Risk Of Cerebral Amyloid Angiopathy Research Articles

Lewy body pathology modifies risk factors for cerebral amyloid angiopathy when comorbid with Alzheimer's disease pathology.

Cerebral amyloid angiopathy (CAA) often accompanies dementia-associated pathologies and is important in the context of anti-amyloid monoclonal therapies and risk of hemorrhage. We conducted a retrospective neuropathology-confirmed study of 2384 participants in the National Alzheimer Coordinating Center cohort (Alzheimer's disease [AD], n=1175; Lewy body pathology [LBP], n=316; and mixed AD and LBP [AD-LBP], n=893). We used logistic regression to evaluate age, sex, education,APOE ε4, neuritic plaques, and neurofibrillary tangles (NFTs) in CAA risk. APOE ε4 increased CAA risk in all three groups, while younger age and higher NFT stages increased risk in AD and AD-LBP. In AD-LBP, male sex and lower education were additional risk factors. The odds of APOE ε4 carrier homozygosity related to CAA was higher in LBP (25.69) and AD-LBP (9.50) than AD (3.17). AD and LBPs modify risk factors for CAA and should be considered in reviewing the risk of CAA. Lewy body pathology modifies risk factors for cerebral amyloid angiopathy (CAA) when present along with Alzheimer's disease (AD) neuropathology. In the context of anti-amyloid monoclonal therapies and their associated risks for hemorrhage, the risk of underlying CAA in mixed dementia with Lewy body pathology needs to be considered.

Abstract WMP67: Pump Brain - A Leading Cause of Cortical Cerebral Microbleeds

Introduction: A major cause of cerebral microbleeds (CMBs) is underrecognized and has been attributed to cerebral amyloid angiopathy (CAA) throughout modern medicine. CMBs are acquired by patients undergoing cardiopulmonary bypass (CPB). CPB is utilized for heart and lung transplants, aorta repairs, valve surgeries, mass resections, and coronary artery bypass grafting (CABG) which alone accounts for 400k patients per year. CABGs can be done off CPB in certain patients. Due to their distribution, these CMBs are attributed to CAA, leading to confounding research and suboptimal patient care, especially in those requiring anticoagulation. Methods: This was a single-center, IRB approved, retrospective cohort study of patients who underwent CPB and had postop MRI between 11/1/11 and 3/1/23. Preop and additional postop MRIs were analyzed if available. Outcomes included number and distribution of CMBs, presence of superficial siderosis, FAZEKAS, and CPB duration. We also analyzed MRIs of patients who had off CPB CABG during the same period. Results: Out of 60 patients who underwent CPB, 60 had predominantly cortical CMBs on postop MRI, with a mean of 50 CMBs, and mean age of 61. The 6 patients who had CABG off CPB had 0 CMBs. Higher CMBs were associated with longer CPB duration and with procedures that are associated with more blood loss (p< 0.05). Despite having CMBs, no CPB patients had superficial siderosis, and they had relatively low FAZEKAS scores. Nineteen of the CPB patients had future MRIs and had no evidence of CMB progression. Conclusion: Cortical CMBs are associated with procedures that use CPB and are not seen in off CPB CABG. The CMBs may be related to utilization of cardiotomy suction that exclusively uses roller pumps. CBP related CMBs are a unique clinical entity that is not associated with the progressive cognitive changes and bleeding risk of CAA. While no significant short-term changes are noted, their mechanism and natural history requires further investigation.

Association of Younger Age and APOE ɛ4 Carrier Status with Cerebral Amyloid Angiopathy in Pure and Mixed Alzheimers Disease Neuropathology (P3-6.004)

<h3>Objective:</h3> To determine how key clinical and neuropathology factors relate to the odds of cerebral amyloid angiopathy (CAA) at autopsy in both ‘pure Alzheimers Disease (AD)’ and mixed neuropathology of AD with Lewy body pathology (AD+LBP). <h3>Background:</h3> Presence of CAA has important therapeutic implications in the clinical decision to use new generation anti-amyloid therapies in AD. <h3>Design/Methods:</h3> A retrospective longitudinal cohort study was conducted among 2068 participants in the National Alzheimer Coordinating Center database with a mean interval of 5.7 (SD 2.8) years from initial visit to autopsy. These included autopsy-confirmed AD, n=1175 or AD +LBP, n=893 with CAA data. Correlations between CAA severity, Braak and neurotic scores and logistic regression models evaluating age (younger &lt;65yrs vs older≥65yrs), sex, APOE <i>ɛ4</i> carrier status, Braak stage and neuritic plaque score were completed in AD and mixed AD+LBP. <h3>Results:</h3> Younger age (O.R. 2.13, [95% CI, 1.33–3.33], p=0.002) and <i>APOE ɛ4</i> (O.R. 2.62, [95% CI, 1.94–3.56], p&lt;0.001) were significant predictors of CAA in AD, while <i>APOE ɛ4</i> (O.R. 3.18, [95% CI, 2.2–4.6], p&lt;0.001) was significant in AD+LBP. Only among older individuals in both groups, CAA severity correlated to Braak stage [AD ρ=0.12 (0.06, 0.18, p&lt;0.001), AD+LBP ρ=0.16 (0.09, 0.24, p&lt;0.001)] and neuritic score [AD ρ=0.10 (0.04, 0.16, p=0.002), AD+LBP ρ=0.12 (0.04, 0.19, p=0.002)]. When controlling for Braak stage, the odds of CAA were lower in AD among older age individuals [O.R. 0.50 (0.30–0.80), p=0.004] but not in AD+LBP [O.R. 0.92(0.56–1.53), p=0.75]. <h3>Conclusions:</h3> Younger age and <i>APOE ɛ4</i> carrier status had a higher odds of CAA despite controlling for Braak stage and neuritic plaque score in ‘pure AD’. Among older individuals higher Braak stage and neuritic plaque score were correlated to CAA severity in AD and AD+LBP. These results are of importance in the recognition of patients at the highest risk of CAA in both AD and mixed AD+LBP. <b>Disclosure:</b> Dr. Pillai has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Springer Nature. Dr. Pillai has received personal compensation in the range of $500-$4,999 for serving as an Editor, Associate Editor, or Editorial Advisory Board Member for Current Treatment Options in Neurology. The institution of Dr. Pillai has received research support from Alzheimer’s Association. The institution of Dr. Pillai has received research support from Keep Memory Alive Foundation . The institution of Dr. Pillai has received research support from NIA. Dr. Pillai has received personal compensation in the range of $500-$4,999 for serving as a Reviewer with DOD. Dr. Pillai has received personal compensation in the range of $500-$4,999 for serving as a Reviewer with RGC Hong kong. James Bena has nothing to disclose. Dr. Leverenz has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Acadia. Dr. Leverenz has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Biogen. Dr. Leverenz has received personal compensation in the range of $5,000-$9,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Eisai.

Simplified Edinburgh CT Criteria for Identification of Lobar Intracerebral Hemorrhage Associated With Cerebral Amyloid Angiopathy.

In patients with lobar intracerebral hemorrhage (ICH), etiologic characterization represents a tradeoff between feasibility, resource allocation, and diagnostic certainty. This study investigated the accuracy and clinical utility of the simplified Edinburgh CT criteria to identify underlying cerebral amyloid angiopathy (CAA). This external validation analyzed 210 consecutive patients with lobar ICH and available CT and MRI studies from a prospective single-center observational cohort study (2006-2015, Longitudinal Cohort Study on ICH Care [UKER-ICH,] NCT03183167). We investigated the interrater variability and diagnostic accuracy of the simplified Edinburgh CT-based criteria for identification of ICH associated with probable CAA according to MRI-based modified Boston criteria as a reference standard. We evaluated the utility of the simplified Edinburgh criteria by decision curve analysis, comparing the theoretical clinical net benefit (weighted benefit-harm at varying threshold probabilities) of the high-risk category (finger-like projections and subarachnoid hemorrhage) for ruling in and the low-risk category (neither finger-like projections nor subarachnoid hemorrhage) for ruling out with the assumptions of no or all patients having CAA (default strategies). Of 210 patients, 70 (33.3%) had high risk, 67 (31.9%) had medium risk, and 73 (34.8%) had low risk for CAA-associated ICH according to simplified Edinburgh CT criteria, showing moderate interrater variability. Discrimination was good (area under the receiver operating characteristics curve 0.74, 95% CI 0.67-0.81) without evidence of poor calibration (Hosmer-Lemeshow, p = 0.54) for validation of MRI-based diagnosis of probable CAA (n = 94 of 210, 44.8%). The rule-in criteria (high risk), had 87.1% (79.3%-92.3%) specificity, and the rule-out criteria (low risk), had 80.9% (71.1%-88.0%) sensitivity. Decision curve analysis suggested a theoretical clinical net benefit for ruling in but not for ruling out probable CAA compared to default strategies. Applying the simplified Edinburgh CT criteria during diagnostic workup seems clinically useful and may accurately identify CAA in patients with lobar ICH. ClinicalTrials.gov Identifier: NCT03183167. This study provides Class II evidence that in patients with lobar hemorrhages, the simplified Edinburgh criteria accurately identify those at high risk of CAA.

Neurodegenerative brain changes are associated with area deprivation in the United Kingdom: findings from the Brains for Dementia Research study

Socioeconomic disadvantage is associated with greater risk of dementia. This has been theorised to reflect inequalities in cognitive reserve, healthcare access, lifestyle, and other health factors which may contribute to the clinical manifestation of dementia. We aimed to assess whether area deprivation in the United Kingdom was associated with greater risk or severity of the specific neurodegenerative diseases which lead to dementia in a multi-centre cohort with autopsy assessment. Participants underwent clinical assessment prior to brain tissue donation post-mortem. Each then underwent detailed, standardised neuropathological assessment. National area deprivation statistics were derived for each participant’s neighbourhood, for use as a predictor in binary and ordinal logistic models assessing the respective presence and severity of staging of key neuropathological changes, adjusting for theorised confounders. Individuals from among the 20% most deprived neighbourhoods in the United Kingdom had significantly higher neurofibrillary tangle and neuritic plaque staging, and increased risk of cerebral amyloid angiopathy. These findings were not explained by a greater risk of diabetes or hypertension, APOE genotype, alcohol misuse or tobacco smoking, sex, or age differences. A sensitivity analysis conditioning on baseline cognitive impairment did not meaningfully change the observed association. Socioeconomic disadvantage may contribute to dementia incidence through a greater severity of specific neuropathological changes (neurofibrillary tangles, neuritic plaques, and cerebral amyloid angiopathy), independent of other indirect influences. Mechanisms through which deprivation is associated with these require further exploration.

Abstract WP427: Thrombolysis in With Patients With Down Syndrome and Ischemic Stroke

Background: Down Syndrome (DS) is a genetic disorder cause by trisomy 21. With improvements in medical care, the life expectancy of individuals with DS has increased. As this population ages, they are at risk of strokes. They may have a higher predisposition for cardio embolic strokes given that DS is associated with congenital heart disease. There is scarce data regarding strokes in the DS population. Methods: Nationwide Inpatient Sample (NIS) from 2005 to 2014 was utilized to identify down syndrome patients using ICD CM code 758.0 in secondary diagnostic field and acute ischemic stroke (AIS) with appropriate diagnostic codes in primary field. Intravascular thrombolysis utilization was identified by ICD9 procedure code 99.10 in any procedural field. Differences between categorical variables were tested using the chi-square test and continuous variables using the Student t-test. Results: We identified 4332783 patients with acute ischemic stroke (AIS), 1333 (0.03%) also had a diagnosis of DS. Average age was 71.2years; 47.2% were male and 52.8% female. Patients with DS and AIS were younger (45.6yo vs 71.2years; p&lt;0.0001). They were also more likely to be female (60.7 % vs. 52.8%; p&lt;0.0001). Despite being younger and having less comorbid conditions, patients with ischemic stroke who have DS are less likely to receive thrombolysis than those with ischemic stroke without DS (3.67% vs 5.77%; p =0.001). Although, there was no statistically significant difference in the use of mechanical thrombectomy. DS patients that received thrombolysis were more likely to be male (61.8% vs 38.2%; p=0.0011), and at a teaching hospital (p=0.0016). However, there was increased in-hospital mortality among those DS patients who received thrombolysis compared to the group without thrombolysis (20.5% vs. 5.7%; p=0.004). Conclusion: Patients with DS and AIS have a decreased rate of thrombolysis, yet similar rates of mechanical thrombectomy. However, those DS patients that received thrombolysis had increased in-hospital mortality. We postulate that this may be secondary to increased beta-amyloid peptide accumulation and risk of cerebral amyloid angiopathy in DS. Thrombolysis in this population needs to be further studied.

Apolipoprotein E and Alzheimer disease: risk, mechanisms and therapy

Apolipoprotein E (Apo-E) is a major cholesterol carrier that supports lipid transport and injury repair in the brain. APOE polymorphic alleles are the main genetic determinants of Alzheimer disease (AD) risk: individuals carrying the ε4 allele are at increased risk of AD compared with those carrying the more common ε3 allele, whereas the ε2 allele decreases risk. Presence of the APOE ε4 allele is also associated with increased risk of cerebral amyloid angiopathy and age-related cognitive decline during normal ageing. Apo-E-lipoproteins bind to several cell-surface receptors to deliver lipids, and also to hydrophobic amyloid-β (Aβ) peptide, which is thought to initiate toxic events that lead to synaptic dysfunction and neurodegeneration in AD. Apo-E isoforms differentially regulate Aβ aggregation and clearance in the brain, and have distinct functions in regulating brain lipid transport, glucose metabolism, neuronal signalling, neuroinflammation, and mitochondrial function. In this Review, we describe current knowledge on Apo-E in the CNS, with a particular emphasis on the clinical and pathological features associated with carriers of different Apo-E isoforms. We also discuss Aβ-dependent and Aβ-independent mechanisms that link Apo-E4 status with AD risk, and consider how to design effective strategies for AD therapy by targeting Apo-E.

CR1 variant increases risk of cerebral amyloid angiopathy

CR1 variant increases risk of cerebral amyloid angiopathy

Genetic variation at CR1 increases risk of cerebral amyloid angiopathy

Accumulated evidence suggests that a variant within the CR1 gene (single nucleotide polymorphism rs6656401), known to increase risk for Alzheimer disease (AD), influences β-amyloid (Aβ) deposition in brain tissue. Given the biologic overlap between AD and cerebral amyloid angiopathy (CAA), a leading cause of intracerebral hemorrhage (ICH) in elderly individuals, we investigated whether rs6656401 increases the risk of CAA-related ICH and influences vascular Aβ deposition. We performed a case-control genetic association study of 89 individuals with CAA-related ICH and 280 individuals with ICH unrelated to CAA and compared them with 324 ICH-free control subjects. We also investigated the effect of rs6656401 on risk of recurrent CAA-ICH in a prospective longitudinal cohort of ICH survivors. Finally, association with severity of histopathologic CAA was investigated in 544 autopsy specimens from 2 longitudinal studies of aging. rs6656401 was associated with CAA-ICH (odds ratio [OR] = 1.61, 95% confidence interval [CI] 1.19-2.17, p = 8.0 × 10(-4)) as well as with risk of recurrent CAA-ICH (hazard ratio = 1.35, 95% CI 1.04-1.76, p = 0.024). Genotype at rs6656401 was also associated with severity of CAA pathology at autopsy (OR = 1.34, 95% CI 1.05-1.71, p = 0.009). Adjustment for parenchymal amyloid burden did not cancel this effect, suggesting that, despite the correlation between parenchymal and vascular amyloid pathology, CR1 acts independently on both processes, thus increasing risk of both AD and CAA. The CR1 variant rs6656401 influences risk and recurrence of CAA-ICH, as well as the severity of vascular amyloid deposition.

APOE genotype and extent of bleeding and outcome in lobar intracerebral haemorrhage: a genetic association study

Carriers of APOE ε2 and ε4 have an increased risk of intracerebral haemorrhage (ICH) in lobar regions, presumably because of the effects of these gene variants on risk of cerebral amyloid angiopathy. We aimed to assess whether these variants also associate with severity of ICH, in terms of haematoma volume at presentation and subsequent outcome. We investigated the association of APOE ε2 and ε4 with ICH volume and outcomes in patients with primary ICH in three phases: a discovery phase of 865 individuals of European ancestry from the Genetics of Cerebral Hemorrhage on Anticoagulation study, and replication phases of 946 Europeans (replication 1) and 214 African-Americans (replication 2) from an additional six studies. We also assessed the association of APOE variants with ICH volume and outcomes in meta-analyses of results from all three phases, and the association of APOE ε4 with mortality in a further meta-analysis including data from previous reports. Admission ICH volume was quantified on CT scan. We assessed functional outcome (modified Rankin scale score 3-6) and mortality at 90 days. We used linear regression to establish the effect of genotype on haematoma volume and logistic regression to assess the effect on outcome from ICH. For patients with lobar ICH, carriers of the APOE ε2 allele had larger ICH volumes than did non-carriers in the discovery phase (p=2·5×10(-5)), in both replication phases (p=0·008 in Europeans and p=0·016 in African-Americans), and in the meta-analysis (p=3·2×10(-8)). In the meta-analysis, each copy of APOE ε2 increased haematoma size by a mean of 5·3 mL (95% CI 4·7-5·9; p=0·004). Carriers of APOE ε2 had increased mortality (odds ratio [OR] 1·50, 95% CI 1·23-1·82; p=2·45×10(-5)) and poorer functional outcomes (modified Rankin scale score 3-6; 1·52, 1·25-1·85; p=1·74×10(-5)) compared with non-carriers after lobar ICH. APOE ε4 was not associated with lobar ICH volume, functional outcome, or mortality in the discovery phase, replication phases, or meta-analysis of these three phases; in our further meta-analysis of 2194 patients, this variant did not increase risk of mortality (1·08, 0·86-1·36; p=0·52). APOE allele variants were not associated with deep ICH volume, functional outcome, or mortality. Vasculopathic changes associated with the APOE ε2 allele might have a role in the severity and clinical course of lobar ICH. Screening of patients who have ICH to identify the ε2 variant might allow identification of those at increased risk of mortality and poor functional outcomes. US National Institutes of Health-National Institute of Neurological Disorders and Stroke, Keane Stroke Genetics Research Fund, Edward and Maybeth Sonn Research Fund, and US National Center for Research Resources.

Association of a polymorphism of the transforming growth factor-β1 gene with cerebral amyloid angiopathy

Background: A recent study showed that transforming growth factor-β1 (TGF-β1) induces amyloid-β deposition in cerebral blood vessels and meninges of a transgenic mouse model of Alzheimer’s disease (AD), and that...

The Role of P-glycoprotein in Cerebral Amyloid Angiopathy; Implications for the Early Pathogenesis of Alzheimers Disease

It has been shown in vitro that beta-amyloid (Abeta) is transported by P-glycoprotein (P-gp). Previously, we demonstrated that Abeta immunoreactivity is significantly elevated in brain tissue of individuals with low expression of P-gp in vascular endothelial cells. These findings led us to hypothesize that P-gp might be involved in the clearance of Abeta in normal aging and particularly in Alzheimer's disease (AD). As we were interested in the early pathogenesis of Abeta deposition, we studied the correlation between cerebral amyloid angiopathy (CAA) and P-gp expression in brain tissue samples from 243 non-demented elderly cases (aged 50 to 91 years). We found that endothelial P-gp and vascular Abeta were never colocalized, i.e., vessels with high P-gp expression showed no Abeta deposition in their walls, and vice versa. Abeta deposition occurred first in arterioles where P-gp expression was primarily low, and disappeared completely with the accumulation of Abeta. At this early stage, P-gp was upregulated in capillaries, suggesting a compensatory mechanism to increase Abeta clearance from the brain. Capillaries were usually affected only at later stages of CAA, at which point P-gp was lost even in these vessels. We hypothesize that Abeta clearance may be altered in individuals with diminished P-gp expression due, e.g., to genetic or environmental effects (such as drug administration). The impairment of Abeta clearance could lead to the accumulation and earlier deposition of Abeta, both in the walls of blood vessels and in the brain parenchyma, thus elevating the risk of CAA and AD.

APOE and cerebral amyloid angiopathy in the elderly.

Over 30% of normal elderly people have cerebral amyloid angiopathy (CAA). Possession of APOE epsilon4 is associated with increased prevalence and severity of CAA in Alzheimer's disease (AD) and in cerebral haemorrhage. We examined CAA in relation to APOE genotype in brains from 152 people aged 60-102 years, without AD or cerebral haemorrhage. Prevalence of CAA increased with age (p = 0.003). CAA was not associated with APOE genotype. The frequency of epsilon4 showed a significant negative association with age (p = 0.016). Age at death was significantly lower in those with than without epsilon4 (p = 0.028). Possession of epsilon4 does not by itself confer an increased risk of CAA but may be associated with reduced longevity even in the absence of AD or cerebral haemorrhage.

Association of neprilysin polymorphism with cerebral amyloid angiopathy

Objectives: The risk of sporadic cerebral amyloid angiopathy (CAA) may be associated with genetic polymorphisms of molecules related to anabolism or catabolism of amyloid β protein (Aβ). The authors investigated...

Risk factors for cerebral amyloid angiopathy in the elderly.

To elucidate risk factors for cerebral amyloid angiopathy (CAA) in the elderly, we have investigated 201 autopsy cases of elderly Japanese (ages: 62-104 years), including 82 patients with Alzheimer's disease (AD). Severity of CAA showed no relationship with the history of hypertension, hyperlipidemia, or diabetes mellitus, nor with severity of atherosclerosis of cerebral and systemic arteries, indicating that common vascular risk factors would not be related to CAA. Incidence and severity of CAA were significantly higher in the AD cases compared with the non-AD cases (p < 0.0001). Severity of CAA correlated with densities of senile plaques and neurofibrillary tangles in total and non-AD cases, although the correlations were not significant within the AD cases. Associations of genetic polymorphisms with CAA have been investigated for genes of apolipoprotein E (APOE), presenilin 1 (PS1), alpha1-antichymotrypsin (ACT), butyrylcholinesterase, alpha2-macroglobulin, and paraoxonase. Severity of CAA in APOE epsilon4 carriers is significantly higher than that in non-epsilon4 carriers in total cases, although no significant difference was found in the CAA severity between the epsilon4 carriers and non-epsilon4 carriers within the AD or non-AD group. An intronic polymorphism of PS1 was significantly associated with the severity of CAA, indicating that the PS1 2/2 genotype may be related to lower risk of CAA. A polymorphism in the signal peptide sequence of ACT was significantly associated with the CAA severity in the AD group. Our results suggest that CAA shares risk factors with AD and that multiple genetic factors would be associated with the risk of CAA in the elderly.

No association of paraoxonase genotype or atherosclerosis with cerebral amyloid angiopathy.

Both cerebral amyloid angiopathy (CAA) and paraoxonase have been reported to be related to lipid metabolism and atherosclerosis. We investigated whether the paraoxonase gene (PON1) polymorphism and atherosclerosis are associated with risk of CAA. Associations of the PON1 polymorphism and atherosclerosis of the aorta and coronary and cerebral arteries with the severity of CAA were investigated in 154 elderly Japanese individuals, including 47 patients with Alzheimer's disease. The PON1 polymorphism or severity of atherosclerosis of the arteries was not associated with the severity of CAA. The PON1 polymorphism and atherosclerosis would not appear to be associated with risk of CAA in the elderly, although further study with larger samples is necessary for confirmation.

Type 2 diabetes, APOE gene, and the risk for dementia and related pathologies: The Honolulu-Asia Aging Study.

Type 2 diabetes may be a risk factor for dementia, but the associated pathological mechanisms remains unclear. We evaluated the association of diabetes alone or combined with the apolipoprotein E (APOE) gene with incident dementia and neuropathological outcomes in a population-based cohort of 2,574 Japanese-American men enrolled in the Honolulu-Asia Aging Study, including 216 subjects who underwent autopsy. Type 2 diabetes was ascertained by interview and direct glucose testing. Dementia was assessed in 1991 and 1994 by clinical examination and magnetic resonance imaging and was diagnosed according to international guidelines. Logistic regression was used to assess the RR of developing dementia, and log-linear regression was used to estimate the incident rate ratio (IRR) of neuropathological outcomes. Diabetes was associated with total dementia (RR 1.5 [95% CI 1.01-2.2]), Alzheimer's disease (AD; 1.8 [1.1-2.9]), and vascular dementia (VsD; 2.3 [1.1-5.0]). Individuals with both type 2 diabetes and the APOE epsilon4 allele had an RR of 5.5 (CI 2.2-13.7) for AD compared with those with neither risk factor. Participants with type 2 diabetes and the epsilon4 allele had a higher number of hippocampal neuritic plaques (IRR 3.0 [CI 1.2-7.3]) and neurofibrillary tangles in the cortex (IRR 3.5 [1.6-7.5]) and hippocampus (IRR 2.5 [1.5-3.7]), and they had a higher risk of cerebral amyloid angiopathy (RR 6.6, 1.5-29.6). Type 2 diabetes is a risk factor for AD and VsD. The association between diabetes and AD is particularly strong among carriers of the APOE epsilon4 allele. The neuropathological data are consistent with the clinical results.