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Figure 1.
Cerebral amyloid angiopathy (CAA) severity scores for each of the apolipoprotein E (APOE) genotype groups. Means (SEs) are shown; sample sizes are in parentheses. Asterisk indicates P<.05 using χ2 test (compared with groups with APOE3/4 and APOE3/3).

Cerebral amyloid angiopathy (CAA) severity scores for each of the apolipoprotein E (APOE) genotype groups. Means (SEs) are shown; sample sizes are in parentheses. Asterisk indicates P<.05 using χ2 test (compared with groups with APOE3/4 and APOE3/3).

Figure 2.
Frequency of vascular lesions in cases of severe amyloid angiopathy (SAA) and mild or absent amyloid angiopathy (MAA). Overall effect of amyloid angiopathy severity shown on the left. Effects within 3 strata of apolipoprotein E (APOE) genotype shown toward the right. Sample sizes are in parentheses. Asterisk indicates P<.05 using the χ2 test.

Frequency of vascular lesions in cases of severe amyloid angiopathy (SAA) and mild or absent amyloid angiopathy (MAA). Overall effect of amyloid angiopathy severity shown on the left. Effects within 3 strata of apolipoprotein E (APOE) genotype shown toward the right. Sample sizes are in parentheses. Asterisk indicates P<.05 using the χ2 test.

Table 1. 
Demographics and Stroke Risk Factors in Cases of Severe (SAA) and Mild Amyloid Angiopathy (MAA)*
Demographics and Stroke Risk Factors in Cases of Severe (SAA) and Mild Amyloid Angiopathy (MAA)*
Table 2. 
Neuropathological and Apolipoprotein E (APOE) Genotype Data for Cases of Severe (SAA) and Mild Amyloid Angiopathy (MAA)*
Neuropathological and Apolipoprotein E (APOE) Genotype Data for Cases of Severe (SAA) and Mild Amyloid Angiopathy (MAA)*
Table 3. 
Severity of Alzheimer Disease Lesions in Cases With vs Without Vascular Lesions, Stratified by Cerebral Amyloid Angiopathy Severity*
Severity of Alzheimer Disease Lesions in Cases With vs Without Vascular Lesions, Stratified by Cerebral Amyloid Angiopathy Severity*
1.
Molsa  PKPaljarvi  LRinne  JD  et al.  Validity of clinical diagnosis in dementia. J Neurol Neurosurg Psychiatry. 1985;481085- 1090Article
2.
Malamud  N Neuropathology of organic brain syndromes associated with aging. Gaitz  CMedAging and the Brain New York, NY Plenum Publishing Corp1972;63- 87
3.
Tomlinson  BEBlessed  SRoth  M Observations on the brains of demented old people. J Neurol Sci. 1970;11205- 242Article
4.
Vinters  HV Cerebral amyloid angiopathy: a critical review. Stroke. 1987;18311- 324Article
5.
Glenner  GGHenry  JHFujihara  S Congophillic angiopathy in the pathogenesis of Alzheimer's degeneration. Ann Pathol. 1981;1120- 129
6.
Mandybur  TI The incidence of cerebral amyloid angiopathy in Alzheimer's disease. Neurology. 1975;25120- 126Article
7.
Olichney  JMHansen  LHofstetter  CRGrundman  MKatzman  RThal  LJ Cerebral infarction in Alzheimer's disease is associated with severe amyloid angiopathy and hypertension. Arch Neurol. 1995;52702- 708Article
8.
Olichney  JMEllis  RJKatzman  RSabbagh  MNHansen  L Types of cerebrovascular lesions associated with severe cerebral amyloid angiopathy in Alzheimer's disease. Ann N Y Acad Sci. 1997;826493- 497Article
9.
Greenberg  SMRebeck  GWVonsattel  JPGomez-Isla  THyman  BT Apolipoprotein E-ϵ4 and cerebral hemorrhage associated with amyloid angiopathy. Ann Neurol. 1995;38254- 259Article
10.
Premkumar  DRDCohen  DLHedera  PFriedland  RPKalaria  RN Apolipoprotein E-ϵ4 alleles in cerebral amyloid angiopathy and cerebrovascular pathology associated with Alzheimer's disease. Am J Pathol. 1996;1482083- 2095
11.
Olichney  JMHansen  LAGalasko  D  et al.  The apolipoprotein E ϵ4 allele is associated with increased neuritic plaques and cerebral amyloid angiopathy in Alzheimer's disease and Lewy body variant. Neurology. 1996;47190- 196Article
12.
Eichner  JEKuller  LHOrchard  TJ  et al.  Relation of apolipoprotein E phenotype to myocardial infarction and mortality from coronary artery disease. Am J Cardiol. 1993;71160- 165Article
13.
Wilson  PWFMyers  RHLarson  MGOrdovas  JMWolf  PASchaefer  EJ Apolipoprotein E alleles, dyslipidemia, and coronary heart disease: the Framingham Offspring Study. JAMA. 1994;2721666- 1671Article
14.
Stengard  JHZerba  KEPekkanen  JEhnholm  CNissinen  ASing  CF Apolipoprotein E polymorphism predicts death from coronary heart disease in a longitudinal study of elderly Finnish men. Circulation. 1995;91265- 269Article
15.
Mahley  RW Apolipoprotein E: cholesterol transport protein with expanding role in cell biology. Science. 1988;240622- 630Article
16.
Khachaturian  ZS Diagnosis of Alzheimer's disease. Arch Neurol. 1985;421097- 1105Article
17.
Mirra  SSHeyman  AMcKeel  D  et al.  The Consortium to Establish a Registry for Alzheimer's Disease (CERAD), part II: standardization of the neuropathological assessment of Alzheimer's disease. Neurology. 1991;41479- 486Article
18.
American Psychiatric Association, Diagnostic and Statistical Manual of Mental Disorders, Revised Third Edition.  Washington, DC American Psychiatric Association1987;
19.
Galasko  DHansen  LAKatzman  R  et al.  Clinical-neuropathological correlations in Alzheimer's disease and related dementias. Arch Neurol. 1994;51888- 895Article
20.
Hachinski  VCIliff  LDZilhka  E  et al.  Cerebral blood flow in dementia. Arch Neurol. 1975;32632- 637Article
21.
Wenham  PRPrice  WHBlundell  G Apolipoprotein E genotyping by one-stage PCR. Lancet. 1991;3371158- 1159Article
22.
Hixson  JEVernier  DT Restriction isotyping of human apolipoprotein E by gene amplification and cleavage with HhaI. J Lipid Res. 1990;31545- 548
23.
Galasko  DSaitoh  TXia  Y  et al.  The apolipoprotein E allele epsillon 4 is overrepresented in patients with the Lewy body variant of Alzheimer's disease. Neurology. 1994;441950- 1951Article
24.
Menzel  HJKladetzky  RGAssmann  G Apolipoprotein E polymorphism and coronary artery disease. Arteriosclerosis. 1983;3310- 315Article
25.
Gray  FDubas  FRoullet  EEscourolle  R Leukoencephalopathy in diffuse hemorrhagic cerebral amyloid angiopathy. Ann Neurol. 1985;1854- 59Article
26.
Okazaki  HReagan  TJCampbell  PJ Clinicopathologic studies of primary cerebral amyloid angiopathy. Mayo Clin Proc. 1979;5422- 31
27.
Greenberg  SMVonsattel  JPStakes  JWGruber  MFinklestein  SP The clinical spectrum of cerebral amyloid angiopathy. Neurology. 1993;432073- 2079Article
28.
Vonsattel  JPMyers  RHHedley-Whyte  ETRopper  AHBird  EDRichardson  EP Cerebral amyloid angiopathy without and with cerebral hemorrhages:a comparative histological study. Ann Neurol. 1991;30637- 649Article
29.
Nicoll  JARBurnett  CLove  S  et al.  High frequency of apolipoprotein E 2 allele in hemorrhage due to cerebral amyloid angiopathy. Ann Neurol. 1997;41716- 721Article
30.
Mandybur  TI Cerebral amyloid angiopathy. J Neuropathol Exp Neurol. 1986;4579- 90Article
31.
Pedro-Botet  JSenti  MNogues  X  et al.  Lipoprotein and apoprotein profile in men with ischemic stroke: role of lipoprotein(a), triglyceride rich lipoproteins, and apolipoprotein E polymorphism. Stroke. 1992;231556- 1562Article
32.
Basun  HCorder  EHGuo  Z  et al.  Apolipoprotein E polymorphism and stroke in a population sample aged 75 years or more. Stroke. 1996;271310- 1315Article
33.
Couderc  RMahieux  FBailleul  SFenelon  GMary  RFermanian  J Prevalence of apolipoprotein E phenotypes in ischemic cerebrovascular disease: a case-control study. Stroke. 1993;24661- 664Article
34.
Shimano  HIshibashi  SMurase  T  et al.  Plasma apolipoproteins in patients with multi-infarct dementia. Atherosclerosis. 1989;79257- 260Article
35.
Frisoni  GBCalabresi  LGeroldi  CBianchetti  A Apolipoprotein E-ϵ4 allele in Alzheimer's disease and vascular dementia. Dementia. 1994;5240- 242
36.
Ji  YUrakami  KAdachi  YMaeda  MIsoe  KNakashima  K Apolipoprotein E polymorphism in patients with Alzheimer's disease, vascular dementia and ischemic cerebrovascular disease. Dement Geriatr Cogn Disord. 1998;9243- 245Article
37.
Kawamata  JTanaka  SShimohama  SUeda  KKimura  J Apolipoprotein E polymorphism in Japanese patients with Alzheimer's disease and vascular dementia. J Neurol Neurosurg Psychiatry. 1994;571414- 1416Article
38.
Palumbo  BParnetti  LNocentini  GCardinali  L Apolipoprotein E genotype in normal aging, age-associated memory impairment, Alzheimer's disease, and vascular dementia patients. Neurosci Lett. 1997;23159- 61Article
39.
Betard  CRobitaille  YGee  M  et al.  Apo E allele frequencies in Alzheimer's disease, Lewy body dementia, Alzheimer's disease with cerebrovascular disease and vascular dementia. Neuroreport. 1994;51893- 1896Article
40.
Olichney  JMSabbagh  MNHofstetter  CR  et al.  The impact of apolipoprotein E4 on cause of death in Alzheimer's disease. Neurology. 1997;4976- 81Article
41.
McKhann  GDrachman  DFolstein  MKatzman  RPrice  DStadian  EM Clinical diagnosis of Alzheimer's disease: report of the NINCDS-ADRDA Work Group under the auspices of the Department of Health and Human Services Task Force on Alzheimer's Disease. Neurology. 1984;34939- 944Article
42.
Farrar  LACupples  LAHaines  JL  et al.  Effects of age, sex, and ethnicity on the association between apolipoprotein E genotype and Alzheimer's disease: a meta-analysis. APOE and Alzheimer's disease meta analysis consortium. JAMA. 1997;2781349- 1356Article
43.
Masuda  JTanaka  KUeda  KOmae  T Autopsy study of incidence and distribution in Hisayama, Japan. Stroke. 1992;231556- 1562Article
44.
Weller  ROMasses  ANewman  TAHutchings  MKuo  YMRoher  AE Cerebral amyloid angiopathy: amyloid beta accumulates in putative interstitial fluid drainage pathways in Alzheimer's disease. Am J Pathol. 1998;153725- 33Article
45.
Urmoneit  BPrikulis  IWihl  G  et al.  Cerebrovascular smooth muscle cells internalize Alzheimer amyloid beta protein via a lipoprotein pathway: implications for cerebral amyloid angiopathy. Lab Invest. 1997;77157- 166
46.
Perry  RHMcKeith  IGPerry  EK Dementia With Lewy Bodies: Clinical, Pathological, and Treatment Issues.  New York, NY Cambridge Press1996;
47.
Jellinger  KDanielczyk  WFischer  PGabriel  E Clinicopathological analysis of dementia disorders in the elderly. J Neurol Sci. 1990;95239- 258Article
48.
Thomas  TThomas  GMcLendon  CSutton  TMullan  M β-Amyloid–mediated vasoactivity and vascular endothelial damage. Nature. 1996;380168- 171Article
49.
Li  QXWhyte  STanner  JEEvin  GBeyreuther  KMasters  CL Secretion of Alzheimer's disease. Lab Invest. 1998;78461- 469
50.
Chen  MInestrosa  NCRoss  GSFernandez  HL Platelets are the primary source of amyloid β-peptide in human blood. Biochem Biophys Res Commun. 1995;21396- 103Article
51.
Van Nostrand  WEDavis-Salinas  JSaporito-Irwin  SM Amyloid β-protein induces the cerebrovascular cellular pathology of Alzheimer's disease and related disorders. Ann N Y Acad Sci. 1996;777297- 302Article
52.
Kingston  IBCastro  MJAnderson  S In vitro stimulation of tissue-type plasminogen activator by Alzheimer amyloid β-peptide analogues. Nature Med. 1995;1138- 142Article
Original Contribution
June 2000

Association Between Severe Cerebral Amyloid Angiopathy and Cerebrovascular Lesions in Alzheimer Disease Is Not a Spurious One Attributable to Apolipoprotein E4

Author Affiliations

From the Alzheimer's Disease Research Center (Drs Olichney, Hansen, Hofstetter, Katzman, and Thal) and the Department of Neurosciences (Drs Olichney and Thal), University of California, San Diego, La Jolla; Neurology Service, Veterans Affairs Medical Center, San Diego (Drs Olichney and Thal); and the Department of Neurology, University of Ulsan, Asan Medical Center, Seoul, South Korea (Dr Lee).

Arch Neurol. 2000;57(6):869-874. doi:10.1001/archneur.57.6.869
Abstract

Background  We have previously reported an association between severe cerebral amyloid angiopathy (CAA) and cerebrovascular lesions in Alzheimer disease (AD), which is particularly strong for microinfarcts, hemorrhages, and multiple lesion types. Cerebral amyloid angiopathy has also been associated with the apolipoprotein E4 (APOE4) genotype, which is in turn associated with premature coronary artery disease and atherosclerosis.

Objective  To test whether severe CAA would be more strongly associated with cerebrovascular lesions than would APOE4 genotype.

Methods  We reviewed 306 cases of autopsy-confirmed AD (from the University of California, San Diego, brain autopsy series) to assess whether APOE genotype and other clinical risk factors were predictive of vascular lesions (VLs) in AD. Cerebral amyloid angiopathy severity was assessed using a semiquantitative scale in 4 brain regions (ie, hippocampus, midfrontal cortex, inferior parietal cortex, and superior temporal cortex) and an average score was computed for each case.

Results  We found that severe CAA was associated with an increased frequency of VLs (33% of the cases of severe CAA had VLs vs 19% of the cases of mild or absent CAA; P=.02). While the APOE4/4 genotype was associated with an increased severity of CAA, there was no significant relationship between APOE genotype and frequency of VLs. Logistic regression models showed that severe CAA, advanced age, atherosclerosis, and Hachinski Ischemia Scale score of 7 or more were all significantly associated with VLs, but the number of APOE4 alleles, history of hypertension, coronary artery disease, sex, and serum cholesterol levels had nonsignificant effects. Within strata of APOE genotype, the presence of severe CAA was associated with increased frequency of VLs (eg, within APOE4/4 homozygotes, VLs were present within 47% of the cases of severe CAA vs 9.5% of the cases of mild or absent CAA; P=.01).

Conclusions  Severe CAA confers a greater risk of VLs in AD, even within strata of APOE genotype. Therefore, the association between severe CAA and VLs in AD is not a spurious one owing to APOE4. Overall, our cases of AD with APOE4 do not seem to be a more "vasculopathic" subtype of AD. The mechanisms by which CAA produces VLs of various types need to be further elucidated, as these are probably important in producing the common entity of "mixed" AD/vascular dementia.

CEREBROVASCULAR lesions are fairly common in autopsied cases of Alzheimer disease (AD),13 but what role these superimposed vascular lesions (VLs) have in producing or exacerbating dementia remains controversial. Most autopsy studies have found that approximately 80% to 95% of the cases of AD have appreciable amyloid accumulations in the walls of the cerebral blood vessels, especially in small arterioles.46 We have previously reported an association between severe cerebral amyloid angiopathy (CAA) and cerebral infarctions in AD. The risk of infarction is particularly high in patients who have both hypertension and severe CAA.7 Patients with severe CAA have the highest relative risk for cortical microinfarcts and hemorrhages, but multiple lesion types are often present (eg, larger cortical infarcts and lacunes).8 The apolipoprotein E-ϵ4 (APOE4) allele, which is the major identified genetic risk factor for AD, is associated with increased β-amyloid deposition in AD-affected brains. The effects of APOE4 have been extended to cerebral blood vessels, where increased CAA is found in carriers, and both within AD and non-AD samples.911 However, APOE4 is also associated with premature coronary artery disease and atherosclerosis.1215 Thus, it is plausible that the association between severe CAA and cerebrovascular lesions is a spurious one mediated by APOE4 and/or generalized atherosclerosis.

Therefore, we reviewed our autopsy series at the San Diego Alzheimer's Disease Research Center to test if severe CAA remains an independent risk factor for cerebrovascular lesions after controlling for the effects of APOE genotype. We hypothesized that severe CAA would be more strongly associated with VLs than would APOE4 genotype.

SUBJECTS AND METHODS
SUBJECTS

Cases included in this autopsy study met the following criteria: (1) neuropathological criteria for AD, according to both National Institute on Aging16 (based on age-adjusted senile plaque densities) and Consortium to Establish a Registry for Alzheimer's Disease criteria17 (definite or probable AD); and (2) Diagnostic and Statistical Manual of Mental Disorders, Revised Third Edition criteria for dementia.18 Most (n=247) had also undergone APOE genotyping. Most patients were followed up longitudinally at the San Diego Alzheimer Disease Research Center ambulatory clinic with the remainder evaluated in either a private practice or nursing home. All San Diego Alzheimer's Disease Research Center subjects underwent at least one standardized evaluation that included a medical history, physical examination, structured neurological examination, cognitive screening tests, blood tests, and a neuroimaging study.19 The history regarding hypertension was obtained from an informant (usually the spouse) by either a neurologist or a nurse as part of the medical history or the Hachinski Ischemia Scale.20 The Hachinski Ischemia Scale was done at the initial visit to the San Diego Alzheimer's Disease Research Center and was repeated annually if any interval history was suggestive of stroke or transient ischemic attack. Hypertension was defined as a recurrent abnormal systolic blood pressure higher than 140 mm Hg or diastolic blood pressure higher than 90 mm Hg by history or direct measurement—taking antihypertensive medications was not required. History of coronary artery disease was defined as either prior myocardial infarction (ie, clinical diagnosis or by electrocardiogram) or a history of exertional angina. Blood samples for nonfasting serum cholesterol levels were drawn in the late morning. Cases with superimposed diffuse Lewy bodies on brain autopsy were included in this analysis. Informed consent for brain autopsy and APOE genotyping had been obtained for all cases.

Three hundred six cases (162 males and 144 females) met these criteria and had the neuropathological measures described below performed. Two subgroups of patients were created—those with severe amyloid angiopathy (SAA) and those with mild or absent amyloid angiopathy (MAA)—using, as we had previously, the midpoint (≥2.0) of the amyloid angiopathy (AA) severity scale (defined below) as the cutoff. The size and characteristics of these groups are summarized in Table 1. The group with MAA (n=248) included 76 cases with no appreciable CAA in the areas sampled. One hundred forty-five of the cases in this study were included in previous articles.7,8 We have not previously reported on the relationship between APOE genotype and VLs in our cohort.

APOE GENOTYPING

Apolipoprotein E genotyping was performed on either brain autopsy or blood samples using a polymerase chain reaction–amplification technique adapted from Wenham et al21 with modifications as have been reported previously.22,23

NEUROPATHOLOGICAL PROCEDURES

The details of our brain autopsy procedures have been published previously.7,11 All brains were divided sagittally. Following 10 days of formalin fixation, the left hemibrain was examined externally, serially sliced into 1-cm-thick coronal sections, and evidence of infarction noted. Tissue blocks were taken from all gross lesions, as well as from 13 other routinely sampled brain regions.7 Hematoxylin-eosin–stained preparations from all tissue blocks were examined. These sections sometimes revealed cortical microinfarcts that had escaped detection at the time of brain sectioning. The cerebral vessels in these sections were examined and cases with prominent intracerebral atherosclerosis, arteriosclerosis, or

arteriolosclerosis were noted. The frozen right hemibrain was examined separately and the presence of grossly detectable infarcts noted. After partial thawing, the right hemibrain was cut in 1-cm-thick sections and any apparent infarcts noted.

NEOCORTICAL SENILE PLAQUE, NEUROFIBRILLARY TANGLE, AND AMYLOID ANGIOPATHY (AA) QUANTIFICATIONS

Neocortical senile plaques, both diffuse and neuritic, neurofibrillary tangles (NFTs), and AA were evaluated in 10-µm-thick, 1% thioflavin-S–stained sections using UV illumination (with a 440-µm band pass excitation filter). Entire neocortical sections were surveyed to find areas with the most lesions. Three ×125 microscopic fields (field size, 1.76 mm2) were counted for total senile plaques (TPs), and three ×500 microscopic fields (field size, 0.1 mm2) for NFTs. The results were then averaged to provide single TP and NFT counts for each brain region from each case. These single TP and NFT counts for each of 4 brain regions (ie, hippocampus, midfrontal cortex, inferior parietal cortex, and superior temporal cortex) were then averaged to provide overall TP and NFT scores. Separate neocortical senile plaque counts for neuritic plaques, which contained filamentous amyloid and swollen neurites, were determined in 217 cases and an overall neuritic plaques score was calculated analogously. Total senile plaque scores included both diffuse and neuritic forms.

The severity of AA was assessed semiquantitatively on thioflavin-S–stained preparations of hippocampus, midfrontal cortex, inferior parietal cortex, and superior temporal gyrus. A score of 0 meant that there was no thioflavin-S positivity in the leptomeningeal or superficial cortical blood vessels. A score of 1 reflected trace to scattered positivity in either the leptomeningeal or the cortical blood vessels. A score of 2 indicated that at least some vessels in the leptomeninges or neocortex had circumferential brightly staining amyloid deposits. A score of 3 corresponded to widespread circumferential thioflavin-S positivity in many leptomeningeal and superficial cortical vessels. A score of 4 meant that similarly SAA was combined with dysphoric changes, ie, thioflavin-S positivity emanating from severely amyloidotic blood vessels into surrounding neuropil. A single AA severity score for each case was calculated by averaging across brain regions. Of the 58 cases who met criteria for SAA, all but 1 case had at least 1 brain section with widespread circumferential vascular amyloid depositions (ie, score ≥3), and 52 cases had at least 2 such brain sections.

All of the AD-affected brains were classified as being with or without VLs. Any cases showing grossly detectable large infarcts, cortical microinfarcts, granular cortical atrophy, intracerebral hemorrhages, or lacunar infarcts were designated as AD with VLs. Acute, subacute, and old lesions were all included. Primary hemorrhages were rare in our cohort and, therefore, were not analyzed separately. Only 2 cases (both with MAA) had primary hemorrhages without infarcts. One case of SAA had a hemorrhagic infarct and 1 case of MAA had an infarction and a hemorrhagic lesion.

STATISTICAL ANALYSES

One-way analyses of variance were applied to continuous variables and χ2 analyses were used for categorical variables. A multiple logistic regression analysis was performed to see which of the following independent variables (ie, AA severity, hypertension, age of death, number of APOE4 alleles, and sex), entered simultaneously, predicted the presence of cerebrovascular lesions. The above regression models were then modified, entering 1 additional independent variable at a time. These additional variables included dichotomous variables indicating if there was history of coronary artery disease, atrial fibrillation, or intracerebral atherosclerosis, and a continuous variable for serum cholesterol level. Two-tailed P≤.05 was considered statistically significant.

RESULTS

Comparisons between cases with vs without severe CAA showed that the group with SAA had significantly more cases with VLs than the group with MAA (32.7% vs 19% of cases, P=.02, χ2 test). When only cases with CAA scores of 2.5 or higher were compared with the group with MAA, the result was essentially unchanged (33.3% vs 19%; P=.04, χ2 test). However, when the cutoff was raised to 3.0 or higher, the intergroup difference did not reach statistical significance (32.1% vs 19%; P=.09, χ2 test), probably owing to an insufficient sample (n=28) of cases with this severity of CAA. Twelve of the 19 cases with SAA and VLs also had multiple infarcts (eg, 5 had multiple lacunes and 5 had multiple cortical microinfarcts). Almost all of the individual infarcts were small (volume <10 mL, except for 3 infarcts between 10 and 50 mL).

The group with SAA also had a higher frequency of the APOE4 allele (55% vs 35%; P<.001, χ2 test), and a modest, but statistically significant, increase in TP and NFT counts relative to the group with MAA (Table 2). The frequency of the APOE2 allele was also higher in the group with SAA relative to the group with MAA (7% vs 2%), with the group with MAA having less APOE2 than is usual in the general population.24 The 2 groups had an almost identical mean age of death (79.8 years), and very similar mean age of onset and duration of illness (Table 1). There was an almost statistically significant increased proportion of males in the group with SAA (64% vs 50%; P=.07, χ2 test). Available data on frequency of hypertension, coronary artery disease, and serum cholesterol levels showed these to be comparable in the groups with SAA and MAA (Table 1). The group with SAA had a greater frequency of atrial fibrillation (chronic or paroxysmal) than did the group with MAA.

To see if the increased cerebrovascular lesions in the cases with SAA could be related to their having somewhat more advanced intraparenchymal AD lesions, the neuropathological scores of cases with vs without VLs were compared within strata of CAA (ie, SAA and MAA). Within the cases of SAA, these analyses showed no significant intergroup differences, with a trend for cases with VLs to have slightly lower NFT counts (Table 3). Within the cases of MAA, those with VLs were older and had significantly lower NFT, TP, and neuritic plaques counts (Table 3).

When we examined CAA severity as a function of APOE genotype, we found the APOE4 homozygous cases had significantly elevated CAA scores (Figure 1). One-way analysis of variance showed the effect of APOE genotype on CAA severity was highly significant (P<.001, χ2 test), and Sheffé-corrected t tests showed that the group with APOE4/4 was significantly different from both groups with APOE3/4 and APOE3/3. However, there was no statistically significant increase in VLs in association with the APOE4 allele—VLs were present in 24% of APOE4 homozygotes, 19% of APOE4 heterozygotes, and in 25% of the noncarriers. Across all cases with VLs, the overall APOE4 allele frequency was 36.6%, which was almost identical to that of the cases without VLs (39.0%). Removing cases with the APOE2 allele did not substantially alter these results.

Next, we stratified our sample by APOE genotype, and performed separate analyses on frequency of VLs within each genotype group (ie, APOE3/3, APOE3/4, and APOE4/4). This showed that within 2 (the APOE4/4 and the APOE3/3 groups) of the 3 strata, there was a statistically significant increase in VLs in association with SAA (Figure 2). For example, within APOE4/4 homozygotes, 47% of the cases of SAA had 1 or more VLs compared with 9.5% of the cases of MAA (P=.01, χ2 test). Within the group with APOE3/4, there was no statistically significant difference in VLs between the 2 subgroups (27% in SAA vs 16% in MAA; P=.29, χ2 test), although the trend was again for more VLs in cases of SAA. We also looked at the effect that hypertension may have on the frequency of VLs. We found that approximately 27% of the cases with AD who had hypertension also had VLs, which was statistically significantly greater than in the cases with AD who did not have hypertension (15.9% had VLs; P=.04, χ2 test).

Our main logistic regression models showed that the presence of SAA (odds ratio [OR]=3.53; 95% confidence interval [CI]=1.49-7.39; P=.002) and advanced age of death (OR=1.07; 95% CI=1.01-1.13; P=.01, χ2 test) were both significantly associated with VLs at autopsy. The effects of hypertension (OR=1.62; 95% CI=0.81-3.25; P=.17, χ2 test), sex (P=.80, χ2 test), and APOE genotype (P=.93, χ2 test) were nonsignificant in this model. The regression models that included atrial fibrillation (OR=1.16; 95% CI=0.37-3.58), coronary artery disease (OR=1.27; 95% CI=0.56-2.88), or serum cholesterol level (OR=1.00; 95% CI=.99-1.01) showed that none of these variables had statistically significant effects. Adding these variables did not appreciably change the effects of SAA. When the Hachinski Ischemia Scale score (applying a cutoff of ≥7 vs ≤6), which is often used as a clinical predictor of vascular or "mixed" dementia, was added, it was a highly significant predictor (OR=5.34; 95% CI=1.66-17.39; P=.005, χ2 test). Both the SAA and age effects remained significant (OR=3.24 and OR=1.07, respectively) in this model. When intracerebral atherosclerosis was added, it was the strongest predictor of VLs (OR=49.3; P<.001, χ2 test), but did not appreciably alter the effects of SAA or age.

COMMENT

This study is the largest neuropathological series we are aware of in which the relationship between CAA, APOE genotype, and VLs has been examined. We show not only that severe CAA confers a greater risk of VLs in AD, but that this risk is elevated even within strata of APOE genotype. Therefore, the association between SAA and VLs in AD is not a spurious one owing to APOE4. Instead, it is very likely that severe CAA is etiologically related to the VLs observed. We have previously shown that patients with CAA are at particularly high risk for specific types of VLs, especially small cortical infarcts, microinfarcts, and cerebral hemorrhages.8 In this study, almost all of the VLs were infarctions rather than hemorrhages. Given that CAA predominantly affects leptomeningeal and small cortical arterioles, a causal relationship is particularly likely with the associated small infarcts in the neocortical ribbon.7 It has also been suggested that CAA may cause deep infarctions by causing stenosis of the meningocortical segments of long perforating arterioles and secondary hypoperfusion of "watershed" areas (eg, deep subcortical white and gray matter prone to infarction).25 Prior work by others has also strongly implicated CAA in producing ischemic lesions,26,27 in addition to the better known association with intracerebral hemorrhage.28 The relative scarcity of cerebral hemorrhages in AD, despite abundant CAA, may be related to their very low prevalence of APOE2 allele, which predisposes toward primary intracerebral hemorrhage to a greater extent than APOE4.29 Mandybur30 described a "cerebral amyloid angiopathy-associated vasculopathy" with fibrinoid necrosis, hyaline arteriolar degeneration, obliteration of the intima, and microaneurysms. Our cases of SAA all had widespread circumferential amyloid deposits in their cerebral vessels, making the obliterative changes associated with advanced CAA a likely cause of infarctions.

Although APOE4 has been well demonstrated to increase the risk of premature coronary artery disease and may increase generalized atherosclerosis,1215 its role in stroke and vascular dementia is much less clear. Among patients with stroke, some have found a modest increase in carriers of APOE431 while other studies have found negative32 or opposing33 results. In studies of clinically defined vascular dementia, the results are also conflicting, with many,3436 but not all,37,38 finding an overrepresentation of APOE4. In contrast, neuropathologically defined groups of "pure" vascular dementia cases have generally been found to have no elevation in APOE4 allele frequency, while mixed AD/vascular dementia cases have shown increased APOE4.10,39 In our cohort with AD, there was no association between specific APOE genotypes and the prevalence of VLs. In this regard, our cases of AD with the APOE4 gene do not seem to have a more "vasculopathic" subtype of AD. However, this does not mean that cerebrovascular factors are unimportant in producing or exacerbating AD dementia independently of APOE. While we previously reported an increase in vascular-related cause of death among APOE4 carriers, this association was owing to a significant increase in cardiac-related deaths, while there was only a weak trend toward an increase in cerebrovascular-related mortality.40 Our results are somewhat in conflict with those of Premkumar et al,10 who reported a moderate increase in the APOE4 allele frequency among their cases of AD with VLs, but a statistically nonsignificant difference in the overall APOE genotype distribution. Differences in patient selection could account for the discrepancies in that our center primarily recruits patients who meet criteria for probable AD,41 rather than vascular or mixed dementia. Supporting this is the very high prevalence of VLs (36%) found by Premkumar et al10 in their autopsied cases of AD, compared with only 22% (66 of the 306 cases) in this study. Unfortunately, Premkumar et al did not report the strength of the association between CAA severity and VLs. Caution is also advised before generalizing our results to younger cohorts: APOE4 confers its risk for AD in a highly age-dependent fashion42 and could conceivably confer its risk for stroke similarly.

Our data on atherosclerosis are consistent with Masuda et al,43 who found no systematic relationship between severity of atherosclerosis and AA. However, we did find an unexpected association between SAA and atrial fibrillation. Since this was based on relatively few cases with atrial fibrillation (n=18 total), independent replication of this finding in another clinicopathological series is necessary. It is conceivable that poor cerebral perfusion caused by atrial fibrillation could facilitate CAA, perhaps by increasing amyloid production by smooth muscle cells and/or neurons.44,45

Although hypertension was not a significant predictor in our regression models, it probably plays an important role in mixed dementia. We previously reported an apparent synergism between severe CAA and hypertension in producing cerebral infarction in AD.7 When an interaction term (severe CAA×hypertension) was added to the regression models in our study, this interaction term was highly significant and all the other potential predictors except age were statistically nonsignificant (results not shown here, but see references 7 and 8). This shows that hypertension particularly predisposes to VLs in the cases of SAA cases and/or that patients with hypertension who develop SAA are the most likely to have VLs.

CONCLUSIONS

While we found severe CAA to be a strong predictor of VLs, APOE4 genotype was not. The mechanisms by which CAA produces VLs of various types need to be further elucidated, as these could allow more effective interventions for patients with mixed AD/vascular dementia, an entity nearly as common as the frequently cited "second most common cause of dementia"—dementia with Lewy bodies.46,47 Direct effects of β-amyloid species on the cerebrovasculature have been recently described. Low concentrations of β-amyloid can induce vasospasm,48 which could be of physiological significance when platelets, the major source of circulating β-amyloid, come into proximity with endothelial cells.49,50 Van Nostrand et al51 showed that β-amyloid can produce smooth muscle cell degeneration in vitro. Also, an agonist effect of aggregated amyloid on tissue-type plasminogen activator has been described, which may help account for the predilection for cerebral hemorrhages.52 This implies that elderly stroke patients with CAA could be particularly prone to hemorrhage after tissue-type plasminogen activator infusion. While knowledge of APOE genotype may help estimate the risk of CAA, most of the variance in CAA severity, within our cohort, remains unexplained by APOE genotype alone.11 It is important that we improve our ability to diagnose CAA during life, which is difficult at present either prior to the first cerebral hemorrhage or in the setting of dementia.

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Article Information

Accepted for publication February 11, 2000.

This investigation was supported by grant AG 05131 from the National Institute on Aging, National Institutes of Health, Bethesda, Md.

Presented in part at the Vascular Factors in Alzheimer's Disease meeting, Newcastle, England, May 26, 1999.

We are grateful to Kathy Foster and Richard DeTeresa for technical assistance, and to Mary Pay, Deborah Fontaine, and Brock Riggins for obtaining and/or reviewing the subjects' medical histories.

Corresponding author: John Olichney, MD, Neurology Service (127), Veterans Administration Medical Center, 3350 La Jolla Village Dr, San Diego, CA 92161.

References
1.
Molsa  PKPaljarvi  LRinne  JD  et al.  Validity of clinical diagnosis in dementia. J Neurol Neurosurg Psychiatry. 1985;481085- 1090Article
2.
Malamud  N Neuropathology of organic brain syndromes associated with aging. Gaitz  CMedAging and the Brain New York, NY Plenum Publishing Corp1972;63- 87
3.
Tomlinson  BEBlessed  SRoth  M Observations on the brains of demented old people. J Neurol Sci. 1970;11205- 242Article
4.
Vinters  HV Cerebral amyloid angiopathy: a critical review. Stroke. 1987;18311- 324Article
5.
Glenner  GGHenry  JHFujihara  S Congophillic angiopathy in the pathogenesis of Alzheimer's degeneration. Ann Pathol. 1981;1120- 129
6.
Mandybur  TI The incidence of cerebral amyloid angiopathy in Alzheimer's disease. Neurology. 1975;25120- 126Article
7.
Olichney  JMHansen  LHofstetter  CRGrundman  MKatzman  RThal  LJ Cerebral infarction in Alzheimer's disease is associated with severe amyloid angiopathy and hypertension. Arch Neurol. 1995;52702- 708Article
8.
Olichney  JMEllis  RJKatzman  RSabbagh  MNHansen  L Types of cerebrovascular lesions associated with severe cerebral amyloid angiopathy in Alzheimer's disease. Ann N Y Acad Sci. 1997;826493- 497Article
9.
Greenberg  SMRebeck  GWVonsattel  JPGomez-Isla  THyman  BT Apolipoprotein E-ϵ4 and cerebral hemorrhage associated with amyloid angiopathy. Ann Neurol. 1995;38254- 259Article
10.
Premkumar  DRDCohen  DLHedera  PFriedland  RPKalaria  RN Apolipoprotein E-ϵ4 alleles in cerebral amyloid angiopathy and cerebrovascular pathology associated with Alzheimer's disease. Am J Pathol. 1996;1482083- 2095
11.
Olichney  JMHansen  LAGalasko  D  et al.  The apolipoprotein E ϵ4 allele is associated with increased neuritic plaques and cerebral amyloid angiopathy in Alzheimer's disease and Lewy body variant. Neurology. 1996;47190- 196Article
12.
Eichner  JEKuller  LHOrchard  TJ  et al.  Relation of apolipoprotein E phenotype to myocardial infarction and mortality from coronary artery disease. Am J Cardiol. 1993;71160- 165Article
13.
Wilson  PWFMyers  RHLarson  MGOrdovas  JMWolf  PASchaefer  EJ Apolipoprotein E alleles, dyslipidemia, and coronary heart disease: the Framingham Offspring Study. JAMA. 1994;2721666- 1671Article
14.
Stengard  JHZerba  KEPekkanen  JEhnholm  CNissinen  ASing  CF Apolipoprotein E polymorphism predicts death from coronary heart disease in a longitudinal study of elderly Finnish men. Circulation. 1995;91265- 269Article
15.
Mahley  RW Apolipoprotein E: cholesterol transport protein with expanding role in cell biology. Science. 1988;240622- 630Article
16.
Khachaturian  ZS Diagnosis of Alzheimer's disease. Arch Neurol. 1985;421097- 1105Article
17.
Mirra  SSHeyman  AMcKeel  D  et al.  The Consortium to Establish a Registry for Alzheimer's Disease (CERAD), part II: standardization of the neuropathological assessment of Alzheimer's disease. Neurology. 1991;41479- 486Article
18.
American Psychiatric Association, Diagnostic and Statistical Manual of Mental Disorders, Revised Third Edition.  Washington, DC American Psychiatric Association1987;
19.
Galasko  DHansen  LAKatzman  R  et al.  Clinical-neuropathological correlations in Alzheimer's disease and related dementias. Arch Neurol. 1994;51888- 895Article
20.
Hachinski  VCIliff  LDZilhka  E  et al.  Cerebral blood flow in dementia. Arch Neurol. 1975;32632- 637Article
21.
Wenham  PRPrice  WHBlundell  G Apolipoprotein E genotyping by one-stage PCR. Lancet. 1991;3371158- 1159Article
22.
Hixson  JEVernier  DT Restriction isotyping of human apolipoprotein E by gene amplification and cleavage with HhaI. J Lipid Res. 1990;31545- 548
23.
Galasko  DSaitoh  TXia  Y  et al.  The apolipoprotein E allele epsillon 4 is overrepresented in patients with the Lewy body variant of Alzheimer's disease. Neurology. 1994;441950- 1951Article
24.
Menzel  HJKladetzky  RGAssmann  G Apolipoprotein E polymorphism and coronary artery disease. Arteriosclerosis. 1983;3310- 315Article
25.
Gray  FDubas  FRoullet  EEscourolle  R Leukoencephalopathy in diffuse hemorrhagic cerebral amyloid angiopathy. Ann Neurol. 1985;1854- 59Article
26.
Okazaki  HReagan  TJCampbell  PJ Clinicopathologic studies of primary cerebral amyloid angiopathy. Mayo Clin Proc. 1979;5422- 31
27.
Greenberg  SMVonsattel  JPStakes  JWGruber  MFinklestein  SP The clinical spectrum of cerebral amyloid angiopathy. Neurology. 1993;432073- 2079Article
28.
Vonsattel  JPMyers  RHHedley-Whyte  ETRopper  AHBird  EDRichardson  EP Cerebral amyloid angiopathy without and with cerebral hemorrhages:a comparative histological study. Ann Neurol. 1991;30637- 649Article
29.
Nicoll  JARBurnett  CLove  S  et al.  High frequency of apolipoprotein E 2 allele in hemorrhage due to cerebral amyloid angiopathy. Ann Neurol. 1997;41716- 721Article
30.
Mandybur  TI Cerebral amyloid angiopathy. J Neuropathol Exp Neurol. 1986;4579- 90Article
31.
Pedro-Botet  JSenti  MNogues  X  et al.  Lipoprotein and apoprotein profile in men with ischemic stroke: role of lipoprotein(a), triglyceride rich lipoproteins, and apolipoprotein E polymorphism. Stroke. 1992;231556- 1562Article
32.
Basun  HCorder  EHGuo  Z  et al.  Apolipoprotein E polymorphism and stroke in a population sample aged 75 years or more. Stroke. 1996;271310- 1315Article
33.
Couderc  RMahieux  FBailleul  SFenelon  GMary  RFermanian  J Prevalence of apolipoprotein E phenotypes in ischemic cerebrovascular disease: a case-control study. Stroke. 1993;24661- 664Article
34.
Shimano  HIshibashi  SMurase  T  et al.  Plasma apolipoproteins in patients with multi-infarct dementia. Atherosclerosis. 1989;79257- 260Article
35.
Frisoni  GBCalabresi  LGeroldi  CBianchetti  A Apolipoprotein E-ϵ4 allele in Alzheimer's disease and vascular dementia. Dementia. 1994;5240- 242
36.
Ji  YUrakami  KAdachi  YMaeda  MIsoe  KNakashima  K Apolipoprotein E polymorphism in patients with Alzheimer's disease, vascular dementia and ischemic cerebrovascular disease. Dement Geriatr Cogn Disord. 1998;9243- 245Article
37.
Kawamata  JTanaka  SShimohama  SUeda  KKimura  J Apolipoprotein E polymorphism in Japanese patients with Alzheimer's disease and vascular dementia. J Neurol Neurosurg Psychiatry. 1994;571414- 1416Article
38.
Palumbo  BParnetti  LNocentini  GCardinali  L Apolipoprotein E genotype in normal aging, age-associated memory impairment, Alzheimer's disease, and vascular dementia patients. Neurosci Lett. 1997;23159- 61Article
39.
Betard  CRobitaille  YGee  M  et al.  Apo E allele frequencies in Alzheimer's disease, Lewy body dementia, Alzheimer's disease with cerebrovascular disease and vascular dementia. Neuroreport. 1994;51893- 1896Article
40.
Olichney  JMSabbagh  MNHofstetter  CR  et al.  The impact of apolipoprotein E4 on cause of death in Alzheimer's disease. Neurology. 1997;4976- 81Article
41.
McKhann  GDrachman  DFolstein  MKatzman  RPrice  DStadian  EM Clinical diagnosis of Alzheimer's disease: report of the NINCDS-ADRDA Work Group under the auspices of the Department of Health and Human Services Task Force on Alzheimer's Disease. Neurology. 1984;34939- 944Article
42.
Farrar  LACupples  LAHaines  JL  et al.  Effects of age, sex, and ethnicity on the association between apolipoprotein E genotype and Alzheimer's disease: a meta-analysis. APOE and Alzheimer's disease meta analysis consortium. JAMA. 1997;2781349- 1356Article
43.
Masuda  JTanaka  KUeda  KOmae  T Autopsy study of incidence and distribution in Hisayama, Japan. Stroke. 1992;231556- 1562Article
44.
Weller  ROMasses  ANewman  TAHutchings  MKuo  YMRoher  AE Cerebral amyloid angiopathy: amyloid beta accumulates in putative interstitial fluid drainage pathways in Alzheimer's disease. Am J Pathol. 1998;153725- 33Article
45.
Urmoneit  BPrikulis  IWihl  G  et al.  Cerebrovascular smooth muscle cells internalize Alzheimer amyloid beta protein via a lipoprotein pathway: implications for cerebral amyloid angiopathy. Lab Invest. 1997;77157- 166
46.
Perry  RHMcKeith  IGPerry  EK Dementia With Lewy Bodies: Clinical, Pathological, and Treatment Issues.  New York, NY Cambridge Press1996;
47.
Jellinger  KDanielczyk  WFischer  PGabriel  E Clinicopathological analysis of dementia disorders in the elderly. J Neurol Sci. 1990;95239- 258Article
48.
Thomas  TThomas  GMcLendon  CSutton  TMullan  M β-Amyloid–mediated vasoactivity and vascular endothelial damage. Nature. 1996;380168- 171Article
49.
Li  QXWhyte  STanner  JEEvin  GBeyreuther  KMasters  CL Secretion of Alzheimer's disease. Lab Invest. 1998;78461- 469
50.
Chen  MInestrosa  NCRoss  GSFernandez  HL Platelets are the primary source of amyloid β-peptide in human blood. Biochem Biophys Res Commun. 1995;21396- 103Article
51.
Van Nostrand  WEDavis-Salinas  JSaporito-Irwin  SM Amyloid β-protein induces the cerebrovascular cellular pathology of Alzheimer's disease and related disorders. Ann N Y Acad Sci. 1996;777297- 302Article
52.
Kingston  IBCastro  MJAnderson  S In vitro stimulation of tissue-type plasminogen activator by Alzheimer amyloid β-peptide analogues. Nature Med. 1995;1138- 142Article
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