Stephen P. McIlroy

Moderately Elevated Plasma Homocysteine, Methylenetetrahydrofolate Reductase Genotype, and Risk for Stroke, Vascular Dementia, and Alzheimer Disease in Northern Ireland

Background and Purpose— Elevated plasma homocysteine level has been associated with increased risk for cardiovascular and cerebrovascular disease. Variation in the levels of this amino acid has been shown to be due to nutritional status and methylenetetrahydrofolate reductase (MTHFR) genotype. Methods— Under a case-control design we compared fasting levels of homocysteine and MTHFR genotypes in groups of subjects consisting of stroke, vascular dementia (VaD), and Alzheimer disease patients and normal controls from Northern Ireland. Results— A significant increase in plasma homocysteine was observed in all 3 disease groups compared with controls. This remained significant after allowance for confounding factors (age, sex, hypertension, cholesterol, smoking, creatinine, and nutritional measures). MTHFR genotype was not found to influence homocysteine levels, although the T allele was found to increase risk for VaD and perhaps dementia after stroke. Conclusions— We report that moderately high plasma levels of homocysteine are associated with stroke, VaD, and Alzheimer disease. This is not due to vascular risk factors, nutritional status, or MTHFR genotype.

Association between polymorphism in regulatory region of gene encoding tumour necrosis factor α and risk of Alzheimer's disease and vascular dementia: a case-control study

Summary Background Deposition of β-amyloid in the brains of patients with Alzheimers disease is thought to precede a chain of events that leads to an inflammatory response by the brain. We postulated that genetic variation in the regulatory region of the gene for the proinflammatory cytokine tumour necrosis factor α (TNF-α) leads to increased risk of Alzheimers disease and vascular dementia. Methods A polymorphism in the regulatory region of the TNF- α gene was analysed in a case-control study. The polymorphism (C-850T) was typed in 242 patients with sporadic Alzheimers disease, 81 patients with vascular dementia, 61 stroke patients without dementia, and 235 normal controls. These groups of individuals were also genotyped for the apolipoprotein E polymorphism, and the vascular dementia and stroke groups were typed at the HLADR locus. Findings The distribution of TNF-α genotypes in the vascular dementia group differed significantly from that in the stroke and normal control groups, giving an odds ratio of 2·51 (95% CI 1·49–4·21) for the development of vascular dementia for individuals with a CT or TT genotype. Logistic regression analysis indicated that the possession of the T allele significantly increased the risk of Alzheimers disease associated with carriage of the apolipoprotein ɛ4 allele (odds ratio 2·73 [1·68–4·44] for those with apolipoprotein E ɛ4 but no TNF-α T, vs 4·62 [2·38–8·96] for those with apolipoprotein E ɛin;4 and TNF-α T; p=0·03). Interpretation Possession of the TNF-α T allele significantly increases the risk of vascular dementia, and increases the risk of Alzheimers disease associated with apolipoprotein E. Although further research is needed, these findings suggest a potential role for anti-inflammatory therapy in vascular dementia and Alzheimers disease, and perhaps especially in patients who have had a stroke.

Butyrylcholinesterase K variant is genetically associated with late onset Alzheimer's disease in Northern Ireland

Alzheimers disease (AD) is a progressive neurodegenerative disorder that has been associated, sometimes controversially, with polymorphisms in a number of genes. Recently the butyrylcholinesterase K variant (BCHE K) allele has been shown to act in synergy with the apolipoprotein E ε4 (APOE ε4) allele to promote risk for AD. Most subsequent replicative studies have been unable to confirm these findings. We have conducted a case-control association study using a clinically well defined group of late onset AD patients (n=175) and age and sex matched control subjects (n=187) from the relatively genetically homogeneous Northern Ireland population to test this association. The BCHE genotypes of patients were found to be significantly different from controls (χ2=23.68, df=2, p<<0.001). The frequency of the K variant allele was also found to differ significantly in cases compared to controls (χ2=16.39, df=1, p<<0.001) leading to an increased risk of AD in subjects with this allele (OR=3.50, 95% CI 2.20-6.07). This risk increased in subjects 75 years and older (OR=5.50, 95% CI 2.56-11.87). At the same time the APOE ε4 associated risk was found to decrease from 6.70 (95% CI 2.40-19.04) in 65-74 year olds to 3.05 (95% CI 1.34-6.95) in those subjects 75 years and older. However, we detected no evidence of synergy between BCHE K and APOE ε4. The results from this study suggest that possession of the BCHE K allele constitutes a significant risk for AD in the Northern Ireland population and, furthermore, this risk increases with increasing age.

Cathepsin D gene exon 2 polymorphism and sporadic Alzheimer's disease

It has recently been reported that a genetic polymorphism in exon 2 of the cathepsin D gene conferred increased risk for development of Alzheimers disease (AD). Because of the potential importance of this report we tested this association in a clinically well-defined group of AD patients and age and sex matched control subjects from the relatively genetically homogeneous Northern Ireland population. This study failed to confirm the reported association between the cathepsin D exon 2 polymorphism and AD. We conclude that if an association exists between this polymorphism and AD it is likely to be small.

Association Analysis of Apolipoprotein E Genotype and Risk of Depressive Symptoms in Alzheimer’s Disease

Objectives: Behavioural and psychological symptoms of dementia (BPSD) are potent predictors of carer distress and admission to institutional care. In Alzheimer’s disease (AD), depressive symptoms are one of the most common complaints affecting around 50% of all patients. There is speculation these symptoms result from known genetic risk factors for AD, therefore we investigated the role of apolipoprotein E Ε4 in the aetiology of depression in AD. Methods: In this well-characterised cohort (n = 404) from the relatively genetically homogeneous Northern Ireland population, we tested the hypothesis that genetic variants of apolipoprotein E influence the risk for depressive symptoms in AD patients using the Neuropsychiatric Inventory (NPI-D) to determine the presence of depressive symptoms during the dementing illness. Results: A total of 55% of patients exhibited a history of depression/dysphoria during the course of the illness as gathered by the NPI-D questionnaire. Forty-six percent were suffering from depression/dysphoria when the analysis was restricted to the month prior to interview. No statistically significant association between genotypes or alleles of apolipoprotein E and depression/dysphoria in AD was observed, nor was any association noted between the presence of severe symptoms and genotypes/alleles of apolipoprotein E. Conclusions: These results suggest apolipoprotein E genotype creates no additional risk for depressive symptoms in AD.

The interleukin 1β gene promoter polymorphism (−511) acts as a risk factor for psychosis in Alzheimer's dementia

The explanation for why some patients develop psychotic change in Alzheimers disease (AD) is unclear. “Psychosis‐modifier genes” may act in the setting of neurodegeneration to produce AD plus psychosis in a similar way to how genetic modulation during neurodevelopment leads to schizophrenia. Because there is increasing interest in the common disruption of cytokine pathways seen in both AD and schizophrenia, we tested the association between the functional interleukin‐1β −511 promoter polymorphism with delusions and hallucinations in AD. Significant associations between psychotic symptoms and the CC genotype (p = 0.001 ‐ p = 0.043) and C allele (p = 0.014 vs p = 0.048) were found, thus confirming the previously noted increased risk in schizophrenia.

Psychotic symptoms in Alzheimer’s disease are not influenced by polymorphic variation at the dopamine receptor DRD3 gene

It has been suggested that genetic influences unmasked during neurodevelopment to produce schizophrenia may appear throughout neurodegeneration to produce AD plus psychosis. Risk of schizophrenia and psychosis in Alzheimers disease (AD) has been linked to polymorphic variation at the dopamine receptor DRD3 gene implying similar causative mechanisms. We tested this association in a large cohort of Alzheimers disease patients with a diagnosis of probable AD of 3 years or more duration from the relatively genetically homogenous Northern Irish population. We assessed relationships between genotypes/alleles of the DRD3 BalI polymorphism and the presence or absence of psychotic symptoms (delusions, hallucinations) in AD patients during the month prior to interview and at any stage during the dementia. No significant associations were found when delusions and hallucinations were cross-tabulated against S and G alleles and SS, SG and GG genotypes. Logistic regression failed to detect any influence of APOE, gender, family history or prior psychiatric history. In conclusion, we were unable to confirm previously reported associations between the DRD3 BalI polymorphism and psychotic symptoms in AD.

Neurobiology and genetics of behavioural syndromes of Alzheimer's disease.

The number of people with cognitive impairment is rising in parallel with changing demographics. As health care budgets are coming under increasing strain with regard to the provision of nursing care, there is a substantial need for effective therapies which encompass greater understanding of the components of dementia that finally necessitate admission to residential or nursing home care. Behavioural and psychological symptoms of dementia (BPSD) are major independent risk factors for admission to institutional care and research into the origin of BPSD is gathering pace. In this review, we evaluate the neurobiological and genetic changes described in individuals with BPSD in Alzheimers disease. Particular emphasis is placed on genetic theories of causation, namely that BPSD results directly or indirectly from known genetic risk factors for AD, or distinct genetic risk factors for psychiatric illness assume clinical significance within the degenerated Alzheimers brain.

Allelic variation at the A218C tryptophan hydroxylase polymorphism influences agitation and aggression in Alzheimer's disease

The behavioural and psychological symptoms of dementia are common, distressing to carers, and directly linked to the requirement for institutional care. Symptoms of aggression and agitation are particularly difficult for carers to tolerate. The origin of these features is unclear although genetic and environmental modification of pre-frontal serotonergic circuitry which regulates the control of negative emotions is proposed. Following the suggestion that the A218C intronic polymorphism of the tryptophan hydroxylase gene influences aggression and anger in non-demented individuals, we tested the influence of A218C on symptoms of agitation/aggression in 396 Alzheimers disease patients using the Neuropsychiatric Inventory. Overall, 50% of participants experienced agitation/aggression in the month prior to interview. It was observed that male patients with a history of agitation/aggression were more likely to possess C-containing genotypes (P = 0.044, OR = 1.65, CI = 0.98-2.76). We conclude that aggression in male subjects with Alzheimers disease may be genetically linked to polymorphic variation at the tryptophan hydroxylase gene.

Association of serum AACT levels and AACT signal polymorphism with late-onset Alzheimer's disease in Northern Ireland.

α1‐antichymotrypsin (AACT) is a serine protease inhibitor that has been associated with amyloid plaques in the brains of patients with Alzheimers disease (AD). It has been reported that AACT serum levels are higher in AD patients than in age and sex matched controls. In addition, polymorphisms in the signal peptide and 5′ of the AACT gene have been reported to increase the risk of developing AD. Serum AACT has also been suggested to be associated with cognitive decline in elderly subjects. Our objective was to investigate whether a relationship existed between serum AACT levels, AACT genotypes and risk for AD in a case control association study using 108 clinically well defined late onset AD cases and 108 age and sex matched controls from Northern Ireland. We also wished to determine whether higher serum AACT affected levels of cognition as had been previously reported. Serum AACT levels were found to be significantly raised in cases compared to controls (t=3.8, df=209, p<0.001). However, we detected no relationship between serum AACT levels and cognitive decline. We report allelic association of the AACT signal polymorphism with AD (χ2=3.70, df=1, p=0.04) but we failed to show any correlation between AACT serum levels and genotype. Copyright