Views & Reviews

Ethnic variation in the incidence of ALS

A systematic review
Simon Cronin, MB, MRCPI; Orla Hardiman, MD, FRCPI; and Bryan J. Traynor, MD, MRCPI

AbstractBackground: The findings of recent genetic polymorphism studies in ALS suggest that the influence of genetic
risk factors for the disease may vary by ethnicity. It is now widely accepted that the incidence of ALS is uniform across
Caucasian populations, but whether racial variation across other ethnicities exists remains unknown. Method: Systematic
review of the known literature on the incidence, prevalence, and mortality of ALS across all ethnicities. To facilitate
comparison, studies were grouped according to the type of data presented and examined for sources of case ascertainment
and inclusion criteria. Results: The literature search identified 61 publications. Lower standardized incidence rates were
observed in Asian than Caucasian populations. Within the United States, several incidence and mortality studies have
identified lower ALS frequency among African American and Hispanic populations than among non-Hispanic Caucasians.
These observations are supported by the other data sources. Conclusions: The incidence of ALS may be lower among
African, Asian, and Hispanic ethnicities than among whites. We conclude with proposals for a prospective epidemiologic
study concentrating on non-Caucasian populations.
NEUROLOGY 2007;68:10021007

Whether ALS frequency varies by ethnicity has been

a source of controversy for many decades.1-3 Recent
genetic polymorphism studies have suggested that
ethnic background may indeed modify predisposition
to ALS.4-6 Therefore, a careful examination of the
population frequency of ALS across different ethnicities is both timely and desirable, as such data may
reveal at-risk ethnicities as candidates for further
genetic study.
With this in mind, we performed a systematic review of the known data concerning ethnic variation
in the occurrence of ALS. We had the dual aims of
summarizing the known data and of appraising
which methodological approaches are most likely to
yield valuable information in future studies.
Methods. Data extraction. A Medline literature search was
performed to identify all published studies on ALS incidence,
prevalence, or mortality from 1966 to March 2006, using the
MeSH terms ALS, motor neuron(e) disease, Lou Gehrigs disease, Charcots disease, incidence, prevalence, mortality,
and epidemiology. Additional references were sought from arti-

Additional material related to this article can be found on the Neurology

Web site. Go to www.neurology.org and scroll down the Table of Contents for the March 27 issue to find the title link for this article.

cle citations. Data were extracted by a single investigator (S.C.)

and reviewed by two ALS neurologists (O.H., B.J.T.). Where
groups reported data from a single population on more than one
occasion, the most recent study was included.7-10 Reports from
high-incidence clusters (such as the Guam/Kii Peninsula of Japan)
were excluded. Included studies were then grouped according to
the type of data presented: 1) studies providing crude incidence or
prevalence rates; among these, studies providing age- and sexadjusted incidence rates allowing standardized comparisons with
other countries were identified; 2) studies that reported data
stratified by ethnic group within a single population; 3) migration
studies; and 4) other mortality studies. A study may appear in
more than one category. To facilitate meaningful comparison between studies, a key to the sources of case ascertainment and
diagnostic criteria11 for inclusion is provided in table E-1 (available on the Neurology Web site at www.neurology.org).
Data analysis. Incidence and prevalence rates are crude and
unadjusted unless otherwise stated. Where published data allowed, incidence rates for the 45- to 74-year-old age bracket were
calculated and age- and sex-adjusted to the US 2000 standard
population by the direct method.12 This age band reflects the peak
ages of presentation where ascertainment is likely to be complete
and has been used by a number of other authors.2,13 CIs were
calculated assuming Poisson distribution. Within individual studies, race-specific confidence limits have been calculated according
to the size of the ethnic population during the time period studied
(information from the US Census Bureau). Ethnic and racial categories were defined according to NIH guidelines (1997 Office of
Management and Budget Directive 15). Significance indicates p
0.05.
Results of data extraction. Classification of included studies.
Sixty-one ALS epidemiologic studies satisfied criteria for consideration in this paper. Forty-five studies7-10,13-53 provided crude inci-

From the Irish ALS Research Group (S.C., O.H.), Neurology Department, Beaumont Hospital, Dublin, Ireland; and Section on Developmental Genetic
Epidemiology (B.J.T.), National Institutes of Health, Bethesda, MD.
This research was supported (in part) by the Intramural Program of the National Institute of Mental Health (BJT).
Disclosure: The authors report no conflicts of interest.
Received September 18, 2006. Accepted in final form December 13, 2006.
Address correspondence and reprint requests to Dr. Orla Hardiman, The Irish ALS Research Group, Neurology Department, Beaumont Hospital, Dublin 9,
Ireland; e-mail: ohard@iol.ie
1002

Copyright 2007 by AAN Enterprises, Inc.

Table 1 Comparison of incidence studies of ALS, standardized to the 2000 US population using the 45 to 74 age band
Incidence rate
Country
Ireland 32
US (WA)

Years

Study type*

19951997

Prospective

M
6.4

F
5.1

Total

05% CI

5.7

5.06.5

19901995

Prospective

5.3

4.9

5.1

4.36.1

1989

Prospective

6.2

3.3

4.7

4.15.3

Italy, Northern 9

19951996

Prospective

5.5

4.0

4.7

4.15.4

Italy, Puglia 13

19981999

Prospective

5.0

2.6

3.8

3.24.4

Japan

54

Scotland 31

19801989

Prospective

2.5

1.4

2.0

1.62.4

Finland 30

19761981

Retrospective

7.4

8.9

8.2

5.012.7

US (MN) 54

19251987

Retrospective

7.1

6.0

6.6

4.59.6

Sweden, North 34

19691980

Retrospective

8.3

4.0

6.0

4.38.2

20

Canada

19781982

Retrospective

6.7

4.9

5.6

4.47.3

Norway 35

19781988

Retrospective

6.5

4.2

5.3

3.38.1

Libya 25

19801985

Retrospective

6.3

3.0

4.6

2.96.8

Denmark 37

19741986

Retrospective

5.0

3.6

4.2

3.15.7

US (TX)

19851988

Retrospective

3.4

3.2

3.3

2.74.0

19861995

Retrospective

4.7

2.0

3.3

1.75.6

21

Estonia 42
Italy, Ferrara

19641982

Retrospective

3.8

2.0

2.8

1.45.1

Greece 43

19902003

Retrospective

3.1

1.8

2.4

1.53.7

Israel 7

19691974

Pre-1970, retrospective, post-1970, register

3.1

1.6

2.3

1.73.0

Italy, Sardinia 52

19651974

Retrospective

2.9

1.5

2.1

1.53.0

49

Italy, Florence 50

19671976

Retrospective

2.1

1.6

1.9

1.22.8

Italy, Turin 51

19711980

Retrospective

2.7

1.0

1.7

1.32.4

China 22

19891992

Retrospective

0.7

0.8

0.8

0.51.0

* See table E-1 for sources of case ascertainment, case inclusion criteria, and comments.
Incidence per 100,000 person-years for the 45 to 74 age band, directly age and gender adjusted to the 2000 US population.
Age band 50 to 79 used for comparison.

dence or prevalence data for ALS (table E-1). Stratified by region,

there were 27 studies from Europe,9,13,29-53 five from Central and
South America,14-18 four from North America and Canada,19-21 two
from Asia,8,22 two from the Pacific,23,24 three from Africa,25-27 and
single studies from the Middle East7 and Russia.28 Twenty-two of
these studies provided sufficient incidence data for age and sex
adjustment to a standard population 7-9,13,19-22,25,30-32,34,35,37,42,43,49-52,54.
Six studies presented incidence or mortality of motor neuron disease (MND) stratified by ethnicity within the observed
population.19,21,24,55-57 Three migration studies were considered.58-60
Twenty mortality studies were identified16-18,20,22,24,36,39,40,49,55,56,61-68.
Sources of case ascertainment. Among studies of ALS incidence and prevalence (table E-1), 17 had a single source of case
and
six
had
ascertainment7,10,14,16,18,26,27,33,37,39,40,43,44,46,48,50,53
two.17,20,24,25,30,35 Only seven register-based studies of ALS incidence
have been published to date, five of which were based in the
Caucasian populations of Europe and North America.9,13,19,31,32 The
other prospective population-based studies described the epidemiology of ALS in Japan and Uruguay.8,15 The majority of studies in
non-Caucasian populations tended to be smaller and to use less
reliable data sources.
Inclusion criteria of cases. Heterogeneity in the definition of
MND was observed among studies. More studies included progressive spinal muscular atrophy in the calculation of incidence rates
than excluded it (table E-1). Three studies included juvenile spinal
muscular atrophy and consequently may have overestimated the
occurrence of MND.26,27,36
Limitations of the data. Further comments and critique of the
studies discussed below are provided in table E-1.

Results. Studies that provide incidence or prevalence

rates by region (table E-1). Within the Caucasian populations of Europe and North America, the highest reported
crude incidence of ALS was 2.4 per 100,000 person-years
in Middle Finland, and the lowest reported was 0.6 in
Italy. Most studies in European and American populations
observed a crude incidence above 1 per 100,000 personyears. Outside of Europe and North America, high incidence was noted only from a single South American
study15 and in the mixed population of Hawaii.24 The remainder of studies outside Europe and North America document a crude incidence below 1 per 100,000 person-years.
However, there was a wide disparity between the epidemiologic methods employed in these regions compared to Europe and North America (table E-1).
To facilitate meaningful comparisons, age- and sexadjusted incidence rates from 22 of the epidemiologic studies were standardized to the 2000 US population (table 1).
A number of observations can be made. First, prospective
designs with multiple sources of case ascertainment provide higher estimates than retrospective studies performed
in the same populations. Second, the incidence of ALS
across Europe is remarkably uniform, as demonstrated by
four prospective, population-based studies from Ireland,
March 27, 2007

NEUROLOGY 68

1003

Table 2 Incidence and mortality studies of motor neuron disease that stratified their findings by ethnicity

Country
US 55

US 56

Years

Sources of case
ascertainment*

Inclusion
criteria of cases*

19992001

H,I

19921998

H,I

US 57

19731978

H,I

US (WA) 19

19901995

A,B,C,K

S,V,Y

US (TX) 21

19851988

B,C,E,I

S,W,Y

Hawaii 24

19521969

B,E

Q,V,Y

Ethnic
group

Mortality per
100,000
population
(95% CI)

Incidence per 100,000

people, years (95% COI)
M

Nonwhite

0.7 (0.02.0)

0.5 (0.01.9)

Overall

2.1 (1.32.9)

1.9 (1.12.7)

Hispanic

1.3 (0.43.0)

0.1 (0.00.5)

Nonwhite

1.0 (0.91.1)

White

2.1 (2.02.2)

Hispanic

0.9 (0.81.1)

African American

1.1 (0.91.2)

Non-Hispanic white

2.0 (1.92.0)

Nonwhite

0.8 (0.70.9)

White

1.3 (1.21.4)

African American

1.1 (0.52.2)

0.7 (0.31.4)

Non-Hispanic white

1.4 (1.01.9)

1.3 (0.91.7)

Filipino

5.1 (0.717.2)

Japanese

1.1 (0.05.7)

0.5 (0.04.6)

White

0.8 (0.04.8)

0.4 (0.04.9)

* See table E-1 for key.

Significant difference from the comparative Caucasian population.

Scotland, and Italy.9,13,31,32 Finally, only a limited number

of the adjustable studies examine incidence of ALS among
non-Caucasian populations.8,22,25
Only three epidemiologic studies of ALS have been performed in black African populations25-27 (table E-1). Among
these, a single incidence study,25 from Benghazi in Libya,
was available. This reports an apparently low crude incidence rate of 0.87 per 100,000 person-years. However,
Libya has a young population, with 81% younger than the
age of 40,25 and thus the standardized incidence for the 45
to 74 age band of 4.6 per 100,000 person-years (95% CI: 2.9
to 6.8) does not differ from rates seen across Southern
Europe (table 1). Conversely, marked differences in ALS
incidence are not to be expected between Libya and Southern Europe because the Libyan population encompasses
mixed descendants of Arabs, Europeans, and Africans, and
1% are of black African origin.25 There have been no
well-conducted ALS incidence studies elsewhere in Africa.
There are two published studies concerning the incidence of ALS in Asian populations (table E-1 and table 1).
A large, prospective incidence study of ALS on Hokkaido
Island, Japan8 reported a standardized incidence for the 45
to 74 age band of 2.0 per 100,000 person-years (95% CI: 1.6
to 2.4). The lowest incidence observed by prospective studies in Caucasian populations is 3.8 per 100,000 personyears (95% CI: 3.2 to 4.4; Puglia, Italy), indicating a
significant difference. This apparently lower ALS incidence
among Asian populations is supported by a retrospective
study of ALS among Hong Kong Chinese,22 in which the
standardized ALS incidence for the 45 to 74 age band was
0.8 (95% CI: 0.5 to 1.0).
Regarding Central and South American populations,
there has been speculation that a resistance to ALS exists among Mexicans, based on a study performed in Mex1004

NEUROLOGY 68

March 27, 2007

ico City reporting an incidence of 0.4 per 100,000.17 Low

incidence rates have also been reported from other Hispanic white populations in South America,14,16,18 particularly a population-based prospective study from Uruguay
(1.4 per 100,000 person-years15). However, these studies
had several methodologic flaws that may explain their observations (table E-1). Furthermore, it may be difficult to
assign a single rate under the term Hispanic, as individual
populations in Central and South America comprise different admixtures of Spanish, European, Amarinidian,
Carthagian, and Arab peoples.69 Thus, the term Hispanic
is likely to be a less homogeneous and useful epidemiologic
category than Asian or African.69
ALS epidemiology studies that stratified their findings
by ethnicity. Differences in case finding methodology and
population demographics hinder comparison of ALS incidence between different continents. An alternative approach is to search for ethnic variation within a single
study employing a uniform method of case ascertainment
within a racially diverse population. Six such studies,
mainly from the United States, are summarized in table 2.
A prospective, population-based study of ALS in Washington State reported lower age-adjusted incidence rates
among nonwhites (mostly African American) compared to
the white population, although the 95% CIs markedly
overlapped.19 In contrast, a retrospective incidence study
in Harris County, TX, found similar incidence rates between African Americans and non-Hispanic whites, but
was underpowered to exclude a decreased incidence among
blacks.21
Three population-wide ALS mortality studies have been
published on the United States (table 2). Mortality studies
have the advantage of providing a larger population for
observation than localized epidemiologic studies. All these

have reported a lower mortality rate among the Hispanic

and African American populations when compared to the
white population. It must be remembered, however, that
limited access to health care among African Americans
may have impeded case ascertainment.70,71
Finally, an incidence study from the Hawaiian Islands
stratified its findings by Filipino, Japanese, and Caucasian
ethnicity.24 In contrast to the lower incidence of ALS observed in other Asian studies,8,22 there was no significant
difference in ALS incidence between Japanese and white
ethnic subgroups.
Migration studies. Migration studies compare the incidence or mortality from ALS among ethnic subgroups that
have migrated to a single location. A study of immigrants
to London during the 10-year period 1979 to 1988 showed
ALS mortality rates to be lower among Asian (standardized mortality ratio [SMR] 37.6%), East African (SMR
55.5%), Caribbean (SMR 73.6%), and West African
(SMR 76.9%) immigrants to London than among native
English.58 In contrast, white immigrants from the Indian
subcontinent had the expected ALS mortality rate (SMR
113%). However, the denominators of ethnic populations
were not known for that time period and ethnicity was
assigned based on the individuals name.
A further migration study reported a lower ALS incidence among Afro-Asians who had migrated to Israel
(standardized incidence ratio 83%) when compared to
the native Israeli Caucasian population.59
A migration study in northwestern Italy showed a
higher incidence of ALS for Southern Italian and other
European immigrants to northern Italy than the native
population.60 Prospective studies have since demonstrated
a uniform incidence across the Caucasian populations of
Europe, highlighting the difficulties in interpreting migration study data. Immigrant populations may not be representative of the nonimmigrant population of the same
ethnic background1 and migration studies do not rule out
the existence of environmental factors in the home
country.
Mortality studies. Crude ALS mortality rates reported
by 20 studies from 22 ethnically diverse populations are
presented in table 3. Of these, five examined rates in the
Hispanic Caucasian populations of Central and South
America,16-18,66,68 and three examined rates in Asian populations.22,65,67 Lower mortality rates are consistently observed in Hispanic and Asian countries compared to
Caucasian populations. However, mortality studies are by
definition based on a single source of data. Local variation
exists in death certificate coding, further complicated by
changes to the International Classification of Diseases in
1979 that have seen separate codes for ALS, progressive
bulbar palsy, and progressive muscular atrophy amalgamated as a single code for MND.2 Furthermore, some mortality studies only include cases where MND is listed as the
underlying cause of death, whereas others accept any
cases where MND appeared anywhere on the death certificate. Overall, mortality studies are more suited to determining the trend of a disease over time within the same
country, rather than international comparisons.3

Discussion. Systematic review of 61 publications

demonstrates uniform occurrence of ALS across the
Caucasian populations of Europe and North Amer-

Table 3 Comparison of worldwide mortality rates from ALS

Country

Years

Crude mortality rate

per 100,000 population

Australia 61

19781987

3.8 (M), 2.7 (F)

New Zealand 61

19781987

4.2 (M), 3.6 (F)

US 56 *

19691998

1.31.8

Canada 20

19781982

1.5

Spain 62

19511990

1.5

France 63

19681990

0.91.8 (M), 0.71.5 (F)

UK 64

19591986

1.21.6

South Africa 61

19781987

1.0

US 55 *

19992001

1.0

Denmark 39

19481975

0.9

Italy 49

19641982

0.8

Japan 65 *

2001

0.7

Iceland 40

19541963

0.7

Hawaii 24

19521968

0.7

Finland 36

1973

0.7 (M), 0.6 (F)

Brazil 66

19651974

0.30.9

Japan 67

19521971

0.40.6

Brazil 68

19711973

0.40.6

China 22

19891992

0.3

Brazil 18

19911994

0.20.4

Mexico 17

19621969

0.3

Chile 16

19721976

0.3

* Age-adjusted mortality rate used for comparison.

Rate for population older than 39 years of age.

ica. By contrast, available epidemiologic data suggest that the incidence of ALS is lower among
African, Asian and Hispanic ethnicities than among
Caucasians. It is difficult to draw firm conclusions,
as there is methodologic heterogeneity among studies performed in non-Caucasian populations.
The performance of adequately designed epidemiologic studies in developing countries is hindered by
the lack of access to adequate medical care. Even in
the United States, underascertainment of neurodegenerative diseases among ethnic minorities70,71 may
account for apparent racial variation in ALS frequency. In other regions, cultural factors complicate
complete case ascertainment, such as the case with
cultural medicine in Hong Kong.22 Finally, life expectancy is generally lower outside of the developed
world, and an earlier age at death from infectious or
cardiovascular diseases may limit the size of the
older, more susceptible population.72,73
Knowledge of how ethnicity modifies an individuals risk of developing ALS may provide important
insights into the pathogenesis of this fatal neurodegenerative condition. Variation in the incidence with
ethnicity would support the notion that genetic factors play a dominant role in the pathogenesis of the
disease. Such information would have direct consequences for ethnicity matching in the design of geMarch 27, 2007

NEUROLOGY 68

1005

netic studies. If the risk of ALS is higher in a

particular ethnic group, then that population should
be prioritized for study, as their higher genetic burden might facilitate mutation detection. Different
risks of disease in different populations are also the
basis of genetic admixture studies, a powerful technique to map susceptibility genes in interbred populations of high- and low-risk racial groups.
Proposals for the design of an epidemiologic study
to address ethnic variation in ALS frequency.
1. Study design: Prospective study designs provide
higher disease rate estimates than comparable retrospective studies in the same populations (table 1),
and are the preferred method.
2. Population size: The relative rarity and rapidly
fatal course of ALS mean that a study with minimum of 3 to 5 years of follow-up of a population no
smaller than one million is required to generate
meaningful incidence data within a single ethnic
group. If the population is racially heterogeneous,
then a larger population cohort will be required to
provide differential race-specific incidence data with
sufficient precision. For example, in a population
composed of two subgroups at an 80:20 ratio, approximately 10 million individuals would require
observation for 5 years to detect a 25% difference
with certainty (see appendix E-1 for statistical
derivation).
3. Complete case ascertainment: ALS incidence
studies without multiple sources of case ascertainment are likely to underestimate disease frequency,
as has been demonstrated in Italy (table E-1). In
populations of mixed ethnicities, particular attention
should be given to case finding among ethnic minorities who may not have access to health insurance or
specialist care through liaison with ethnic minority
organizations and community-based medical
services.
4. Representation of older age groups: It is desirable that such a study be performed in an area of
long-established ethnic diversity so that older age
strata are well represented across all ethnic groups.
5. Uniform diagnostic criteria must be applied.
The gold standard El Escorial criteria are suggested,
although access to neurophysiologic confirmation
may be limited in economically underserved regions.
6. Reporting of age bands and ethnic subgroups:
We suggest that all future studies of ALS incidence
report their data stratified by ethnicity and also provide age- and sex-specific incidence rates, so that
results can be standardized and meaningful comparisons can be made between different populations.
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