点击显示 收起
Rush AD Center and Rush Institute for Healthy Aging (D.A.B., R.S.W., D.A.E., J.A.S., J.L.B.), Department of Psychology (R.S.W.), Department of Neurological Sciences (D.A.B., R.S.W., D.A.E., J.A.S.), Department of Pathology (J.A.S.), Department of Internal Medicine (D.A.E., J.L.B.), Rush University Medical Center, Chicago, Ill.
Abstract
Background and Purpose— Studies investigating the relation of the apolipoprotein E (apoE) 4 allele to clinical stroke and to vascular changes on magnetic resonance imaging have been conflicting. Little data are available regarding the relation of apoE 4 to cerebral infarctions documented on postmortem examination.
Methods— We studied the apoE 4 allele in 214 deceased members of the Religious Orders Study, a longitudinal clinical–pathologic study of aging and Alzheimer disease. The apoE genotype was determined using DNA from lymphocytes. Brains were removed a median of 5 hours (interquartile range, 5.5) after death. At postmortem examination, age, location, and size of macroscopic chronic cerebral infarctions were recorded from 1-cm coronal slabs after paraformaldehyde fixation. We also examined 20-μm paraffin-embedded sections of midfrontal and calcarine cortex for amyloid angiopathy on a scale of 1 to 4.
Results— Subjects included 96 males and 118 females with a mean age at death of 86 years (SD, 7). Sixty-five subjects (30.4%) had at least 1 apoE 4 allele and 76 (35.5%) exhibited cerebral infarctions. More than 74% of the subjects exhibited amyloid angiopathy with a mean score of 1.4±1.2. After controlling for age and sex, apoE 4 increased the odds of cerebral infarction by 2.3-fold (95% CI, 1.2 to 4.2). apoE 4 increased the odds of cortical 3.2-fold (95% CI, 1.3 to 7.7) and subcortical infarctions 2.3-fold (95% CI, 1.2 to 4.5). The effect was unchanged after accounting for amyloid angiopathy.
Conclusions— apoE 4 increases the odds of chronic cerebral infarction detected at autopsy in older persons.
Key Words: cerebral infarction epidemiologic methods genetics pathology
Introduction
The apolipoprotein E 4 genotype is a common polymorphism, present in 25% of the population.1 A known risk factor for Alzheimer disease (AD),2 the 4 allele is also related to indicators of vascular disease.3 apoE is related to serum lipid profiles,1 particularly cholesterol,3 atherosclerosis,4 and increased thickness of large arteries, such as the thoracic and abdominal aorta and coronary arteries.3 Although not considered one of the major risk factors for cardiovascular disease, the effect of the apoE 4 genotype on risk of coronary heart disease is generally well-accepted.3–4 Much less clear is the role of the apoE polymorphism on the cerebral vasculature and cerebral infarction. Although some cross-sectional studies have supported a role for apoE 4 allele in carotid artery atherosclerosis,5 clinical stroke,6 and recurrent clinical cerebral infarction,7 numerous other clinical studies refute a significant role for the apoE 4 allele in cerebral vascular disease.8–10 The majority of studies on the 4 allele and cerebrovascular disease have focused on clinical stroke, in which diagnostic misclassification is a potential bias.11–12 We are unaware of any autopsy-based studies of older persons with and without dementia that examined the relation of allele status to cerebral infarctions. We used genotype and autopsy data from the Religious Orders Study, a longitudinal clinical–pathologic study of older persons to study apoE allele status with cerebral infarction found at postmortem examination.
Subjects and Methods
We used data from 214 deceased subjects from the Religious Orders Study, a longitudinal clinical–pathologic study of aging and dementia, who agreed to clinical evaluation and brain donation. The study was approved by the Institutional Review Board of Rush University Medical Center, and each participant signed an informed consent and an Anatomical Gift Act. Since January of 1994, >1000 persons have enrolled in the study and annual follow-ups have exceeded 95% of survivors. Details of the study have been previously reported.13 The interview included structured questions regarding myocardial infarction and claudication and used standard criteria.14 Participants were evaluated in person by an expert physician, and were classified with respect to AD, stroke, and other common conditions. The diagnosis of AD followed the recommendations of the joint working group of the National Institute of Neurological and Communicative Disorders and Stroke and the Alzheimer Disease and Related Disorders Association (NINCDS/ADRDA).15 The diagnosis of clinical stroke was based on review of the medical history, neurological examination, and review of neuroimaging when available as previously described.13 After death, clinical data were reviewed blinded to postmortem data and the most likely clinical diagnoses at the time of death was rendered. As of March 22, 2004, of 270 deceased subjects, autopsies have been performed on 253. These analyses are performed on the 214 subjects on whom data on both cerebral infarctions and apoE genotype were available.
ApoE Genotyping
Blood was collected with acid citrate dextrose anticoagulant. DNA was extracted using a Puregene DNA isolation kit (Gentra). ApoE genotype was determined according to the method described by Hixson and Vernier16 as previously reported.17
Neuropathologic Evaluation
Brains were removed in a standard fashion as described previously.13,18–19 The median postmortem interval was 5.00 (median interquartile range, 5.5). Each brain was cut into 1-cm coronal slabs and examined for pathology at the time of autopsy. Slabs from one hemisphere and slabs from the opposite hemisphere with notable pathology were fixed for 3 to 14 days in 4% paraformaldehyde. The remainder of the brain was frozen.
Cerebral Infarctions
The entire brain was examined for gross cerebral infarctions (any infarction visualized by the naked eye). We recorded the age of each infarction (microscopic review was performed when age was uncertain). Of 26 cases with recent infarctions, only 11 had acute or subacute infarctions without chronic infarctions, 3 of which were considered fatal symptomatic infarction. Because acute and subacute infarctions may result from perimortem medical conditions (eg, hypotension, anoxia), primary analyses focused on chronic infarctions.
We recorded the location, number, and volume of each infarction. Location was designated as cortical, subcortical, or brain stem/cerebellum. The 3 dimensions were recorded to determine each infarct volume (mm3), which was summed for total volume. Ischemic infarctions that included hemorrhage were not separately designated. Primary intraparenchymal hemorrhages were recorded and analyzed separately.
Blocks of midfrontal, superior, or middle temporal, entorhinal, and inferior parietal cortex, basal ganglia, thalamus, and midbrain were paraffin-embedded, cut into 6-μm sections, and mounted on glass slides. All sections were examined by a board-certified neuropathologist for microscopic infarctions. Microscopic infarctions were recorded.
Cortical and subcortical infarctions were coded as present or absent; number of infarctions as none, 1, and >1; and volume with a median split. We determined an infarction to be symptomatic (clinically evident) or asymptomatic (subclinical) by using the final clinical summary diagnosis of stroke. We also summarized perimortem infarctions (acute or subacute infarctions), primary intraparenchymal hemorrhages, and microscopic infarctions as present or absent for analyses.
We also documented the severity of lipohyalinosis on a scale from 0 to 7: 0, no lipohyalinosis; 1, possible; 2, mild; 3, mild to moderate; 4, moderate; 5, moderate to severe; 6, severe; and 7, completely occluded blood vessel(s). Data were available on 195 consecutive subjects (91% of the cohort).
Amyloid Angiopathy
We evaluated amyloid angiopathy on 20-μm paraffin-embedded sections from blocks of midfrontal and calcarine cortex. Sections were stained with antibodies to amyloid protein (DAKO; 1:1000) using a standard protocol as previously described.20 We used a semiquantitative grading system similar to that used in other studies:21–22 0 (none), no evidence of amyloid in cerebral or meningeal vessels; 1 (mild), rare amyloid in cerebral or meningeal vessels; 2 (moderate), circumferential staining in several leptomeningeal or cortical vessels; 3 (severe), widespread circumferential staining involving most vessels in the cortex and meninges; and 4 (very severe), same as severe with amyloid positivity emanating from vessels into neuropil. We found that the severity of midfrontal and occipital cortex amyloid angiopathy was strongly related (r=0.74; P<0.001). For analyses, we averaged the grade from both regions to determine an average severity score for each case. We also created a dichotomous measure and considered amyloid angiopathy present if the average severity score was >0 and amyloid angiopathy absent if the severity score was 0. Data were available on 208 consecutive subjects (97% of the cohort).
AD Pathology
Slides from the hippocampus, entorhinal, midfrontal, middle temporal, and inferior parietal cortices were stained with Bielschowsky silver stain. In each of the 4 regions, we counted total number of neuritic plaques, diffuse plaques, and neurofibrillary tangles in a 1-mm2 area (x100 magnification) using a graticule. The counting and derivation of the summary measure of AD pathology were performed as previously described.19
Statistical Analysis
To test for differences between those with and without an 4 allele, we used t tests for continuous variables and the 2 test for categorical data. Because amyloid angiopathy and the AD pathology measure were not normally distributed, a Wilcoxon test was used. Wilcoxon test was also used to compare the AD pathology measure in persons with and without infarction. We used Spearman correlations to determine the unadjusted relationships between continuous variables.
We used multiple logistic regression models to determine the odds of infarctions in persons with and without an 4 allele. All models controlled for age and sex, and the reference group was persons without infarctions. We first determined the odds of any infarctions and then used separate models to evaluate the odds of having cortical or subcortical infarctions. Similar analyses were performed for single and multiple infarctions, and for those with small and large infarctions.
In secondary analyses we used logistic regression, controlling for age and sex to investigate the relationship of apoE 4 to symptomatic infarctions, perimortem infarctions, primary intraparenchymal hemorrhages, and microscopic infarctions.
We also used logistic regression to investigate the odds of amyloid angiopathy in persons with and without an 4 allele. To determine whether amyloid angiopathy accounted for relationship of the 4 allele and infarction, we performed separate models including amyloid angiopathy as a covariate. Similar analyses were used to investigate AD pathology, large vessel disease (myocardial infarction and claudication), and small vessel disease (lipohyalinosis). All analyses were performed using SAS/STAT software Version 823 on a SunUltraSparc workstation.
Results
The apoE genotypes were available for 214 persons. Sixty-five had 4 (2/4=8; 3/4=51; 4/4=6) allele and 149 did not (2/3=23; 3/3=126). Age and sex were not different in persons with and without 4 allele. Amyloid angiopathy was more frequent and severe in the presence of an 4 allele (Table 1).
Cerebral infarctions were present in 76 persons, with 27 persons with cortical and 64 persons with subcortical infarctions. As noted in Table 2, there was a lot of overlap such that cortical and subcortical infarctions were present together in 16 persons, >20% of the cohort. Only 4 persons had brain stem infarctions, and 3 of these persons also had cortical and/or subcortical infarctions. More than half (n=41) of the persons with infarctions had multiple infarctions including 19 with 2, 9 with 3, 7 with 4, and 6 with 5 to 9. Total infarction size per case ranged from 8 mm3 (2 mm in diameter) to 294 512 mm3 (6.7 cm in diameter of total infarction volume). The mean volume of infarctions was 7925.5 mm3 and the median was 525 mm3 (8 mm in diameter).
ApoE 4 and the Presence of Cerebral Infarctions
Of the 65 persons with 4 allele, almost half had 1 or more cerebral infarctions compared with less than one-third among those without 4 allele (Table 2). Macroscopic chronic cerebral infarctions were evident in 22 of 51 persons with 4/3 genotype; 7 of 8 persons with 2/4, and 2 of 6 persons with 4/4 genotype. In logistic regression analyses controlling for age and sex, persons with 4 allele(s) had a 2.3-fold higher (95% CI, 1.2 to 4.2) odds of cerebral infarction compared with those without an 4 allele (Table 3).
The Apolipoprotein E 4 Allele and the Location of Cerebral Infarctions
To examine the effect of apoE 4 on location of infarctions, we constructed 2 separate multiple logistic regression models for cortical and subcortical infarctions. All models controlled for age and sex. Compared with persons without an infarction, the odds of having a cortical infarction were 3.2-fold higher (95% CI, 1.3 to 7.7), and a subcortical infarction 2.3-fold higher (95% CI, 1.2 to 4.5), in persons with an 4 allele compared with those without (Table 3).
ApoE 4 and Number and Volume of Cerebral Infarctions
We examined the relation of the apoE 4 to the number and volume of infarctions in separate multiple regression models, controlling for age and sex. In persons with 4 allele, the odds of having a single infarction were 2.1 (95% CI, 1.2 to 4.6) and the odds of having multiple infarctions were 2.5 (95% CI, 1.2 to 5.4), compared with persons without 4 allele (Table 3). Similarly, in persons with 4 allele, the odds of smaller infarctions were 2.2 (95% CI, 1.0 to 4.7) and the odds of larger infarcts were 2.4 (95% CI, 1.1 to 5.1) (Table 3).
ApoE 4 and Other Types of Cerebral Infarctions
In additional regression analyses, the odds of a symptomatic infarction (n=33) was 3.0 (95% CI, 1.3 to 6.6), whereas the odds of an asymptomatic infarction was 1.8 (95% CI, 0.8 to 3.9). The odds of perimortem infarctions (n=26, with 15 also having chronic infarctions) was 1.6 (95% CI, 0.6 to 2.8). The odds of primary intraparenchymal hemorrhages (n=9, with 2 also having chronic ischemic infarctions) was 1.5 (95% CI, 0.4 to 6.6). The odds of microscopic infarctions (n=74, with 38 also having macroscopic infarctions) was 1.3 (95% CI, 0.6 to 2.5).
Apo4, Amyloid Angiopathy, AD Pathology, and Cerebral Infarctions
We found the presence of amyloid angiopathy in nearly 75% of the subjects (155 of 208 for which data were available). The median amyloid angiopathy severity score was 1 (range, 0 to 4) (Table 1). Amyloid angiopathy showed a wide spectrum of severity with no disease (score=0) in 53 of 208 subjects (25%), mild disease (score 0.5 to 1.0) in 58 (28%), moderate disease (score 1.5 to 2.0) in 47 (23%), severe disease (score=2.5 to 3.0) in 26 (12%), and very severe disease (score=3.5 to 4) in 24 (12%). The severity of amyloid angiopathy was related to AD pathology (r=0.55; P<0.001), primary intraparenchymal hemorrhages (OR, 1.9; 95% CI, 1.0 to 3.1), but not cerebral infarctions (OR, 1.0; 95% CI, 0.7 to 1.3). Persons with 4 allele had nearly a 7-fold increase in the odds of exhibiting any amyloid angiopathy (OR, 6.9; 95% CI, 2.5 to 18.6). After controlling for the severity of amyloid angiopathy, there was no change in association between the 4 allele and the odds infarction (OR, 2.4; 95% CI, 1.2 to 4.8). Finally, the AD pathology summary measure was not related to the presence of infarction (Wilcoxon test, P=0.32) and after controlling for AD pathology, the odds of infarction in persons with 4 allele was also essentially unchanged (OR, 2.2; 95% CI, 1.1 to 4.5).
ApoE 4 and Other Vascular Disease
Myocardial infarction or claudication, conditions associated with large vessel atherosclerosis, was present in 93 persons and was associated with a 3-fold increased odds of cerebral infarction (OR, 3.0; 95% CI, 1.56 to 5.90). However, it did not the change the relationship between 4 and cerebral infarction (OR, 2.1; 95% CI, 1.2 to 3.9). Lipohyalinosis was present in half the subjects; 12% with minimal, mild, or mild-to-moderate disease; 25% with moderate disease; and 13% with moderate-to-severe, severe, or very severe disease. Each scale increase of lipohyalinosis increased the odds of cerebral infarction by 35% (OR, 1.35; 95% CI, 1.16 to 1.58), such that a person with severe lipohyalinosis (90% percentile) had 2-fold increase in the odds of having infarction. However, controlling for lipohyalinosis did not alter the relationship between the apoE 4 allele and cerebral infarction (OR, 2.9; 95% CI, 1.4 to 5.8).
Discussion
In this study of 214 older Catholic Clergy, we found that the apoE 4 allele was associated with 2-fold increase in the odds of chronic cerebral infarctions detected at autopsy. Persons with an apoE 4 allele were more likely to have symptomatic infarctions. We did not find evidence that the association was mediated by amyloid angiopathy.
The results of previous clinical or neuroimaging studies investigating the apoE 4 genotype to cerebrovascular disease are inconsistent. A meta-analysis of 9 case-control studies found that the 4 allele frequency was increased in the group with clinical stroke.6 apoE 4, however, has not been found to be an important risk factor for cerebrovascular disease in other studies,24–25 including several population-based studies.8–10 A possible explanation for the ambiguity among studies is the potential for misclassification bias in studies of clinical stroke as asymptomatic infarctions are common in older individuals.26 Neuroimaging provides more information regarding infarction with a lesser chance for misclassification. In a neuroimaging study of apoE 4 and infarction, the effect of apoE 4 effect was found to be "marginal."27 Another neuroimaging study found no relationship between apoE 4 and magnetic resonance imaging changes, including infarctions.28 Few autopsy studies have addressed this issue in older persons and none in a cohort with and without dementia. In an autopsy-based study investigating apoE 4 and vascular lesions in cases of AD, apoE 4 was not found to have a relationship with cerebral infarctions.29 We found that the odds of chronic symptomatic infarctions associated with the 4 allele was higher than the odds of asymptomatic infarctions, suggesting that misclassification bias may not play a large role in discrepant findings among clinical studies.
Some have proposed that apoE 4 may be related to factors influencing degree of injury or recovery from stroke rather than stroke itself.24,30 Improved stroke outcome could lead to survival bias. We found an association between the 4 allele and odds of chronic symptomatic infarctions, whereas the odds of perimortem infarctions were not significantly increased. Although these results are consistent with a survival bias (ie, persons with 4 allele have a greater likelihood of surviving a cerebral infarction), an alternate explanation is that perimortem infarctions may be related to perimortem systemic factors rather than chronic risk factors for stroke.
The apoE 4 may increase the odds of detecting cerebral infarctions by 1 or more of several other mechanisms. The 4 allele has been associated with amyloid angiopathy.31 Amyloid angiopathy has been related to cortical microinfarctions, lobar hemorrhages, and subcortical white matter changes.32–33 In a study of AD brains, the association of amyloid angiopathy with vascular lesions was independent of the apoE 4 allele.29 In our study, amyloid angiopathy was strongly associated with the 4 allele; however, amyloid angiopathy was not associated with chronic infarctions grossly identified at autopsy and did not account for the relationship between the 4 allele and cerebral infarctions.
ApoE 4 modulates metabolism of lipoproteins alters serum cholesterol and lipid levels1,3 and has been associated with atherosclerotic vascular disease,3,4 suggesting these changes may be a factor in the higher odds of cerebral infarction in persons with an 4 allele. Although persons with symptomatic atherosclerosis and small vessel disease in the brain had higher odds of cerebral infarctions, we did not find evidence that atherosclerosis or small vessel disease accounted for the association between the 4 allele and cerebral infarctions. Thus, the mechanism underlying the association remains enigmatic.
There are several strengths to this study. The cohort has excellent access to medical care and high education, which may aid in the detection of genetic risk factors. The study has high follow-up participation and participation in brain autopsy. We were able to classify infarctions in multiple different ways, investigate coexisting amyloid angiopathy, AD pathology, and other vascular changes. The study also has several limitations. Using postmortem material could accentuate survival bias. Because the brain was cut into 1-cm slabs, infarctions on average <5 mm in size could have been missed. Amyloid angiopathy was only assessed in 2 brain regions. Numbers were too small to determine if there was a trend for the 4 allele to be associated with the number or size of cerebral infarctions. Finally, the cohort may not be representative of the general population.
Acknowledgments
We thank the hundreds of nuns, priests and brothers from the following groups participating in the Religious Orders Study: Archdiocesan priests of Chicago, Dubuque, and Milwaukee; Benedictine Monks, Lisle, Illinois and Collegeville, Minnesota; Benedictine Sisters of Erie, Erie, Pennsylvania; Benedictine Sisters of the Sacred Heart, Lisle, Illinois; Capuchins, Appleton, Wisconsin; Christian Brothers, Chicago, Illinois and Memphis, Tennessee; Diocesan priests of Gary, Indiana; Dominicans, River Forest, Illinois; Felician Sisters, Chicago, Illinois; Franciscan Handmaids of Mary, New York, New York; Franciscans, Chicago, Illinois; Holy Spirit Missionary Sisters, Techny, Illinois; Maryknolls, Los Altos, California and Maryknoll, New York; Norbertines, DePere, Wisconsin; Oblate Sisters of Providence, Baltimore, Maryland; Passionists, Chicago, Illinoins; Presentation Sisters, B.V.M., Dubuque, Iowa; Servites, Chicago, Illinois; Sinsinawa Dominican Sisters, Chicago, Illinois and Sinsinawa, Wisconsin; Sisters of Charity, B.V.M., Chicago, Illinois and Dubuque, Iowa; Sisters of the Holy Family, New Orleans, Louisiana; Sisters of the Holy Family of Nazareth, Des Plaines, Illinois; Sisters of Mercy of the Americas, Chicago, Illinois, Aurora, Illinois, and Erie, Pennsylvania; Sisters of St. Benedict, St. Cloud and St. Joseph, Minnesota; Sisters of St. Casimir, Chicago, Illinois; Sisters of St. Francis of Mary Immaculate, Joliet, Illinois; Sisters of St. Joseph of LaGrange, LaGrange Park, Illinois; Society of Divine Word, Techny, Illinois; Trappists, Gethsemani, Kentucky and Peosta, Iowa; Wheaton Franciscan Sisters, Wheaton, Illinois. We thank Zhenxin Wang, PhD, for his technical expertise, Julie Bach, MSW, and Tracy Colvin, Religious Orders Study Coordinators; and data and analytic programmers George Dombrowski, Greg Klein, and Woojeong Bang, and the staff of the Rush AD Center and Rush Institute for Healthy Aging. This study was supported by the National Institute on Aging grants R01 AG15819, K08 AG000849, and P30 AG10161
References
Breslow JL. Genetics of lipoprotein abnormalities associated with coronary heart disease susceptibility. Annu Rev Genet. 2000; 34: 233–254.
Strittmatter WJ, and Roses AD. Apolipoprotein E and Alzheimer’s disease. PNAS. 1995; 92: 4725–4727.
Eichner JE, Dunn ST, Perveen G, Thompson DM, Stewart KE, Stroehla BC. Human Genome Epidemiology (HuGE) review: apolipoprotein E polymorphism and cardiovascular disease: a HuGE review. Am J Epidemiol. 2002; 155: 487–495.
Wilson PW, Myers FH, Larson MG, Ordovas JM, Wolf PA, Schaefer EJ. Apolipoprotein E alleles, dyslipidemia, and coronary heart disease: the Framingham offspring study. JAMA. 1994; 272: 1666–1671.
Cattin L, Fisicaro M, Tonizzo M, Valenti M, Danek GM, Fonda M, Da Col PG. Polymorphism of the apolipoprotein E gene and early carotid atherosclerosis defined by ultrasonography in asymptomatic adults. Arterioscler Thromb Vasc Biol. 1997; 17: 91–94.
McCarron MO, Delong D, Alberts MJ. APOE genotype as a risk factor for ischemic cerebrovascular disease. Neurology. 1999; 53: 1308–1311.
Kim JS, Han SR, Chung SW, Kim BS, Lee KS, Kim YI, Yang DW, Kim KS, Kim JW. The apolipoprotein E 4 haplotype is an important predictor for recurrence in ischemic cerebrovascular disease. J Neurol Sci. 2003; 206: 31–37.
Basun H, Corder EH, Guo Z, Lannfelt L, Corder LS, Manton KG, Winblad B, Viitanen M. Apolipoprotein E polymorphism and stroke in a population sample of 75 years or more. Stroke. 1996; 27: 1310–1315.
Zhu L, Fratiglioni L, Guo Z, Basun H, Corder EH, Winblad B, Viitanen M. Incidence of dementia in relation to stroke and the apolipoprotein E 4 allele in the very old. Stroke. 2000; 31: 53–60.
Frikke-Schmidt R, Nordestgaard BG, Tudium K, Moes Grnholdt M-L, Tybjrg-Hansen A. APOE genotype predicts AD and other dementia but not ischemic cerebrovascular disease. Neurology. 2001; 56: 194–200.
Robinson Jr Young TK, Roos LL, Gelskey DE. Estimating the burden of disease: comparing administrative data and self-reports. Med Care. 1997; 35: 932–947.
Schneider JA, Wilson RS, Bienias JL, Evans DA, Bennett DA. Cerebral infarctions and the likelihood of dementia from Alzheimer’s disease pathology. Neurology. 2004; 62: 1148–1156.
Wilson RS, Mendes De Leon CF, Barnes LL, Schneider JA, Bienias JL, Evans DA, Bennett DA. Participation in cognitively stimulating activities and risk of incident AD. JAMA. 2002; 287: 742–748.
Rose GA. The diagnosis of ischaemic heart pain and intermittent claudication in field surveys. Bull World Health Organ. 1962; 27: 645–658.
McKhann G, Drachmann D, Folstein M, Katzman R, Price D, Stadlan E. Clinical diagnosis of AD. Report of the NINCDS-ADRDA Work Group under the auspices of Department of Health and Human Services Task Force on AD. Neurology. 1984; 34: 939–944.
Hixon JE, Vernier DT. Restriction isotyping of human apolipoprotein E by gene amplification and cleavage with HhaI. J Lipid Res. 1990; 31: 545–548.
Wilson RS, Schneider JA, Barnes LL, Beckett LA, Aggarwal NT, Cochran EJ. Berry-Kravis E, Bach J, Fox JH, Evans DA, Bennett DA. The apolipoprotein E 4 allele and decline in different cognitive systems during a 6-year period Arch Neurol. 2002; 59: 1154–1160.
Schneider, Wilson RS, Cochran EJ, Bienias JL, Evans DA, Bennett DA. Relation of cerebral infarctions to dementia and cognitive function in older persons. Neurology. 2003; 60: 1082–1089.
Bennett DA, Wilson RS, Schneider JA, Evans DA, Aggarwal NT, Arnold SE, Cochran EJ, Berry-Kravis E, Bienias JL. Apolipoprotein E 4 allele, AD pathology, and the clinical expression of Alzheimer’s disease. Neurology. 2003; 60: 246–252.
Bennett DA, Schneider JA, Wilson RS, Bienias JL, Arnold SE. Neurofibrillary tangles mediate the association of amyloid load and with clinical Alzheimer’s disease and level of cognitive function. Arch Neurol. 2004; 61: 378–384.
Attems J, Jellinger KA. Only cerebral capillary amyloid angiopathy correlates with Alzheimer’s pathology—a pilot study. Acta Neuropathol. 2004; 107: 83–90.
Zekry D, Kuyckaerts C, Belmin J, Belmin J, Geoffre C, Moulias R, Hauw JJ. Cerebral amyloid angiopathy in the elderly: vessel wall changes and the relationship with dementia. Acta Neuropathol. 2003; 106: 367–373.
SAS Institute Inc. SAS/STAT Users Guide, Version 8. Cary, NC: SAS Institute Inc; 2000.
Marin DB, Breuer B, Marin M. The relationship between apolipoprotein E, dementia, and vascular illness. Atherosclerosis. 1998; 140: 173–180.
MacLeod MJ, De Lange RP, Breen G, Meiklejohn D, Lemmon H, Clair DS. Lack of association between apolipoprotein E genotype and ischaemic stroke in a Scottish population. Eur J Clin Invest. 2001; 31: 570–573.
Manolio TA, Kronmal RA, Burke GL, Poirier V, O’Leary DH, Gardin JM, Fried LP, Steinberg EP, Bryan RN. Magnetic resonance abnormalities and cardiovascular disease in older adults: the Cardiovascular Health Study. Stroke. 1994; 25: 318–327.
DeCarli C, Reed T, Miller BL, Wolf PA, Swan GE, Carmelli D. Impact of apolipoprotein E 4 and vascular disease on brain morphology in men from the NHLBI Twin Study. Stroke. 1999; 30: 1548–1553.
Kuller LH, Shemanski L, Manolio T, Haan M, Fried L, Bryan N, Burke GL, Tracy R, Bhadelia R. Relationship between apoE, MRI findings, and cognitive function in the cardiovascular health study. Stroke. 1998; 29: 388–398.
Olichney JM, Hansen LA, Hofstetter CR, Lee JH, Katzman R, Thal LJ. Association between severe cerebral amyloid angiopathy and cerebrovascular lesions in Alzheimer’s disease is not a spurious one attributable to apolipoprotein E4. Arch Neurol. 2000; 57: 869–874.
Horsburgh K, McCarron MO, White F, Nicoll JAR. The role of apolipoprotein E in Alzheimer’s disease, acute brain injury and cerebrovascular disease: evidence of common mechanisms and utility of animal models. Neurobiol Aging. 2000; 21: 245–255.
Premkumar DR, Cohen DL, Hedera P, Friedland RP, Kalaria RN. Apolipoprotein E-epsilon4 alleles in cerebral amyloid angiopathy and cerebrovascular pathology associated with Alzheimer’s disease. Am J Pathol. 1996; 148: 2083–2095.
Silbert PL, Bartleson JD, Miller GM, Parisi JE, Goldman MS, Meyer FB. Cortical petechial hemorrhage, leukoencephalopathy, and subacute dementia associated with seizures due to cerebral amyloid angiopathy. Mayo Clin Proc. 1995; 70: 477–480.
Rensink AAM, deWaak RMW, Kremer B, Verbeek MM. Pathogenesis of cerebral amyloid angiopathy. Brain Res Rev. 2003; 43: 207–223.