Background: This study delineates the role of the interaction of apolipoprotein E (APOE) and MAPT alleles in contributing to disease risks of dementia in a southern Indian population. Methods: A sample of 419 patients comprising Alzheimer's disease (AD; n = 156), mild cognitive impairment (MCI; n = 87), frontotemporal dementia (FTD; n = 127), vascular dementia (VD; n = 37), and dementia with Lewy bodies (DLB; n = 12) was analysed in comparison with a control group (n = 138). APOE genotyping and MAPT haplotyping were performed on all study subjects. Results: Multivariate logistic regression analysis showed that variability on the APOE locus influenced the relative risk of dementia in the study population. The APOE ε4 allele increased the disease risk most significantly for AD (OR = 3.468, p < 0.0001) and MCI (OR = 2.901, p < 0.0001). The APOE ε2 allele remained protective for AD (OR = 0.205, p < 0.05). For FTD, VD, and DLB, the APOE ε4 allele was ineffectual in modulating disease risk. The MAPT H1 haplotype was not an overrepresented marker of neurodegenerative diseases. The H1H1 genotype had an additive effect in contributing to either disease risk in combination with the APOE ε4 allele or protection in combination with the APOE ε2 or ε3 allele. Conclusions: This study is a reappraisal of the strong association of APOE variability with AD in southern India when compared to other dementia groups, while the transcriptional differences between MAPT haplotypes have a limited role in Indian dementia patients.

Keywords:
Dementia, Alzheimer’s disease, Risk factors, Apolipoprotein E, MAPT haplotypes, Genotypic frequency
1.
Saunders AM, Strittmatter WJ, Schmechel D, George-Hyslop PH, Pericak-Vance MA, Joo SH, et al: Association of apolipoprotein E allele epsilon 4 with late-onset familial and sporadic Alzheimer's disease. Neurology 1993;43:1467-1472.
2.
Genin E, Hannequin D, Wallon D, Sleegers K, Hiltunen M, Combarros O, et al: APOE and Alzheimer disease: a major gene with semi-dominant inheritance. Mol Psychiatry 2011;16:903-907.
3.
Singh PP, Singh M, Mastana SS: APOE distribution in world populations with new data from India and the UK. Ann Hum Biol 2006;33:279-308.
4.
Mayeux R, Saunders AM, Shea S, Mirra S, Evans D, Roses AD, et al: Utility of the apolipoprotein E genotype in the diagnosis of Alzheimer's disease. Alzheimer's Disease Centers Consortium on Apolipoprotein E and Alzheimer's Disease. N Engl J Med 1998;338:506-511.
5.
Mayeux R, Stern Y: Epidemiology of Alzheimer disease. Cold Spring Harbor Perspect Med 2012;2:a006239.
6.
Myers AJ, Kaleem M, Marlowe L, Pittman AM, Lees AJ, Fung HC, et al: The H1c haplotype at the MAPT locus is associated with Alzheimer's disease. Hum Mol Genet 2005;14:2399-2404.
7.
Di Maria E, Tabaton M, Vigo T, Abbruzzese G, Bellone E, Donati C, et al: Corticobasal degeneration shares a common genetic background with progressive supranuclear palsy. Ann Neurol 2000;47:374-377.
8.
Sobrido MJ, Miller BL, Havlioglu N, Zhukareva V, Jiang Z, Nasreddine ZS, et al: Novel tau polymorphisms, tau haplotypes, and splicing in familial and sporadic frontotemporal dementia. Arch Neurol 2003;60:698-702.
9.
Verpillat P, Camuzat A, Hannequin D, Thomas-Anterion C, Puel M, Belliard S, et al: Association between the extended tau haplotype and frontotemporal dementia. Arch Neurol 2002;59:935-939.
10.
Mukherjee O, Kauwe JS, Mayo K, Morris JC, Goate AM: Haplotype-based association analysis of the MAPT locus in late onset Alzheimer's disease. BMC Genet 2007;8:3.
11.
Mathuranath PS, Cherian PJ, Mathew R, Kumar S, George A, Alexander A, et al: Dementia in Kerala, South India: prevalence and influence of age, education and gender. Int J Geriatr Psychiatry 2010;25:290-297.
12.
McKhann G, Drachman D, Folstein M, Katzman R, Price D, Stadlan EM: Clinical diagnosis of Alzheimer's disease: report of the NINCDS-ADRDA Work Group under the auspices of Department of Health and Human Services Task Force on Alzheimer's Disease. Neurology 1984;34:939-944.
13.
McKeith IG, Galasko D, Kosaka K, Perry EK, Dickson DW, Hansen LA, et al: Consensus guidelines for the clinical and pathologic diagnosis of dementia with Lewy bodies (DLB): report of the consortium on DLB international workshop. Neurology 1996;47:1113-1124.
14.
Brun A, Englund B, Gustafson L, Passant U, Mann DMA, Neary D: Clinical and neuropathological criteria for frontotemporal dementia. The Lund and Manchester Groups. J Neurol Neurosurg Psychiatry 1994;57:416-418.
15.
Roman GC, Tatemichi TK, Erkinjuntti T, Cummings JL, Masdeu JC, Garcia JH, et al: Vascular dementia: diagnostic criteria for research studies. Report of the NINDS-AIREN International Workshop. Neurology 1993;43:250-260.
16.
Mathuranath PS, Nestor PJ, Berrios GE, Rakowicz W, Hodges JR: A brief cognitive test battery to differentiate Alzheimer's disease and frontotemporal dementia. Neurology 2000;55:1613-1620.
17.
Petersen RC, Smith GE, Waring SC, Ivnik RJ, Kokmen E, Tangelos EG: Aging, memory, and mild cognitive impairment. Int Psychogeriatr 1997;9(suppl 1):65-69.
18.
Mathuranath PS, Hodges JR, Mathew R, Cherian PJ, George A, Bak TH: Adaptation of the ACE for a Malayalam speaking population in southern India. Int J Geriatr Psychiatry 2004;19:1188-1194.
19.
Hixson JE, Vernier DT: Restriction isotyping of human apolipoprotein E by gene amplification and cleavage with Hha I. J Lipid Res 1990;31:545-548.
20.
Pantelidis P, Lambert-Hammill M, Wierzbicki AS: Simple sequence-specific-primer-PCR method to identify the three main apolipoprotein E haplotypes. Clin Chem 2003;49:1945-1948.
21.
Bernardi L, Maletta RG, Tomaino C, Smirne N, Di Natale M, Perri M, et al: The effects of APOE and tau gene variability on risk of frontotemporal dementia. Neurobiol Aging 2006;27:702-709.
22.
Aswathy PM, Jairani PS, Verghese J, Gopala S, Mathuranath PS: Microtubule-associated protein tau genetic variations are uncommon cause of frontotemporal dementia in south India. Neurobiol Aging 2014;35:443 e23-e24.
23.
Farrer LA, Cupples LA, Haines JL, Hyman B, Kukull WA, Mayeux R, et al: Effects of age, sex, and ethnicity on the association between apolipoprotein E genotype and Alzheimer disease. A meta-analysis. APOE and Alzheimer Disease Meta Analysis Consortium. JAMA 1997;278:1349-1356.
24.
Bharath S, Purushottam M, Mukherjee O, Bagepally BS, Prakash O, Kota L, et al: Apolipoprotein E polymorphism and dementia: a hospital-based study from southern India. Dement Geriatr Cogn Disord 2010;30:455-460.
25.
Maestre G, Ottman R, Stern Y, Gurland B, Chun M, Tang MX, et al: Apolipoprotein E and Alzheimer's disease: ethnic variation in genotypic risks. Ann Neurol 1995;37:254-259.
26.
Tang MX, Maestre G, Tsai WY, Liu XH, Feng L, Chung WY, et al: Effect of age, ethnicity, and head injury on the association between APOE genotypes and Alzheimer's disease. Ann NY Acad Sci 1996;802:6-15.
27.
Harwood DG, Barker WW, Loewenstein DA, Ownby RL, St George-Hyslop P, Mullan M, et al: A cross-ethnic analysis of risk factors for AD in white Hispanics and white non-Hispanics. Neurology 1999;52:551-556.
28.
Jacquier M, Arango D, Villareal E, Torres O, Serrano ML, Cruts M, et al: APOE ε4 and Alzheimer's disease: positive association in a Colombian clinical series and review of the Latin-American studies. Arq Neuropsiquiatr 2001;59:11-7.
29.
Quiroga P, Calvo C, Albala C, Urquidi J, Santos JL, Perez H, et al: Apolipoprotein E polymorphism in elderly Chilean people with Alzheimer's disease. Neuroepidemiology 1999;18:48-52.
30.
Almeida OP, Shimokomaki CM: Apolipoprotein E4 and Alzheimer's disease in São Paulo-Brazil. Arq Neuropsiquiatr 1997;55:1-7.
31.
Morelli L, Leoni J, Castano EM, Mangone CA, Lambierto A: Apolipoprotein E polymorphism and late onset Alzheimer's disease in Argentina. J Neurol Neurosurg Psychiatry 1996;61:426-427.
32.
Hallman DM, Boerwinkle E, Saha N, Sandholzer C, Menzel HJ, Csazar A, et al: The apolipoprotein E polymorphism: a comparison of allele frequencies and effects in nine populations. Am J Hum Genet 1991;49:338-349.
33.
Ganguli M, Chandra V, Kamboh MI, Johnston JM, Dodge HH, Thelma BK, et al: Apolipoprotein E polymorphism and Alzheimer disease: the Indo-US Cross-National Dementia Study. Arch Neurol 2000;57:824-830.
34.
Chandak GR, Sridevi MU, Vas CJ, Panikker DM, Singh L: Apolipoprotein E and presenilin-1 allelic variation and Alzheimer's disease in India. Hum Biol 2002;74:683-693.
35.
Hardy J, Duff K, Hardy KG, Perez-Tur J, Hutton M: Genetic dissection of Alzheimer's disease and related dementias: amyloid and its relationship to tau. Nat Neurosci 1998;1:355-358.
36.
Kwok JB, Teber ET, Loy C, Hallupp M, Nicholson G, Mellick GD, et al: Tau haplotypes regulate transcription and are associated with Parkinson's disease. Ann Neurol 2004;55:329-334.
37.
Rademakers R, Melquist S, Cruts M, Theuns J, Del-Favero J, Poorkaj P, et al: High-density SNP haplotyping suggests altered regulation of tau gene expression in progressive supranuclear palsy. Hum Mol Genet 2005;14:3281-3292.
38.
Samaranch L, Cervantes S, Barabash A, Alonso A, Cabranes JA, Lamet I, et al: The effect of MAPT H1 and APOE ε4 on transition from mild cognitive impairment to dementia. J Alzheimers Dis 2010;22:1065-1071.
39.
Wood H: Alzheimer disease: the MAPT H1 haplotype is associated with reduced severity of Alzheimer disease pathology. J Alzheimers Dis 2012;8:8.
40.
Luthra K, Tripathi M, Grover R, Dwivedi M, Kumar A, Dey A: Apolipoprotein E gene polymorphism in Indian patients with Alzheimer's disease and vascular dementia. Dement Geriatr Cogn Disord 2004;17:132-135.
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