 41.8% of their EOFTD
sample showed a familial component. A family history score was also used to categorize the sample, considering any relative affected with AD, FTD, and MND to determine the full scope of familial contribution, beyond the typical first-degree family members. On the basis of this score, 35% of the EOAD population and 30.5% of the EOFTD population sample did have some degree of family history; however, the nature of this differed from that of an autosomal dominant pattern to that of a single affected relative. It should be borne in mind that family size will impact upon the Goldman classification, with individuals coming from larger families having more people in categories 2, 3, and 4—probably due to the fact that larger families will have a high probability of someone developing a neurodegenerative disorder. All patients within the study were regularly offered and tested for common mutations causing EOD. This was repeated with the availability of novel screening technology or with the discovery of new mutations. Despite continued testing, only 1.6% of the total population with EOAD and 7.3% of the total population with EOFTD were found to possess a known mutation. Within autosomal dominant inheritance patterns, 11.8% of EOAD and 54.5% of EOFTD were explained by known mutations. The small number of mutations found is possibly explained by differences in populations studied and study design; however, screening procedures allowed for the detection of rare mutations.30 Other studies have reported an inability to determine genetic factors for a major proportion of patients with AD—approximately 23% to 25%.31,32 Similarly, Janssen et al33 were unable to find pathogenic mutations in 32% of their EOAD sample. It is possible that the clinical heterogeneity of EOAD might explain the differences in genetic load; however, over 90% of our patients with EOD had an
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American Journal of Alzheimer’s Disease & Other Dementias®
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AD
FTD
Mother
Mother
n = 18
n = 12
Father
Father
n = 15
n=8
Aunt
Aunt
n = 12
n = 11
n = number of families
Figure 2. The patterns of inheritance in early-onset dementia.
amnestic presentation (remainder posterior cortical atrophy and apraxic variants). It is likely that there are susceptibility genes yet to be discovered and rare variants that have not been identified. It is also possible that the genetic risk of autosomal dominant inheritance for AD is influenced by age where younger patients with age of onset less than 40 years are more likely to possess mutations. Genome-wide association studies may be able to explain this genetic heritability in the future.34 Furthermore, cerebrospinal fluid (CSF) analysis of cognitively normal individuals with a family history of AD showed, independent of APOE4, changes to CSF biomarkers.35 This further suggests that there may be other susceptibility genes that can influence disease progression. Affected mothers, fathers, and, surprisingly, aunts featured in patterns of inheritance within this sample. A mitochondrial association might be inferred from this pattern, supported by approximately equal numbers of male and female probands.36 Maternal patterns of inheritance have been considered in AD37 and documented in other neurological disorders such as multiple sclerosis.38 The preponderance of mothers being the most commonly affected relative might also relate to the more detailed family history obtained from mothers and the prevalence of AD greater in women. We acknowledge that there are difficulties comparing families of different sizes with members
having different ages of death; when considering differences in family history in siblings and aunts, however, the data set is as complete as possible, given the 6 monthly follow-up over at least 10 years in some families—this minimizes any possibility of missing data. Mitochondrial mechanisms might relate to chronic oxidative stress leading to synaptic abnormalities and degeneration.39 Recently discovered genotypic features such as TOMM40 demonstrate possible biological pathways for mitochondrial DNA to impact upon dementia disease progression.40 These factors may hint at yet to be discovered genetic susceptibility in the mitochondrial genome. Oligogenetic inheritance patterns have been recently discovered for some neurological diseases, including FTD. Van Blitterswijk et al41 found a co-occurrence of C9orf72 and either PGRN or MAPT in 1.8% of the North American and Italian families studied. Within our sample, 1 patient was identified carrying 2 genes known to increase the risk of EOFTD, SIGMAR1 and C9orf72. Recombination and coinheritance of these genes may or may not occur as they are located 7Mbases apart within the genome; it is possible that the SIGMAR1 mutation is not pathogenic and may be a rare, normal variant. Heterogeneity of genes within a single pathway has also complicated determining causative genes for EOAD.42 These genetic processes have implications for genetic counseling of dominantly inherited disorders and the penetrance within families as each genetic mutation may present a different relative risk. The National Society of Genetic Counsellors recommends that first-degree relatives of an affected individual should be advised that they have an estimated 15% to 39% lifetime risk of developing AD.43 This is increased compared to the general population by 2 to 4. This, however, does not distinguish familial from sporadic cases, which can be a clinically difficult and ambiguous process.44 The family of a sporadic case may have a risk more akin to population level while within a family with a strong autosomal genetic risk factor could have a risk of 50% or greater. Loy et al45 also highlights the distinction between a relative of an individual with dementia possessing a lower risk (20% lifetime risk) when compared to a relative with a Mendelian form (up to 95% lifetime risk). These issues bring into question the meaning of family history in terms of EOD diagnosis. More than 70% of our patients are seemingly sporadic with small percentages possessing a known mutation. Within autosomal dominant patterns, the chance of finding a mutation is greater (11.8% and 54.5% in EOAD and EOFTD, respectively). From these results it appears there is little benefit from gene testing of relatives, unless a known mutation has been verified within an individual family.
Conclusion A major limitation of this study was that medical records were not available to confirm relative’s diagnosis for all cases; despite this, EOD does not appear to be a dominantly inherited condition within our sample, with more than 70% of patients being sporadic in nature. Furthermore, known mutations were found in only 1.6% of the total population with EOAD and
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Jarmolowicz et al
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7.3% of the total population with EOFTD. Future research involving whole genome sequencing might uncover novel and potentially rare variants46 of EOD predisposing genes possibly involving mitochondrial and oligogenic inheritance pathways but only if these are frequent causes of EOAD or EOFTD. There is a need to combine this new technology with larger sample sizes as well as careful meta-analysis to bring together the variability between countries and studies with small numbers. Declaration of Conflicting Interests The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.
Funding The authors disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This research was funded by Neurodegenerative Disorders Research Pty Ltd. No editorial service was provided.
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