Accelerated memory decline in Alzheimer's disease with apolipoprotein epsilon4 allele

To investigate a possible effect of the apolipoprotein (APOE) epsilon4 allele on memory decline in Alzheimer's disease (AD), we examined 64 AD patients with the APOE epsilon3/3, epsilon3/4, or epsilon4/4 allele using the Alzheimer Disease Assessment Scale-Cognitive subscale (ADAS-Cog) and its subtests at the initial examination and at the 1-year follow-up visit. One-year changes in the scores of the Word Recall subtest, Word Recognition subtest, and total ADAS-Cog were significantly correlated with the number of APOE epsilon4 alleles after controlling for the effects of age, sex, education, test interval, and baseline scores. Findings revealed that APOE epsilon4 allele is related to an accelerated memory decline in AD.     

The apolipoprotein E epsilon 4 allele and decline in different cognitive systems during a 6-year period

CONTEXT: Impairment of episodic memory is an early and defining feature of Alzheimer disease (AD). The apolipoprotein E (APOE) epsilon 4 allele is known to influence risk of AD but it has been difficult to establish whether it affects episodic memory differently from other cognitive functions. OBJECTIVE: To examine the association of epsilon 4 with decline in different cognitive systems. DESIGN: Longitudinal cohort study. SETTING: More than 40 groups of Catholic clergy from across the United States. PARTICIPANTS: Older Catholic clergy members without clinical evidence of dementia at baseline underwent annual clinical evaluations for up to 6 years. Of 624 persons eligible for follow-up, 611 (98%) participated, of whom 161 (26%) had at least 1 epsilon 4 allele. They completed an average of 5.5 evaluations (range, 2-7). MAIN OUTCOME MEASURES: Incident AD and annual rates of change in episodic memory, semantic memory, working memory, perceptual speed, and visuospatial ability. RESULTS: The presence of epsilon 4 was associated with risk of developing AD on follow-up (relative risk, 1.92; 95% confidence interval, 1.27-2.89). In a series of random effects models, epsilon 4 was associated with impaired baseline function in episodic memory and visuospatial ability and with more rapid decline in all domains. The effect of epsilon 4 on annual decline in episodic memory (>3-fold increase) was significantly stronger than its effect on decline in other cognitive systems (P<.01), and at baseline, its effect on episodic memory was marginally stronger than its effect on other cognitive domains (P =.06). CONCLUSION: The results suggest that the APOE epsilon 4 allele influences risk of AD by a relatively selective effect on episodic memory.     

The apolipoprotein E epsilon2 allele and the pathological features in cerebral amyloid angiopathy-related hemorrhage.

Cerebral amyloid angiopathy (CAA) is associated with apolipoprotein E (APOE gene, apoE protein) polymorphism: current evidence suggests that the epsilon4 allele is a risk factor for the development of CAA and the epsilon2 allele predisposes to hemorrhage. We sought to determine the relationship between the APOE epsilon2 allele and both the immunoreactivity profiles and vascular complications of CAA. We performed immunohistochemistry for amyloid beta-protein (A beta), apoE, cystatin C, and activated microglia, and examined the morphology of cortical and leptomeningeal vessels in 37 CAA-related hemorrhage (CAAH), 26 Alzheimer disease (AD) patients, and 20 controls. The extent of immunostaining of vessels for A beta, apoE, cystatin C, and perivascular activated microglia increased from controls through AD to a maximum in CAAH patients. Among cases with CAA (37 CAAH, 19 AD, and 6 controls, n = 62) vascular apoE (p < 5 x 10(-4)), cystatin C (p < 10(-4)), activated microglia (p < 10(-4)), vessels with a high ratio of wall thickness to lumen diameter (p < 0.003) as well as dilated/microaneurysmal vessels (p < 0.01) were present more frequently in patients with hemorrhage than without; however, these features were not associated with the APOE epsilon2 allele. Fibrinoid necrosis alone was associated with the APOE epsilon2 allele (p < 0.04) and we suggest that over-representation of APOE epsilon2 in CAAH may result from its association with fibrinoid necrosis.     

High apolipoprotein E ε4 allele frequency in Age-related memory decline

Many studies have demonstrated a strong association between the presence of one or two ε4 alleles and Alzheimer's disease (AD), although few data are available on the apolipoprotein E (APOE) ε4 frequencies at the preclinical stages of AD. Thus, with a view to determining whether APOE genotyping could be useful in the early detection of AD, we determined the APOE allele frequencies in patients with memory complaints without dementia (age-related memory decline, ARMD). We found an APOE ε4 allele frequency of 0.315 in the ARMD group, similar to 0.293 in the AD group, in contrast to 0.057 in the control group. Significant differences (t= ?2.91, df=25,p=0.008) were found between the Alzheimer's Disease Assessment Scale (ADAS) total scores in the ARMD patients with at least one ε4 allele (mean=24.2) compared with the ARMD patients without the ε4 allele (mean= 14.7). Our results suggest that the patients with memory complaints, a high ADAS score, and the presence of one or two APOE-4 alleles could be at high risk for developing AD. Thus, we propose that genotyping in conjunction with the ADAS scale may prove useful as diagnostic markers of AD in the presymptomatic stages.     

The allele interaction between apolipoprotein epsilon2 and epsilon4 in Taiwanese Alzheimer's disease patients

OBJECTIVE: This study aimed to determine the impact of the present of apolipoprotein epsilon (Apoepsilon) 2 on the relationship between Apoepsilon4 and Alzheimer's disease (AD). METHOD: We examined ApoE genotypes in 428 Taiwanese patients with AD and 807 controls; all participants were older than 65 years. RESULTS: The allele frequency of Apoepsilon4 was greater in AD patients than controls, but significantly lower than in Caucasians. The presence of an epsilon2 allele alone was not associated with lower risk for AD, but the presence of an epsilon2 allele was associated with an epsilon4 allele frequency similar to that of controls. CONCLUSION: The low allele frequency of epsilon4 in persons with an epsilon2 allele suggests that this may be part of the protective effect of epsilon2 against AD.     

Olfactory identification and apolipoprotein E epsilon 4 allele in mild cognitive impairment

To investigate olfactory identification and apolipoprotein E ε4 allele in patients with mild cognitive impairment (MCI), we used Cross-Cultural Smell Identification Test (CC-SIT) from University of Pennsylvania to assess olfactory identification performance and polymerase chain reaction (PCR) to detect apolipoprotein E ε4 (ApoE ε4) allele in 28 patients with MCI and the 30 age-matched control subjects in present study. The Mann-Whitney U test demonstrated that the MCI group performed significantly worse on CC-SIT than the normal aging group (P<0.01). For MCI patients olfaction scores correlated positively with CAMCOG-C (r=0.61, P<0.01), but not with age, gender or years of education. In normal subjects, the CC-SIT score showed no significant associations with age, gender, years of education, or CAMCOG-C. As the least common allele in Chinese, ε4 was found in 13.3% of controls and in 35.8% of MCI in this study. ApoE ε4 was significantly higher in MCI group than normal group (χ²=4.65, P<0.01). There was a significant effect of allele status on odor identification: subjects with ε4 allele were not able to identify as many odors as the subjects without ε4 allele (P<0.01). These results suggested that the decreased olfactory identification in MCI may be a marker for the early diagnosis of Alzheimer’s disease, and ApoE genotype may be part of the basis of olfactory identification decline.     

Absence of the apolipoprotein E epsilon4 allele is associated with working memory impairment in Parkinson's disease

The apolipoprotein E (APOE) epsilon4 allele has been associated with an increased risk of Alzheimer's disease (AD) and weaker episodic memory among elderly. Although this APOE allele has been linked to earlier onset of Parkinson's disease (PD), an association with dementia in PD has been only inconsistently demonstrated. Given the heterogeneity of cognitive impairment patterns in PD, this study sought to determine whether an association exists between APOE genotype and specific cognitive deficits in PD. The neuropsychological test performance of 42 PD patients without an epsilon4 allele (PD-Non4) and of 20 with at least one epsilon4 allele (PD-epsilon4) was compared to that of 146 elderly control subjects (NC). The PD groups were comparable in overall severity of cognitive impairment and disease duration, but the PD-epsilon4 group was younger, had an earlier disease onset, and contained a higher proportion of persons with dementia. Both PD groups showed wide-ranging cognitive impairments relative to NC. Once age differences between groups were controlled for, the PD groups generally did not differ from each other in cognitive performance. However, only the PD-Non4 group demonstrated working memory/attention impairments (digit span, visual span, Trailmaking test) relative to the NC group. Results suggest that the APOE genotype may influence the cognitive phenotype of PD, and specifically that absence of the epsilon4 allele is associated with working memory impairment. Additionally, results are consistent with prior findings showing an association between the epsilon4 allele and earlier onset of PD and presence of dementia.     

Association between apolipoprotein E epsilon4 allele and apathy in probable Alzheimer's disease

OBJECTIVE: There have been inconclusive results to date on the association between the Apolipoprotein E (ApoE) genotype and neuropsychiatric symptoms (NPS) in Alzheimer's disease (AD). We investigated whether ApoE epsilon4 allele is associated with NPS in probable AD. METHOD: Data for 197 subjects with probable AD were analysed. The Neuropsychiatric Inventory was used to evaluate the frequency and severity of NPS. Multiple logistic regression models were used to test the association between ApoE genotype and NPS in AD. RESULTS: The ApoE epsilon3/3 genotype was present in 52.3%, epsilon3/4 in 44.1%, and epsilon4/4 in 3.6% of patients. ApoE epsilon4 carriers showed a higher frequency of apathy than non-carriers. After multiple adjustments, the ApoE epsilon4 allele was significantly associated with apathy. CONCLUSION: Our results suggest a relationship between the ApoE epsilon4 allele and apathy in patients with AD.     

Accelerated hippocampal atrophy in Alzheimer's disease with apolipoprotein E epsilon4 allele

Although apolipoprotein E epsilon4 is an established risk factor for Alzheimer's disease, its effect on the rate of progression of Alzheimer's disease remains unknown. The purpose of this longitudinal study was to elucidate whether the rate of hippocampal atrophy is a function of the apolipoprotein E genotypes and severity of disease. Fifty-five patients with probable Alzheimer's disease were the subjects. The annual rate of hippocampal atrophy was determined by using magnetic resonance imaging repeated at a 1-year interval. On a two-way analysis of variance, the effect of the apolipoprotein E epsilon4 allele on hippocampal atrophy was significant, but neither the effect of severity nor the interaction term was significant. In further analysis with one-way analysis of variance, the mean annual rate of hippocampal atrophy was significantly different between the groups of patients with (9.76 +/- 4.27%) and without the apolipoprotein E epsilon4 allele (6.99 +/- 4.24%). Apolipoprotein E epsilon4 dose was significantly correlated with the rate of hippocampal atrophy (rs = 0.277, Spearman rank correlation coefficient), suggesting a gene dose effect. The involvement of the apolipoprotein E epsilon4 allele in the progression of hippocampal atrophy has implications for therapeutic approaches in Alzheimer's disease and should be taken into consideration in longitudinal studies including clinical drug trials.     

The apolipoprotein E epsilon4 allele and the response to tacrine therapy in Alzheimer's disease.

The objective of our study was to evaluate the effects of the apolipoprotein E (ApoE) phenotype and gender on the response to tacrine treatment in Alzheimer's disease (AD). ApoE phenotyping was performed on 76 patients treated with tacrine for AD. This group comprised 33 ApoE epsilon4 allele carriers (epsilon4+) and 43 non-epsilon4 carriers (epsilon4-). Patients were treated blindly in relation to the ApoE phenotype, with incremental tacrine dosages ranging from 40 mg/day up to the highest dosage (160 mg) tolerated without side-effects. At least 6 weeks elapsed between each increase. Changes in the scores for the Alzheimer Disease Assessment Scale-Cognitive Component (ADAS-Cog) between baseline and each increment in dosage were assessed in the epsilon4- and epsilon4+ groups. The cut-off point for being considered as responsive to tacrine treatment was a 4-point decrease in the ADAS-Cog score. There was no tendency for the epsilon4- carriers to respond better than the epsilon4+ carriers. When patients were stratified by gender, no differences were found between the effects of the treatment on men and women. Consequently, these results do not support the hypothesis that the ApoE phenotype and gender are predictors of the response to tacrine in AD patients.     

The apolipoprotein E epsilon4 allele and antidepressant efficacy in cognitively intact elderly depressed patients.

BACKGROUND: Patients vary in response to antidepressant medications. Apolipoprotein E (APOE) genotype affects vulnerability to stress and risk for cognitive impairment. We sought to determine if the APOE epsilon4 allele influences response in geriatric depression to mirtazapine and paroxetine, two frequently prescribed antidepressants. We hypothesized that epsilon4 carriers would show impaired antidepressant response. METHODS: The study was a double-blind, randomized, 8-week trial with a 16-week extension phase involving 246 cognitively intact patients aged 65 years or older with major depression. Patients were treated with mirtazapine 15-45 mg (n = 124) or paroxetine 20-40 mg (n = 122). The outcome measures were the Hamilton Depression Rating Scale, the Geriatric Depression Scale, and the Clinical Global Impression Scale. APOE genotype was determined by restriction isotyping. RESULTS: Patients carrying the epsilon4 allele showed a rapid onset of mirtazapine action, whereas paroxetine-treated patients with the epsilon4 allele were slow to respond. This difference could not be attributed to dosage, compliance, severity of adverse events, ethnicity, baseline depression or cognition, gender, or age. CONCLUSIONS: The APOE epsilon4 allele may affect antidepressant treatment outcome, but the effect depends on the medication. Further studies should determine if this result applies to other samples and medications.     

The apolipoprotein E epsilon4 allele and incident Alzheimer's disease in persons with mild cognitive impairment

Possession of one or more copies of the apolipoprotein E (APOE) epsilon4 allele is a known risk factor for Alzheimer's disease (AD), but it is uncertain whether the epsilon4 allele is associated with disease incidence among persons with mild cognitive impairment (MCI). We addressed this issue with data from the Religious Orders Study. Participants were 181 older Catholic clergy members who met criteria for MCI based on a uniform structured clinical evaluation; 56 (30.9%) had at least one epsilon4 allele. Clinical evaluations, which included clinical classification of dementia and AD, were repeated annually. During a mean of 5.7 years of observation, 79 persons (43.6%) developed AD. In a proportional hazards model that controlled for age, sex, and education, possession of an epsilon4 allele was associated with a 93% increase in the risk of developing Alzheimer's disease (95% CI; 1.02, 2.63). There was a marginally significant reduction in the effect of epsilon4 in older compared to younger participants (p=.053). The results suggest that possession of an epsilon4 allele does increase risk of AD in persons with MCI.     

Association of the apolipoprotein E epsilon4 allele with late-onset depression.

Apolipoprotein E (ApoE) phenotyping was determined in 42 subjects with Alzheimer's disease (AD), 49 with depression, including 26 with early-onset depression (EOD) and 23 with late-onset depression (LOD), and 49 controls. In the EOD group, the frequency of the ApoE epsilon4 allele was not different from the control frequency (p = 0.532) but was significantly lower than in AD (p < 0.001). In the LOD group, the ApoE epsilon4 frequency was significantly higher than in the controls (p = 0.034) but was not different from that in the AD group (p = 0.229). Individuals with ApoE epsilon4 were at greater risk of getting AD (odds ratio, OR = 5.5, 95% confidence interval, CI, 2.0-14.0) or LOD (OR = 6.1, 95% CI, 1.9-19.0) than of EOD (OR = 0.7, 95% CI, 0.2-2.5). These results suggest an association between the ApoE epsilon4 allele frequency and LOD. Patients with LOD could be at risk of developing AD by an epsilon4-dependent pathway.     

The apolipoprotein E epsilon4 allele selectively increases the risk of frontotemporal lobar degeneration in males

OBJECTIVE: To determine whether polymorphic variations in the apolipoprotein E gene (APOE) are associated with increased risk of frontotemporal lobar degeneration (FTLD) when mutation in tau gene is absent. METHODS: The APOE gene was genotyped by polymerase chain reaction from DNA routinely extracted from blood or brain tissues. The APOE epsilon4 allele frequency in 198 patients with FTLD not associated with mutations in tau gene was compared with that of a control group of 756 normal individuals drawn from the same geographical region. Analyses were done according to clinical subtype or sex. RESULTS: The APOE epsilon4 allele frequency (19.4%) was increased (p = 0.01) in FTLD v the whole control group (14.1%), while the APOE epsilon2 allele frequency in FTLD (6.5%) was slightly lower than in controls (8.0%) (NS). The APOE epsilon4 allele frequency in men with FTLD (22.3%) was greater (p = 0.002) than in male controls (12.3%); the frequency in women (16.3%) was similar to that in female controls (14.8%) (NS). The APOE epsilon2 allele frequency in men with FTLD was 4.9% while in male controls it was 9.5% (p = 0.06), but there was no difference in women (7.5% v 7.9%, NS). Neither the APOE epsilon2 nor APOE epsilon4 allele frequency varied significantly between any of the clinical subtypes. CONCLUSIONS: In FTLD not associated with mutations in tau gene, possession of APOE epsilon4 allele in men roughly doubles the chances of developing disease, whereas this has no impact upon disease risk in women.     

The apolipoprotein E epsilon 4 allele increases the risk of drug-induced hallucinations in Parkinson's disease.

To determine whether the apolipoprotein E (APOE) epsilon 4 allele is a risk factor of drug-induced hallucinations in nondemented patients with Parkinson's disease (PD), the proportions of patients with hallucinations in groups with and without the APOE epsilon 4 allele were compared with a chi 2 test. The contribution of the APOE epsilon 4 allele to the occurrence of hallucinations was further evaluated by means of logistic regression models, adjusting for potential prognostic variables. Thirteen (76%) of the 17 patients who had the epsilon 4 allele had visual hallucinations, compared with 20 (23%) of the 88 patients without the epsilon 4 allele (p < 0.0001; odds ratio = 11.05; 95% CI 3.24-37.67). In addition, treatment with dopamine agonists also contributed to an increased risk of hallucinations (p = 0.0011). After adjustment for age, severity of parkinsonism, duration of treatment, dose of levodopa, and treatment with dopamine agonists, the association between the presence of the epsilon 4 allele and the occurrence of visual hallucinations remained significant (p = 0.0003). Nondemented PD patients with the APOE epsilon 4 allele have a high risk of developing drug-induced visual hallucinations. Further studies are needed to evaluate which proportion of these patients will end up developing dementia.     

Effect of the apolipoprotein E epsilon4 allele on white matter hyperintensities in dementia

BACKGROUND AND PURPOSE: The clinical significance of the apoE epsilon4 allele in white matter changes in patients with dementia has been a subject of debate. We studied the association between the apoE epsilon4 allele and white matter hyperintensities (WMHs) before and after control for (1) potential vascular risk factors and (2) the presence of lacunar infarcts in patients with dementia. METHODS: The subjects were 131 patients with dementia who had either Alzheimer's disease or vascular dementia, or a combination of these 2 types of dementia, with or without WMHs, lacunar infarcts, or both. The association of the epsilon4 allele with WMHs was examined before and after control for age, sex, duration of symptoms, education level, severity of dementia, presence of lacunar infarcts, and potential vascular risk factors, including hypertension, diabetes mellitus, lipid disorders, smoking habit, drinking habit, and cardiac diseases. RESULTS: WMHs were observed in 73 (55.7%) of the patients. Neither the number of apoE epsilon4 alleles nor their presence was significantly associated with WMHs before or after control for the potential confounding factors. Multiple logistic regression analyses revealed that age, the presence of hypertension, and the presence of lacunar infarcts were independently associated with WMHs. CONCLUSIONS: The apoE epsilon4 allele was not associated with WMHs in patients with dementia. The fact that WMHs were significantly associated with hypertension and lacunar infarcts may indicate an ischemic origin of WMHs.     

Apolipoprotein E epsilon4 allele and lorazepam effects on memory in high-functioning older adults

CONTEXT: The apolipoprotein E (APOE) epsilon4 allele has been implicated as a significant risk factor in the development of late-onset Alzheimer disease, but the evidence of cognitive sequelae in healthy individuals has been mixed. OBJECTIVE: To determine if the APOE epsilon4 allele increases susceptibility to lorazepam-induced verbal learning impairment in nondemented older adults. DESIGN: A placebo-controlled crossover design. SETTING: A community-based sample of subjects. PARTICIPANTS: Sixty-four cognitively intact and highly educated (>12 years) adults. Twenty-four subjects (mean age, 66.3 years) were carriers of an APOE epsilon4 allele (epsilon4 positive) and 40 (mean age, 66.0 years) were not (epsilon4 negative). INTERVENTIONS: All subjects received a single oral dose of placebo and lorazepam (0.5 and 1.0 mg) 1 week apart. MAIN OUTCOME MEASURE: We used the Buschke Selective Reminding Test to assess verbal learning during a 5-hour period after placebo or lorazepam administration. RESULTS: We found a time-related, dose-dependent effect of lorazepam, with long-term recall generally decreasing with higher doses of lorazepam at up to 2.5 hours. At 5 hours, the epsilon4-negative group showed significant improvement in long-term memory, but the epsilon4-positive group demonstrated a persistent deficit. Subsequent analysis revealed that the poor performance at 5 hours was found in an epsilon4-positive subgroup with lower baseline performance. CONCLUSIONS: In cognitively intact, older adults, the effect of the APOE epsilon4 allele is not necessarily seen in the immediate response to benzodiazepine challenge. Rather, the APOE epsilon4 allele appears to affect the carrier's ability to recover from a cognitive challenge in a normal fashion, at least in a subgroup of subjects with relatively low baseline performance. This suggests that although carrying an APOE epsilon4 allele increases the risk for cognitive toxic effects, allele status alone is not a sufficient predictor of such effects. Studying the response to and the recovery from cognitive challenges may provide insights into the role of the APOE epsilon4 allele and its interaction with other factors in the development of Alzheimer disease and other age-related cognitive problems.     

SPECT and MRI analysis in Alzheimer''s disease: relation to apolipoprotein E epsilon 4 allele.

OBJECTIVES--The epsilon 4 allele of apolipoprotein E (ApoE) is a risk factor for late onset Alzheimer's disease. ApoE is present in senile plaques, neurofibrillary tangles, and cerebrovascular amyloid, and it is implicated in synaptogenesis. The effect of ApoE polymorphism on the volumes of hippocampus, amygdala, and frontal lobe was studied. The hypothesis was that the patients with Alzheimer's disease carrying the epsilon 4 allele have more pronounced atrophy. The relation of ApoE and cerebral blood flow on cortical areas was also assessed. METHODS--Fifty eight patients with Alzheimer's disease at the early stage of the disease and 34 control subjects were studied. Patients with Alzheimer's disease were divided into subgroups according to the number of the epsilon 4 alleles. Volumes were measured by MRI and regional cerebral blood flow ratios referred to the cerebellum were examined by 99mTc-HMPAO SPECT. ApoE genotypes were determined by digestion of ApoE polymerase chain reaction products with the restriction enzyme Hha1. RESULTS--patients with Alzheimer's disease had smaller volumes of hippocampi and amygdala compared with control subjects, and the patients with Alzheimer's disease homozygous for the epsilon 4 allele had the most prominent volume loss in the medial temporal lobe structures. The frontal lobe volumes did not differ significantly. All patients with Alzheimer's disease had bilateral temporoparietal hypoperfusion and the subgroups with one or no epsilon 4 alleles also had frontal hypoperfusion compared with control subjects. The occipital perfusion ratios tended to decrease with increasing number of epsilon 4 alleles. CONCLUSIONS--Patients with Alzheimer's disease homozygous for the epsilon 4 allele seem to have severe damage in the medial temporal lobe structures early in the disease process and differ from the patients with Alzheimer's disease with one or no epsilon 4 alleles.     

Lower levels of N-acetylaspartate in multiple sclerosis patients with the apolipoprotein E epsilon4 allele

BACKGROUND: In multiple sclerosis (MS), the epsilon4 allele of apolipoprotein E (APOE epsilon4) has been associated with more rapid clinical worsening and more severe tissue damage on magnetic resonance imaging. OBJECTIVE: To use proton magnetic resonance spectroscopy ((1)H-MRS) to further explore the biochemical changes in the brains of patients with MS associated with APOE epsilon4. DESIGN: A 2-year clinical and (1)H-MRS follow-up cohort study. SETTING: The MS outpatient clinic, Department of Neurology, and Magnetic Resonance Center of Karl-Franzens University. PATIENTS: We performed (1)H-MRS of the central portion of both hemispheres and APOE genotyping in 72 patients (52 women and 20 men; mean +/- SD age, 34.8 +/- 8.8 years) with clinically definite relapsing-remitting MS. Repeated studies were performed in 44 patients after a mean +/- SD interval of 34 +/- 9 months. MAIN OUTCOME MEASURE: Levels of N-acetylaspartate as measured by (1)H-MRS. RESULTS: Patients with MS and an epsilon4 allele (n = 19) had a significantly lower mean +/- SD N-acetylaspartate-creatine ratio than those without an epsilon4 allele (n = 53) (1.73 +/- 0.26 vs 1.89 +/- 0.24; P =.04) despite the absence of significant differences in age at onset, disease duration, Expanded Disability Status Scale score, and number of previous relapses between subgroups. During follow-up, the drop in the N-acetylaspartate-creatine ratio of epsilon4 carriers was also significantly larger (-0.31 vs -0.10; P =.01). This was paralleled by a higher number of relapses (mean +/- SD, 4.1 +/- 2.7 vs 1.7 +/- 1.6; P =.02) and a faster although nonsignificant progression of disability (mean +/- SD (Delta)Expanded Disability Status Scale score, 0.9 +/- 1.8 vs 0.3 +/- 1.1; P =.19). CONCLUSIONS: The APOE epsilon4 allele has a negative effect on the course of MS, and increasing axonal damage may be an important mechanism.