The effect of the apolipoprotein E gene polymorphisms and haplotypes on behavioural and psychological symptoms in probable Alzheimer's disease

A L Pritchard; J Harris; C W Pritchard; J Coates; S Haque; R Holder; P Bentham; C L Lendon

doi:10.1136/jnnp.2006.092122

. 2006 Sep 15;78(2):123–126. doi: 10.1136/jnnp.2006.092122

The effect of the apolipoprotein E gene polymorphisms and haplotypes on behavioural and psychological symptoms in probable Alzheimer's disease

A L Pritchard ^1,^2,^3,⁴, J Harris ^1,^2,^3,⁴, C W Pritchard ^1,^2,^3,⁴, J Coates ^1,^2,^3,⁴, S Haque ^1,^2,^3,⁴, R Holder ^1,^2,^3,⁴, P Bentham ^1,^2,^3,⁴, C L Lendon ^1,^2,^3,⁴

PMCID: PMC2077651 PMID: 16980336

Abstract

Background

Patients with Alzheimer's disease and dementia commonly suffer from behavioural and psychological symptoms of dementia (BPSD). A genetic component to BPSD development in Alzheimer's disease has been demonstrated. Several studies have investigated whether the exon 4 ε2/ε3/ε4 haplotype of the apolipoprotein E (APOE) gene is associated with BPSD, with variable results.

Objective

We investigated the exon 4 polymorphisms and extended this study to include promoter polymorphisms and the resultant haplotypes across the gene.

Methods

Our large independent cohort of 388 patients with longitudinal measures of BPSD assessed by the Neuropsychiatric Inventory was used to analyse whether any of these variants were associated with the presence of BPSD.

Results

We revealed several significant relationships before correction for multiple testing. The exon 4 haplotype was associated with hallucinations and anxiety, A‐491T with irritability, T‐427C with agitation/aggression and appetite disturbances, and T‐219C with depression. Haplotype analyses of all variants did not reveal any statistically significant findings.

Conclusions

Our data and a review of previous studies showed a diversity of relationships, suggesting that these findings might be due to chance and so collectively do not support a role for the APOE gene in BPSD.

Many patients with dementia display behavioural and psychological symptoms of dementia (BPSD). Unlike cognitive decline, BPSD do not continuously exist in a patient once they have occurred. Genetic determinants of BPSD in Alzheimer's disease have been proposed from studies on families.¹,²,³ It has been hypothesised that the genes that increase the risk for Alzheimer's disease may also determine the presence of BPSD.⁴ The ε4 allele of the apolipoprotein E (APOE) gene is the only risk factor robustly associated with Alzheimer's disease. However, previous investigations on APOE have produced inconsistent findings on BPSD, with some researchers reporting associations with a variety of different symptoms and alleles⁴,⁵,⁶,⁷,⁸,⁹,¹⁰,¹¹,¹²,¹³,¹⁴,¹⁵,¹⁶ (summarised in the table provided online at http://jnnp.bmjjournals.com/supplemental), whereas others find no relevant relationships.¹⁷,¹⁸,¹⁹,²⁰,²¹,²²,²³,²⁴,²⁵,²⁶,²⁷,²⁸,²⁹,³⁰,³¹,³²,³³ We used a large independent clinical cohort of patients with Alzheimer's disease, with longitudinal data on BPSD to further extend these studies, and additionally investigated promoter polymorphisms of APOE, which have been shown to independently incur risk of Alzheimer's disease in some studies.³⁴

Methods

Our cohort consists of 388 patients, classified as having mild to moderate dementia (Mini Mental State Examination score 10–25) at baseline, with Diagnostic and Statistical Manual of Mental Disorders‐IV criteria for dementia of Alzheimer type. Also, 15% had an additional diagnosis of vascular dementia. The mean (standard deviation (SD)) age of onset of dementia was 74.4 (6.99) years and 56% were women.³⁵ Ethical approval and informed consent were obtained from participants and relatives (for a complete description of the cohort, see Courtney et al³⁵). Patients were assessed using the carer rated Neuropsychiatric Inventory up to 12 times over 166 weeks; all patients had at least three assessments, and the mean (SD) number of visits was 7.00 (2.65). Patients were dichotomised into those having experienced a particular symptom and those that did not, over the study period. Genotype:phenotype correlations were examined using Pearson's χ² test, and by logistic regression using genotype, sex and age as covariates. Linkage disequilibrium and haplotypes were assessed using the Haploview program (http://www.broad.mit.edu/mpg/haploview/) and power calculations using http://calculators.stat.ucla.edu/powercalc/.

Results

For a symptom existing in 50% of patients, our cohort had 80% power to detect associations of a modest effect size of 1.75. Statistical significance is presented before correction for multiple testing. Previous associations have been reported with the ε2/ε3/ε4 haplotype for delusions, hallucinations, psychosis, depression, agitation/aggression and anxiety, therefore these symptoms were investigated. A significant increase in the ε3/ε3 genotype and a decrease in the ε3/ε4 genotype were observed in patients with hallucinations compared with those without (χ² = 12.02, p = 0.017; table 1). A significant decrease in the ε3/ε3 genotype and an increase in the ε3/ε4 genotype were observed in patients with anxiety compared with those without (χ² = 15.84, p = 0.003; table 1). No associations were found with delusions, psychosis, depression or agitation/aggression (table 1).

Table 1 Apolipoprotein E gene ε2/ε3/ε4 and promoter polymorphism genotype and allele frequencies in patients with or without specific behavioural and psychological symptoms, measured in our cohort of 388 patients with Alzheimer's disease.

ε2/ε3/ε4	%	Genotype							Allele
ε2/ε3/ε4	%	22/24	23	33	34	44	χ²	p Value	2	3	4	χ²	p Value
Delusions absent	38	0.01	0.12	0.28	0.47	0.13	7.98	0.92	0.07	0.57	0.36	4.70	0.095
Delusions present	62	0.03	0.06	0.24	0.50	0.18			0.05	0.52	0.43
Hallucinations absent	57	0	0.10	0.24	0.51	0.15	12.02	0.017*	0.05	0.52	0.41	0.33	0.85
Hallucinations present	43	0.04	0.06	0.28	0.46	0.16			0.06	0.54	0.40
Agitation/aggression absent	18	0	0.06	0.29	0.52	0.12	2.95	0.57	0.03	0.58	0.38	2.25	0.32
Agitation/aggression present	82	0.02	0.09	0.25	0.48	0.16			0.06	0.53	0.41
Depression absent	20	0	0.10	0.26	0.51	0.14	2.12	0.72	0.05	0.56	0.39	0.35	0.84
Depression present	80	0.02	0.08	0.26	0.48	0.16			0.06	0.54	0.41
Anxiety absent	13	0.04	0.04	0.46	0.30	0.17	15.84	0.003*	0.06	0.63	0.31	3.9	0.14
Anxiety present	87	0.02	0.09	0.23	0.51	0.15			0.05	0.53	0.42

	%	Genotype					Alleles
	%				χ²	p Value			χ²	p Value
A‐491T		AA	AT	TT			A	T
Irritability absent	18	0.82	0.12	0.06	6.27	0.04*	0.88	0.12	0.14	0.71
Irritability present	82	0.80	0.19	0.01			0.89	0.11

T‐427C		TT	CT	CC			T	C
Agitation/aggression absent	18	0.77	0.24	0	7.19	0.03*	0.88	0.12	1.71	0.19
Agitation/aggression present	82	0.86	0.12	0.02			0.92	0.08
Appetite disturbances absent	35	0.79	0.18	0.04	6.64	0.04*	0.88	0.12	6.82	0.009*
Appetite disturbances present	65	0.87	0.12	0.01			0.93	0.07

T‐219G		TT	TG	GG			T	G
Depression absent	20	0.21	0.40	0.39	4.69	0.09	0.41	0.59	5.45	0.02
Depression present	80	0.33	0.42	0.26			0.54	0.46

Open in a new tab

*Statistically significant before correction for multiple testing.

As no previous studies have examined the promoter polymorphisms, all symptoms were considered. Four significant associations were found (table 1). An increase in the AT genotype of the A‐491T polymorphism was observed in patients with irritability, compared with those without (χ² = 6.27; p = 0.04). An increase in the TT genotype of the T‐427C polymorphism was observed in patients with agitation/aggression (χ² = 7.19; p = 0.03) and with appetite disturbances (χ² = 6.64; p = 0.04). Finally, an increase in the T allele of the T‐219G polymorphism was found in patients with depression (χ² = 5.45; p = 0.02). Haplotype analysis showed linkage disequilibrium between the variants (D = 0.86–1), which only correlated weakly (r² = 0.01–0.03), and no significant associations with any of the symptoms (data not shown).

Logistic regression showed that small (between 1% and 4%), but statistically significant, contributions were made by age and sex to a model predicting symptoms, but no effect of any of the APOE variants was found.

Discussion

Apolipoprotein E has many roles, and one or more of these actions could be involved in the development of BPSD.³⁴ Inconsistent findings have been found in previous studies of the exon 4 APOE polymorphisms with BPSD, with statistically significant relationships to anxiety, delusions, hallucinations, psychosis, depression and agitation/aggression being reported.⁴,⁵,⁶,⁷,⁸,⁹,¹⁰,¹¹,¹²,¹³,¹⁴,¹⁵,¹⁶ It should be noted that in several reports, corrections for multiple testing were not made. Our findings do not remain significant after correction for multiple testing, and so our data and a large number of previous studies conclude that there is no association with BPSD.¹⁷,¹⁸,¹⁹,²⁰,²¹,²²,²³,²⁴,²⁵,²⁶,²⁷,²⁸,²⁹,³⁰,³¹,³²,³³

Not all measures of BPSD reported in the literature include an assessment of anxiety. Two studies using longitudinal assessments with the Neuropsychiatric Inventory found no association with anxiety,²²,²⁴ and no association was found when assessed by the Behavioural Pathology in Alzheimer's Disease Rating Scale in a cross‐sectional study design.²⁹ Robertson et al¹⁶ reported higher levels of anxiety in ε4/ε4 carriers compared with ε3/ε3 in both men and women (p<0.05) and higher levels compared with ε3/ε4 only in men (p<0.05), in 125 patients. We do not support these findings using the same methods of analysis (data not shown). Interestingly, Robertson et al reported that APOE null mice carrying the human ε4 transgene had higher anxiety ratings than those expressing either wild‐type murine APOE or the human ε3.¹⁶ We found an association with the ε3/ε4 genotype, but not with the ε4/ε4 genotype or the ε4 allele.

Previous associations with hallucinations have been contradictory, with two copies of ε4 being reported as protective,¹⁴ and ε4 being associated with increased risk.¹³ We found association with the ε3/ε4 genotype, adding further inconsistencies to reported findings. Hallucinations are sometimes incorporated into a measure of psychosis. Previous associations have again been inconsistent, with significant associations being reported for the ε4 allele,⁹ and for ε3/ε4 versus ε4/ε4 carriers.⁷ To allow similar comparisons, we investigated a measure of psychosis in our cohort; we observed a non‐significant increase in the ε4 allele (data not shown). However, a larger number of studies found no associations with hallucinations or measures incorporating this symptom.¹²,¹⁷,¹⁹,²⁰,²¹,²²,²⁵,²⁹

The associations we found between anxiety and hallucinations with the ε3/ε4 heterozygote but not with the ε4/ε4 genotype or the ε4 allele are difficult to explain by a simple model. Nevertheless, the possibility that there are complex mechanisms whereby the heterozygote form may modify risk cannot be ruled out. However, it is more likely our findings are due to chance.

Our findings do not support the protective effect of the ε2 allele,¹⁵ or the risk associated with absence of the ε4 allele¹⁰ for depression. Our findings are consistent with those of others.⁷,⁹,¹³,¹⁴,²¹,²³,²⁶,²⁷,²⁹,³⁰,³¹,³² Our findings also do not support the previous association for the ε4 allele being a risk factor for agitation/aggression.¹²

This is the first reported investigation of associations between BPSD and A‐491T, T‐427C and T‐219G APOE promoter polymorphisms. Our preliminary hypothesis‐generating findings require further exploration in large independent cohorts.

We have reviewed and extended the literature reporting studies of APOE in BPSD. Despite some reasonably sized cohorts having been investigated, it is clear that there are no consistent effects between studies, unlike the robust effect of the ε4 allele and the risk of Alzheimer's disease. The inconsistencies observed could be due to spurious associations, particularly where studies are subject to considerable multiple testing. Variability in study design is also a likely contributing factor, particularly where there is focus on certain symptoms, different assessment tools and analytical procedures used, variation between cohort selection criteria, and size and stage of dementia examined. We, along with some others in the field, advocate the use of longitudinal follow‐up because BPSD are often transiently expressed. It is also possible that APOE plays only a minor part in the development or modulation of certain behavioural symptoms that will only be detectable in appropriately large and well‐designed studies. However, collectively, our findings and those reviewed do not support a role for APOE in BPSD.

Supplementary table available at http://jnnp.bmjjournals.com/supplemental

Supplementary Material

[web only table]

jnnpsyc_jnnp.2006.092122_index.html^{(1.3KB, html)}

Acknowledgements

We thank the patients and their carers who took part in this study and generously gave their time. We thank all the clinicians and nurses involved in this study.

Abbreviations

APOE - apolipoprotein E

BPSD - behavioural and psychological symptoms of dementia

Footnotes

Funding: This study was funded by the Birmingham and Solihull NHS.

Competing interests: None declared.

Supplementary table available at http://jnnp.bmjjournals.com/supplemental

References

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Associated Data

This section collects any data citations, data availability statements, or supplementary materials included in this article.

Supplementary Materials

[web only table]

jnnpsyc_jnnp.2006.092122_index.html^{(1.3KB, html)}

jnnpsyc_jnnp.2006.092122_1.pdf^{(85.6KB, pdf)}

[ref1] 1.Lyketsos C G, Tune L, Pearlson G.et al Major depression in Alzheimer's disease. An interaction between gender and family history. Psychosomatics 199637380–384. [DOI] [PubMed] [Google Scholar]

[ref2] 2.Sweet R A, Nimganokar V, Devlin B.et al Increased familial risk of the psychotic phenotype of Alzheimer's disease. Neurology 200258907–911. [DOI] [PubMed] [Google Scholar]

[ref3] 3.Tunstall N, Owen M, Williams J.et al Familial influence on variation in age of onset and behavioural phenotype in Alzheimer's disease. Br J Psychiatry 2000176156–159. [DOI] [PubMed] [Google Scholar]

[ref4] 4.Holmes C, Levy R, McLoughlin D M.et al Apolipoprotein E: non‐cognitive symptoms and cognitive decline in late onset Alzheimer's disease. J Neurol Neurosurg Psychiatry 199661580–583. [DOI] [PMC free article] [PubMed] [Google Scholar]

[ref5] 5.Cacabelos R, Rodriguez B, Carrera C.et al Behavioral changes associated with different apolipoprotein E genotypes in dementia. Alzheimer Dis Assoc Disord 199711(Suppl 4)S27–S34. [PubMed] [Google Scholar]

[ref6] 6.Cacabelos R, Rodriguez B, Carrera C.et al APOE‐related frequency of cognitive and noncognitive symptoms in dementia. Methods Find Exp Clin Pharmacol 199618693–706. [PubMed] [Google Scholar]

[ref7] 7.Ramachandran G, Marder K, Tang M.et al A preliminary study of apolipoprotein E genotype and psychiatric manifestations of Alzheimer's disease. Neurology 199647256–259. [DOI] [PubMed] [Google Scholar]

[ref8] 8.Murphy G M, Jr, Taylor J, Tinklenberg J R.et al The apolipoprotein E epsilon 4 allele is associated with increased behavioral disturbance in Alzheimer's disease. Am J Geriatr Psychiatry 1997588–89. [DOI] [PubMed] [Google Scholar]

[ref9] 9.Harwood D G, Barker W W, Ownby R L.et al Apolipoprotein‐E (APO‐E) genotype and symptoms of psychosis in Alzheimer's disease. Am J Geriatr Psychiatry 19997119–123. [PubMed] [Google Scholar]

[ref10] 10.Ballard C, Massey H, Lamb H.et al Apolipoprotein E: non‐cognitive symptoms and cognitive decline in late onset Alzheimer's disease. J Neurol Neurosurg Psychiatry 199763273–274. [DOI] [PubMed] [Google Scholar]

[ref11] 11.Holmes C, McLoughlin D M, Powell J.et al Reply. J Neurol Neurosurg Psychiatry 199763273–374. [Google Scholar]

[ref12] 12.Craig D, Hart D, McCool K.et al Apolipoprotein E e4 allele influences aggressive behaviour in Alzheimer's disease. J Neurol Neurosurg Psychiatry 2004751327–1330. [DOI] [PMC free article] [PubMed] [Google Scholar]

[ref13] 13.Chang J B, Wang P N, Chen W T.et al ApoE epsilon4 allele is associated with incidental hallucinations and delusions in patients with AD. Neurology 2004631105–1107. [DOI] [PubMed] [Google Scholar]

[ref14] 14.Scarmeas N, Brandt J, Albert M.et al Association between the APOE genotype and psychopathologic symptoms in Alzheimer's disease. Neurology 2002581182–1188. [DOI] [PMC free article] [PubMed] [Google Scholar]

[ref15] 15.Holmes C, Russ C, Kirov G.et al Apolipoprotein E: depressive illness, depressive symptoms and Alzheimer's disease. Bio Psychiatry 199843159–164. [DOI] [PubMed] [Google Scholar]

[ref16] 16.Robertson J, Curley J, Kaye J.et al APOE isoforms and measures of anxiety in probable AD patients and apoe ‐/‐ mice. Neurobiol Aging 200526637–643. [DOI] [PubMed] [Google Scholar]

[ref17] 17.Lehtovirta M, Soininen H, Helisalmi S.et al Clinical and neuropsychological characteristics in familial and sporadic Alzheimer's disease: relation to apolipoprotein E polymorphism. Neurology 199646413–419. [DOI] [PubMed] [Google Scholar]

[ref18] 18.Lopez‐Alberola R, Gilchirst D, Barker W W.et al Analysis of phenotype in Alzheimer's disease (AD) associated with apolipoprotein E (APOE) alleles. Neurology 199444(Suppl 2)A207 [Google Scholar]

[ref19] 19.Lopez O L, Kamboh M I, Becker J T.et al The apolipoprotein E epsilon 4 allele is not associated with psychiatric symptoms or extrapyramidal signs in probable Alzheimer's disease. Neurology 199749794–797. [DOI] [PubMed] [Google Scholar]

[ref20] 20.Forsell Y, Basun H, Corder E H.et al Psychotic symptoms and apolipoprotein E genotypes in an elderly population. Biol Psychiatry 199844139–140. [DOI] [PubMed] [Google Scholar]

[ref21] 21.Lyketsos C G, Baker L, Warren A.et al Depression, delusions, and hallucinations in Alzheimer's disease: no relationship to apolipoprotein E genotype. J Neuropsychiatry Clin Neurosci 1997964–67. [DOI] [PubMed] [Google Scholar]

[ref22] 22.Hirono N, Mori E, Yasuda M.et al Lack of effect of apolipoprotein E E4 allele on neuropsychiatric manifestations in Alzheimer's disease. J Neuropsychiatry Clin Neurosci 19991166–70. [DOI] [PubMed] [Google Scholar]

[ref23] 23.Forsell Y, Corder E H, Basun H.et al Depression and dementia in relation to apolipoprotein E polymorphism in a population sample age 75+. Biol Psychiatry 199742898–903. [DOI] [PubMed] [Google Scholar]

[ref24] 24.Levy M L, Cummings J L, Fairbanks L A.et al Apolipoprotein E genotype and noncognitive symptoms in Alzheimer's disease. Biol Psychiatry 199945422–425. [DOI] [PubMed] [Google Scholar]

[ref25] 25.Hirono N, Mori E, Yasuda M.et al Factors associated with psychotic symptoms in Alzheimer's disease. J Neurol Neurosurg Psychiatry 199864648–652. [DOI] [PMC free article] [PubMed] [Google Scholar]

[ref26] 26.Cantillon M, Harwood D, Barker W.et al No association between apolipoprotein E genotype and late‐onset depression in Alzheimer's disease. Biol Psychiatry 199741246–248. [DOI] [PubMed] [Google Scholar]

[ref27] 27.Weiner M F, Vega G, Risser R C.et al Apolipoprotein E epsilon 4, other risk factors, and course of Alzheimer's disease. Biol Psychiatry 199945633–638. [DOI] [PubMed] [Google Scholar]

[ref28] 28.Mauricio M, O'Hara R, Yesavage J A.et al A longitudinal study of apolipoprotein‐E genotype and depressive symptoms in community‐dwelling older adults. Am J Geriatr Psychiatry 20008196–200. [PubMed] [Google Scholar]

[ref29] 29.Gabryelewicz T, Religa D, Styczynska M.et al Behavioural pathology in Alzheimer's disease with special reference to apolipoprotein E genotype. Dement Geriatr Cogn Disord 200214208–212. [DOI] [PubMed] [Google Scholar]

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PERMALINK

The effect of the apolipoprotein E gene polymorphisms and haplotypes on behavioural and psychological symptoms in probable Alzheimer's disease

A L Pritchard

J Harris

C W Pritchard

J Coates

S Haque

R Holder

P Bentham

C L Lendon

Abstract

Background

Objective

Methods

Results

Conclusions

Methods

Results

Table 1 Apolipoprotein E gene ε2/ε3/ε4 and promoter polymorphism genotype and allele frequencies in patients with or without specific behavioural and psychological symptoms, measured in our cohort of 388 patients with Alzheimer's disease.

Discussion

Supplementary Material

Acknowledgements

Abbreviations

Footnotes

References

Associated Data

Supplementary Materials

ACTIONS

PERMALINK

RESOURCES

Cite

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PERMALINK

The effect of the apolipoprotein E gene polymorphisms and haplotypes on behavioural and psychological symptoms in probable Alzheimer's disease

A L Pritchard

J Harris

C W Pritchard

J Coates

S Haque

R Holder

P Bentham

C L Lendon

Abstract

Background

Objective

Methods

Results

Conclusions

Methods

Results

Table 1 Apolipoprotein E gene ε2/ε3/ε4 and promoter polymorphism genotype and allele frequencies in patients with or without specific behavioural and psychological symptoms, measured in our cohort of 388 patients with Alzheimer's disease.

Discussion

Supplementary Material

Acknowledgements

Abbreviations

Footnotes

References

Associated Data

Supplementary Materials

ACTIONS

PERMALINK

RESOURCES

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