Skip to main content

Replication of the association of HLA-B7 with Alzheimer's disease: a role for homozygosity?



There are reasons to expect an association with Alzheimer's disease (AD) within the HLA region. The HLA-B & C genes have, however, been relatively understudied. A geographically specific association with HLA-B7 & HLA-Cw*0702 had been suggested by our previous, small study.


We studied the HLA-B & C alleles in 196 cases of 'definite' or 'probable' AD and 199 elderly controls of the OPTIMA cohort, the largest full study of these alleles in AD to date.


We replicated the association of HLA-B7 with AD (overall, adjusted odds ratio = 2.3, 95% confidence interval = 1.4–3.7, p = 0.001), but not the previously suggested interaction with the ε4 allele of apolipoprotein E. Results for HLA-Cw*0702, which is in tight linkage disequilibrium with HLA-B7, were consistent with those for the latter. Homozygotes of both alleles appeared to be at particularly high risk of AD.


HLA-B7 and HLA-Cw*0702 are associated with AD in the Oxford population. Because of the contradictions between cohorts in our previous study, we suggest that these results may be geographically specific. This might be because of differences between populations in the structure of linkage disequilibrium or in interactions with environmental, genetic or epigenetic factors. A much larger study will be needed to clarify the role of homozygosity of HLA alleles in AD risk.


There are grounds to suspect a connection between Alzheimer's disease (AD) and variation in the major histocompatibility complex at the chromosomal region, 6p21.3. AD is characterised by chronic inflammation and altered immune function, including activation of immunocompetent glia expressing high levels of human leukocyte antigen (HLA) molecules, complement and pro-inflammatory cytokines [1]. Many of these proteins are encoded in the region. Genome scans [2, 3] have implicated the region. Long-term use of non-steroidal anti-inflammatory drugs is associated with reduced risk of AD [46].

The region has proved a challenge for the study of disease associations, because it is highly variable, with a complex structure of linkage disequilibrium. However, it is also true that, apart from the study of certain genes, e.g. TNF [7], and alleles, e.g. HLA-A2 [8], most studies of HLA genes in AD have been seriously underpowered. This is particularly so for HLA-B and C (see Discussion). Our own previous study [9], with 55 cases of AD and 73 controls from the Oxford Project to Investigate Memory and Ageing (OPTIMA), suggested an association with AD of two alleles in linkage disequilibrium with each other, HLA-B7 and HLA-Cw*0702, especially in people without the ε4 allele of apolipoprotein E (APOE 4). As that association was not replicated in two other cohorts involved in the study [9], it remains possible that these contrasts were due to geographical differences, for instance in the fine structure of linkage disequilibrium or in interactions with other risk factors (see Discussion).

We now examined HLA-B and C alleles in a further 141 cases of AD and 143 controls from the longitudinal, observational cohort of OPTIMA. Thus, altogether 196 cases of AD and 199 controls were studied, i.e. including 55 cases and 56 controls from our previous study [9] (17 of the 73 controls from that study now have other diagnoses, e.g. mild cognitive impairment, and have therefore been excluded from analysis). We aimed to replicate the association with HLA-B7 and HLA-Cw*0702 and to examine other alleles at those loci.


All 196 cases of AD (110 women) and 199 controls (107 women) were Caucasians in OPTIMA, drawn from the Oxford region and followed with detailed annual assessments [10] for up to 15 years. The cohorts for both our studies were drawn from the same Oxford population and ascertained in a similar way. OPTIMA protocols [10] have been approved by the Central Oxford Ethics Committee No 1656. Mean onset age of AD was 70.5 (± 8.9) years and of death or last examination of controls was 76.7 (± 9.2) years. Of the AD cases, 122 were neuropathologically confirmed by CERAD criteria [11] (104 "definite" and 18 "probable") and 74 were diagnosed "probable AD" by NINCDS-ADRDA criteria [12]. Possible autosomal dominant cases were excluded, based on family history. All 199 controls were without cognitive impairment and with CAMCOG scores [13] > 80.

HLA-B and Cw genotyping was performed by PCR-SSP using a modification of the Phototyping method [14]. Standard PCR methods were used for APOE 4 [15]. All genotyping was undertaken blind to diagnosis. Unadjusted p values were by Fisher's exact test; odds ratios were also adjusted for age, gender and APOE 4 status by logistic regression analysis. Potential interactions were examined by logistic regression analysis. Of the 26 studied alleles, 14 had a minor allele frequency > 5%. In the overall analyses of each allele, therefore, a Bonferroni correction factor of 14 was applied, except in the replication study of HLA-B7 and HLA-Cw*0702. In subgroup analyses, stratified by gender and by APOE 4 status, a correction factor of 14 × 4 = 56 was used.


Hardy-Weinberg equilibrium

Out of 52 Hardy-Weinberg analyses (26 analyses of controls and 26 of cases), three resulted in disequilibrium at p < 0.05, as expected by chance: HLA-B39 controls, HLA-B51 cases and HLA-B65 cases, each due to a single homozygote of a relatively rare allele. All other alleles were in Hardy-Weinberg equilibrium in both cases and controls (Tables 1 &2).

Table 1 HLA-B alleles in controls and in Alzheimer's disease
Table 2 HLA-C alleles in controls and in Alzheimer's disease

Linkage disequilibrium

Four well-known examples of linkage disequilibria were confirmed: HLA-B7 and HLA-Cw*0702 (overall D' = 96%, r2 = 0.82), HLA-B8 and HLA-Cw*0701 (99%, 0.75), HLA-B35 and Cw4 (96%, 0.58), and HLA-B44 and Cw5 (76%, 0.36). Similar patterns were seen both in controls and in cases.

Possible associations of AD with HLA-B & C alleles

Tables 1 and 2 show the overall results for the 26 studied alleles. Apart from the associations with HLA-B7 and HLA-Cw*0702 (see below), there was one other apparently significant association, i.e. with HLA-Cw15, before correction for multiple testing. Subgroup analysis, stratifying by gender and by APOE 4 status, revealed various other associations before correction: HLA-B27 in APOE 4 negatives (odds ratio = 2.95, 95% confidence interval = 1.1–7.9, p = 0.035); HLA-Cw1 in APOE 4 negatives (3.4, 1.2–9.6, 0.03) and in men (11.3, 1.4–89, 0.004); HLA-Cw15 in APOE 4 positives (0.11, 0.01–0.99, 0.03) and in men (0.11, 0.01–0.9, 0.02). There was also a significant interaction between HLA-Cw1 and sex (p = 0.03, logistic regression). However, none of these apparently significant results survived Bonferroni correction. Only a weak tendency towards an association with HLA-Cw15 overall remained after correction (p = 0.1). All further results reported below relate to HLA-B7 and HLA-Cw*0702.

Replication study of HLA-B7 and HLA-Cw*0702

Table 3 shows the results for HLA-B7 and HLA-Cw*0702 by study, i.e. our previous study (included in our 2001 report [9]) and the replication study. The association of HLA-B7 with AD was replicated and that of HLA-Cw*0702 tended also to be replicated. As expected, similar overall results were found for the HLA-B7/HLA-Cw*0702 haplotype (data not shown). In view of the consistency between the results of the two studies, we pooled the two datasets for further analysis of HLA-B7 and HLA-Cw*0702.

Table 3 Associations of AD with HLA-B7 and HLA-Cw*0702 by study

Possible interactions of HLA-B7 and HLA-Cw*0702 with other factors

Table 4 shows the associations of AD with HLA-B7 and HLA-Cw*0702 by APOE 4 status. Although the odds ratios were higher in APOE 4 negatives than in positives and were only significant in the former, the differences were not significant. Moreover, neither interaction of HLA-B7 nor of HLA-Cw*0702 with APOE 4 was significant (p = 0.27 and 0.55, respectively) by logistic regression analysis. Nor were there any significant interactions with age or gender (data not shown).

Table 4 Associations of AD with HLA-B7 and HLA-Cw*0702 by APOE 4 status

Effects of homozygosity of HLA-B7 and HLA-Cw*0702

Table 5 shows that the odds ratios of AD were much higher for homozygotes than for heterozygotes. In the case of HLA-Cw*0702, the odds ratio was only significant for homozygotes.

Table 5 Associations of AD with HLA-B7 and HLA-Cw*0702 by zygosity

The effect on onset age

Neither HLA-B7 nor HLA-Cw*0702 was associated with onset age of AD (data not shown).


We suggest that the only results meriting further scrutiny are those for HLA-B7 and HLA-Cw*0702 and possibly the potentially reduced risk associated with HLA-Cw15. All other apparently significant results, i.e. before correction, are probably due to multiple testing. However, our replication of the HLA-B7 finding, which was significant in both studies, implies that that allele is indeed associated with increased risk of AD in the Oxford population. The results for HLA-Cw*0702 were consistent with those for HLA-B7. Because of the tight linkage disequilibrium between these two alleles and also their similar frequency, we cannot be certain which is closer to the true risk locus.

Previous studies

To our knowledge, there have been 17 previous AD association studies that included HLA-B or C alleles or both. Fifteen of those were before 1990, based on phenotyping methods, using AD cases that were nearly all clinically diagnosed, usually by an unspecified method. Two of those early studies [16, 17] reported an increased risk of AD associated with HLA-B7. Of the 17 studies, only three had more than 60 AD cases: one Japanese study [18] (122 AD cases) and two Caucasian, Middleton et al 1999 [19] (95 AD cases) and our previous study [9] (299 AD cases from three cohorts; however, full HLA-B &C typing was only performed in the OPTIMA cohort, with 55 AD cases). Thus surprisingly, the present study is the largest, full study of HLA-B &C genes so far, and the only one large enough to examine the effects of homozygosity (Table 5).

Population-specific risk

Since the association with HLA-B7 was not replicated in the two other cohorts in our previous study [9], one mainly from Cambridge and the other from Montreal, the association reported here is likely to be geographically specific, although chance variation doubtless also played a part. This geographical specificity could be due to differences in the fine structure of linkage disequilibrium between populations or to different interactions with other risk factors: environmental, genetic or epigenetic. Epigenetic patterns, such as DNA methylation and chromatin modifications, affect gene expression and are thought to be stably maintained during somatic cell divisions, i.e. they are mitotically heritable. But they vary between tissues and between populations and degenerate with age [20, 21]. Most complex diseases are age-related. Thus epigenetic patterns, as well as genetic and environmental factors, will contribute to variation between populations.

Potential interactions

In the present study, we found no interactions of HLA-B7 or of HLA-Cw*0702 with age, gender or APOE 4; we consider the apparent difference between APOE 4 positives and negatives (Table 4) to be most likely due to chance. This result thus contradicts our previous suggestion [9] of an interaction with APOE 4. Large numbers, however, are needed to demonstrate interactions.


The odds ratios for HLA-B7 and HLA-Cw*0702 homozygotes appear striking (Table 5). However, they are partly due to partial (i.e. not significant at 0.05) Hardy-Weinberg disequilibrium in controls (p = 0.1 for HLA-B7, p = 0.2 for HLA-Cw*0702). Nevertheless, if one were artificially to restore precise Hardy-Weinberg equilibrium to controls, the odds ratios for homozygotes of each allele would still be approximately 4 and those for heterozygotes would remain just below 2. This would still suggest a codominant or dose effect of these alleles. Incidentally, one study [22] reported an association of homozygotes, not of heterozygotes of HLA-A2 with earlier onset of AD; however, HLA-A2 is on a different haplotype from HLA-B7/HLA-Cw*0702/HLA-A3.

Alternatively, could the lack of homozygotes in controls (Table 5) be a true effect due to their selective vulnerability, not only to AD? Low natural killer (NK) cell activity has been associated with homozygosity for both the HLA-B7/HLA-Cw*0702 and the HLA-B8/HLA-Cw*0701 haplotypes in Caucasians [23, 24] and for HLA-B7 in Chinese [25]. This low NK cell activity may be due to a recessive gene or variable site in linkage disequilibrium with these haplotypes. In our previous study [9], AD was associated with HLA-B7 in one cohort and with HLA-B8 in another, mainly or only in subjects without APOE 4.

Homozygosity at HLA class I loci has been associated with greater susceptibility to viral infection [26, 27], perhaps partly due to an inadequate defence by NK cells [24]. However, this effect was not seen in our cohort, since there was no overall shortage of homozygotes, only in controls. Alternatively therefore, could it be that low NK cell activity increases vulnerability to AD?

NK cells and AD

NK activity has been rather little studied in AD. However, there may be changes in the peripheral activity of NK cells in AD, although reports conflict [2831]. It has been proposed that the dysregulation of NK activity and of cytokine release by NK cells in AD could contribute to neurodegeneration, via disrupted release of cortisol, growth hormone, insulin-like growth factors and melatonin [30]. However, the effect if any of lifelong, reduced NK activity on AD risk is unknown.


The HLA-B7 & HLA-Cw*0702 alleles, which are in tight linkage disequilibrium, are associated with AD in the Oxford population. Homozygotes may be at particular risk. Although surprisingly, this is the largest study to date of the association of HLA-B & C alleles with AD, a much larger, probably collaborative study will be needed fully to examine the association with homozygosity. If that association is confirmed, further studies will be needed to provide an explanation, including the possible role of low NK cell activity. The association is geographically specific. That may be partly due to differences in linkage disequilibrium with other genes or variable sites. There are many, highly polymorphic loci in the region, including those in retroelements, some of which may interfere with the transcription of nearby genes [32]. The geographical specificity may also be due to different interactions in different populations with environmental, genetic or epigenetic factors.



Alzheimer's disease


apolipoprotein E


Cambridge Cognitive Examination


The Consortium to Establish a Registry for Alzheimer's Disease


confidence interval


human leukocyte antigen


National Institute of Neurological, Communicative Diseases and Stroke-Alzheimer's Disease and Related Diseases Association


natural killer


Oxford Project to Investigate Memory and Ageing


polymerase chain reaction


sequence-specific primers


tumour necrosis factor


  1. Akiyama H, Barger S, Barnum S, Bradt B, Bauer J, Cole GM, Cooper NR, Eikelenboom P, Emmerling M, Fiebich BL, Finch CE, Frautschy S, Griffin WST, Hampel H, Hull M, Landreth G, Lue LF, Mrak R, Mackenzie IR, McGeer PL, O'Banion MK, Pachter J, Pasinetti G, Plata-Salaman C, Rogers J, Rydel R, Shen Y, Streit W, Strohmeyer R, Tooyoma I, Van Muiswinkel FL, Veerhuis R, Walker D, Webster S, Wegrzyniak B, Wenk G, Wyss-Coray T: Inflammation and Alzheimer's disease. Neurobiol Aging. 2000, 21: 383-421. 10.1016/S0197-4580(00)00124-X.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  2. Kehoe P, Wavrant-De Vrieze F, Crook R, Wu WS, Holmans P, Fenton I, Spurlock G, Norton N, Williams H, Williams N, Lovestone S, Perez-Tur J, Hutton M, Chartier-Harlin MC, Shears S, Roehl K, Booth J, Van Voorst W, Ramic D, Williams J, Goate A, Hardy J, Owen MJ: A full genome scan for late onset Alzheimer's disease. Hum Mol Genet. 1999, 8: 237-245. 10.1093/hmg/8.2.237.

    Article  CAS  PubMed  Google Scholar 

  3. Collins JS, Perry RT, Watson BJ, Harrell LE, Acton RT, Blacker D, Albert MS, Tanzi RE, Bassett SS, McInnis MG, Campbell RD, Go RCP: Association of a haplotype for tumor necrosis factor in siblings with late-onset Alzheimer disease: the NIMH Alzheimer Disease Genetics Initiative. Am J Med Genet (Neuropsychiatr Genet). 2000, 96: 823-830. 10.1002/1096-8628(20001204)96:6<823::AID-AJMG26>3.0.CO;2-I.

    Article  CAS  Google Scholar 

  4. in t' Veld BA, Ruitenberg A, Hofman A, Launer LJ, van Duijn CM, Stijnen T, Breteler MM, Stricker BH: Nonsteroidal antiinflammatory drugs and the risk of Alzheimer's disease. N Engl J Med. 2001, 345: 1515-1521. 10.1056/NEJMoa010178.

    Article  PubMed  Google Scholar 

  5. Zandi PP, Anthony JC, Hayden KM, Mehta K, Mayer L, Breitner JC: Reduced incidence of AD with NSAID but not H2 receptor antagonists: the Cache County Study. Neurology. 2002, 59: 880-886.

    Article  CAS  PubMed  Google Scholar 

  6. Etminan M, Gill S, Samii A: Effect of non-steroidal anti-inflammatory drugs on risk of Alzheimer's disease: systematic review and meta-analysis of observational studies. BMJ. 2003, 327: 128-132. 10.1136/bmj.327.7407.128.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  7. McCusker SM, Curran MD, Dynan KB, McCullagh CD, Urquhart DD, Middleton D, Patterson CC, McIlroy SP, Passmore AP: Association between polymorphism in regulatory region of gene encoding tumour necrosis factor alpha and risk of Alzheimer's disease and vascular dementia: a case-control study. Lancet. 2001, 357: 436-439. 10.1016/S0140-6736(00)04008-3.

    Article  CAS  PubMed  Google Scholar 

  8. Small GW, Scott WK, Komo S, Yamaoka LH, Farrer LA, Auerbach SH, Saunders AM, Roses AD, Haines JL, Pericak-Vance MA: No association between the HLA-A2 allele and Alzheimer disease. Neurogenetics. 1999, 2: 177-182. 10.1007/s100480050080.

    Article  CAS  PubMed  Google Scholar 

  9. Lehmann DJ, Wiebusch H, Marshall SE, Johnston C, Warden DR, Morgan K, Schappert K, Poirier J, Xuereb J, Kalsheker N, Welsh KI, Smith AD: HLA class I, II & III genes in confirmed late-onset Alzheimer's disease. Neurobiol Aging. 2001, 22: 71-77. 10.1016/S0197-4580(00)00180-9.

    Article  CAS  PubMed  Google Scholar 

  10. Clarke R, Smith AD, Jobst KA, Refsum H, Sutton L, Ueland PM: Folate, vitamin B12 and serum total homocysteine levels in confirmed Alzheimer's disease. Arch Neurol. 1998, 55: 1449-1455. 10.1001/archneur.55.11.1449.

    Article  CAS  PubMed  Google Scholar 

  11. Mirra SS, Heyman A, McKeel D, Sumi SM, Crain BJ, Brownlee LM, Vogel FS, Hughes JP, van Belle G, Berg L: The Consortium to Establish a Registry for Alzheimer's Disease (CERAD). Part II. Standardization of the neuropathologic assessment of Alzheimer's disease. Neurology. 1991, 41: 479-486.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  13. Roth M, Huppert FA, Tym E, Mountjoy CQ: CAMDEX: The Cambridge examination for mental disorders of the elderly. 1988, Cambridge, Cambridge University Press

    Google Scholar 

  14. Bunce M, O'Neill CM, Barnardo MC, Krausa P, Browning MJ, Morris PJ, Welsh KI: Phototyping: comprehensive DNA typing for HLA-A, B, C, DRB1, DRB3, DRB4, DRB5 & DQB1 by PCR with 144 primer mixes utilizing sequence-specific primers (PCR-SSP). Tissue Antigens. 1995, 46: 355-367.

    Article  CAS  PubMed  Google Scholar 

  15. Wenham PR, Price WH, Blundell G: Apolipoprotein E genotyping by one-stage PCR. Lancet. 1991, 337: 1158-1159. 10.1016/0140-6736(91)92823-K.

    Article  CAS  PubMed  Google Scholar 

  16. Cohen D, Zeller E, Eisdorfer C, Walford R: Alzheimer's disease and the main histocompatibility complex (HLA system) [Abstract]. Gerontologist. 1979, 19 (5, part 2): 57-

    Google Scholar 

  17. Walford RL, Hodge SE: HLA distribution in Alzheimer's Disease. Histocompatibility Testing. Edited by: Terasaki PI. 1980, 727-729.

    Google Scholar 

  18. Endo H, Yamamoto T, Kuzuya F: HLA system in senile dementia of Alzheimer type and multi-infarct dementia in Japan. Arch Gerontol Geriatr. 1986, 5: 51-56. 10.1016/0167-4943(86)90007-5.

    Article  CAS  PubMed  Google Scholar 

  19. Middleton D, Mawhinney H, Curran MD, Edwardson JA, Perry R, McKeith I, Morris C, Ince PG, Neill D: Frequency of HLA-A and B alleles in early and late-onset Alzheimer's disease. Neurosci Lett. 1999, 262: 140-142. 10.1016/S0304-3940(99)00045-2.

    Article  CAS  PubMed  Google Scholar 

  20. Rakyan VK, Hildmann T, Novik KL, Lewin J, Tost J, Cox AV, Andrews TD, Howe KL, Otto T, Olek A, Fischer J, Gut IG, Berlin K, Beck S: DNA methylation profiling of the human major histocompatibility complex: a pilot study for the Human Epigenome Project. PLoS Biology. 2004, 2: 0001-14. 10.1371/journal.pbio.0020405.

    Article  Google Scholar 

  21. Bjornsson HT, Fallin MD, Feinberg AP: An integrated epigenetic and genetic approach to common human disease. Trends Genet. 2004, 20: 350-358. 10.1016/j.tig.2004.06.009.

    Article  CAS  PubMed  Google Scholar 

  22. Zareparsi S, James DM, Kaye JA, Bird TD, Schellenberg GD, Payami H: HLA-A2 homozygosity but not heterozygosity is associated with Alzheimer disease. Neurology. 2002, 58: 973-975.

    Article  CAS  PubMed  Google Scholar 

  23. Dubey DP, Alper CA, Mirza NM, Awdeh Z, Yunis EJ: Polymorphic Hh genes in the HLA-B(C) region control natural killer cell frequency and activity. J Exp Med. 1994, 179: 1193-1203. 10.1084/jem.179.4.1193.

    Article  CAS  PubMed  Google Scholar 

  24. Husain Z, Levitan E, Larsen CE, Mirza NM, Younes S, Yunis EJ, Alper CA, Dubey DP: HLA-Cw7 zygosity affects the size of a subset of CD158b+ natural killer cells. J Clin Immunol. 2002, 22: 28-36. 10.1023/A:1014204519468.

    Article  CAS  PubMed  Google Scholar 

  25. Zhang H, An J, Jiang Z, Yang Q, Sun L, Guo Y, Sun Y: Linkage of the genes controlling natural killer cell activity to HLA-B. Zhonghua Yi Xue Yi Chuan Xue Za Zhi. 2000, 17: 188-191.

    PubMed  Google Scholar 

  26. Carrington M, Nelson GW, Martin MP, Kissner T, Vlahov D, Goedert JJ, Kaslow R, Buchbinder S, Hoots K, O'Brien SJ: HLA and HIV-1: heterozygote advantage and B*35-Cw*04 disadvantage. Science. 1999, 283: 1748-1752. 10.1126/science.283.5408.1748.

    Article  CAS  PubMed  Google Scholar 

  27. Jeffery KJ, Siddiqui AA, Bunce M, Lloyd AL, Vine AM, Witkover AD, Izumo S, Usuku K, Welsh KI, Osame M, Bangham CR: The influence of HLA class I alleles and heterozygosity on the outcome of human T cell lymphotropic virus type I infection. J Immunol. 2000, 165: 7278-7284.

    Article  CAS  PubMed  Google Scholar 

  28. Araga S, Kagimoto H, Funamoto K, Takahashi K: Reduced natural killer cell activity in patients with dementia of the Alzheimer type. Acta Neurol Scand. 1991, 84: 259-263.

    Article  CAS  PubMed  Google Scholar 

  29. Solerte SB, Fioravanti M, Pascale A, Ferrari E, Govoni S, Battaini F: Increased natural killer cell cytotoxicity in Alzheimer's disease may involve protein kinase C dysregulation. Neurobiol Aging. 1998, 19: 191-199. 10.1016/S0197-4580(98)00050-5.

    Article  CAS  PubMed  Google Scholar 

  30. Ferrari E, Fioravanti M, Magri F, Solerte SB: Variability of interactions between neuroendocrine and immunological functions in physiological aging and dementia of the Alzheimer's type. Ann N Y Acad Sci. 2000, 917: 582-596.

    Article  CAS  PubMed  Google Scholar 

  31. Masera RG, Prolo P, Sartori ML, Staurenghi A, Griot G, Ravizza L, Dovio A, Chiapelli F, Angeli A: Mental deterioration correlates with response of natural killer (NK) cell activity to physiological modifiers in patients with short history of Alzheimer's disease. Psychoneuroendocrinology. 2002, 27: 447-461. 10.1016/S0306-4530(01)00062-2.

    Article  CAS  PubMed  Google Scholar 

  32. Whitelaw E, Martin DIK: Retrotransposons as epigenetic mediators of phenotypic variation in mammals. Nat Genet. 2001, 27: 361-365. 10.1038/86850.

    Article  CAS  PubMed  Google Scholar 

Download references


We would like to express our gratitude to all those who volunteered for the OPTIMA study over many years and to the staff of OPTIMA for their contribution to this project. We thank MG Lehmann for help with the data analysis. We are most grateful to Dr Abderrahim Oulhaj for advice on statistics. We greatly appreciate very helpful discussions with Professor AVS Hill. We are grateful to the following for financial support: Bristol-Myers Squibb Inc, the Southern Trust, the Norman Collisson Foundation, the Takayama Foundation, the John Coates Foundation, the Linbury Trust, and Merck & Co Inc. RH and SB were supported by the Wellcome Trust.

Author information

Authors and Affiliations


Corresponding author

Correspondence to Donald J Lehmann.

Additional information

Competing interests

The author(s) declare that they have no competing interests.

Authors' contributions

All authors contributed to the design of the study and approved the final draft. In addition, MB, SF, RH and SB gave expert advice on the HLA region and on search strategies in the region; MB supervised the HLA genotyping and was responsible for quality control; IQ and AS performed the HLA genotyping; DRW isolated the DNA and performed the APOE genotyping; LB supplied all the background data on the OPTIMA cohort; DJL was responsible for the data analysis and drafted the manuscript; MB, SB and ADS also made important contributions to the final draft.

Rights and permissions

This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Reprints and permissions

About this article

Cite this article

Lehmann, D.J., Barnardo, M.C., Fuggle, S. et al. Replication of the association of HLA-B7 with Alzheimer's disease: a role for homozygosity?. J Neuroinflammation 3, 33 (2006).

Download citation

  • Received:

  • Accepted:

  • Published:

  • DOI: