**1. Introduction**

[18] Linn J, Herms J, Dichgans M, Brückmann H, Fesl G, Freilinger T, et al. Subarachnoid hemosiderosis and superficial cortical hemosiderosis in cerebral amyloid angiopathy.

[19] Fazekas F, Chawluk JB, Alavi A, Hurtig HI, Zimmerman RA. MR signal abnormali‐ ties at 1. 5T in Alzheimer's dementia and normal aging. AJNR Am J Neuroradiol

[20] Loes DJ, Biller J, Yuh WT, Hart MN, Godersky JC, Adams HP, et al. Leukoencephal‐ opathy in cerebral amyloid angiopathy: MR imaging in four cases. AJNR Am J Neu‐

[21] Chung KK, Anderson NE, Hutchinson D, Synek B, Barber PA. Cerebral amyloid an‐ giopathy related inflammation: three case reports and a review. J Neurol Neurosurg

[22] Greenberg SM, Finklestein SP, Schaefer PW. Petechial hemorrhages accompanying lobar hemorrhage: detection by gradient-echo MRI. Neurology 1996;46:1751-4. [23] Izumihara A, Ishihara T, Iwamoto N, Yamashita K, Ito H. Postoperative outcome of 37 patients with lobar intracerebral hemorrhage related to cerebral amyloid angiop‐

[24] Kloppenborg RP, Richard E, Sprengers ME, Troost D, Eikelenboom P, Nederkoorn PJ. Steroid responsive encephalopathy in cerebral amyloid angiopathy: a case report and review of evidence for immunosuppressive treatment. J Neuroinflammation

[25] Greenberg SM, Rosand J, Schneider AT, Creed Pettigrew L, Gandy SE, Rovner B, et al. A phase 2 study of tramiprosate for cerebral amyloid angiopathy. Alzheimer Dis

AJNR Am J Neuroradiol 2008;29:184-6.

1987;8:421-6.

50 Intracerebral Hemorrhage

roradiol 1990;11:485-8.

Psychiatry 2011;82:20-6.

athy. Stroke 1999;30:29-33.

Assoc Disord 2006;20:269-74.

2010;7:18.

Cerebral amyloid angiopathies (CAA) can be divided into sporadic and hereditary forms. This chapter is focused on the genetics of sporadic CAA, but will first consider hereditary forms in brief.

#### **1.1. Hereditary CAA**

Amyloid-β protein (Aβ), the commonest amyloid subunit implicated in sporadic forms of CAA, is also involved in certain hereditary forms. Several other proteins are also associated with rare familial diseases in which CAA is a characteristic morphological feature. [1] Missense mutations within or just outside the Aβ peptide coding region of the APP gene result in clinicopathological phenotypes of early onset Alzheimer's disease (AD) and are associated with a neuropathological phenotype which includes prominent CAA – for example hereditary cerebral haemorrhage with amyloidosis of Dutch type (HCHWA-D), or with Italian, Arctic, Iowa, Piedmont and Flemish mutations. Severe Aβ CAA has also been well documented in cases of familial AD due to mutations in the presenilin (PSEN1 and PSEN2) genes. Familial CAAs associated with other proteins include BRI2 gene-related dementias (familial British dementia and familial Danish dementia), cystatin C gene mutations in hereditary cerebral haemorrhage with amyloidosis of Icelandic type, TTR gene mutations in meningo-vascular amyloidosis, hereditary prion disease with premature stop codon mutations and mutated gelsolin gene in familial amyloidosis of Finnish type. [1]

### **1.2. Sporadic CAA**

Sporadic cerebral amyloid angiopathy is characterised by deposition of Aβ in leptomeningeal and cortical blood vessels. It has a prevalence in population-based autopsy studies of 20-40%

© 2014 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

in non-demented and 50-60% in demented elderly people. [2] Neuropathological case-control and cross-sectional studies, as well as the increased incidence of intracerebral haemorrhage (ICH) in patients with Alzheimer's disease, suggest that CAA causes lobar ICH. [3, 4] CAA is also associated with increasing age, dementia, lobar brain microbleeds, leukoaraiosis, small cortical infarcts and superficial siderosis. [3, 5-7]

It is unknown why only a few people with CAA pathology develop an ICH, but it seems likely to involve biological pathways additional to and distinct from those involved in vascular amyloid deposition. Cases of CAA with ICH not only have a greater proportion of amyloidladen blood vessels, [8] but also more often demonstrate severe CAA with associated vascul‐ opathy. [8-11]

Non APOE polymorphisms/ sporadic CAA

24 studies 4,703 participants

Studies with data for meta-analysis 5 studies 497 participants

**Figure 1.** Selection of included studies

Electronic database searches (2,445 publications)

Studies without data for meta-analysis 22 studies 3,125 participants

49 publications excluded because of overlapping participants

12 studies excluded because no. of participants <35

1,642 publications excluded on the basis of screening titles, abstracts ± full texts

702 duplicate publications

excluded

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Studies with data for meta-analysis 24 studies 3,520 participants

APOE/ severe CAA-associated vasculopathy

Publications screened (1,754 publications)

> Relevant studies (112 publications)

> > 8 studies ~557 participants

APOE/ severe CAA-associated vasculopathy 6 studies 543 participants

> Studies without data for meta-analysis 1 study 46 participants

2 studies excluded because no. of participants <10

APOE / sporadic CAA (107 publications)

Hand search and bibliography screening (11 publications)

> APOE/ presence vs absence of CAA

> > 58 studies 6,855 participants

APOE/ presence vs absence of CAA 46 studies 6,645 participants

Identifying genetic polymorphisms associated with the presence of histopathologically confirmed CAA in general, as well as with the severe form of CAA thought to cause vessel rupture and ICH, should increase our understanding of the mechanisms leading to CAA and associated diseases, including CAA associated ICH.

Polymorphisms in the apolipoprotein E gene (APOE) [12] are associated with ICH as well as with other conditions in which CAA may be involved, including subarachnoid haemorrhage, lobar brain microbleeds, and AD. [7, 13-18] In vitro studies have shown that APOE influences Aβ conformation, fibril formation and toxicity, [19, 20] while in vivo mouse studies have confirmed a critical role for apolipoprotein E in Aβ deposition, toxicity and possibly clearance. [21, 22] It therefore seems likely that APOE influences risk of developing histopathologically confirmed, sporadic CAA. Other genetic polymorphisms are also likely to contribute to development of sporadic CAA.

Below we present and summarise the evidence for associations of polymorphisms in APOE or any other gene with histopathologically confirmed, sporadic CAA in adult humans. We then go on to consider the evidence for associations of APOE with the severe form of CAA. The evidence presented is based mainly on our two recently published systematic reviews of all relevant published studies, both of which incorporated a comprehensive search strategy, a thorough assessment of study quality, a series of meta-analyses, and an evaluation of the robustness of any positive findings to small study and other methodological biases. [23, 24] Figure 1 summarises the strategy used for identifying relevant studies and the numbers of studies (and study participants) identified.

## **2. Genetic associations with histopathologically-confirmed, sporadic CAA**

While robust, large-scale evidence exists for an association of APOE with ICH attributed to CAA on the basis of clinical criteria, [15] studies assessing association of APOE with histopa‐ thologically confirmed CAA have had various methodological shortcomings (including small size), and reported results vary. Our systematic review of genetic associations with histopa‐ thologically confirmed, sporadic CAA sought all studies in which participants had been

**Figure 1.** Selection of included studies

in non-demented and 50-60% in demented elderly people. [2] Neuropathological case-control and cross-sectional studies, as well as the increased incidence of intracerebral haemorrhage (ICH) in patients with Alzheimer's disease, suggest that CAA causes lobar ICH. [3, 4] CAA is also associated with increasing age, dementia, lobar brain microbleeds, leukoaraiosis, small

It is unknown why only a few people with CAA pathology develop an ICH, but it seems likely to involve biological pathways additional to and distinct from those involved in vascular amyloid deposition. Cases of CAA with ICH not only have a greater proportion of amyloidladen blood vessels, [8] but also more often demonstrate severe CAA with associated vascul‐

Identifying genetic polymorphisms associated with the presence of histopathologically confirmed CAA in general, as well as with the severe form of CAA thought to cause vessel rupture and ICH, should increase our understanding of the mechanisms leading to CAA and

Polymorphisms in the apolipoprotein E gene (APOE) [12] are associated with ICH as well as with other conditions in which CAA may be involved, including subarachnoid haemorrhage, lobar brain microbleeds, and AD. [7, 13-18] In vitro studies have shown that APOE influences Aβ conformation, fibril formation and toxicity, [19, 20] while in vivo mouse studies have confirmed a critical role for apolipoprotein E in Aβ deposition, toxicity and possibly clearance. [21, 22] It therefore seems likely that APOE influences risk of developing histopathologically confirmed, sporadic CAA. Other genetic polymorphisms are also likely to contribute to

Below we present and summarise the evidence for associations of polymorphisms in APOE or any other gene with histopathologically confirmed, sporadic CAA in adult humans. We then go on to consider the evidence for associations of APOE with the severe form of CAA. The evidence presented is based mainly on our two recently published systematic reviews of all relevant published studies, both of which incorporated a comprehensive search strategy, a thorough assessment of study quality, a series of meta-analyses, and an evaluation of the robustness of any positive findings to small study and other methodological biases. [23, 24] Figure 1 summarises the strategy used for identifying relevant studies and the numbers of

**2. Genetic associations with histopathologically-confirmed, sporadic CAA**

While robust, large-scale evidence exists for an association of APOE with ICH attributed to CAA on the basis of clinical criteria, [15] studies assessing association of APOE with histopa‐ thologically confirmed CAA have had various methodological shortcomings (including small size), and reported results vary. Our systematic review of genetic associations with histopa‐ thologically confirmed, sporadic CAA sought all studies in which participants had been

cortical infarcts and superficial siderosis. [3, 5-7]

associated diseases, including CAA associated ICH.

development of sporadic CAA.

studies (and study participants) identified.

opathy. [8-11]

52 Intracerebral Hemorrhage

genotyped for any genetic polymorphism and had CAA assessed pathologically (using autopsy or biopsy). [23] Studies that had assessed genetic associations with CAA-associated ICH (CAAH) versus CAA-free controls were excluded, because these would not be able to distinguish a genetic association with the presence of CAA histopathology from an association with ICH.

#### **2.1. APOE ε2/ε3/ε4 polymorphism and sporadic CAA**

We identified 46 studies including 6645 participants with data about the APOE ε2/ε3/ε4 polymorphism and sporadic CAA (Figure 1). [25-70] These studies had used autopsy brains from clinical autopsy collections, a brain bank or a population-based prospective study. Participants' mean age was 70 to 85 years in most studies and about half were male. Almost 90% of participants were of European ancestry while around 10% were from Asian populations (all Japanese). About 30% of participants had clinical dementia (mainly AD), about 10% were known not to be demented and dementia status was not specified for the remainder. There was substantial variation in overall study quality. Genotyping reporting quality [71, 72] was generally limited and methods for pathological assessment were very variable. Larger studies tended to be of higher quality. [23]

#### *2.1.1. APOE ε4 and CAA*

Meta-analyses were possible of data from just over half of these studies (including just over half of the participants), and showed a significant association between ε4+ genotypes and presence of CAA (OR 2.67, 95% CI 2.31 to 3.08), although there was significant heterogeneity between the studies' results (Figure 2). There were no significant differences between sub‐ groups of studies based on dementia status, ethnicity or overall study quality score (Figures 2 and 3). Six studies (443 participants) made only a qualitative statement, [27, 30, 33, 37, 40, 42] reporting either no significant association or a trend towards association with APOE ε4, while 16 studies (2682 participants) provided no information about the association. [25, 28, 29, 31, 32, 34-36, 38, 39, 41, 43, 46, 47, 50, 57]

Failsafe N calculations [73] showed that a null study of >137, 000 participants would be re‐ quired to bring the association of ε4+ genotypes with CAA from the meta-analysis to a just statistically non-significant level. This makes it unlikely that there might plausibly be enough participants in unpublished, unreported or otherwise unretrieved null studies to make this significant result non-significant, and suggests that the association of APOE ε4+ genotypes with histopathologcally confirmed, sporadic CAA is real and robust. Meta-analy‐ sis of the association of APOE ε4 allele dose with CAA among 12 studies (1706 participants) providing quantitative data showed a significant increase in the odds of having CAA with increasing dose of the ε4 allele (Figure 4). Two further studies (117 participants) provided a qualitative statement about the association supported this result. [40, 64] Failsafe N calcula‐ tions showed that it would require a null study of >7000 participants to bring the stronger association with CAA of ε4 homozygous versus heterozygous genotypes to a just non-sig‐ nificant level, suggesting that the finding of a dose-response relationship between APOE ε4 and CAA is real and robust.

The squares represent study-specific odds ratios (ORs), with their size proportional to their statistical weight by the generic inverse variance method. Horizontal lines represent 95% confidence intervals (CIs). Diamonds represent

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Reproduced from "Genetics of cerebral amyloid angiopathy: systematic review and meta-analysis" Rannikmäe K, Sa‐ marasekera N, Martīnez-Gonzālez NA, Al-Shahi Salman R, Sudlow C. Journal of Neurology Neurosurgery and Psychia‐

**Figure 2.** Meta-analysis of association of APOE ε4+ vs ε4- genotypes with CAA by participants' dementia status

pooled ORs, and their width represents the 95% CI. Higher score represents better study quality.

try 2013;84(901-8), with permission from BMJ Publishing Group Ltd.


genotyped for any genetic polymorphism and had CAA assessed pathologically (using autopsy or biopsy). [23] Studies that had assessed genetic associations with CAA-associated ICH (CAAH) versus CAA-free controls were excluded, because these would not be able to distinguish a genetic association with the presence of CAA histopathology from an association

We identified 46 studies including 6645 participants with data about the APOE ε2/ε3/ε4 polymorphism and sporadic CAA (Figure 1). [25-70] These studies had used autopsy brains from clinical autopsy collections, a brain bank or a population-based prospective study. Participants' mean age was 70 to 85 years in most studies and about half were male. Almost 90% of participants were of European ancestry while around 10% were from Asian populations (all Japanese). About 30% of participants had clinical dementia (mainly AD), about 10% were known not to be demented and dementia status was not specified for the remainder. There was substantial variation in overall study quality. Genotyping reporting quality [71, 72] was generally limited and methods for pathological assessment were very variable. Larger studies

Meta-analyses were possible of data from just over half of these studies (including just over half of the participants), and showed a significant association between ε4+ genotypes and presence of CAA (OR 2.67, 95% CI 2.31 to 3.08), although there was significant heterogeneity between the studies' results (Figure 2). There were no significant differences between sub‐ groups of studies based on dementia status, ethnicity or overall study quality score (Figures 2 and 3). Six studies (443 participants) made only a qualitative statement, [27, 30, 33, 37, 40, 42] reporting either no significant association or a trend towards association with APOE ε4, while 16 studies (2682 participants) provided no information about the association. [25, 28, 29,

Failsafe N calculations [73] showed that a null study of >137, 000 participants would be re‐ quired to bring the association of ε4+ genotypes with CAA from the meta-analysis to a just statistically non-significant level. This makes it unlikely that there might plausibly be enough participants in unpublished, unreported or otherwise unretrieved null studies to make this significant result non-significant, and suggests that the association of APOE ε4+ genotypes with histopathologcally confirmed, sporadic CAA is real and robust. Meta-analy‐ sis of the association of APOE ε4 allele dose with CAA among 12 studies (1706 participants) providing quantitative data showed a significant increase in the odds of having CAA with increasing dose of the ε4 allele (Figure 4). Two further studies (117 participants) provided a qualitative statement about the association supported this result. [40, 64] Failsafe N calcula‐ tions showed that it would require a null study of >7000 participants to bring the stronger association with CAA of ε4 homozygous versus heterozygous genotypes to a just non-sig‐ nificant level, suggesting that the finding of a dose-response relationship between APOE ε4

**2.1. APOE ε2/ε3/ε4 polymorphism and sporadic CAA**

tended to be of higher quality. [23]

31, 32, 34-36, 38, 39, 41, 43, 46, 47, 50, 57]

and CAA is real and robust.

*2.1.1. APOE ε4 and CAA*

with ICH.

54 Intracerebral Hemorrhage

The squares represent study-specific odds ratios (ORs), with their size proportional to their statistical weight by the generic inverse variance method. Horizontal lines represent 95% confidence intervals (CIs). Diamonds represent pooled ORs, and their width represents the 95% CI. Higher score represents better study quality.

Reproduced from "Genetics of cerebral amyloid angiopathy: systematic review and meta-analysis" Rannikmäe K, Sa‐ marasekera N, Martīnez-Gonzālez NA, Al-Shahi Salman R, Sudlow C. Journal of Neurology Neurosurgery and Psychia‐ try 2013;84(901-8), with permission from BMJ Publishing Group Ltd.

**Figure 2.** Meta-analysis of association of APOE ε4+ vs ε4- genotypes with CAA by participants' dementia status

*2.1.3. Summary and discussion*

There is, therefore, robust evidence for a highly significant, dose-dependent association between APOE ε4 and pathologically proven CAA, which does not vary significantly with dementia status, ethnicity, or study quality. However, there is no clear overall association between APOE ε2 and histopathologically confirmed CAA. Lack of variation in the effect of APOE ε4 by study size and the very large failsafe N showed that this association could not plausibly be explained by publication, reporting or any other small study bias. It is important to note that the quality of studies included in our systematic review was generally limited when assessed against current reporting standards. [71, 72] However, there were - reassuringly

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The prevalence of CAA in Alzheimer's disease is over 70% but the relationship between CAA and AD is still poorly understood. Although the diagnostic criteria for dementia and the participant inclusion criteria varied between the studies in our systematic review (some excluding cases with severe dementia), the demonstration of a similar association in those with and without clinical dementia suggests that the association of APOE ε4 with CAA is inde‐

Pathological assessment in the included studies was very variable. Indeed, there is no widely accepted, standardized histopathological grading system for CAA, [74] and no comparative studies to determine the most accurate method for assessing CAA (although the suggested method is a combination of Thioflavin S/T or Congo Red with immunohistochemistry). [75] CAA assessment location also varied widely, possibly influencing the rate of CAA detection, since a greater burden of CAA is generally reported in the occipital or parietal lobes, albeit with a higher frequency of frontal lobe involvement reported in studies from China and Japan. [74] This is important because genetic associations may differ by CAA location and subtype. For example, there is preliminary evidence that APOEε4 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] In addition, since APOE effects on ICH may vary with ethnicity, there may also be ethnic variation in genetic associations with CAA, but these have not yet been widely enough studied

pendent of its known association with dementia (mainly Alzheimer's disease).

**2.2. Associations between other genetic polymorphisms and sporadic CAA**

In our systematic review, few polymorphisms other than APOE had been studied in more than a few hundred participants or in more than one study and there were not enough data for meta-analysis (Figure 1, Table 1). [39, 46, 50, 61, 63, 77-95] Thus, there were too few studies and participants to draw firm conclusions about the effect of other genetic polymorphisms. However, there were some suggestive positive associations with CAA. First, there was a consistent trend towards an association with CAA of a single nucleotoide polymorphism (SNP) in the transforming growth factor-β1 (TGF-β1) gene in two studies (449 participants). [82, 85] If real, this may occur through an influence of TGF-β1 on Aβ clearance and deposition through activation of astrocytes and microglia. Second, there were significant associations in one study (723 participants) of SNPs in the translocase of outer mitochondrial membrane 40 (TOMM40)


in non-white populations to assess this reliably. [76]

The squares represent pooled ORs and their width represents the 95% CI. Higher score represents better study quality. Reproduced from "Genetics of cerebral amyloid angiopathy: systematic review and meta-analysis" Rannikmäe K, Sa‐ marasekera N, Martīnez-Gonzālez NA, Al-Shahi Salman R, Sudlow C. Journal of Neurology Neurosurgery and Psychia‐ try 2013;84(901-8), with permission from BMJ Publishing Group Ltd. The squares represent pooled ORs and their width represents the 95% CI. Reproduced from "Genetics of cerebral amyloid angiopathy: systematic review and meta-

Figure 4. Meta-analysis of effects of APOE ε4 dose (ε4--/ε4+-/ε4++ genotypes) on presence

**Figure 3.** Subgroup analysis based on study quality scores. analysis" Rannikmäe K, Samarasekera N, Martīnez-Gonzālez NA, Al-Shahi Salman R, Sudlow C. Journal of Neurology Neurosurgery and Psychiatry 2013;84(901-8),

vs absence of

CAA

with permission from BMJ Publishing Group Ltd.

Generic inverse variance fixed effects method. \*Refers to number of participants included in the analysis.

The squares represent pooled ORs and their width represents the 95% CI. The squares represent pooled ORs and their width represents the 95% CI.

**Figure 4.** Meta-analysis of effects of APOE ε4 dose (ε4--/ε4+-/ε4++genotypes) on presence vs absence of CAA

#### *2.1.2. APOE ε2 and CAA*

Meta-analysis of the association of APOE ε2+ versus ε2- genotypes with CAA among 11 studies (1640 participants) showed borderline significant decreased odds of CAA with APOE ε2+ genotypes (OR 0.73, 95% CI 0.53 to 1.00, p=0.05). Two studies (213 participants) provided a qualitative statement; neither reported a significant association. [60, 64]

4

#### *2.1.3. Summary and discussion*

*2.1.2. APOE ε2 and CAA*

Meta-analysis of the association of APOE ε2+ versus ε2- genotypes with CAA among 11 studies (1640 participants) showed borderline significant decreased odds of CAA with APOE ε2+ genotypes (OR 0.73, 95% CI 0.53 to 1.00, p=0.05). Two studies (213 participants) provided a

**Figure 4.** Meta-analysis of effects of APOE ε4 dose (ε4--/ε4+-/ε4++genotypes) on presence vs absence of CAA

4

The squares represent pooled ORs and their width represents the 95% CI. Higher score represents better study quality. Reproduced from "Genetics of cerebral amyloid angiopathy: systematic review and meta-analysis" Rannikmäe K, Sa‐ marasekera N, Martīnez-Gonzālez NA, Al-Shahi Salman R, Sudlow C. Journal of Neurology Neurosurgery and Psychia‐

> Reproduced from "Genetics of cerebral amyloid angiopathy: systematic review and metaanalysis" Rannikmäe K, Samarasekera N, Martīnez-Gonzālez NA, Al-Shahi Salman R, Sudlow C. Journal of Neurology Neurosurgery and Psychiatry 2013;84(901-8),

> Figure 4. Meta-analysis of effects of APOE ε4 dose (ε4--/ε4+-/ε4++ genotypes) on presence

No.\* OR (95% CI)

ε4/x vs εx/x 1538 2.09 (1.69 to 2.58)

ε4/4 vs ε4/x 824 3.26 (2.24 to 4.74)

ε4/4 vs εx/x 1050 6.60 (4.47 to 9.75)

0.1 1 10 Presence of CAA decreased with ε4 allele Presence of CAA increased with ε4 allele

The squares represent pooled ORs and their width represents the 95% CI.

Figure 3. Subgroup analysis based on study quality scores.

try 2013;84(901-8), with permission from BMJ Publishing Group Ltd.

Generic inverse variance fixed effects method. \*Refers to number of participants included in the analysis.

with permission from BMJ Publishing Group Ltd.

**Figure 3.** Subgroup analysis based on study quality scores.

vs absence of

CAA

56 Intracerebral Hemorrhage

qualitative statement; neither reported a significant association. [60, 64]

The squares represent pooled ORs and their width represents the 95% CI. The squares represent pooled ORs and their width represents the 95% CI.

There is, therefore, robust evidence for a highly significant, dose-dependent association between APOE ε4 and pathologically proven CAA, which does not vary significantly with dementia status, ethnicity, or study quality. However, there is no clear overall association between APOE ε2 and histopathologically confirmed CAA. Lack of variation in the effect of APOE ε4 by study size and the very large failsafe N showed that this association could not plausibly be explained by publication, reporting or any other small study bias. It is important to note that the quality of studies included in our systematic review was generally limited when assessed against current reporting standards. [71, 72] However, there were - reassuringly - no significant subgroup differences by study quality score.

The prevalence of CAA in Alzheimer's disease is over 70% but the relationship between CAA and AD is still poorly understood. Although the diagnostic criteria for dementia and the participant inclusion criteria varied between the studies in our systematic review (some excluding cases with severe dementia), the demonstration of a similar association in those with and without clinical dementia suggests that the association of APOE ε4 with CAA is inde‐ pendent of its known association with dementia (mainly Alzheimer's disease).

Pathological assessment in the included studies was very variable. Indeed, there is no widely accepted, standardized histopathological grading system for CAA, [74] and no comparative studies to determine the most accurate method for assessing CAA (although the suggested method is a combination of Thioflavin S/T or Congo Red with immunohistochemistry). [75] CAA assessment location also varied widely, possibly influencing the rate of CAA detection, since a greater burden of CAA is generally reported in the occipital or parietal lobes, albeit with a higher frequency of frontal lobe involvement reported in studies from China and Japan. [74] This is important because genetic associations may differ by CAA location and subtype. For example, there is preliminary evidence that APOEε4 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] In addition, since APOE effects on ICH may vary with ethnicity, there may also be ethnic variation in genetic associations with CAA, but these have not yet been widely enough studied in non-white populations to assess this reliably. [76]

#### **2.2. Associations between other genetic polymorphisms and sporadic CAA**

In our systematic review, few polymorphisms other than APOE had been studied in more than a few hundred participants or in more than one study and there were not enough data for meta-analysis (Figure 1, Table 1). [39, 46, 50, 61, 63, 77-95] Thus, there were too few studies and participants to draw firm conclusions about the effect of other genetic polymorphisms. However, there were some suggestive positive associations with CAA. First, there was a consistent trend towards an association with CAA of a single nucleotoide polymorphism (SNP) in the transforming growth factor-β1 (TGF-β1) gene in two studies (449 participants). [82, 85] If real, this may occur through an influence of TGF-β1 on Aβ clearance and deposition through activation of astrocytes and microglia. Second, there were significant associations in one study (723 participants) of SNPs in the translocase of outer mitochondrial membrane 40 (TOMM40) 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).

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

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. Proposed theory and current state of evidence about associations between APOE

CAA

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 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‐

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

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

Severe CAA vasculopathy

ε4 ε4? ε2 and ε4

ε4 ε2 ε2 and ε4

CAA related ICH

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No CAA Mild/Moderate

5

**vasculopathy**

(Figure 5). [8, 25, 98]

and CAA phenotype

Popular theory:

Current state of evidence:

ence and Business Media and Professor Attems.


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

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

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