Alzheimer's disease (AD) is a complex neurodegenerative disease that affects millions of people across the globe. It is also a topic of interest in the East Asian population, especially as the burden of disease increases due to aging and population growth. The pathogenesis of AD between ethnic groups is different. However, prior studies in AD pathology have focused primarily on populations of European ancestry and may not give adequate insight on the genetic, clinical, and biological differences found in East Asians with AD. Gaps in knowledge regarding Alzheimer's disease in the East Asian population introduce serious barriers to screening, early prevention, diagnosis, treatment, and timely intervention.
Prevalence
The prevalence of Alzheimer's disease and other dementias is significant in East Asian countries compared to the global average, which has 667 cases per 100,000 people. Japan has the highest prevalence of AD in the world at 3,079 cases per 100,000 population. South Korea and China have 1119 and 924 cases per 100,000 people, respectively. China has the highest number of people with dementia in the world at 13.1 million cases. Women were found to have higher rates of AD,Chang MH, Moonesinghe R, Athar HM, Truman BI (2016) Trends in Disparity by Sex and Race/Ethnicity for the Leading Causes of Death in the United States-1999-2010. Journal of public health management and practice 22 Suppl 1, S13–24 potentially due to higher estrogen levels.Espeland MAB RD; Hugenschmidt C; Manson JE; Craft S; Yaffe K; Weitlauf J; Vaughan L; Johnson KC; Padula CB; Jackson RD; Resnick SM (2015) Impact of Type 2 Diabetes and Postmenopausal Hormone Therapy on Incidence of Cognitive Impairment in Older Women. Diabetes Care 38, 2316–2324. According to a study, early menopause could be a contributing factor to an increased risk of AD. The prevalence is higher in older individuals and in rural areas.
In North America, the rates of Alzheimer's disease in Asian Americans were found to be similar to Non-Hispanic whites and lower compared to Black Americans and Hispanic Americans. Japanese Americans were found to have increased AD prevalence compared to other Asian American subgroups.Hastings KG, Jose PO, Kapphahn KI, Frank ATH, Goldstein BA, Thompson CA, Eggleston K, Cullen MR, Palaniappan LP (2015) Leading causes of death among Asian American subgroups (2003–2011). PLoS ONE 10 (4) (no pagination) In terms of trends, Japan has experienced a rapid increase in prevalence rates relative to the global average, from 772 cases per 100,000 in 1990 to 3029 cases per 100,000 in 2019. Japan is also expected to have the highest dementia-related death rates by 2040.
Risk factors and co-morbidities
Age and genetics have consistently been the strongest predictors of dementia and AD. However, lifestyle factors and other co-morbidities can play a significant role in contributing to AD susceptibility.
Demographic risk factors Older age is a significant risk factor for dementia, with the rate of cognitive decline being tenfold greater in the last three years of life. Income, occupation, and education are associated with the risk of developing AD in East Asian populations. Higher education generally indicates lower risk of AD. More physical or unsafe workplace conditions are associated with increased risk of AD.
Behavioral and physiological risk factors Smoking,Tyas SL, White LR, Petrovitch H, Webster Ross G, Foley DJ, Heimovitz HK, Launer LJ (2003) Mid-life smoking and late-life dementia: the Honolulu-Asia Aging Study. Neurobiology of aging 24, 589–596. low social activity,Sacznski JS, Pfeifer LA, Masaki K, Korf ESC, Laurin D, White L, Launer LJ (2007) The effect of social engagement on incident dementia: The Honolulu-Asia aging study. Research and Practice in Alzheimer's Disease 12, 42–48. and low physical activitySmith TL, Masaki KH, Fong K, Abbott RD, Ross GW, Petrovitch H, Blanchette PL, White LR (2010) Effect of walking distance on 8-year incident depressive symptoms in elderly men with and without chronic disease: the Honolulu-Asia Aging Study. Journal of the American Geriatrics Society 58, 1447–1452. are risk factors for AD in East Asian populations. Vascular conditions such as high blood pressure are also linked to dementia later in life. A sedentary lifestyle or obesity are believed to contribute to dementia susceptibility. Specifically, lower body mass index (BMI) may contribute to a lower likelihood of dementia. A healthy diet high in fish, fruit, Vegetables, and legumes but lower in meat and dairy is associated with decreased risk of AD. Regular consumption of vegetable and fruit juices may decrease AD risk due to the intake of popyphenols.Dai Q, Borenstein AR, Wu Y, Jackson JC, Larson EB (2006) Fruit and vegetable juices and Alzheimer's disease: the Kame Project. The American journal of medicine 119, 751–759. Abnormal levels of insulin and impaired glucose tolerance is connected to increased dementia susceptibility in East Asians. Poor early life environmental factors contribute to longer duration or more rapidly progressing AD later in life. Moreover, heavy metal exposures, such as lead, cadmium, mercury and arsenic, have been found to induce neurotoxicity, leading to an increased risk of AD. Daytime sleepiness and sleep apnea may have a relationship with later cognitive decline and dementia. A study of Japanese Americans found that mid-life proteinuria and impaired renal function may be an independent predictor of late-life dementia.
Comorbidities Diabetes, hypertension, cardiovascular diseases, stroke, and cancer are comorbidities in East Asian people with AD. In a review of AD patients in Taiwan, the co-prevalence of hypertension, diabetes, and stroke was reported to range from 30.2% to 60.7%, 15.1% to 24.2%, and 10.8 to 13.7% respectively. A study of Korean AD patients identified elevated prevalence of hypertension (71.6% AD vs 55% control) and diabetes (44.9% AD vs 30.1% control) in AD patients compared to control patients. Depressive symptoms and diabetes were also more increased in cognitively impaired Chinese Americans compared to White Americans.
Genetics Alzheimer's disease is influenced by a multitude of contributing genetic factors. The heritability of AD is estimated to range from 58 to 79%, making the elucidation of the genetic determinants of disease a crucial component to understanding the pathology of AD in East Asians.
Genetic studies Genetic studies such as genome-wide association studies (GWAS) are used to scan the genomes of many individuals to identify genetic variations that may be associated with a certain disease or trait. GWAS in Alzheimer's disease patients have been able to identify a number of risk variants and genetic factors that are linked to disease. Prior genetic studies have been focused primarily on populations with European ancestry, which prevents a comprehensive understanding of AD in other ethnic groups. It is important for GWAS to be conducted across diverse populations because the genetic differences between ethnic groups may influence the underlying biology of AD and identify unique genetic determinants. Only seven GWAS have been conducted using East Asian populations to identify race-specific genetic factors and susceptibility loci associated with AD. These GWAS focused on using cohorts from China, South Korea, and Japan. Compared to GWAS in Caucasians, GWAS in East Asians are also much smaller and have revealed 26 AD-associated loci in total. In comparison, a single recent GWAS in European populations involved over a million individuals and have identified 38 susceptibility loci.
ApoE
The genotype of apolipoprotein E (ApoE) is the strongest genetic risk factor for sporadic AD. ApoE is a multifunctional protein that is involved in lipid transport and exists in several different forms or alleles. +Genetic risk of ApoE genotypes: .Odds Ratio (OR) of 1 is normal risk. Higher OR indicates higher risk.PopulationTwo copies of ε2 alleleNo copies of ε4 alleleOne copy of ε4 alleleTwo copies of ε4 alleleReferenceCaucasian0.912.712.5Japanese1.115.633.1African American2.411.15.5Hispanic2.612.22.2 The most common APOE alleles are the ε2, ε3, and ε4 alleles, which were discovered to each be associated with varying levels of risk for AD. The ε4 allele has been confirmed to be a major risk factor for AD whereas the ε2 allele has been shown to be protective. However, the effects of ApoE genotype on AD risk are different across ethnic groups. Notably, the ε4 allele has a stronger effect in East Asian populations compared to other populations. The regional prevalence estimates of ε4 allele carrier frequencies are lowest in Asia, compared to Northern Europe where the regional prevalence estimates are highest. The ApoE ε4 allele was shown to lead to an increased rate of cognitive function decline in Han Chinese in Taiwan. +Rare missense variants of ApoE detected only in East AsiansVariant IDAmino acid ChangePathogenicityRelated diseasers121918392p.Glu21LysPathogenicHyperlipoproteinemia, type III; atherosclerosis (APOE ε5)rs587778876p. Leu122MetUnknownMajor depressive disorderrs121918397p.Arg163HisPathogenicFamilial hyperlipoproteinemia, type IIIrs121918397p.Arg163ProPathogenicLipoprotein glomerulopathyrs267606663p.Arg242GlnPathogenicFamilial hyperlipoproteinemia, type IIIrs140808909p.Glu262LysPathogenicHyperlipoproteinemia, type III; atherosclerosis (APOE ε7)rs190853081p.Glu263LysPathogenicHyperlipoproteinemia, type III; atherosclerosis (APOE ε7) Low frequency genetic variants linked to the pathophysiology of AD are important for elucidating disease etiology. Rare missense variants of ApoE may have differing prevalence in East Asians with AD. Recent research has focused on the Christchurch (rs121918393) and Jacksonville (rs199768005) variants, which appear to have protective effects against AD in Caucasians. However, these variants have not yet been identified in AD patients of Japanese ancestry, suggesting that these variants may be exclusive to Caucasians. Other ApoE variants that are detected only in East Asians have also been identified but they have not yet been linked to AD.
APP, PSEN1, and PSEN2
Mutations in APP (amyloid-beta precursor protein), PSEN1 (Presenilin-1), and PSEN2 (Presenilin-2) are known genetic causes of autosomal dominant forms of early-onset Alzheimer's disease (EOAD). APP encodes the precursor protein to amyloid-beta. Cleavage of APP by β-secretase and γ-secretase produces the pathogenic Aβ peptide in AD. PSEN1 and PSEN2 encode presenilin 1 and presenilin 2, which are major core components of the γ-secretase complex. There are over 400 mutations in these genes reported worldwide and classification of variants in these genes across ethnic groups is difficult. PSEN1 is the most frequently mutated and leads to the youngest age of onset, followed by APP, and subsequently, PSEN2. A small study of 200 early-onset AD patients in four East Asian countries found that 16% of patients presented pathogenic APP, PSEN1, or PSEN2 variants, 25% presented APP variants, 59% presented PSEN variants, and 16% presented PSEN2 variants. Over 40 mutations in PSEN1/PSEN2/APP have been found in Han Chinese patients with EOAD, with 31 mutations in PSEN1, 4 mutations in PSEN2, and 5 mutations in APP. The Chinese Familial AD Network, which enrolls 1330 patients in 404 pedigrees, found that 13.12% of pedigrees carry missense mutations in APP, PSEN1, and PSEN2.
BIN1