Apolipoprotein E Genotype and its Effect on Duration and Severity of Early and Late Onset Alzheimer's Disease

Norrman, Jennie; Brookes, A J; Yates, Celia M.; Clair, David St

doi:10.1192/bjp.167.4.533

Cited by 30 publications

(23 citation statements)

References 10 publications

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“…Consistent with previous studies (Basun et al, 1995;Bondi et al, 1999;Corder et al, 1995;Normann et al, 1995;Dal Forno et al, 1996;DeKosky et al, 1995;Gomez-Isla et al, 1996;Growdon et al, 1996;Kurz et al, 1996;Small et al, 1998;Smith et al, 1998), there was little overall effect of APOE genotype on the cognitive performance of the NC participants or AD patients in the Very-Old or Young-Old cohorts (e.g., no main effect of APOE genotype in the multivariate analysis and in all but one of the ANOVAs). However, there were interactions between age and the presence of the APOE ε4 allele on the severity of impairment exhibited by patients with AD on some measures of memory, visuomotor sequencing, and perseverative responding, but these interaction effects were not consistent across measures.…”

Section: Discussionsupporting

confidence: 90%

Neuropsychological deficits associated with Alzheimer's disease in the very-old: Discrepancies in raw vs. standardized scores

Bondi

Houston

Salmon

et al. 2003

J Int Neuropsychol Soc

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The profiles of neuropsychological deficits associated with Alzheimer's disease (AD) in Young-Old (M age < 70) and Very-Old (M age > 80) patients were compared, along with possible modifying effects of apolipoprotein E (APOE) genotype on these profiles. A comprehensive battery of neuropsychological tests was administered to the two AD patient groups (Young-Old: n = 33; VeryOld: n = 48) and their respective age-matched normal control (NC) groups who remained free of dementia on follow-up examinations over a 1 to 10 year period (Young-Old: n = 43; Very-Old: n = 36). AD and NC groups did not differ in education levels or gender distributions. Young-Old AD and Very-Old AD groups were comparable in education, gender, dementia severity, and disease duration. Results showed that both AD groups achieved comparable raw scores on all the neuropsychological measures. However, when scores were standardized on the basis of performance of their respective NC groups (i.e., age-corrected z scores), Very-Old AD patients significantly outperformed Young-Old AD patients on tests of executive functions, visuospatial skills, and delayed memory. Furthermore, the relationship between age and memory and executive function deficits in AD was modified by APOE genotype. These data suggest that the profile of neuropsychological deficits associated with AD in the Very-Old lacks the disproportionate saliency of episodic memory and executive function deficits typical of the Young-Old.

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Section: Discussionsupporting

confidence: 90%

Neuropsychological deficits associated with Alzheimer's disease in the very-old: Discrepancies in raw vs. standardized scores

Bondi

Houston

Salmon

et al. 2003

J Int Neuropsychol Soc

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“…The large size of our study population provided enough statistical power to identify the association of the Â2 allele with a higher age at AD onset, consistent with the protective role which has been suggested for this allele [27]. Most likely due to the relative small sample sizes used, a number of earlier reports could not confirm the association of APOE genotype with age at onset [6,9,12,14,17,28]. Consistent with the literature [3,29], we observed a significant association between the Â4 allele and the presence of first-degree relatives with probable AD: a higher copy number of APOE Â4 alleles was associated with an increased frequency of individuals with first-degree AD relatives.…”

Section: Discussionmentioning

confidence: 61%

“…Individuals harboring two copies of the APOE Â4 allele (homozygotes) are at significantly increased risk to develop AD compared to individuals lacking an Â4 allele in the APOE genotype [3][4][5]. However, some controversy remains whether the Â4 allele is also associated with the Aerssens/Raeymaekers/Lilienfeld/Geerts/ Konings/Parys onset of the disease [6][7][8], differences in disease severity [9,10], rate of decline [6,7,[11][12][13][14][15], and/or other clinical characteristics observed in (subpopulations of) AD patients [3,16,17]. A possible explanation for such controversies might be that genetic findings identified in a specific population are not necessarily present and can thus not be found in another population with a different ethnic and/or genetic background.…”

Section: Introductionmentioning

confidence: 99%

<i>APOE</i> Genotype: No Influence on Galantamine Treatment Efficacy Nor on Rate of Decline in Alzheimer’s Disease

Aerssens

Raeymaekers

Lilienfeld

et al. 2001

Dement Geriatr Cogn Disord

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Apolipoprotein E (APOE) has been extensively demonstrated to be a genetic risk factor for Alzheimer’s disease (AD). Associations of APOE genotype have been reported with age at AD onset, rate of decline, and responsiveness to therapy. This study aimed to test these hypotheses in a large study population of AD patients. APOE genotype was determined from 1,528 Caucasian subjects, diagnosed by NINCDS/ADRDA criteria as probable AD patients, enrolled in four international placebo-controlled clinical trials of 3–12 months duration, designed to evaluate efficacy of treatment with galantamine or sabeluzole. In addition to patient demographics and baseline scores for Mini Mental State Examination, scores on the Disability Assessment for Dementia (DAD) and the cognitive subscale of the Alzheimer’s Disease Assessment Scale (ADAS-cog) were recorded at the start, during, and at the end of the study. APOE Ε4 homozygotes had a significantly lower age at disease onset compared to patients with other APOE genotypes. The Ε4 allele was significantly over-represented in females compared to males, and in the group of subjects with an AD family history. Based on longitudinal data of 504 placebo-treated AD patients, the linear annual rate of change in score was 5 points on the ADAS-cog scale and 11 on the DAD scale. The Ε4 allele copy number did not influence these rates of decline. Sabeluzole treatment was not effective in the overall group compared to the placebo-treated group, nor in any subgroup stratified by Ε4 allele count. Galantamine produced cognitive and functional improvement that were not affected by Ε4 allele count. In conclusion, our data confirm a strong association between Ε4 homozygotes and age at onset of AD but do not support an effect of Ε4 allele copy number on rate of cognitive and functional decline nor on the efficacy of galantamine in patients with AD.

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“…Although the e4 allele has been shown to promote the neuropathological features of AD, including b-amyloid (Ab) deposition Nagy et al, 1995;Norrman et al, 1995;GomezIsla et al, 1996) and neurofibrillary tangle formation Nagy et al, 1995;Norrman et al, 1995;Gomez-Isla et al, 1996), attempts to relate these features to psychotic symptoms in AD have yielded conflicting results (Zubenko et al, 1991;Förstl et al, 1994;Mukaetova-Ladinska et al, 1995;Sweet et al, 2000). Additionally, ApoE e4 has been linked with more profound cholinergic loss in the frontal cortex (Soininen et al, 1995) and medial temporal lobe (Poirier et al, 1995), and acetylcholine levels have in turn been implicated in psychotic disturbances in AD (Cummings and Kaufer, 1996).…”

Section: Interpretation Of An Increased Risk Of Psychosis In Apoe E4 mentioning

confidence: 99%

“…Among the three major isoforms of ApoE (e2, e3, and e4), the e4 allele has been reported to increase an individual's risk of developing AD, and decrease age of disease onset, in proportion to the number of e4 alleles present (Corder et al, 1993;Farrer et al, 1997). The search for phenotypic correlates of e4 has included neuropathological studies of the rate of b-amyloid (Ab) deposition Nagy et al, 1995;Norrman et al, 1995;Gomez-Isla et al, 1996), neurofibrillary tangle formation Nagy et al, 1995;Norrman et al, 1995;Gomez-Isla et al, 1996), cholinergic markers (Poirier et al, 1995;Soininen et al, 1995), and medial temporal lobe atrophy (Lehtovirta et al, 1996b;Hashimoto et al, 2001;Basso et al, in press).…”

Section: Introductionmentioning

confidence: 99%

Apolipoprotein E ɛ4 Allele Increases Risk for Psychotic Symptoms in Alzheimer's Disease

Zdanys

Kleiman

MacAvoy

et al. 2006

Neuropsychopharmacol

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The apolipoprotein E (ApoE) e4 allele is a well-documented genetic risk factor for sporadic Alzheimer's disease (AD). Its association with psychopathology among AD patients has been the subject of discrepant reports. We aimed to determine whether ApoE e4 + and e4-AD patients exhibit a different risk profile for psychotic symptoms and other behavioral disturbances. The Neuropsychiatric Inventory (NPI) was administered to determine the frequency and severity of psychotic and other behavioral symptoms in a sample of n ¼ 266 AD patients who had been genotyped for ApoE. Multiple logistic regression models were used to calculate the association between the ApoE e4 allele and the presence of psychotic symptoms (delusions or hallucinations). Exploratory analyses were also conducted to determine the impact of disease severity on e4 effects and to examine the association between e4 and other behavioral symptoms. ApoE e4 was significantly associated with psychotic symptoms (odds ratio (OR) ¼ 1.87, 95% CI ¼ 1.07-3.29, P ¼ 0.029), adjusting for age, sex, education, and MMSE score. More stringent definitions of clinically significant psychosis yielded similar results. Exploratory analyses suggested that this effect accrued specifically from patients with severe-stage AD and primarily from an association between e4 and delusions. The e4 allele did not appear to influence the development of most other behavioral symptoms in our sample. In conclusion, AD patients who carry the ApoE e4 allele are at greater risk than noncarriers for developing psychotic symptoms, particularly as the severity of their dementia progresses.

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Apolipoprotein E Genotype and its Effect on Duration and Severity of Early and Late Onset Alzheimer's Disease

Abstract: It appears that the rate of progress of AD as a whole is independent of the ApoE genotype.

Cited by 30 publications

References 10 publications

Neuropsychological deficits associated with Alzheimer's disease in the very-old: Discrepancies in raw vs. standardized scores

Neuropsychological deficits associated with Alzheimer's disease in the very-old: Discrepancies in raw vs. standardized scores

<i>APOE</i> Genotype: No Influence on Galantamine Treatment Efficacy Nor on Rate of Decline in Alzheimer’s Disease

Apolipoprotein E ɛ4 Allele Increases Risk for Psychotic Symptoms in Alzheimer's Disease

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