Alzheimer's disease Alzheimer's disease (AD) is a neurodegenerative disease and the cause of 60–70% of cases of dementia. The most common early symptom is difficulty in remembering recent events. As the disease advances, symptoms can include problems wit ...

(AD) is a complex

neurodegenerative disease A neurodegenerative disease is caused by the progressive loss of neurons, in the process known as neurodegeneration. Neuronal damage may also ultimately result in their death. Neurodegenerative diseases include amyotrophic lateral sclerosis, mul ...

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 Ageing (or aging in American English) is the process of becoming Old age, older until death. The term refers mainly to humans, many other animals, and fungi; whereas for example, bacteria, perennial plants and some simple animals are potentiall ...

and

population growth Population growth is the increase in the number of people in a population or dispersed group. The World population, global population has grown from 1 billion in 1800 to 8.2 billion in 2025. Actual global human population growth amounts to aroun ...

. The

pathogenesis In pathology, pathogenesis is the process by which a disease or disorder develops. It can include factors which contribute not only to the onset of the disease or disorder, but also to its progression and maintenance. The word comes . Descript ...

of AD between

ethnic groups An ethnicity or ethnic group is a group of people with shared attributes, which they collectively believe to have, and long-term endogamy. Ethnicities share attributes like language, culture, common sets of ancestry, traditions, society, rel ...

is different. However, prior

studies Study or studies may refer to: General * Education **Higher education * Clinical trial * Experiment * Field of study * Observational study * Scientific study * Research * Study skills, abilities and approaches applied to learning Other * Study ...

in AD

pathology Pathology is the study of disease. The word ''pathology'' also refers to the study of disease in general, incorporating a wide range of biology research fields and medical practices. However, when used in the context of modern medical treatme ...

have focused primarily on populations of European ancestry and may not give adequate insight on the genetic, clinical, and

biological Biology is the scientific study of life and living organisms. It is a broad natural science that encompasses a wide range of fields and unifying principles that explain the structure, function, growth, origin, evolution, and distribution of ...

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 Diagnosis (: diagnoses) is the identification of the nature and cause of a certain phenomenon. Diagnosis is used in a lot of different academic discipline, disciplines, with variations in the use of logic, analytics, and experience, to determine " ...

, treatment, and timely intervention.

Prevalence

The prevalence of

and other

dementia Dementia is a syndrome associated with many neurodegenerative diseases, characterized by a general decline in cognitive abilities that affects a person's ability to perform activities of daily living, everyday activities. This typically invo ...

s is significant in

East Asian countries East is one of the four cardinal directions or points of the compass. It is the opposite direction from west and is the direction from which the Sun rises on the Earth. Etymology As in other languages, the word is formed from the fact that eas ...

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 South Korea, officially the Republic of Korea (ROK), is a country in East Asia. It constitutes the southern half of the Korea, Korean Peninsula and borders North Korea along the Korean Demilitarized Zone, with the Yellow Sea to the west and t ...

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, potentially due to higher

estrogen Estrogen (also spelled oestrogen in British English; see spelling differences) is a category of sex hormone responsible for the development and regulation of the female reproductive system and secondary sex characteristics. There are three ...

levels. 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 area In general, a rural area or a countryside is a geographic area that is located outside towns and cities. Typical rural areas have a low population density and small settlements. Agricultural areas and areas with forestry are typically desc ...

s. In North America, the rates of Alzheimer's disease in Asian Americans were found to be similar to

Non-Hispanic whites Non-Hispanic Whites, also referred to as White Anglo Americans or Non-Latino Whites, are White Americans who are classified by the United States census as "White" and not of Hispanic or Latino origin. According to annual estimates from the Unit ...

and lower compared to

Black Americans African Americans, also known as Black Americans and formerly also called Afro-Americans, are an Race and ethnicity in the United States, American racial and ethnic group that consists of Americans who have total or partial ancestry from an ...

and

Hispanic Americans Hispanic and Latino Americans are Americans who have a Spaniards, Spanish or Latin Americans, Latin American background, culture, or family origin. This demographic group includes all Americans who identify as Hispanic or Latino (demonym), ...

Japanese Americans are Americans of Japanese ancestry. Japanese Americans were among the three largest Asian Americans, Asian American ethnic communities during the 20th century; but, according to the 2000 United States census, 2000 census, they have declined in ...

were found to have increased AD prevalence compared to other Asian American subgroups. 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 Age or AGE may refer to: Time and its effects * Age, the amount of time someone has been alive or something has existed ** East Asian age reckoning, an Asian system of marking age starting at 1 * Ageing or aging, the process of becoming older ...

and

genetics Genetics is the study of genes, genetic variation, and heredity in organisms.Hartl D, Jones E (2005) It is an important branch in biology because heredity is vital to organisms' evolution. Gregor Mendel, a Moravian Augustinians, Augustinian ...

have consistently been the strongest predictors of dementia and AD. However, lifestyle factors and other

co-morbidities In medicine, comorbidity refers to the simultaneous presence of two or more medical conditions in a patient; often wikt:co-occur#Verb, co-occurring (that is, wikt:concomitant#Adjective, concomitant or wikt:concurrent#Adjective, concurrent) with a ...

can play a significant role in contributing to AD susceptibility.

Demographic risk factors

Older age is a significant risk factor for

, with the rate of

cognitive decline Cognitive impairment is an inclusive term to describe any characteristic that acts as a barrier to the cognition process or different areas of cognition. Cognition, also known as cognitive function, refers to the mental processes of how a person ...

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 East Asia is a geocultural region of Asia. It includes China, Japan, Mongolia, North Korea, South Korea, and Taiwan, plus two special administrative regions of China, Hong Kong and Macau. The economies of Economy of China, China, Economy of Ja ...

populations. Higher education generally indicates lower risk of AD. More physical or unsafe

workplace A workplace is a location where someone works, for their employer or themselves, a place of employment. Such a place can range from a home office to a large office building or factory. For industrialized societies, the workplace is one of the ...

conditions are associated with increased risk of AD.

Behavioral and physiological risk factors

Smoking, low social activity, and low

physical activity Physical activity is defined as any voluntary movement produced by skeletal muscles that requires energy expenditure.Global Recommendations on Physical Activity for Health, 2009. World Health Organization. Geneva, Switzerland. Accessed 13/07/2018 ...

are risk factors for AD in East Asian populations. Vascular conditions such as

high blood pressure Hypertension, also known as high blood pressure, is a long-term medical condition in which the blood pressure in the arteries is persistently elevated. High blood pressure usually does not cause symptoms itself. It is, however, a major ri ...

are also linked to dementia later in life. A

sedentary lifestyle Sedentary lifestyle is a Lifestyle (social sciences), lifestyle type, in which one is physically inactive and does little or no physical movement and/or exercise. A person living a sedentary lifestyle is often sitting or lying down while enga ...

obesity Obesity is a medical condition, considered by multiple organizations to be a disease, in which excess Adipose tissue, body fat has accumulated to such an extent that it can potentially have negative effects on health. People are classifi ...

are believed to contribute to dementia susceptibility. Specifically, lower body mass index (BMI) may contribute to a lower likelihood of dementia. A

healthy diet A healthy diet is a diet that maintains or improves overall health. A healthy diet provides the body with essential nutrition: fluid, macronutrients such as protein, micronutrients such as vitamins, and adequate fibre and food energy. A he ...

high in fish, fruit,

Vegetable Vegetables are edible parts of plants that are consumed by humans or other animals as food. This original meaning is still commonly used, and is applied to plants collectively to refer to all edible plant matter, including edible flower, flo ...

s, and

legume Legumes are plants in the pea family Fabaceae (or Leguminosae), or the fruit or seeds of such plants. When used as a dry grain for human consumption, the seeds are also called pulses. Legumes are grown agriculturally, primarily for human consum ...

s but lower in meat and

dairy A dairy is a place where milk is stored and where butter, cheese, and other dairy products are made, or a place where those products are sold. It may be a room, a building, or a larger establishment. In the United States, the word may also des ...

is associated with decreased risk of AD. Regular consumption of vegetable and

fruit juices Juice is a drink made from the extraction or pressing of the natural liquid contained in fruit and vegetables. It can also refer to liquids that are flavored with concentrate or other biological food sources, such as meat or seafood, such a ...

may decrease AD risk due to the intake of popyphenols. Abnormal levels of

insulin Insulin (, from Latin ''insula'', 'island') is a peptide hormone produced by beta cells of the pancreatic islets encoded in humans by the insulin (''INS)'' gene. It is the main Anabolism, anabolic hormone of the body. It regulates the metabol ...

and impaired

glucose tolerance Prediabetes is a component of metabolic syndrome and is characterized by elevated blood sugar levels that fall below the threshold to diagnose diabetes mellitus. It usually does not cause symptoms, but people with prediabetes often have obesity ( ...

is connected to increased dementia susceptibility in East Asians. Poor

early life Early life may refer to: Biology In relation to Earthly history of life * RNA world, early in the history of terrestrial life *Ediacaran period, early in the history of terrestrial life * Cambrian Explosion period, early in the history of terrest ...

environmental factor An environmental factor, ecological factor or eco factor is any factor, abiotic or biotic, that influences living organisms. Abiotic factors include ambient temperature, amount of sunlight, air, soil, water and pH of the water soil in which an ...

s 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 Sleep apnea (sleep apnoea or sleep apnœa in British English) is a sleep-related breathing disorder in which repetitive Apnea, pauses in breathing, periods of shallow breathing, or collapse of the upper airway during sleep results in poor vent ...

may have a relationship with later cognitive decline and dementia. A study of

found that mid-life

proteinuria Proteinuria is the presence of excess proteins in the urine. In healthy persons, urine contains very little protein, less than 150 mg/day; an excess is suggestive of illness. Excess protein in the urine often causes the urine to become fo ...

and impaired

renal function Assessment of kidney function occurs in different ways, using the presence of symptoms and signs, as well as measurements using urine tests, blood tests, and medical imaging. Functions of a healthy kidney include maintaining a person's flu ...

may be an independent predictor of late-life dementia.

Comorbidities

Diabetes Diabetes mellitus, commonly known as diabetes, is a group of common endocrine diseases characterized by sustained high blood sugar levels. Diabetes is due to either the pancreas not producing enough of the hormone insulin, or the cells of th ...

hypertension Hypertension, also known as high blood pressure, is a Chronic condition, long-term Disease, medical condition in which the blood pressure in the artery, arteries is persistently elevated. High blood pressure usually does not cause symptoms i ...

cardiovascular disease Cardiovascular disease (CVD) is any disease involving the heart or blood vessels. CVDs constitute a class of diseases that includes: coronary artery diseases (e.g. angina, heart attack), heart failure, hypertensive heart disease, rheumati ...

s, stroke, and cancer are

comorbidities In medicine, comorbidity refers to the simultaneous presence of two or more medical conditions in a patient; often co-occurring (that is, concomitant or concurrent) with a primary condition. It originates from the Latin term (meaning "sickness" ...

in East Asian people with AD. In a review of AD patients in

Taiwan Taiwan, officially the Republic of China (ROC), is a country in East Asia. The main geography of Taiwan, island of Taiwan, also known as ''Formosa'', lies between the East China Sea, East and South China Seas in the northwestern Pacific Ocea ...

, 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 Korean may refer to: People and culture * Koreans, people from the Korean peninsula or of Korean descent * Korean culture * Korean language **Korean alphabet, known as Hangul or Korean **Korean dialects **See also: North–South differences in t ...

AD patients identified elevated prevalence of

(71.6% AD vs 55% control) and

diabetes Diabetes mellitus, commonly known as diabetes, is a group of common endocrine diseases characterized by sustained high blood sugar levels. Diabetes is due to either the pancreas not producing enough of the hormone insulin, or the cells of th ...

(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 White Americans (sometimes also called Caucasian Americans) are Americans who identify as white people. In a more official sense, the United States Census Bureau, which collects demographic data on Americans, defines "white" as " person hav ...

Genetics

is influenced by a multitude of contributing genetic factors. The

heritability Heritability is a statistic used in the fields of Animal husbandry, breeding and genetics that estimates the degree of ''variation'' in a phenotypic trait in a population that is due to genetic variation between individuals in that population. T ...

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

of AD in East Asians.

Genetic studies

Genetic studies Genetic analysis is the overall process of studying and researching in fields of science that involve genetics and molecular biology. There are a number of applications that are developed from this research, and these are also considered parts ...

such as genome-wide association studies (GWAS) are used to scan the

genome A genome is all the genetic information of an organism. It consists of nucleotide sequences of DNA (or RNA in RNA viruses). The nuclear genome includes protein-coding genes and non-coding genes, other functional regions of the genome such as ...

s of many individuals to identify

genetic variation Genetic variation is the difference in DNA among individuals or the differences between populations among the same species. The multiple sources of genetic variation include mutation and genetic recombination. Mutations are the ultimate sources ...

s 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 Biology is the scientific study of life and living organisms. It is a broad natural science that encompasses a wide range of fields and unifying principles that explain the structure, function, growth, History of life, origin, evolution, and ...

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,

, and

Japan Japan is an island country in East Asia. Located in the Pacific Ocean off the northeast coast of the Asia, Asian mainland, it is bordered on the west by the Sea of Japan and extends from the Sea of Okhotsk in the north to the East China Sea ...

. 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 The genotype of an organism is its complete set of genetic material. Genotype can also be used to refer to the alleles or variants an individual carries in a particular gene or genetic location. The number of alleles an individual can have in a ...

apolipoprotein E Apolipoprotein E (Apo-E) is a protein involved in the metabolism of fats in the body of mammals. A subtype is implicated in Alzheimer's disease and cardiovascular diseases. It is encoded in humans by the gene ''APOE''. Apo-E belongs to a family ...

(ApoE) is the strongest genetic risk factor for sporadic AD. ApoE is a multifunctional

protein Proteins are large biomolecules and macromolecules that comprise one or more long chains of amino acid residue (biochemistry), residues. Proteins perform a vast array of functions within organisms, including Enzyme catalysis, catalysing metab ...

that is involved in

lipid transport Lipids are a broad group of organic compounds which include fats, waxes, sterols, fat-soluble vitamins (such as vitamins A, D, E and K), monoglycerides, diglycerides, phospholipids, and others. The functions of lipids include storing energ ...

and exists in several different forms or

allele An allele is a variant of the sequence of nucleotides at a particular location, or Locus (genetics), locus, on a DNA molecule. Alleles can differ at a single position through Single-nucleotide polymorphism, single nucleotide polymorphisms (SNP), ...

s. 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

on AD risk are different across

. 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 In telecommunications, a carrier wave, carrier signal, or just carrier, is a periodic waveform (usually sinusoidal) that conveys information through a process called ''modulation''. One or more of the wave's properties, such as amplitude or frequ ...

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 The Han Chinese, alternatively the Han people, are an East Asian people, East Asian ethnic group native to Greater China. With a global population of over 1.4 billion, the Han Chinese are the list of contemporary ethnic groups, world's la ...

. Low frequency genetic variants linked to the

pathophysiology Pathophysiology (or physiopathology) is a branch of study, at the intersection of pathology and physiology, concerning disordered physiological processes that cause, result from, or are otherwise associated with a disease or injury. Pathology is ...

of AD are important for elucidating disease

etiology Etiology (; alternatively spelled aetiology or ætiology) is the study of causation or origination. The word is derived from the Greek word ''()'', meaning "giving a reason for" (). More completely, etiology is the study of the causes, origins ...

. Rare

missense In genetics, a missense mutation is a point mutation in which a single nucleotide change results in a codon that codes for a different amino acid. It is a type of nonsynonymous substitution. Missense mutations change amino acids, which in turn al ...

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

Mutation In biology, a mutation is an alteration in the nucleic acid sequence of the genome of an organism, virus, or extrachromosomal DNA. Viral genomes contain either DNA or RNA. Mutations result from errors during DNA or viral replication, ...

s in APP (amyloid-beta precursor protein),

PSEN1 Presenilin-1 (PS-1) is a presenilin protein that in humans is encoded by the ''PSEN1'' gene. Presenilin-1 is one of the four core proteins in the gamma secretase complex, which is considered to play an important role in generation of amyloid bet ...

(Presenilin-1), and

PSEN2 Presenilin-2 is a protein that (in humans) is encoded by the ''PSEN2'' gene. Function Alzheimer's disease (AD) patients with an inherited form of the disease carry mutations in the presenilin proteins ( PSEN1; PSEN2) or the amyloid precursor ...

(Presenilin-2) are known genetic causes of

autosomal dominant In genetics, dominance is the phenomenon of one variant (allele) of a gene on a chromosome masking or overriding the Phenotype, effect of a different variant of the same gene on Homologous chromosome, the other copy of the chromosome. The firs ...

forms of

early-onset Alzheimer's disease Early-onset Alzheimer's disease (EOAD), also called younger-onset Alzheimer's disease (YOAD), is Alzheimer's disease diagnosed before the age of 65. It is an uncommon form of Alzheimer's, accounting for only 5–10% of all Alzheimer's cases. Ab ...

(EOAD). APP encodes the precursor protein to

amyloid-beta Amyloid beta (Aβ, Abeta or beta-amyloid) denotes peptides of 36–43 amino acids that are the main component of the amyloid plaques found in the brains of people with Alzheimer's disease. The peptides derive from the amyloid-beta precursor prot ...

. Cleavage of APP by

β-secretase Beta-secretase is a protein family that includes in humans Beta-secretase 1 Beta-secretase 1, also known as beta-site amyloid precursor protein cleaving enzyme 1, beta-site APP cleaving enzyme 1 (BACE1), membrane-associated aspartic protease 2, ...

and γ-secretase produces the pathogenic Aβ peptide in AD. PSEN1 and PSEN2 encode presenilin 1 and

presenilin 2 Presenilin-2 is a protein that (in humans) is encoded by the ''PSEN2'' gene. Function Alzheimer's disease (AD) patients with an inherited form of the disease carry mutations in the presenilin proteins (PSEN1; PSEN2) or the amyloid precursor p ...

, 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

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 mutation In genetics, a missense mutation is a point mutation in which a single nucleotide change results in a codon that codes for a different amino acid. It is a type of nonsynonymous substitution. Missense mutations change amino acids, which in turn alt ...

s in APP, PSEN1, and PSEN2. Protein_BIN1_PDB_1bb9

BIN1

Genetic variants of bridging integrator 1 (BIN1) gene have been shown to be significantly associated with Alzheimer's disease in East Asians. BIN1 is involved in endocytosis regulation and membrane remodeling,

calcium homeostasis Calcium metabolism is the movement and regulation of calcium ions (Ca2+) ''in'' (via the gut) and ''out'' (via the gut and kidneys) of the body, and ''between'' body compartments: the blood plasma, the extracellular and intracellular fluids, an ...

DNA repair DNA repair is a collection of processes by which a cell (biology), cell identifies and corrects damage to the DNA molecules that encode its genome. A weakened capacity for DNA repair is a risk factor for the development of cancer. DNA is cons ...

, cytoskeletal regulation,

apoptosis Apoptosis (from ) is a form of programmed cell death that occurs in multicellular organisms and in some eukaryotic, single-celled microorganisms such as yeast. Biochemistry, Biochemical events lead to characteristic cell changes (Morphology (biol ...

, and

inflammation Inflammation (from ) is part of the biological response of body tissues to harmful stimuli, such as pathogens, damaged cells, or irritants. The five cardinal signs are heat, pain, redness, swelling, and loss of function (Latin ''calor'', '' ...

. Importantly, BIN1 has been identified as a critical genetic susceptibility loci for late-onset AD and is believed to modulate the tau pathology pathway. Elevated BIN1 expression is associated with higher susceptibility for late-onset AD. Three SNP (

single nucleotide polymorphisms In genetics and bioinformatics, a single-nucleotide polymorphism (SNP ; plural SNPs ) is a germline substitution of a single nucleotide at a specific position in the genome. Although certain definitions require the substitution to be present in ...

) variants (rs12989701, rs744373, and rs7561528) in the BIN1

locus Locus (plural loci) is Latin for "place". It may refer to: Mathematics and science * Locus (mathematics), the set of points satisfying a particular condition, often forming a curve * Root locus analysis, a diagram visualizing the position of r ...

have been widely reported to be strongly associated with late-onset AD in Caucasian patients. However, information on the risk profile of these SNPs in East Asians is missing or inconsistent across studies. For instance, studies concerning the rs12989701 polymorphism have been primarily conducted in Caucasian patients, with limited data from the East Asian population. Mutations in the other two SNPs, rs7561528 and rs744373, are reported to be generally associated with increased AD risk, although the results in East Asians are varied. A few studies in East Asians have failed to reliably replicate a significant association between these polymorphisms and AD risk due to small sample size. A 2012 study found no significant connection between rs7561528 or rs744373 and late-onset AD in patients of northern Han Chinese ancestry. Similarly, 2015 study identified no association between rs7561528 and sporadic AD in Han Chinese populations and a study in Japanese AD patients reported no significant association of rs744373 with late-onset AD. Conversely, a 2015 study identified a significant link between rs7561528 and sporadic AD in the Han Chinese population.

Meta-analysis Meta-analysis is a method of synthesis of quantitative data from multiple independent studies addressing a common research question. An important part of this method involves computing a combined effect size across all of the studies. As such, th ...

of multiple independent studies provides a more comprehensive picture of the role of

BIN1 Myc box-dependent-interacting protein 1, also known as Bridging Integrator-1 and Amphiphysin-2 is a protein that in humans is encoded by the ''BIN1'' gene. This gene encodes several isoforms of a nucleocytoplasmic adaptor protein, one of which ...

polymorphisms in disease. A recent meta-analysis of 18 independent studies on rs7561528 in East Asians concluded that the A allele of this SNP is a protective factor against AD whereas the G allele confers elevated disease risk. Similarly, a 2013 meta-analysis of pooled samples from two studies found that the rs744373 polymorphism had a similar genetic risk in Caucasian and East Asian populations. Specifically, the AG and GG genotype of rs744373 is associated with increased AD risk.

ABCA7

SNPs found in ABCA7, or ATP binding cassette subfamily A member 7, have been associated with increased early-onset and late-onset AD risk. ABCA7 is an ATP-binding cassette (ABC) transporter protein that is important in the transport of lipids,

cholesterol Cholesterol is the principal sterol of all higher animals, distributed in body Tissue (biology), tissues, especially the brain and spinal cord, and in Animal fat, animal fats and oils. Cholesterol is biosynthesis, biosynthesized by all anima ...

(ApoE), and

high density lipoprotein High-density lipoprotein (HDL) is one of the five major groups of lipoproteins. Lipoproteins are complex particles composed of multiple proteins which transport all fat molecules (lipids) around the body within the water outside cells. They are t ...

(HDL) across membranes. ABCA7 plays a role in the regulation of

amyloid-β Amyloid beta (Aβ, Abeta or beta-amyloid) denotes peptides of 36–43 amino acids that are the main component of the amyloid plaques found in the brains of people with Alzheimer's disease. The peptides derive from the amyloid-beta precursor prot ...

homeostasis including amyloid clearance and tau fibril formation. Functional interference of ABCA7 can lead to elevated amyloid-β production. In the

Southern Chinese South China ( zh, s=, p=Huá'nán, j=jyut6 naam4) is a geographical and cultural region that covers the southernmost part of China. Its precise meaning varies with context. A notable feature of South China in comparison to the rest of China is ...

population, polymorphisms rs3764650 and rs4147929 were reported to result in increased susceptibility for AD in ApoE ε4 carriers. The rs3764650 variant is also associated with an earlier trajectory of

individuals in

Other genetic loci

Genetic studies have reported a connection between

(SNPs) and AD risk. The associated SNPs and genetic factors identified in East Asians are different compared to those found in other ethnic groups and can be an important early screening tool for AD in the East Asian population.

GWAS GWAS may refer to: *Genome-wide association study, study of mutations' correlations with disease or other phenotypic expressions *''gwas'', a Welsh term for a valet * Great Western Ambulance Service, the ambulance service serving Somerset, Gloucest ...

in Japanese cohorts conducted in 2013 and 2015 discovered disease-associated SNPs near

SORL1 Sortilin-related receptor, L(DLR class) A repeats containing is a protein that in humans is encoded by the SORL1 gene. SORL1 (also known as SORLA, SORLA1, or LR11; SORLA or SORL1 are used, often interchangeably, for the protein product of the ...

CNTNAP2 Contactin-associated protein-like 2 is a protein that in humans is encoded by the ''CNTNAP2'' gene. This gene encodes a member of the neurexin family which functions in the vertebrate nervous system as cell adhesion molecules and receptors. Thi ...

SUDS3 Sin3 histone deacetylase corepressor complex component SDS3 is an enzyme that in humans is encoded by the ''SUDS3'' gene. Function SDS3 is a subunit of the histone deacetylase (see HDAC1; MIM 601241)-dependent SIN3A (MIM 607776) corepressor co ...

, FAM47E, and

SCARB2 Lysosomal integral membrane protein 2 (LIMP-2) is a protein that in humans is encoded by the ''SCARB2'' gene. LIMP-2 is expressed in brain, heart, liver, lung and kidney, mainly in the membrane of lysosome organelles; however, in cardiac muscle, ...

. GWAS from Chinese cohorts identified SNPs in

GCH1 GTP cyclohydrolase I (GTPCH) () is a member of the GTP cyclohydrolase protein family, family of enzymes. GTPCH is part of the folate and pterin, biopterin biosynthesis metabolic pathway, pathways. It is responsible for the hydrolysis of guanosine ...

APOC1 Apolipoprotein C-I is a protein component of lipoproteins that in humans is encoded by the ''APOC1'' gene. Function The protein encoded by this gene is a member of the apolipoprotein C family. This gene is expressed primarily in the liver, ...

, KCNJ15, LINC01413, RHOBTB3,

GLRX Glutaredoxin-1 is a protein that in humans is encoded by the ''GLRX'' gene In biology, the word gene has two meanings. The Mendelian gene is a basic unit of heredity. The molecular gene is a sequence of nucleotides in DNA that is transcribe ...

, and other regions. In

, two recent GWAS of ApoE ε4 carriers identified novel AD-risk variants near SORCS1,

CHD2 Chromodomain-helicase-DNA-binding protein 2 is an enzyme that in humans is encoded by the ''CHD2'' gene. Function The Chromodomain helicase DNA-binding (CHD) protein subfamily, CHD family of proteins is characterized by the presence of chromod ...

, CACNA1A, and

LRIG1 Leucine-rich repeats and immunoglobulin-like domains protein 1 is a protein that in humans is encoded by the ''LRIG1'' gene. It encodes a transmembrane protein that has been shown to interact with receptor tyrosine kinases of the EGFR family and w ...

Pathogenesis

Neurotransmitter regulation

The regulation of

monoaminergic Monoaminergic means "working on monoamine neurotransmitters", which include serotonin, dopamine, norepinephrine, epinephrine, and histamine. A monoaminergic, or monoaminergic drug, is a chemical, which functions to directly modulate the seroton ...

and

cholinergic Cholinergic agents are compounds which mimic the action of acetylcholine and/or butyrylcholine. In general, the word " choline" describes the various quaternary ammonium salts containing the ''N'',''N'',''N''-trimethylethanolammonium cation ...

neurotransmitter A neurotransmitter is a signaling molecule secreted by a neuron to affect another cell across a Chemical synapse, synapse. The cell receiving the signal, or target cell, may be another neuron, but could also be a gland or muscle cell. Neurotra ...

s are relevant in

. Specifically, polymorphisms in

(GTP cyclohydrolase I) and

ChAT Chat or chats may refer to: Communication * Conversation, particularly casual * Online chat, text message communication over the Internet in real-time * Synchronous conferencing, a formal term for online chat * SMS chat, a form of text messagi ...

(choline acetyltransferase) affect AD susceptibility in

East Asians East Asian people (also East Asians) are the people from East Asia, which consists of China, Japan, Mongolia, North Korea, South Korea, and Taiwan. The total population of all countries within this region is estimated to be 1.677 billion and 21% ...

. GTP cyclohydrolase I is an

enzyme An enzyme () is a protein that acts as a biological catalyst by accelerating chemical reactions. The molecules upon which enzymes may act are called substrate (chemistry), substrates, and the enzyme converts the substrates into different mol ...

that synthesizes a

tetrahydrobiopterin Tetrahydrobiopterin (BH4, THB), also known as sapropterin ( INN), is a cofactor of the three aromatic amino acid hydroxylase enzymes, used in the metabolism of amino acid phenylalanine and in the biosynthesis of the neurotransmitters serotoni ...

(THB) that necessary for monamine neurotransmitter synthesis. The SNP rs72713460 of GCH1 impacts monoamine neurotransmitter synthesis and leads to increased AD susceptibility in East Asians.

Choline acetyltransferase Choline acetyltransferase (commonly abbreviated as ChAT, but sometimes CAT) is a transferase enzyme responsible for the synthesis of the neurotransmitter acetylcholine. ChAT catalyzes the transfer of an acetyl group from the coenzyme acetyl-Co ...

(ChAT) is needed to generate

acetylcholine Acetylcholine (ACh) is an organic compound that functions in the brain and body of many types of animals (including humans) as a neurotransmitter. Its name is derived from its chemical structure: it is an ester of acetic acid and choline. Par ...

from

choline Choline is a cation with the chemical formula . Choline forms various Salt (chemistry), salts, such as choline chloride and choline bitartrate. An essential nutrient for animals, it is a structural component of phospholipids and cell membrane ...

and

acetyl COA Acetyl-CoA (acetyl coenzyme A) is a molecule that participates in many biochemical reactions in protein, carbohydrate and lipid metabolism. Its main function is to deliver the acetyl group to the citric acid cycle (Krebs cycle) to be oxidized fo ...

Inhibition Inhibitor or inhibition may refer to: Biology * Enzyme inhibitor, a substance that binds to an enzyme and decreases the enzyme's activity * Reuptake inhibitor, a substance that increases neurotransmission by blocking the reuptake of a neurotransm ...

of acetylcholine (Ach) breakdown has been used to treat AD. The rs3810950 polymorphism of ChAT was found to confer higher risk of AD in East Asians and may impact acetylcholine functionality.

Amyloid-β production and clearance

The dynamics of amyloid-beta production and clearance are critically dysregulated in AD. Based on the amyloid cascade hypothesis, synthesized APP is transported to the

cell surface The cell membrane (also known as the plasma membrane or cytoplasmic membrane, and historically referred to as the plasmalemma) is a biological membrane that separates and protects the interior of a cell from the outside environment (the extra ...

and internalized by

endocytosis Endocytosis is a cellular process in which Chemical substance, substances are brought into the cell. The material to be internalized is surrounded by an area of cell membrane, which then buds off inside the cell to form a Vesicle (biology and chem ...

for processing by α- or β- secretase, followed by γ-secretase. β- and γ-secretases cleave APP into Aβ in the amyloidogenic pathway whereas α- and γ-secretase inhibit Aβ generation in the non-amyloidogenic pathway. β-site APP-cleaving enzyme 1 (BACE1) is the β-secretase important for Aβ generation.

SNPs In genetics and bioinformatics, a single-nucleotide polymorphism (SNP ; plural SNPs ) is a germline substitution of a single nucleotide at a specific position in the genome. Although certain definitions require the substitution to be present in ...

associated with AD risk have been identified on multiple genes involved in amyloid-β production and clearance.

and

CD2AP CD2-associated protein is a protein that in humans is encoded by the ''CD2AP'' gene. Function This gene encodes a scaffolding molecule that regulates the actin cytoskeleton. The protein directly interacts with filamentous actin and a variety ...

work together in facilitating the

of APP and

BACE1 Beta-secretase 1, also known as beta-site amyloid precursor protein cleaving enzyme 1, beta-site APP cleaving enzyme 1 (BACE1), membrane-associated aspartic protease 2, memapsin-2, aspartyl protease 2, and ASP2, is an enzyme that in humans is enc ...

into

endosome Endosomes are a collection of intracellular sorting organelles in eukaryotic cells. They are parts of the endocytic membrane transport pathway originating from the trans Golgi network. Molecules or ligands internalized from the plasma membra ...

s to produce amyloid-β. The rs744373 SNP of BIN1 and rs934940 SNP of CD2AP confers increased AD susceptibility in East Asians. FERMT2 (Kindlin-2) modulates APP metabolism and controls synaptic connectivity and

axon An axon (from Greek ἄξων ''áxōn'', axis) or nerve fiber (or nerve fibre: see American and British English spelling differences#-re, -er, spelling differences) is a long, slender cellular extensions, projection of a nerve cell, or neuron, ...

al growth in an APP-dependent manner. The rs7143400 SNP of FERMT2 is associated with a higher

odds ratio An odds ratio (OR) is a statistic that quantifies the strength of the association between two events, A and B. The odds ratio is defined as the ratio of the odds of event A taking place in the presence of B, and the odds of A in the absence of B ...

of AD risk in East Asians compared to Caucasians. Glycogen synthase kinase-3beta (GSK-3B) impacts the expression of BACE1, leading to effects on APP cleavage and amyloid-β deposition. The rs334558 AD risk SNP of BACE1 has a higher odds ratio of risk in Caucasians relative to East Asians.

PICALM Phosphatidylinositol binding clathrin assembly protein, also known as PICALM, is a protein which in humans is encoded by the ''PICALM'' gene. Interactions PICALM has been shown to interact with CLTC. Clinical significance In humans, certa ...

(phosphatidylinositol binding clathrin assembly protein) regulates the formation of

vesicles Vesicle may refer to: ; In cellular biology or chemistry * Vesicle (biology and chemistry), a supramolecular assembly of lipid molecules, like a cell membrane * Synaptic vesicle In a neuron, synaptic vesicles (or neurotransmitter vesicles) s ...

clathrin-mediated endocytosis Receptor-mediated endocytosis (RME), also called clathrin-mediated endocytosis, is a process by which cells absorb metabolites, hormones, proteins – and in some cases viruses – by the inward budding of the plasma membrane (invagination). This ...

. Reduction of PICALM leads to decreased BACE1 activity, endocytosis, and Aβ production. The rs3851179 polymorphism of PICALM, in association with the ε4 allele of ApoE, was significantly associated with a decreased risk of AD in a Korean population.

Vascular dysfunction

Vascular Vascular can refer to: * blood vessels, the vascular system in animals * vascular tissue Vascular tissue is a complex transporting tissue, formed of more than one cell type, found in vascular plants. The primary components of vascular tissue ...

dysfunction is a contributor to

. Pathological pathways include

blood brain barrier Blood is a body fluid in the circulatory system of humans and other vertebrates that delivers necessary substances such as nutrients and oxygen to the cells, and transports metabolic waste products away from those same cells. Blood is compo ...

(BBB) dysfunction, disrupted clearance of

amyloid beta Amyloid beta (Aβ, Abeta or beta-amyloid) denotes peptides of 36–43 amino acids that are the main component of the amyloid plaques found in the brains of people with Alzheimer's disease. The peptides derive from the amyloid-beta precursor prot ...

, and altered neuromuscular coupling. Multiple vascular processes are impacted by EXOC3L2 (Exocyst complex component 3-like 2) in East Asians with AD. The rs597668 SNP on EXOC3L2 is a protective polymorphism in East Asians. EXOC3L2 encodes a protein that is associated with an

exocyst The exocyst is an octameric protein complex involved in vesicle trafficking, specifically the tethering and spatial targeting of post- Golgi vesicles to the plasma membrane prior to vesicle fusion. It is implicated in a number of cell processes, in ...

complex that regulates

membrane A membrane is a selective barrier; it allows some things to pass through but stops others. Such things may be molecules, ions, or other small particles. Membranes can be generally classified into synthetic membranes and biological membranes. Bi ...

dynamics. EXOC3L2 influences vascular processes by decreasing

vascular endothelial growth factor Vascular endothelial growth factor (VEGF, ), originally known as vascular permeability factor (VPF), is a signal protein produced by many cells that stimulates the formation of blood vessels. To be specific, VEGF is a sub-family of growth factors ...

(VEGF). Reduced VEGF leads to inhibition of

angiogenesis Angiogenesis is the physiological process through which new blood vessels form from pre-existing vessels, formed in the earlier stage of vasculogenesis. Angiogenesis continues the growth of the vasculature mainly by processes of sprouting and ...

and increased leucocyte adhesion, which results in obstructed

cerebral blood flow Cerebral circulation is the movement of blood through a network of cerebral arteries and veins supplying the brain. The rate of cerebral blood flow in an adult human is typically 750 milliliters per minute, or about 15% of cardiac output. ...

. Additionally, reduced VEGF increases breakdown of the

by amyloid-beta via inhibition of

endothelial cells The endothelium (: endothelia) is a single layer of squamous endothelial cells that line the interior surface of blood vessels and lymphatic vessels. The endothelium forms an interface between circulating blood or lymph in the lumen and the res ...

. The resulting vascular dysfunction potentiates the deleterious effects of Alzheimer's disease.

Immune regulation

The

immune system The immune system is a network of biological systems that protects an organism from diseases. It detects and responds to a wide variety of pathogens, from viruses to bacteria, as well as Tumor immunology, cancer cells, Parasitic worm, parasitic ...

plays an important role in AD pathogenesis.

Neuroinflammation Neuroinflammation is inflammation of the nervous tissue. It may be initiated in response to a variety of cues, including infection, traumatic brain injury,Ebert SE, Jensen P, Ozenne B, Armand S, Svarer C, Stenbaek DS ''et al.'' Molecular imaging of ...

has been found to be increased in the presence of elevated amyloid-beta deposition and abnormal tau aggregates. Genetic mutations in immune-related

genetic loci In genetics, a locus (: loci) is a specific, fixed position on a chromosome where a particular gene or genetic marker is located. Each chromosome carries many genes, with each gene occupying a different position or locus; in humans, the total numb ...

can also increase risk of AD via interference of normal immune function. The immune system is believed undergo dynamic alterations and become dysregulated during disease progression. In the East Asian population, multiple SNPs found in immune-related genes point to the role of immune system imbalance in AD. Certain SNPs have been correlated with increased susceptibility for AD in East Asians.

TOMM40 Mitochondrial import receptor subunit TOM40 homolog is a protein which in humans is encoded by the ''TOMM40'' gene. Function ''TOMM40'' codes for a protein that is embedded into outer membranes of mitochondria and is required for the movement ...

encodes a translocase protein on the

outer mitochondrial membrane A mitochondrion () is an organelle found in the cells of most eukaryotes, such as animals, plants and fungi. Mitochondria have a double membrane structure and use aerobic respiration to generate adenosine triphosphate (ATP), which is used ...

that is involved in the import of Aβ into the

mitochondria A mitochondrion () is an organelle found in the cells of most eukaryotes, such as animals, plants and fungi. Mitochondria have a double membrane structure and use aerobic respiration to generate adenosine triphosphate (ATP), which is us ...

. A number of

on TOMM40 have been identified in East Asian AD patients and correlate with significantly increased susceptibility for disease. TOMM40 variants can lead to increased

oxidative stress Oxidative stress reflects an imbalance between the systemic manifestation of reactive oxygen species and a biological system's ability to readily detoxify the reactive intermediates or to repair the resulting damage. Disturbances in the normal ...

and mitochondrial function dysregulation. Similarly, Complement receptor type 1 (CR1) activation is deleterious to neurons because it inhibits microglia-mediated

phagocytosis Phagocytosis () is the process by which a cell (biology), cell uses its plasma membrane to engulf a large particle (≥ 0.5 μm), giving rise to an internal compartment called the phagosome. It is one type of endocytosis. A cell that performs ph ...

and stimulates

reactive oxygen species In chemistry and biology, reactive oxygen species (ROS) are highly Reactivity (chemistry), reactive chemicals formed from diatomic oxygen (), water, and hydrogen peroxide. Some prominent ROS are hydroperoxide (H2O2), superoxide (O2−), hydroxyl ...

(ROS) levels in the presence of amyloid-β. The CR1 rs6656401 polymorphism has a slightly higher correlation with AD risk in Asians (

1.76) compared to Caucasians (odds ratio 1.28). KCNJ15 encodes the

voltage-gated potassium channel Voltage-gated potassium channels (VGKCs) are potassium channel, transmembrane channels specific for potassium and Voltage-gated ion channel, sensitive to voltage changes in the cell's membrane potential. During action potentials, they play a ...

Kir4.2 protein and is highly used in the immune system. The rs928771 SNP of KCNJ15 leads to increased blood levels of KCNJ15 in AD patients as well as elevated disease risk in East Asians.

HLA-DRB1 HLA class II histocompatibility antigen, DRB1 beta chain is a protein that in humans is encoded by the ''HLA-DRB1'' gene. DRB1 encodes the most prevalent beta subunit of HLA-DR. DRB1 alleles, especially those encoding amino acid sequence changes ...

(HLA class II histocompatibility anteigen) is expressed on

antigen-presenting cell An antigen-presenting cell (APC) or accessory cell is a Cell (biology), cell that displays an antigen bound by major histocompatibility complex (MHC) proteins on its surface; this process is known as antigen presentation. T cells may recognize the ...

s and is involved in presenting peptides from

extracellular This glossary of biology terms is a list of definitions of fundamental terms and concepts used in biology, the study of life and of living organisms. It is intended as introductory material for novices; for more specific and technical definitions ...

proteins to

T cell T cells (also known as T lymphocytes) are an important part of the immune system and play a central role in the adaptive immune response. T cells can be distinguished from other lymphocytes by the presence of a T-cell receptor (TCR) on their cell ...

s of the immune system. The rs9271192 polymorphism of HLA-DRB1 is correlated with slightly increased risk in East Asians and Caucasians. MTHFD1L (methylenetetrahydrofolate dehydrogenase (NADP + dependent) 1-like protein) is correlated with higher disease susceptibility but not much is known about what role it plays in AD. Protective polymorphisms in immune-related genes have also been identified in East Asians. DAPK1 (death-associated protein kinase) is a

serine/threonine kinase A serine/threonine protein kinase () is a kinase enzyme, in particular a protein kinase, that phosphorylates the OH group of the amino-acid residues serine or threonine, which have similar side chains. At least 350 of the 500+ human prote ...

that regulates various cellular pathways including

and

autophagy Autophagy (or autophagocytosis; from the Greek language, Greek , , meaning "self-devouring" and , , meaning "hollow") is the natural, conserved degradation of the cell that removes unnecessary or dysfunctional components through a lysosome-depe ...

. The rs4878104 variant of DAPK has been found to be protective in both Asians and Caucasians. Reduction of DAPK1 decreases caspase activation and was found to reduce memory deficits in

mice A mouse (: mice) is a small rodent. Characteristically, mice are known to have a pointed snout, small rounded ears, a body-length scaly tail, and a high breeding rate. The best known mouse species is the common house mouse (''Mus musculus' ...

injected with amyloid-β. DAPK1 inhibition is also thought to reduce interleukin-18 (IL-18) production. IL-18 is a

proinflammatory cytokine An inflammatory cytokine or proinflammatory cytokine is a type of signaling molecule (a cytokine) that is secreted from immune cells like helper T cells (Th) and macrophages, and certain other cell types that promote inflammation. They include int ...

that is linked to increased levels of amyloid-β accumulation though alterations of the APP processing. The rs187238 variant of IL-18 is associated with more decreased risk of AD in East Asians, compared to Caucasians.

CD33 CD33 or Siglec-3 (sialic acid binding Ig-like lectin 3, SIGLEC3, SIGLEC-3, gp67, p67) is a transmembrane receptor expressed on cells of myeloid lineage. It is usually considered myeloid-specific, but it can also be found on some lymphoid cells. ...

(sialic acid binding Ig-like lectin 3) is a

transmembrane receptor Cell surface receptors (membrane receptors, transmembrane receptors) are receptor (biochemistry), receptors that are embedded in the cell membrane, plasma membrane of cell (biology), cells. They act in cell signaling by receiving (binding to) ex ...

protein that controls microglial activation. In AD, it can be overactive in the presence of amyloid and contribute to excess

neuroinflammation Neuroinflammation is inflammation of the nervous tissue. It may be initiated in response to a variety of cues, including infection, traumatic brain injury,Ebert SE, Jensen P, Ozenne B, Armand S, Svarer C, Stenbaek DS ''et al.'' Molecular imaging of ...

. East Asians that carry a T

of rs3865444 on the CD33 gene exhibit decreased levels of CD33 and may have decreased AD susceptibility. Microglial inactivation due to CD33 inhibition results in decreased

and

cytokine Cytokines () are a broad and loose category of small proteins (~5–25 kDa) important in cell signaling. Cytokines are produced by a broad range of cells, including immune cells like macrophages, B cell, B lymphocytes, T cell, T lymphocytes ...

release. This SNP does not have a protective effect in Caucasians. MS4A6A (Membrane Spanning 4-Domains A6A) is a member of the MS4A gene cluster and is important for immune cell activation. The rs610932 risk variant of MS4A6A is associated with increased levels of MS4A6A expression in patients with mild cognitive impairment and AD. High levels of MS4A6A expression is believed to have adverse effects in AD progression but limited research has been conducted on the exact role of MS4A6A in AD.

Cultural and societal influences

Attitudes relating to Alzheimer's disease

Social stigma Stigma, originally referring to the visible marking of people considered inferior, has evolved to mean a negative perception or sense of disapproval that a society places on a group or individual based on certain characteristics such as their ...

associated with

mental illness A mental disorder, also referred to as a mental illness, a mental health condition, or a psychiatric disability, is a behavioral or mental pattern that causes significant distress or impairment of personal functioning. A mental disorder is ...

and lack of knowledge about AD prevent proper management of disease in East Asians. The misconception of AD as "

insanity Insanity, madness, lunacy, and craziness are behaviors caused by certain abnormal mental or behavioral patterns. Insanity can manifest as violations of societal norms, including a person or persons becoming a danger to themselves or to other ...

" is prevalent in East Asians as well as other ethnic groups. Patients and

caregiver A caregiver, carer or support worker is a paid or unpaid person who helps an individual with activities of daily living. Caregivers who are members of a care recipient's family or social network, who may have specific professional training, are o ...

s may be reluctant to seek medical care due to this negative perception. One study of elderly

Korean American Korean Americans () are Americans of full or partial Korean ethnic descent. While the broader term Overseas Korean in America () may refer to all ethnic Koreans residing in the United States, the specific designation of Korean American impli ...

immigrants found that there was limited use of mental health services despite elevated rates of

cognitive impairment Cognitive impairment is an inclusive term to describe any characteristic that acts as a barrier to the cognition process or different areas of cognition. Cognition, also known as cognitive function, refers to the mental processes of how a person ...

and depression this community. Chinese patients were reported to seek care at later stages of dementia relative to American patients.

Memory loss Amnesia is a deficit in memory caused by brain damage or brain diseases,Gazzaniga, M., Ivry, R., & Mangun, G. (2009) Cognitive Neuroscience: The biology of the mind. New York: W.W. Norton & Company. but it can also be temporarily caused by t ...

forgetfulness Forgetting or disremembering is the apparent loss or modification of information already encoded and stored in an individual's short or long-term memory. It is a spontaneous or gradual process in which old memory, memories are unable to be recall ...

, and mental deterioration are also perceived to be a normal part of

in East Asian American groups. Multiple qualitative studies suggest this misconception is prevalent in

Chinese Chinese may refer to: * Something related to China * Chinese people, people identified with China, through nationality, citizenship, and/or ethnicity **Han Chinese, East Asian ethnic group native to China. **'' Zhonghua minzu'', the supra-ethnic ...

Vietnamese Vietnamese may refer to: * Something of, from, or related to Vietnam, a country in Southeast Asia * Vietnamese people, or Kinh people, a Southeast Asian ethnic group native to Vietnam ** Overseas Vietnamese, Vietnamese people living outside Vietna ...

, and

Korean Americans Korean Americans () are Americans of full or partial Korean ethnicity, Korean ethnic descent. While the broader term Overseas Korean in America () may refer to all ethnic Koreans residing in the United States, the specific designation of Kore ...

. The cultural normalization of mental decline in old age may mask the initial symptoms of disease and delay formal evaluation in AD patients.Guo Z, Levy BR, Hinton WL, Weitzman PF, Levkoff SE. 2000. The poser of labels: recruiting dementia-affected Chinese American elders and their caregivers. J Ment Health Aging 6: 103–112. Feelings of

shame Shame is an unpleasant self-conscious emotion often associated with negative self-evaluation; motivation to quit; and feelings of pain, exposure, distrust, powerlessness, and worthlessness. Definition Shame is a discrete, basic emotion, d ...

linked to AD and limitations in AD-related knowledge are further accentuated in individuals with lower education levels and lower

acculturation Acculturation refers to the psychological, social, and cultural transformation that takes place through direct contact between two cultures, wherein one or both engage in adapting to dominant cultural influences without compromising their essent ...

of AD.

Barriers to medical care

A number of barriers result in disparities in adequate medical management and timely intervention for East Asians with AD or other dementias. Delayed intervention due to insufficient healthcare, cultural influences, stigma against mental illness, and lack of AD knowledge inhibit proper management of disease. Lack of accessible health care makes early recognition of AD symptoms challenging. Additionally, healthcare systems and

social services Social services are a range of public services intended to provide support and assistance towards particular groups, which commonly include the disadvantaged. Also available amachine-converted HTML They may be provided by individuals, private and i ...

may not be able to meet the rising demand of AD treatment caused by aging and

. Most significant is the growing burden of dementia in Japan, which is experiencing the fastest increase in AD prevalence in the world. In China, the healthcare system is poorly prepared to deliver new disease-modifying AD treatments, with wait times predicted to be over two years. The urban-rural divide in China is another infrastructure challenge for access to AD treatment. In rural areas of China, local community centers or village doctors may be the primary point of contact for medical care, but may not have the formal training to assess cognitive impairment. Social and cultural factors may also be a barrier to medical care. The cultural norm of " saving face" in East Asians prevents public disclosure of negative family events, including AD. Lack of community discourse about AD may decrease awareness and knowledge about the early signs of disease. Prior exposure to AD from multiple sources, such as via family members, media, or friends, is important in increasing disease awareness and AD knowledge. Additionally, fear of

social stigma Stigma, originally referring to the visible marking of people considered inferior, has evolved to mean a negative perception or sense of disapproval that a society places on a group or individual based on certain characteristics such as their ...

makes it challenging for East Asian groups to seek proper

medical services Health care, or healthcare, is the improvement or maintenance of health via the prevention, diagnosis, treatment, amelioration or cure of disease, illness, injury, and other physical and mental impairments in people. Health care is deliver ...

and poses a barrier for recruitment of East Asians in studies of mental illness. Chinese AD patients were found to delay seeking care until they exhibited severe neuropsychiatric symptoms compared to Caucasian patients. Elders in Asian American groups are not likely to be diagnosed with AD until later stages of disease. These patients were more likely to be at a more severe stage of dementia by the time they sought medical attention, which poses consequences for treatment options. Limited knowledge of AD results in delayed symptom recognition and poor disease management. In

and Chinese Americans, lower levels of

formal education Education is the transmission of knowledge and skills and the development of character traits. Formal education occurs within a structured institutional framework, such as public schools, following a curriculum. Non-formal education also fol ...

and

were shown to be linked to lower levels of AD knowledge and decreased awareness of AD-related resources. East Asians may interpret their mental health as a somatic issue and are less likely to use mental health services. Some level of

folk wisdom Folklore is the body of expressive culture shared by a particular group of people, culture or subculture. This includes oral traditions such as tales, myths, legends, proverbs, poems, jokes, and other oral traditions. This also includes ma ...

and skepticism of the availability of effective

therapies A therapy or medical treatment is the attempted remediation of a health problem, usually following a medical diagnosis. Both words, ''treatment'' and ''therapy'', are often abbreviated tx, Tx, or Tx. As a rule, each therapy has indications an ...

are also factors that limit treatment-seeking behavior.

Diagnosis

Fluid biomarkers

The current research framework for diagnosis of Alzheimer's disease is based on the amyloid, tau, and neurodegeneration (ATN) classification system. This framework relies on

cerebrospinal fluid Cerebrospinal fluid (CSF) is a clear, colorless Extracellular fluid#Transcellular fluid, transcellular body fluid found within the meninges, meningeal tissue that surrounds the vertebrate brain and spinal cord, and in the ventricular system, ven ...

sampling,

MRI imaging Magnetic resonance imaging (MRI) is a medical imaging technique used in radiology to generate pictures of the anatomy and the physiological processes inside the body. MRI scanners use strong magnetic fields, magnetic field gradients, and rad ...

, and

PET imaging Positron emission tomography (PET) is a functional imaging technique that uses radioactive substances known as radiotracers to visualize and measure changes in metabolic processes, and in other physiological activities including blood flow, re ...

. There is also interest in the use of blood-based biomarkers that may be more cost-effective and less invasive. Plasma measurements of

neurofilament light chain Neurofilament light polypeptide is a protein that in humans is encoded by the NEFL gene. Structure Neurofilament light polypeptide is a member of the intermediate filament protein family. This protein family consists of over 50 human proteins ...

(NfL), and phosphorylated

tau Tau (; uppercase Τ, lowercase τ or \boldsymbol\tau; ) is the nineteenth letter of the Greek alphabet, representing the voiceless alveolar plosive, voiceless dental or alveolar plosive . In the system of Greek numerals, it has a value of 300 ...

(p-tau) can be used to diagnose or predict the development of AD. Unfortunately, the studies highlighting the relationship between these biomarkers and future AD were performed primarily in Western patients. Recent research has focused on the diagnostic and predictive capacity of fluid biomarkers in the East Asian population. A study conducted in a

Chinese population The People's Republic of China is the second most-populous country in the world with a population exceeding 1.4 billion, only surpassed by India. Historically, China has always been one of the nation-states with the most population. Ch ...

has shown that the combination of p-tau 181 and Aβ42 in plasma had excellent performance in diagnosing AD. Several studies since have determined that combinations of plasma biomarkers, including NfL, Aβ42, and p-tau in plasma, can predict AD

prognosis Prognosis ( Greek: πρόγνωσις "fore-knowing, foreseeing"; : prognoses) is a medical term for predicting the likelihood or expected development of a disease, including whether the signs and symptoms will improve or worsen (and how quickly) ...

4.8–6 years prior to

. Assessment of a combination of biomarkers has more predictive value than using just one biomarker. These studies show that the relationship between plasma biomarkers and AD is preserved in East Asian populations and similar to findings in European populations.

Imaging

PET A pet, or companion animal, is an animal kept primarily for a person's company or entertainment rather than as a working animal, livestock, or a laboratory animal. Popular pets are often considered to have attractive/ cute appearances, inte ...

and

are important

diagnostic tool Diagnosis (: diagnoses) is the identification of the nature and cause of a certain phenomenon. Diagnosis is used in a lot of different disciplines, with variations in the use of logic, analytics, and experience, to determine " cause and effect". ...

s but East Asians and other ethnic groups are underrepresented in studies on imaging-based AD biomarkers. One large multisite study of patients with mild cognitive impairment and

found that amyloid PET positivity rates were 7–12% lower in Asian individuals compared to White individuals. In China, amyloid PET is rarely performed due to costs, coverage, and availability. However, China is rapidly expanding its use of PET scanners. In 2023, Neuraceq (florbetaben F-18) was approved as the first PET imaging

radiotracer A radioactive tracer, radiotracer, or radioactive label is a synthetic derivative of a natural compound in which one or more atoms have been replaced by a radionuclide (a radioactive atom). By virtue of its radioactive decay, it can be used to ...

targeting β-amyloid in China in response to recent approvals of promising AD treatments in the United States. Neuraceq obtained approval in the U.S. in 2014, and is one of three PET

radiopharmaceutical Radiopharmaceuticals, or medicinal radiocompounds, are a group of pharmaceutical drugs containing radioactive isotopes. Radiopharmaceuticals can be used as diagnostic and therapeutic agents. Radiopharmaceuticals emit radiation themselves, which ...

s approved by the U.S.

Food and Drug Administration The United States Food and Drug Administration (FDA or US FDA) is a List of United States federal agencies, federal agency of the United States Department of Health and Human Services, Department of Health and Human Services. The FDA is respo ...

References

{{Reflist Alzheimer's disease East Asian people Health in East Asia Race and health