Although the molecular basis of Alzheimer's disease (AD) is often studied in Caucasians, its genetic basis in Bangladesh remains elusive.
Objective
We explored the association between single-nucleotide variants (SNVs) of Apolipoprotein E (APOE) and other genes for AD risk among Bangladeshis.
Methods
We recruited AD patients and controls aged ≥18 years and conducted next generation sequencing (NGS) to analyze ∼30 Mb of the human exome. The NGS targets ∼99% of the Consensus Coding Sequence and RefSeq annotations, along with the complete mitochondrial genome.
Results
A total of 132 (72 AD: 60 control) age- and sex-matched participants were sequenced. The average age of AD was comparable to that of controls (64.5 ± 11.3 versus 63.6 ± 9.8, p = 0.69), and the gender distribution (p = 0.49) was similar between the study groups. Following NGS analysis 23 SNVs from 16 potential genes were identified. The APOE variant rs429358 was associated with a significantly increased age- and sex- adjusted risk of AD (OR) 8.0 (95% CI: 2.3–27.9, p = 0.001) in the additive model, 10.5 (95% CI: 2.8–39.5, p < 0.001) in the dominant model, and 6.9 (95% CI: 1.8–26.9, p = 0.005) in the heterozygous genotype model, as determined using the Bonferroni adjustment method. The top SNV for predicting AD was the APOE variant rs429358 with a -logP value of 3, followed by BDNF gene variant rs6265 at 1.3, and CR1 gene variant rs1349409945 at 1.2.
Conclusions
The APOE variant rs429358 is linked to an 8-fold increased risk of AD among Bangladeshis.
LarsonEBKukullWAKatzmanRL. Cognitive impairment: dementia and Alzheimer's disease. Annu Rev Public Health1992; 13: 431–449.
8.
GauthierSCummingsJBallardC, et al.Management of behavioral problems in Alzheimer's disease. Int Psychogeriatr2010; 22: 346–372.
9.
GrabherBJ. Effects of Alzheimer disease on patients and their family. J Nucl Med Technol2018; 46: 335–340.
10.
WimoASeeherKCataldiR, et al.The worldwide costs of dementia in 2019. Alzheimers Dement2023; 19: 2865–2873.
11.
WittenbergRKnappMHuB, et al.The costs of dementia in England. Int J Geriatr Psychiatry2019; 34: 1095–1103.
12.
GetsiosDBlumeSIshakKJ, et al.An economic evaluation of early assessment for Alzheimer's disease in the United Kingdom. Alzheimers Dement2012; 8: 22–30.
13.
NandiACountsNBrökerJ, et al.Cost of care for Alzheimer's disease and related dementias in the United States: 2016 to 2060. NPJ Aging2024; 10: 13.
14.
RobinsonRLRentzDMAndrewsJS, et al.Costs of early stage Alzheimer's disease in the United States: cross-sectional analysis of a prospective cohort study (GERAS-US)1. J Alzheimers Dis2020; 75: 437–450.
15.
CummingsJLGoldmanDPSimmons-SternNR, et al.The costs of developing treatments for Alzheimer's disease: a retrospective exploration. Alzheimers Dement2022; 18: 469–477.
16.
MarešováPDolejsJMohelskaH, et al.Cost of treatment and care for people with Alzheimer's disease: a meta-analysis. Curr Alzheimer Res2019; 16: 1245–1253.
AbdiSAlghamdiAAAlGhunaimNNA, et al.Association of Alzheimer's disease with genetic variants of apolipoprotein E, clusterin, TNF-α, and IL-6 among elderly Saudis. Curr Pharm Biotechnol2022; 23: 1893–1902.
19.
DiasDPortugalCCRelvasJ, et al.From genetics to neuroinflammation: the impact of ApoE4 on microglial function in Alzheimer's disease. Cells2025; 14: 243.
20.
BlueEEChengAChenS, et al.Association of uncommon, noncoding variants in the APOE region with risk of Alzheimer disease in adults of European ancestry. JAMA Netw Open2020; 3: e2017666.
21.
AbanmyNAlsabhanJGardP, et al.Association between the Val66Met polymorphism (rs6265/G196A) of the BDNF gene and cognitive performance with SSRI use in Arab Alzheimer's disease patients. Saudi Pharm J2021; 29: 1392–1398.
22.
BertramLMcQueenMBMullinK, et al.Systematic meta-analyses of Alzheimer disease genetic association studies: the AlzGene database. Nat Genet2007; 39: 17–23.
23.
LambertJCHeathSEvenG, et al.Genome-wide association study identifies variants at CLU and CR1 associated with Alzheimer's disease. Nat Genet2009; 41: 1094–1099.
24.
KirchnerKGarvertLKühnL, et al.Detrimental effects of ApoE ε4 on blood-brain barrier integrity and their potential implications on the pathogenesis of Alzheimer's disease. Cells2023; 12: 2512.
25.
ChungJDasASunX, et al.Genome-wide association and multi-omics studies identify MGMT as a novel risk gene for Alzheimer's disease among women. Alzheimers Dement2023; 19: 896–908.
26.
WangPLynnAMiskimenK, et al.Genome-wide association studies identify novel loci in rapidly progressive Alzheimer's disease. Alzheimers Dement2024; 20: 2034–2046.
27.
MarioniREHarrisSEZhangQ, et al.GWAS On family history of Alzheimer's disease. Transl Psychiatry2018; 8: 99.
28.
Escott-PriceVHardyJ. Genome-wide association studies for Alzheimer's disease: bigger is not always better. Brain Commun2022; 4: fcac125.
29.
KangSGimJLeeJ, et al.Potential novel genes for late-onset Alzheimer's disease in east-Asian descent identified by APOE-stratified genome-wide association study. J Alzheimers Dis2021; 82: 1451–1460.
30.
ChoMChaudhuriSLiuS, et al.Functional insight into east Asian-specific genetic risk loci for Alzheimer's disease. Alzheimers Dement2025; 21: e14553.
31.
BakerEEscott-PriceV. Polygenic risk scores in Alzheimer's disease: current applications and future directions. Front Digit Health2020; 2: 14.
32.
D'AoustTClocchiatti-TuozzoSRivierCA, et al.Polygenic score integrating neurodegenerative and vascular risk informs dementia risk stratification. Alzheimers Dement2025; 21: e70014.
33.
ClarkKLeungYYLeeWP, et al.Polygenic risk scores in Alzheimer’s disease genetics: methodology, applications, inclusion, and diversity. J Alzheimers Dis2022; 89: 1–12.
34.
YuCRyanJOrchardSG, et al.Validation of newly derived polygenic risk scores for dementia in a prospective study of older individuals. Alzheimers Dement2023; 19: 5333–5342.
35.
ZhaoWSmithJAWangYZ, et al.Polygenic risk scores for Alzheimer's disease and general cognitive function are associated with measures of cognition in older South Asians. J Gerontol A Biol Sci Med Sci2023; 78: 743–752.
36.
LakeJWarly SolsbergCKimJJ, et al.Multi-ancestry meta-analysis and fine-mapping in Alzheimer's disease. Mol Psychiatry2023; 28: 3121–3132.
37.
ReitzCPericak-VanceMAForoudT, et al.A global view of the genetic basis of Alzheimer disease. Nat Rev Neurol2023; 19: 261–277.
38.
HakimMIslamMHossainM, et al.Correlation of cognitive status and atrophy score in Alzheimer’s disease among the Bangladeshi population. Cureus2024; 16: e65833.
39.
NaheedAHakimMIslamMS, et al.Prevalence of dementia among older age people and variation across different sociodemographic characteristics: a cross-sectional study in Bangladesh. Lancet Reg Health Southeast Asia2023; 17: 100257.
40.
American College of Radiology. ACR Appropriateness Criteria® Dementia. [Jul; 2024]. 2020.
41.
ScheltensPLeysDBarkhofF, et al.Atrophy of medial temporal lobes on MRI in “probable” Alzheimer's disease and normal ageing: diagnostic value and neuropsychological correlates. J Neurol Neurosurg Psychiatry1992; 55: 967–972.
42.
KoedamELLehmannMvan der FlierWM, et al.Visual assessment of posterior atrophy development of a MRI rating scale. Eur Radiol2011; 21: 2618–2625.
43.
Arevalo-RodriguezISmailagicNRoqué-FigulsM, et al.Mini-Mental State Examination (MMSE) for the early detection of dementia in people with mild cognitive impairment (MCI). Cochrane Database Syst Rev2021; 7: CD010783.
44.
LandrumMJLeeJMBensonM, et al.Clinvar: public archive of interpretations of clinically relevant variants. Nucleic Acids Res2016; 44: D862–D868.
45.
WelterDMacArthurJMoralesJ, et al.The NHGRI GWAS catalog, a curated resource of SNP-trait associations. Nucleic Acids Res2014; 42: D1001–D1006.
46.
MillerDTLeeKGordonAS, et al.Recommendations for reporting of secondary findings in clinical exome and genome sequencing, 2021 update: a policy statement of the American College of Medical Genetics and Genomics (ACMG). Genet Med2021; 23: 1391–1398.
47.
GeninEHannequinDWallonD, et al.APOE And Alzheimer disease: a major gene with semi-dominant inheritance. Mol Psychiatry2011; 16: 903–907.
48.
CreanSWardAMercaldiCJ, et al.Apolipoprotein E ε4 prevalence in Alzheimer's disease patients varies across global populations: a systematic literature review and meta-analysis. Dement Geriatr Cogn Disord2011; 31: 20–30.
49.
ZhouXShiQZhangX, et al.ApoE4-mediated blood-brain barrier damage in Alzheimer's disease: progress and prospects. Brain Res Bull2023; 199: 110670.
50.
Serrano-PozoADasSHymanBT. APOE And Alzheimer's disease: advances in genetics, pathophysiology, and therapeutic approaches. Lancet Neurol2021; 20: 68–80.
51.
RaulinACDossSVTrottierZA, et al.Apoe in Alzheimer's disease: pathophysiology and therapeutic strategies. Mol Neurodegener2022; 17: 72.
52.
BabenkoVNAfonnikovDAIgnatievaEV, et al.Haplotype analysis of APOE intragenic SNPs. BMC Neurosci2018; 19: 16.
53.
KulminskiAMShuLLoikaY, et al.Genetic and regulatory architecture of Alzheimer's disease in the APOE region. Alzheimers Dement (Amst)2020; 12: e12008.
54.
FatmaRChauhanWShahiMH, et al.Association of BDNF gene missense polymorphism rs6265 (Val66Met) with three quantitative traits, namely, intelligence quotient, body mass index, and blood pressure: a genetic association analysis from North India. Front Neurol2023; 13: 1035885.
55.
LinYChengSXieZ, et al.Association of rs6265 and rs2030324 polymorphisms in brain-derived neurotrophic factor gene with Alzheimer's disease: a meta-analysis. PLoS One2014; 9: e94961.
56.
LiGDBiRZhangDF, et al.Female-specific effect of the BDNF gene on Alzheimer's disease. Neurobiol Aging2017; 53: 192.e11–192.e19.
57.
VoineskosANLerchJPFelskyD, et al.The brain-derived neurotrophic factor Val66Met polymorphism and prediction of neural risk for Alzheimer disease. Arch Gen Psychiatry2011; 68: 198–206.
58.
BrouwersNVan CauwenbergheCEngelborghsS, et al.Alzheimer risk associated with a copy number variation in the complement receptor 1 increasing C3b/C4b binding sites. Mol Psychiatry2012; 17: 223–233.
59.
BiffiAShulmanJMJagiellaJM, et al.Genetic variation at CR1 increases risk of cerebral amyloid angiopathy. Neurology2012; 78: 334–341.
60.
ZhuXCYuJTJiangT, et al.CR1 In Alzheimer's disease. Mol Neurobiol2015; 51: 753–765.
61.
DasMPalSGhoshA. Apolipoprotein E gene polymorphism and dyslipidaemia in adult Asian Indians: a population based study from Calcutta, India. Indian J Hum Genet2008; 14: 87–91.
62.
MisraAChakrabartiSSGambhirIS, et al.APOE4 Allele in north Indian elderly patients with dementia or late onset depression-a multiple-disease case control study. Mol Biol Res Commun2019; 8: 135–140.
63.
JiYLiuMHuoYR, et al.Apolipoprotein Ε ε4 frequency is increased among Chinese patients with frontotemporal dementia and Alzheimer's disease. Dement Geriatr Cogn Disord2013; 36: 163–170.
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