**3. APOE allele-specific associations with severe CAA-associated vasculopathy**

and CAA phenotype

gene with vascular amyloid burden but not with ICH attributed to CAA, [88] which could be through interaction of TOMM40 with APOE ε2 or through its effects on Aβ mitochondrial transport. Finally, one study (544 participants) found an association of a SNP in the comple‐ ment component receptor 1 (CR1) gene with both CAA severity and ICH attributed to CAA, possibly occurring via altered clearance of Aβ peptide. [96] Other studies found no overall significant associations, although some reported associations in particular subgroups (Table 1).

CR1 gene rs6656401 1 544 Associated with severity

Adapted by permission from BMJ Publishing Group Limited, from "Genetics of cerebral amyloid angiopathy: systematic review and meta-analysis" Rannikmäe K, Samarasekera N, Martīnez-Gonzālez NA, Al-Shahi Salman R, Sudlow C. Journal

rs1799986 3 597

**No. of studies** **No. of**

1 723

2 235

2 239

18 50-380\*

**participants Summary of results**

Consistent trend for positive association between T allele and CAA

SNPs associated with vascular amyloid burden

of CAA pathology

No overall significant associations (inconsistent trends and in some cases associations in subgroups)

**Gene Location / Polymorphism**

TOMM40

58 Intracerebral Hemorrhage

LRP1 (low-density lipoprotein receptor 1)

ACE (angiotensin 1 converting enzyme)

and AβPppromoter;

Gene

ACT (α1 antichymotrypsin)

TGF-β1 rs1800470 2 449

rs2075650, rs34404554, rs11556505, rs769449, rs12972156, rs12972970, rs157582, rs184017, rs157581, rs283815, rs157580, rs439401, rs34095326, rs10119

signal region of the gene → A/T alleles that determine the aminoacid alanine or threonine\*\*

intron 16 insertion/deletion of a 287 bp sequence

CYP46 rs754203 2 524

PS1 (presenilin-1);BCHE (butyrylcholinesterase);DXS1047 locus;APOE promoter;A2M (α2 macroglobulin);PON1 (paraoxonase);NEP (neprilysin);OLR1 (oxidized low-density lipoprotein receptor 1);LRP (low density lipoprotein receptor related protein);CYP46;

\*Range of participant numbers in individual studies \*\*probably rs4943

**Table 1.** Summary of studies of non-APOE polymorphisms and CAA

factor);IL-1A;IL-1B;IL-33;GSTO1-1 (glutathione S-transferase omega-1);SORL1 (sortilin related receptor);CTSD (cathepsin D); AβPP

of Neurology Neurosurgery and Psychiatry 2013;84(901-8)

CH25H\*1;VEGF (vascular endothelial growth

The systematic review and series of meta-analyses presented in the previous section confirmed an association between histopathologically diagnosed CAA and APOE ε4, but not APOE ε2. However a recent large scale genetic association study found that both ε2 and ε4 containing genotypes were associated with clinically diagnosed CAA, manifesting as lobar ICH attributed to CAA. [15] Furthermore, APOE ε2 has been found to predict initial haematoma volume, haematoma expansion, increased mortality and poor functional outcome after lobar ICH. [17, 97] The currently favoured popular explanation for these findings is, that APOE ε4 enhances deposition of amyloid-β in cerebral blood vessel walls, while ε2 promotes haemorrhage from amyloid-laden blood vessels by increasing specific CAA-related vasculopathic changes (Figure 5). [8, 25, 98] Figure 5. Proposed theory and current state of evidence about associations between APOE

Adapted from Figure 1 in Acta Neuropathologica 2005;110: 345–359 "Sporadic cerebral amyloid angiopathy: pathology, clinical implications, and possible pathomechanisms", Johannes Attems, with kind permission from Springer Science and Business Media and

In a further recent systematic review, we reviewed the evidence for this hypothesis. [24] The main focus of this work was on assessing the potential influence of APOE genotypes on severe CAA preceding rupture. To avoid selection bias, we excluded studies with participants selected on the basis of having had a CAA-related ICH, since APOE ε2 and ε4 are already known to be associated with this phenotype, and severe CAA is commoner in such cases. This review sought all studies, which had conducted both APOE genotyping and histopathological assessment for CAA, including assessment for severe CAA with associated vasculopathic

5

Adapted from Figure 1 in Acta Neuropathologica 2005;110: 345–359 "Sporadic cerebral amyloid angiopathy: pathol‐ Professor Attems. ogy, clinical implications, and possible pathomechanisms", Johannes Attems, with kind permission from Springer Sci‐ ence and Business Media and Professor Attems.

**Figure 5.** Proposed theory and current state of evidence about associations between APOE and CAA phenotype

changes (blood vessel dilatation, microaneurysm formation, fibrinoid degeneration, cracking and double-barrelling of the vessel wall, and paravascular leakage of blood). The assessment for this severe form of CAA could have occurred either as part of the Vonsattel grading scale, [9] which includes such changes in its 'severe' category or through specifically reporting on some or all of the relevant histopathological characteristics. From 1754 publications screened, we identified six eligible studies, which included 543 eligible participants (Figure 1). [8, 25, 62, 64, 99, 100] Only one of the six studies had previously reported on the association between the APOE genotype and severe CAA (assessed using Vonsattel scale), finding a significantly greater frequency of APOE ε2 in severe versus moderate CAA cases. [25] This study and four others that had rated CAA on the Vonsattel scale, between them including 497 eligible participants (92% of all 543 potentially eligible participants), [62, 64, 99, 100] were able to share their unpublished data for collaborative meta-analyses.

The five studies included in the meta-analyses used autopsy brains either from brain tissue banks or from a population-based prospective study with an autopsy component. There were 57 to 227 eligible participants per study, mean age at death was 78 to 84 years and about half of all participants were male. Three studies (357 participants) were conducted in predomi‐ nantly white populations in the USA while information on ethnicity was unavailable for two studies (140 participants). About 50% of participants had clinical dementia (mainly neuropa‐ thologically confirmed AD), about 20% were known not to be demented and in the remaining 30% dementia status was unknown. The quality of genotyping and of pathology assessment was generally very good when assessed against current reporting standards. [71, 72] As in the first of our two systematic reviews, methods for pathological assessment were variable, reflecting a lack of agreed standards for CAA pathology assessment at the time these studies were conducted. [24]

Among the 353 individuals in these five studies who had CAA present on histopathological assessment, meta-analyses found a significant association of ε4+ versus ε4- genotypes with severe versus mild/moderate CAA (OR 2.5, 95% CI 1.4 to 4.5, p=0.002) but no significant association with severe versus moderate CAA (OR 1.7, 95% CI 0.9 to 3.1, p=0.11) (Figure 6). There was no significant heterogeneity between individual studies' results. For ε2+ versus ε2 genotypes, the associations with severe CAA versus mild/moderate CAA and with severe versus moderate CAA were non-significant, with wide confidence intervals due to small numbers of participants, particularly in the ε2+ group, which included 22 individuals, only seven of whom had severe CAA (Figure 7). There was moderate heterogeneity between individual studies' results for severe versus mild/moderate CAA (I2 =52%; χ<sup>2</sup> 3df=6.2; p=0.1) and minimal heterogeneity for severe versus moderate CAA (I2 =11%; χ<sup>2</sup> 3df=3.4; p=0.3). Results were similar and conclusions unchanged for the ε4+ and ε2+ genotypes when ε3ε3 genotypes were used as the comparison group (rather than ε4- or ε2-). Associations with the presence versus absence of CAA were consistent with results from the previous published systematic review [23], showing a clearly significant association with ε4+ (ε4+ versus ε4-: OR 4.8, 95% CI 3.0 to 7.6, p<0.00001) but not with ε2+ genotypes (ε2+ versus ε2-: OR 0.38, 95% CI 0.1 to 1.0, p=0.05).

6

6

Less severe CAA with ε2+ More severe CAA with ε2+

Less severe CAA with ε2+ More severe CAA with ε2+

0.01 1 100

0.01 1 100

2.7 (0.6 to 11.4) p = 0.19

> 2.7 (0.6 to 11.4) p = 0.19

2.3 (0.5 to 11.3) p = 0.3

OR (95% CI)

2.3 (0.5 to 11.3) p = 0.3

OR (95% CI)

The diamonds represent pooled OR across studies and the width of the diamonds represents 95%

0.01 1

Less severe CAA with ε4+ More severe CAA with ε4+

Less severe CAA with ε4+ More severe CAA with ε4+

0.01 1

1.7 (0.9 to 3.1) p = 0.11

> 1.7 (0.9 to 3.1) p = 0.11

2.5 (1.4 to 4.5) p = 0.002

OR (95% CI)

Genetics of Sporadic Cerebral Amyloid Angiopathy

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61

100

100

2.5 (1.4 to 4.5) p = 0.002

OR (95% CI)

\*ε4+: number of subjects with an ε4 allele and severe CAA / total number of subjects with an ε4 allele

The diamonds represent pooled OR across studies and the width of the diamonds represents 95%

\*ε4+: number of subjects with an ε4 allele and severe CAA / total number of subjects with an ε4 allele

ε4-: number of subjects without an ε4 allele and severe CAA / total number of subjects without an ε4

Adapted by permission from BMJ Publishing Group Limited, from "APOE associations with severe CAA-associated vasculpathic changes: collaborative meta-analysis" Rannikmäe K, Kalaria RN, Greenberg SM, Chui HC, Schmitt FA, Samarasekera N, et al. Journal of

ε4-: number of subjects without an ε4 allele and severe CAA / total number of subjects without an ε4

Adapted by permission from BMJ Publishing Group Limited, from "APOE associations with severe CAA-associated vasculpathic changes: collaborative meta-analysis" Rannikmäe K, Kalaria RN, Greenberg SM, Chui HC, Schmitt FA, Samarasekera N, et al. Journal of

Results of two studies conducted in one centre were combined for the analyses.[25,64]

The diamonds represent pooled OR across studies and the width of the diamonds represents 95% confidence inter‐

3df=1.2; p=0.75

3df=1.2; p=0.76

\*ε4+: number of subjects with an ε4 allele and severe CAA / total number of subjects with an ε4 allele and any severity

ε4-: number of subjects without an ε4 allele and severe CAA / total number of subjects without an ε4 allele and any

Adapted by permission from BMJ Publishing Group Limited, from "APOE associations with severe CAA-associated vas‐ culpathic changes: collaborative meta-analysis" Rannikmäe K, Kalaria RN, Greenberg SM, Chui HC, Schmitt FA, Samara‐

Results of two studies conducted in one centre were combined for the analyses.[25,64]

Figure 6. Meta-analysis of APOE-ε4 associations with severe CAA

Figure 6. Meta-analysis of APOE-ε4 associations with severe CAA

ε4 +\* ε4 -\* 74/224 19/129

ε4 +\* ε4 -\* 74/224 19/129

74/169 19/69

74/169 19/69

3df=1.2; p=0.75

3df=1.2; p=0.76

confidence intervals (CIs).

confidence intervals (CIs).

vals (CIs).

of CAA *or* severe/moderate CAA

severity of CAA *or* severe/moderate CAA

Severe vs moderate CAA: I<sup>2</sup>=0%; χ<sup>2</sup>

Severe vs less severe CAA: I<sup>2</sup>=0%; χ<sup>2</sup>

Severe vs moderate CAA: I<sup>2</sup>=0%; χ<sup>2</sup>

Severe vs mild/moderate CAA

Severe vs mild/moderate CAA

**Figure 6.** Meta-analysis of APOE-ε4 associations with severe CAA

Severe vs moderate CAA: I<sup>2</sup>=11%; χ<sup>2</sup>

Severe vs less severe CAA: I<sup>2</sup>=52%; χ<sup>2</sup>

asekera N, et al. Journal of Neurology Neurosurgery and Psychiatry 2014;85(3):300-5.

Severe vs moderate CAA: I<sup>2</sup>=11%; χ<sup>2</sup>

Severe vs moderate CAA

Severe vs moderate CAA

Random effects model Tests for heterogeneity: Severe vs less severe CAA: I<sup>2</sup>=52%; χ<sup>2</sup>

Random effects model Tests for heterogeneity:

ed in one centre were combined for the analyses. [25, 64]

**Figure 7.** Meta-analysis of APOE ε2 associations with severe CAA

Random effects model Tests for heterogeneity: Severe vs less severe CAA: I<sup>2</sup>=0%; χ<sup>2</sup>

Random effects model Tests for heterogeneity:

Severe vs mild/moderate CAA

Severe vs mild/moderate CAA

Severe vs moderate CAA

Severe vs moderate CAA

and any severity of CAA or severe/moderate CAA

allele and any severity of CAA or severe/moderate CAA

and any severity of CAA or severe/moderate CAA

Results of two studies conducted in one centre were combined for the analyses. [25, 64]

allele and any severity of CAA or severe/moderate CAA

sekera N, et al. Journal of Neurology Neurosurgery and Psychiatry 2014;85(3):300-5.

Neurology Neurosurgery and Psychiatry 2014;85(3):300-5.

Figure 7. Meta-analysis of APOE-ε2 associations with severe CAA

Neurology Neurosurgery and Psychiatry 2014;85(3):300-5.

ε2 +\* ε2 -\* 7/22 86/331

Figure 7. Meta-analysis of APOE-ε2 associations with severe CAA

7/12 86/226

ε2 +\* ε2 -\* 7/22 86/331

7/12 86/226

3df=6.2; p=0.1

3df=6.2; p=0.1

The diamonds represent pooled OR across studies and the width of the diamonds represents 95% confidence inter‐ vals (CIs). \*ε2+: Number of subjects with an ε2 allele and severe CAA / total number of subjects with an ε2 allele and any severity of CAA *or* severe/moderate CAA ε2-: number of subjects without an ε2 allele and severe CAA / total num‐ ber of subjects without an ε2 allele and any severity of CAA *or* severe/moderate CAA. Results of two studies conduct‐

Adapted by permission from BMJ Publishing Group Limited, from "APOE associations with severe CAA-associated vas‐ culpathic changes: collaborative meta-analysis." Rannikmäe K, Kalaria RN, Greenberg SM, Chui HC, Schmitt FA, Samar‐

3df=3.4; p=0.3

3df=3.4; p=0.3

2.3 (0.5 to 11.3)

OR (95% CI)

Figure 6. Meta-analysis of APOE-ε4 associations with severe CAA

The diamonds represent pooled OR across studies and the width of the diamonds represents 95% confidence intervals (CIs). The diamonds represent pooled OR across studies and the width of the diamonds represents 95% confidence inter‐ vals (CIs). Severe vs less severe CAA: I<sup>2</sup>=0%; χ<sup>2</sup> 3df=1.2; p=0.75 Severe vs moderate CAA: I<sup>2</sup>=0%; χ<sup>2</sup> 3df=1.2; p=0.76

\*ε4+: number of subjects with an ε4 allele and severe CAA / total number of subjects with an ε4 allele and any severity of CAA or severe/moderate CAA ε4-: number of subjects without an ε4 allele and severe CAA / total number of subjects without an ε4 \*ε4+: number of subjects with an ε4 allele and severe CAA / total number of subjects with an ε4 allele and any severity of CAA *or* severe/moderate CAA The diamonds represent pooled OR across studies and the width of the diamonds represents 95% confidence intervals (CIs).

allele and any severity of CAA or severe/moderate CAA Results of two studies conducted in one centre were combined for the analyses.[25,64] ε4-: number of subjects without an ε4 allele and severe CAA / total number of subjects without an ε4 allele and any severity of CAA *or* severe/moderate CAA \*ε4+: number of subjects with an ε4 allele and severe CAA / total number of subjects with an ε4 allele and any severity of CAA or severe/moderate CAA

Results of two studies conducted in one centre were combined for the analyses. [25, 64] ε4-: number of subjects without an ε4 allele and severe CAA / total number of subjects without an ε4

Neurology Neurosurgery and Psychiatry 2014;85(3):300-5.

Neurology Neurosurgery and Psychiatry 2014;85(3):300-5.

Adapted by permission from BMJ Publishing Group Limited, from "APOE associations with severe CAA-associated vasculpathic changes: collaborative meta-analysis" Rannikmäe K, Kalaria RN, Greenberg SM, Chui HC, Schmitt FA, Samarasekera N, et al. Journal of Adapted by permission from BMJ Publishing Group Limited, from "APOE associations with severe CAA-associated vas‐ culpathic changes: collaborative meta-analysis" Rannikmäe K, Kalaria RN, Greenberg SM, Chui HC, Schmitt FA, Samara‐ sekera N, et al. Journal of Neurology Neurosurgery and Psychiatry 2014;85(3):300-5. allele and any severity of CAA or severe/moderate CAA Results of two studies conducted in one centre were combined for the analyses.[25,64] Adapted by permission from BMJ Publishing Group Limited, from "APOE associations with

> ε2 +\* ε2 -\* 7/22 86/331

Figure 7. Meta-analysis of APOE-ε2 associations with severe CAA

Figure 7. Meta-analysis of APOE-ε2 associations with severe CAA **Figure 6.** Meta-analysis of APOE-ε4 associations with severe CAA severe CAA-associated vasculpathic changes: collaborative meta-analysis" Rannikmäe K, Kalaria RN, Greenberg SM, Chui HC, Schmitt FA, Samarasekera N, et al. Journal of

Tests for heterogeneity:

Severe vs mild/moderate CAA

changes (blood vessel dilatation, microaneurysm formation, fibrinoid degeneration, cracking and double-barrelling of the vessel wall, and paravascular leakage of blood). The assessment for this severe form of CAA could have occurred either as part of the Vonsattel grading scale, [9] which includes such changes in its 'severe' category or through specifically reporting on some or all of the relevant histopathological characteristics. From 1754 publications screened, we identified six eligible studies, which included 543 eligible participants (Figure 1). [8, 25, 62, 64, 99, 100] Only one of the six studies had previously reported on the association between the APOE genotype and severe CAA (assessed using Vonsattel scale), finding a significantly greater frequency of APOE ε2 in severe versus moderate CAA cases. [25] This study and four others that had rated CAA on the Vonsattel scale, between them including 497 eligible participants (92% of all 543 potentially eligible participants), [62, 64, 99, 100] were able to share

The five studies included in the meta-analyses used autopsy brains either from brain tissue banks or from a population-based prospective study with an autopsy component. There were 57 to 227 eligible participants per study, mean age at death was 78 to 84 years and about half of all participants were male. Three studies (357 participants) were conducted in predomi‐ nantly white populations in the USA while information on ethnicity was unavailable for two studies (140 participants). About 50% of participants had clinical dementia (mainly neuropa‐ thologically confirmed AD), about 20% were known not to be demented and in the remaining 30% dementia status was unknown. The quality of genotyping and of pathology assessment was generally very good when assessed against current reporting standards. [71, 72] As in the first of our two systematic reviews, methods for pathological assessment were variable, reflecting a lack of agreed standards for CAA pathology assessment at the time these studies

Among the 353 individuals in these five studies who had CAA present on histopathological assessment, meta-analyses found a significant association of ε4+ versus ε4- genotypes with severe versus mild/moderate CAA (OR 2.5, 95% CI 1.4 to 4.5, p=0.002) but no significant association with severe versus moderate CAA (OR 1.7, 95% CI 0.9 to 3.1, p=0.11) (Figure 6). There was no significant heterogeneity between individual studies' results. For ε2+ versus ε2 genotypes, the associations with severe CAA versus mild/moderate CAA and with severe versus moderate CAA were non-significant, with wide confidence intervals due to small numbers of participants, particularly in the ε2+ group, which included 22 individuals, only seven of whom had severe CAA (Figure 7). There was moderate heterogeneity between

similar and conclusions unchanged for the ε4+ and ε2+ genotypes when ε3ε3 genotypes were used as the comparison group (rather than ε4- or ε2-). Associations with the presence versus absence of CAA were consistent with results from the previous published systematic review [23], showing a clearly significant association with ε4+ (ε4+ versus ε4-: OR 4.8, 95% CI 3.0 to 7.6, p<0.00001) but not with ε2+ genotypes (ε2+ versus ε2-: OR 0.38, 95% CI 0.1 to 1.0, p=0.05).

=52%; χ<sup>2</sup>

=11%; χ<sup>2</sup>

3df=6.2; p=0.1) and

3df=3.4; p=0.3). Results were

individual studies' results for severe versus mild/moderate CAA (I2

minimal heterogeneity for severe versus moderate CAA (I2

their unpublished data for collaborative meta-analyses.

were conducted. [24]

60 Intracerebral Hemorrhage

Severe vs less severe CAA: I<sup>2</sup>=52%; χ<sup>2</sup> 3df=6.2; p=0.1 Severe vs moderate CAA: I<sup>2</sup>=11%; χ<sup>2</sup> 3df=3.4; p=0.3

6

Adapted by permission from BMJ Publishing Group Limited, from "APOE associations with severe CAA-associated vas‐ culpathic changes: collaborative meta-analysis." Rannikmäe K, Kalaria RN, Greenberg SM, Chui HC, Schmitt FA, Samar‐ asekera N, et al. Journal of Neurology Neurosurgery and Psychiatry 2014;85(3):300-5.

**Figure 7.** Meta-analysis of APOE ε2 associations with severe CAA

<sup>6</sup>  The diamonds represent pooled OR across studies and the width of the diamonds represents 95% confidence inter‐ vals (CIs). \*ε2+: Number of subjects with an ε2 allele and severe CAA / total number of subjects with an ε2 allele and any severity of CAA *or* severe/moderate CAA ε2-: number of subjects without an ε2 allele and severe CAA / total num‐ ber of subjects without an ε2 allele and any severity of CAA *or* severe/moderate CAA. Results of two studies conduct‐ ed in one centre were combined for the analyses. [25, 64]

Thus, contrary to what has been suggested, [8, 25] a systematic assessment of the relevant evidence suggests a possible association of APOE ε4 but not of APOE ε2 with progression to severe CAA (Figure 5). However, this does not exclude a biologically meaningful association with APOE ε2 since, despite including data from almost all relevant cases from the published literature, total numbers of individuals included in our meta-analyses were relatively small and confidence intervals wide, especially for analyses of the effects of APOE ε2. There were other limitations too. First, methods for histopathological assessment varied between studies, potentially introducing heterogeneity and reducing the likelihood of detecting a consistent effect across studies. Second, APOE allele-specific effects on severe CAA may differ according to the presence or absence of Alzheimer's disease, particularly for APOE ε2, which has been associated with a decreased risk of Alzheimer's dementia. [101] Informative subgroup analysis to explore potential causes of heterogeneity could not be performed, however, because of the small overall numbers of participants and because dementia status was unknown for a large number of participants. Third, while the studies included assessed those severe CAAassociated vasculopathic changes that are specifically alluded to in the Vonsattel scale, other vasculopathic changes may also be relevant. Fourth, both APOE allele-specific and other genetic associations may differ by CAA subtype. The preliminary evidence that APOE ε4 may be associated with CAA type 1 (where CAA is found in cortical capillaries), and ε2 with CAA type 2 (where amyloid is deposited in leptomeningeal and cortical vessels with the exception of cortical capillaries) [26] suggests that CAA types 1 and 2 may represent different patholog‐ ical entities, and – if so-the mechanisms and genetic risk factors for severe CAA and ICH could also differ. Finally, there may be other genetic influences that interact with APOE ε2 to increase risk of or protect against severe CAA and ICH.

**Acknowledgements**

Lexington, Kentucky, USA).

and Cathie Sudlow1,2

1 Centre for Clinical Brain Sciences, University of Edinburgh, Edinburgh, UK

2 Institute for Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, UK

[1] Revesz T, Holton JL, Lashley T, Plant G, Frangione B, Ristagno A et al. Genetics and molecular pathogenesis of sporadic and hereditary cerebral amyloid angiopathies.

[2] Charidiomou A, Gang Q, Werring DJ. Sporadic cerebral amyloid angiopathy revisit‐ ed: recent insights into pathophysiology and clinical spectrum. Journal of Neurology

[3] Samarasekera N, Smith C, Al-Shahi Salman R. The association between cerebral amy‐ loid angiopathy and intracerebral haemorrhage: systematic review and meta-analy‐

[4] Chi NF, Chien LN, Ku HL, Hu CJ, Chiou HY. Alzheimer disease and risk of stroke: a

[5] Masuda J, Tanaka K, Ueda K, Omae T. Autopsy study of incidence and distribution of cerebral amyloid angiopathy in Hisayama, Japan. Stroke 1988;19(2)205-10.

[6] Neuropathology Group.Medical Research Council Cognitive Function and Aging Study. Pathological correlates of late-onset dementia in a multicentre, community

sis. Journal of Neurology Neurosurgery and Psychiatry 2012;83(3)275-81.

population-based cohort study. Neurology 2013;80(8)705-11.

\*Address all correspondence to: cathie.sudlow@ed.ac.uk

Acta Neuropathololgica 2009;118:115–30.

Neurosurgery and Psychiatry 2012;83(2)124-37.

**Author details**

**References**

Kristiina Rannikmäe1

The authors would like to acknowledge for their scientific input Professor Rustam Al-Shahi Salman, Dr Neshika Samarasekera and Nahara Anani Martînez-Gonzâlez (Centre for Clinical Brain Sciences, University of Edinburgh, Edinburgh, UK), Professor Rajesh N Kalaria (Institute for Ageing and Health, Newcastle University, Newcastle upon Tyne, UK), Professor Steven M Greenberg (Department of Neurology, Stroke Research Centre, Massachusetts General Hospital, Boston, Massachusetts, USA), Professor Helena C Chui (Department of Neurology, University of Southern California, Los Angeles, California, USA) and Professor Frederick A Schmitt (Department of Neurology, Sanders-Brown Center on Aging, University of Kentucky,

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#### **4. Conclusions**

There is strong evidence that APOE ε4 promotes cerebral amyloid angiopathy, and further evidence to suggest that ε4 may increase the risk of developing severe CAA among those with CAA. However, there is not convincing evidence to support the theory that APOE ε2 promotes progression to severe CAA-related vasculopathic changes so leading to vessel rupture and ICH. Much larger numbers of individuals will need to be included in CAA histopathology studies if reliable conclusions are to be drawn about the specific effects of APOE ε2, while bearing in mind that APOE genotype will not be the only genetic influence on CAA. Future research efforts in this area will also be helped substantially by the development and use of an internationally-agreed, standardised histopathological grading system for CAA (including assessment of CAA types 1 and 2), and by the consistent reporting of dementia – and specifi‐ cally Alzheimer's disease – status [102] among individuals included in CAA histopathology studies.
