Vascular risk factors and Alzheimer's disease: are these risk factors for plaques and tangles or for concomitant vascular pathology that increases the likelihood of dementia? An evidence-based review

Recent epidemiologic studies have noted that risk factors for atherosclerosis (for example, diabetes mellitus, hypertension, and hyperlipidemia) are associated with increased risk of incident Alzheimer's disease (AD). In this evidence-based review, we frame the proposition as a question: are vascular risk factors also risk factors for plaques and tangles or just for concomitant vascular pathology that increases the likelihood of dementia? To date, no representative, prospective studies with autopsy (evidence level A) show significant positive associations between diabetes mellitus, hypertension, or intracranial atherosclerosis and plaques or tangles. Some prospective, representative, epidemiologic studies (evidence level B) show associations between diabetes, hypertension, hyperlipidemia, and aggregated risk factors with clinically diagnosed incident AD. However, the strength of association diminishes in the following order: vascular dementia (VaD) > AD + VaD > AD. This pattern is arguably more consistent with the hypothesis that atherosclerosis promotes subclinical vascular brain injury, thereby increasing the likelihood of dementia and in some cases making symptoms present earlier. Several autopsy studies from AD brain banks (evidence level C) have observed positive associations between intracranial atherosclerosis and severity of plaques and tangles. However, these studies may reflect selection bias; these associations are not confirmed when cases are drawn from non-dementia settings. We conclude that, at the present time, there is no consistent body of evidence to show that vascular risk factors increase AD pathology.

risk factors -diabetes mellitus, hypertension, and hyperlipidemia -as the independent measures. Because of space limitations, we do not cover other common risk factors for atherosclerosis, including smoking, hyperhomo cysteinemia, or infl ammatory factors. In this review, we also leave aside cerebral amyloid angiopathy, a type of cerebrovascular disease closely associated with the cerebral hallmarks of AD as well as the mutual risk factor apolipoprotein E (APOE) ε4.

Quality of evidence
Quality of evidence is determined by study design, sampling method, and accuracy of diagnosis (Table 1). Since AD is currently defi ned as a clinical-pathological entity, the ideal methodology for the question posed in this review is a population-based cohort, established in midlife and followed prospectively to autopsy. In this review, we group the literature related to vascular risk factors and AD into three methodological categories: 1) representative and non-representative prospective longitu dinal cohort studies including autopsy (level A); 2) representative and non-representative prospective longitu dinal studies without autopsy (level B); and 3) crosssectional neuropathological studies (level C). Crosssectional clinical studies without autopsy are not included in this review (level D).
Th e quality of ascertaining vascular risk factors, the criteria for diagnosis of dementia, and the method of rating distribution and severity of neuropathology vary considerably. Information about vascular risk factors ranges from self-report, proxy informants, medical records, to direct clinical and laboratory measures that are ascertained cross-sectionally or longitudinally. Diff erential misclassifi cation of risk factors by self-report (for example, over-reported in AD group and under-reported in control group) will bias the associations between vascular risk factors and AD positively. In addition, temporality of risk factor assessment (for example, midlife versus late life) may aff ect the associations observed since neurodegenerative brain changes begin by middle age and exposure to risk factors changes over time. Besides the simple presence versus absence of a risk factor, the duration and magnitude of exposure to a risk factor should also be ideally considered. Epidemiological studies have diagnostic limitations since cases are usually defi ned based on a predetermined cutoff . Consequently, there is a possibility that 'mild dementia' cases are included in the normal group, which may attenuate the association between dementia and its risk factors.
A pathological diagnosis of AD, based on severity and distribution of NFTs and NPs [4], remains the gold standard for diagnosis. Using the Consortium to Establish a Registry for Alzheimer's Disease (CERAD) criteria as the reference standard, a clinical diagnosis of AD, based on typical clinical presentation and the exclusion of other causes of dementia [5], showed 93% sensitivity but only 55% specifi city [6]. An evidenced-based review of the literature in 2002 [7] showed small positive likelihood ratios for the diagnosis of dementia subtype (that is, 2 to 5) compared to the generic diagnosis of dementia (that is, >10). It is even more diffi cult to diagnose dementia due to mixed pathologies, yet in community-based studies, over half of older subjects with dementia harbor mixed pathologies at autopsy [8][9][10], often showing infarcts up to half of which were not detected during life [11]. In the absence of a true association between vascular risk factors and AD, misclassifi cation of mixed AD/vascular dementia (VaD) cases as clinical AD would positively bias the associations between vascular risk factors and AD. Cerebrospinal fl uid markers of amyloid-beta (Aβ) and phospho-tau and amyloid PET imaging have recently been incorporated into clinical research criteria [12] and promise to improve specifi city of the clinical diagnosis in the future.
While autopsy studies minimize errors in diagnosis, neuropathological data may be limited in many important ways. Neuropathological data are themselves cross-sectional (that is, can only be collected once); it is diffi cult, therefore, to determine sequence and causality based on neuropathological fi ndings. At autopsy, severity of atherosclerosis, NFTs, NPs, and number of infarcts are often limited to semi-ordinal measures of severity, which may limit the power to detect small associations. Autopsy samples of convenience are likely to include signifi cant selection bias (level of evidence = C). When a participant is selected from hospitals, memory clinics, or tertiary referral centers, the underlying population is usually not defi nable. Vascular pathology is relatively under-represented in autopsy studies drawn from memory clinics versus the community [13]. Figure 2 illustrates highly overlapping atherosclerosis, stroke, and AD pathologies in an older population. Figure 2 also shows how retrospective selection of cases may lead to a comparison between AD cases and super healthy controls (CN1) that have neither AD nor vascular disease, leading to a spurious association between vascular risk factors and AD.
A much stronger study design would be a populationbased sample, followed prospectively from midlife to autopsy (level of evidence = A1). In such a cohort, the distribution of vascular risk factors of the cohort should be representative of the population (Figure 3). Establishment of the cohort in midlife, well before the expression of disease, eliminates important aspects of selection bias. If the cohort is established later in life, when subjects at highest risk have already died, associations may be weakened and even reverse direction. If the cohort is assembled later in life and followed prospectively, comparable diagnostic thresholds can be used to fi rst identify and remove prevalent cases and then prospectively identify incident cases (Figures 4 and 5). Th is prospective design strengthens the etiological signifi cance of associations between risk factors and incident disease (level of evidence = B). Ideally, prospective longitudinal studies will include autopsy to confi rm associations between risk factors and neuropathologically defi ned disease (level of evidence = A).

Level A evidence
A summary of level A evidence is provided in Table 2. In a 2006 review [14], six studies were identifi ed as true population-based autopsy studies of dementia (grade A1). Th ree of these studies have published data relevant to our question: 1) the Hisayama study (Japan); 2) the Honolulu Asia Aging Study (HAAS; Hawaii, USA); and 3) the Vantaa 85+ study (Finland). Th ere are also several longitudinal, neuropathological studies drawn from special but non-representative co horts (grade A2): 1) the Baltimore Longitudinal Study on Aging; 2) the Religious Orders Study (ROS); and 3) the Adult Changes in Th ought study.
Among 216 autopsied cases of Japanese-American men enrolled in HAAS [15], diabetes was associated with  Green shows two samples of normal controls (CN): CN1 is highly selected and CN2 is randomly sampled. In a cohort of Alzheimer's disease subjects (AD) and CN1, an association will be found between arteriosclerosis and Alzheimer's disease. In a cohort of AD and CN2, no such association will be found. increased risk of large cerebral infarcts (relative risk (RR) = 1.8, 95% confi dence interval (CI) 1.1 to 3.0), but not with NPs or NFTs. Strengths in the HAAS study design included a representative autopsy sample (high 42% autopsy rate for an epidemiological study), ascertainment of diabetes in midlife by history, fasting, and 2 hour postprandial glucose, and adjustment for potential confounders (that is, age, education, APOE4 ε4 status, and other vascular risk factors). Th e Vantaa 85+ study focused on diabetes among 553 residents of Vantaa, Finland aged ≥85 years [16]. Autopsies were performed in nearly half (48%; n = 291) of the total population. Diabetes at baseline doubled the incidence of clinically defi ned dementia, AD, and VaD. However, at autopsy, subjects with diabetes were less likely to have Aβ (odds ratio (OR) = 0.48, 95% CI 0.23 to 0.98) and tangles (OR = 0.72, 95% CI 0.39 to 1.33), but more likely to have cerebral infarcts (OR = 1.88, 95% CI 1.06 to 3.34), after adjustment for age, education, APOE ε4 status, and other vascular risk factors. Th e investigators concluded that older patients with diabetes develop more extensive vascular, but not AD, pathology, proposing that vascular pathology, alone or together with AD, could explain the elevated risk of all-cause dementia associated with diabetes.
In the ROS, diabetes was associated with elevated risk for incident AD (hazard ratio = 1.65, 95% CI 1.10 to 2.47) [17]. In an autopsy study (n = 233) from the same cohort, diabetes was associated with cerebral infarcts (OR = 2.47, 95% CI 1.16 to 5.24), but not with global AD pathology or specifi c measures of NPs, diff use plaques, amyloid burden, tangles or tangle densities [18]. Th ese ROS fi ndings strongly suggest that the relationship between diabetes and incident AD may be mediated by the additive eff ects on dementia of subclinical cerebral infarction.
In the Adult Changes in Th ought study, blood pressure measured later in life was associated with cortical microinfarcts, but not with plaques or tangles [19]. Since microinfarcts are too small to be detected by clinical exam or neuroimaging, these dementia cases may be clinically diagnosed as AD.
Among 200 autopsy cases in the prospective Baltimore Longitudinal Study on Aging, quantitative measures of atherosclerosis in the aorta, heart, and intracranial vessels were not associated with the degree of AD-type brain pathology [20]. However, intracranial athero sclerosis signifi cantly increased the odds of dementia within 18 months of death, independent of cerebral infarction, through still unclear pathways.
In summary, no level A evidence supports the hypothesis that diabetes, hypertension or atherosclerosis increases plaques and tangles, although these factors all increase the risk of vascular lesions and dementia. Increased risk of dementia appears to be mediated, at least in part, through subclinical ischemic brain injury, including microinfarcts that escape clinical detection.

Level B evidence
Th e concept that risk factors for atherosclerosis and stroke (for example, diabetes mellitus, hypertension, hyperlipidemia) are also risk factors for AD stems largely from epidemiologic studies conducted over the past 20 years. Th e fundamental limitation to interpreting these studies is that disease state is clinically defi ned. While it is highly likely that AD pathology is present in clinically diagnosed dementia, it is also likely that vascular pathology is also present. In the absence of  sympto matic stroke, however, the default etiologic diagnosis is often AD. With respect to the clinical diagnosis of VaD, the sensitivity, specifi city and degree to which 'pure' vascular cases are identifi ed varies widely depending upon choice of criteria and the availability of neuro imaging studies [21]. Th us, one cannot assume that 'clinical AD' means that vascular brain injury is absent, or that 'clinical VaD' means that AD is absent, or that an association between vascular risk factors and incident dementia is necessarily refl ected in an association between risk factors and AD pathology.

Diabetes mellitus
A systematic overview of 25 pros pective studies with clinical outcomes [22] concluded that people with diabetes have: 1) a greater rate of decline in cognitive function; 2) a 1.5-fold greater risk of cognitive decline; and 3) a 1.6-fold greater risk of future dementia, especially vascular cognitive impairment and dementia, relative to persons without diabetes. Below we discuss several particularly important population-or community-based studies (Table 3).
In the Rotterdam Study, diabetes increased the risk of dementia, mostly for VaD, followed by AD + VaD, then AD [23]. Th e investigators proposed either that diabetes contributes to AD pathology or that silent cerebral infarcts may uncover imminent AD. In two cohorts recruited successively in the multi-ethnic Washington Heights-Inwood Columbia Aging Project (WHICAP) study, history of diabetes mellitus signifi cantly increased the risk of AD [24], but the association weakened when cases with mixed AD/cerebrovascular disease were removed [25]. In the HAAS [15], diabetes was defi ned by laboratory testing, and showed progressively diminishing risk with VaD (RR = 2.3, 95% CI 1.1 to 5.0), AD with VaD (RR = 1.8, 95% CI 1.1 to 2.9), and AD without VaD (RR = 1.6, 95% CI 0.9 to 3.0), controlling for age, education, APOE e4 status, and other vascular risk factors. In the ROS, diabetes was associated with a 65% increase in the risk of developing AD (hazard ratio = 1.65, 95% CI 1.10 to 2.47) [17]. In fi ndings that deviate somewhat from the pattern above, subjects with diabetes in the Canadian Study on Health and Aging had a higher risk of incident vascular cognitive impairment (RR = 1.62, 95% CI 1.12 to 2.33) and its subtypes, VaD (RR = 2.03, 95% CI 1.15 to 3.57), and vascular cognitive impairment-no dementia (vascular CIND; RR = 1.68, 95% CI 1.01 to 2.78), but not AD or mixed AD/VaD [26]. In the Hisayama Study (done without neuroimaging), diabetes doubled the risk for VaD, but not AD [11].
In sum, there is robust evidence that diabetes increases cerebral infarcts and cognitive decline; the evidence that diabetes specifi cally increases AD pathology is mixed at best. Associations between diabetes and clinical AD could refl ect additive eff ects of subclinical vascular disease (elevated by diabetes) and AD pathology (that is perhaps independent of diabetes).

Hypertension
Measurement of blood pressure is complex: parameters relevant to dementia outcomes include the stage of life during which blood pressure is measured, modeling of diastolic versus systolic measures, and whether or not blood pressure is treated. Systolic blood pressure increases, while diastolic blood pressure decreases with age. Measures such as blood pressure variability and reactivity have also been considered. Here we summarize studies of systolic or diastolic blood pressure in longi tudinal population or community studies with incident clinical dementia outcomes (Table 4).
In an initial report from HAAS, untreated, elevated systolic or diastolic midlife blood pressure predicted higher rates of all cause dementia and, specifi cally, AD dementia in late life [27]. Th is fi nding has not been clearly replicated. In the Uppsala study, midlife systolic blood pressure in men was positively associated with vascular and mixed dementias, but not AD [3]. Th e ROS found no eff ects of late-life blood pressure on dementia incidence [28]. A recent report from the Kungholmen project showed positive associations between late-life systolic blood pressure and AD as well as all-cause dementia [2]. In the Hisayama study [11], every 1 standard deviation (23 mmHg) increase in systolic blood pressure was associated with a 53% increase in the risk of VaD (RR = 1.53, 95% CI 1.16 to 2.01), but was not associated with AD risk. Studies have shown additive eff ects on cognitive decline related to hypertension alone and combined with other risk factors, including diabetes [29] and APOE ε4 [30].
Th e literature on blood pressure eff ects is often interpreted as showing that midlife, but not late life, elevations are associated with dementia and AD. However, the evidence does not entirely support that conclusion; the epidemiological literature is inconsistent with respect to both late-life and midlife blood pressure eff ects. Th e limited data from longitudinal autopsy studies do not clarify the picture.

Hyperlipidemia
APOE is associated with cholesterol transport. Th e ε4 allele is the strongest known genetic risk factor for AD [31], and is also associated with dys lipidemia and coronary heart disease [32]. Cholesterol levels decrease with increasing age [33,34]. Th erefore, in seeking associations between cholesterol and risk of AD, it is important to control for apoE genotype and to consider age at the time cholesterol was measured as well as the use of lipid-lowering medications.
Th e literature regarding cholesterol and risk of AD is inconsistent and diffi cult to interpret (Table 5). Regarding midlife cholesterol, studies from two community cohorts report ed positive associations between elevated total choles terol and development of dementia and AD [33,35]; a third study showed a similar trend [36]. In contrast, measured cholesterol later in life tends to show either no association [37] or an inverse association [38][39][40]. Interestingly, analysis of longitudinal cholesterol data from Finland [33] showed that, compared to men who remained dementia free, men who developed AD had higher cholesterol levels in midlife but greater declines in total cholesterol levels over 30 years, and thus lower cholesterol levels in late life. Th is trajectory would explain the reversal of associations depending on the age at which cholesterol levels were determined. However, in the Framingham study neither midlife cholesterol averaged over 30 years nor late-life cholesterol were associated with AD risk [34]. Inverse associations are found in more recent studies that adjusted for cerebrovascular disease and APOE genotype [38,39]. Th us, the relationship between cholesterol and risk of AD remains far from clear. Sample mean age and pooled standard deviation (SD) calculated based on mean age ± SD of the male and female groups provided in the paper. b Adjusted for age. c Adjusted for age, education, APOE ε4 status, smoking and alcohol consumption. d Adjusted for age, APOE ε4 status, education, gender, smoking and alcohol consumption. e Adjusted for age, gender, education, APOE ε4 status, follow-up survival status, baseline Mini-Mental State Examination, body mass index, coronary heart disease, and use of blood pressure lowering drugs. f Adjusted for age and education. g Adjusted for age, gender, and education. Entries in bold indicate signifi cant relative risk (RR) ratios. AD, Alzheimer's disease; DBP, diastolic blood pressure; HAAS, Honolulu Asia Aging Study; HTN, hypertension; NL, normal; ROS, Religious Orders Study; SBP, systolic blood pressure; SD, standard deviation; VaD, vascular dementia.

Aggregate risk factors
Because vascular risk factors frequently, but variably, cluster and because they may modify dementia risk through a common pathogenic pathway, examination of single risk factors may fail to identify true associations. A small number of epidemiological studies have examined the eff ects of aggregate vascular risk (Table 6). In WHICAP, the risk of incident AD increased in a doserelated fashion in relation to the number of vascular risk factors [24]. Qiu and colleagues [2] defi ned two distinct Note that 1 mmol/L cholesterol = 38.6 mg/dl cholesterol. a Adjusted for age and APOE4. b Adjusted for age and APOE4, education, sex, smoking, alcohol. c Adjusted for age, sex, APOE4, coronary artery disease, body mass index, and lipid-lowering medication. d Adjusted for sex, age, education and race. e Adjusted for body mass index, APOE4, diabetes, heart disease, hyperten sion. f Adusted for age, sex, education, Cognitice Abilities Screening Instrument, body mass index, hypertension, coronary artery disease, cerebrovascular disease, diabetes mellitus. g Adjusted for body mass index, diastolic blood pressure, sex, education, smoking. h Adjusted for age, sex, education, ethnic group APOE ε4 genotype, diabetes, hypertension, heart disease, body mass index, lipid-lowering treatment. Entries in bold indicate signifi cant relative risk (RR) ratios. Age@Chol, age of subject when cholesterol was measured; AD, Alzheimer's disease; Chol, cholesterol; FIN-MONICA, Finnish part of Multinational Monitoring of Trends and Determinants in Cardiovascular Disease; HAAS, Honolulu Asia Aging Study; HDLc, high-density lipoprotein cholesterol; LDLc, low-density lipoprotein cholesterol; NA, not available; NL, normal; SD, standard deviation; VaD, vascular dementia; WHICAP, Washington Heights-Inwood Columbia Aging Project.
risk profi les, one for atherosclerotic risk, the other for hypoperfusion risk; both risk profi les were associated with elevated risk of incident dementia and AD. However, fi ndings from the Uppsala Longitudinal Study of Adult Men found a graded association between number of vascular risk factors and all-cause dementia, mixed AD/ VaD, and VaD, but no association with AD alone [3].
Th us, although the data are not entirely consistent, the preponderance of evidence suggests that higher aggregate levels of vascular risk raise the risk of clinically diagnosed incident AD.
In summary, diabetes, hypertension, and hyperlipidemia in midlife, as well as aggregate risk factors for athero sclerosis, are associated with increased risk for incident dementia; fi rst for VaD, but also for AD + VaD, and to a lesser extent for AD alone. When relative risk was reported by subgroup, the strength of association diminished in the following order: VaD > AD + VaD > AD (fi ve of fi ve studies for diabetes mellitus; four of four studies for HTN; one study for high cholesterol and one study of aggregate risk). Th e trends across dementia subgroups is consistent with the hypothesis that vascular risk factors increase atherosclerosis, which promotes subclinical vascular brain injury that exerts an additive eff ect with AD pathology to symptomatically unmask dementia. Th ese data cannot prove or disprove the alternative hypothesis that vascular risk factors or atherosclerosis increase AD pathology. Th e advent of biochemical markers for AD (for example, amyloid imaging and cerebrospinal fl uid Aβ and phospho-tau) may allow this question to be revisited in the future with improved specifi city for the diagnosis of AD in clinical settings.

Level C evidence
Several sources of selection bias may occur in convenience autopsy samples, including why the patient presented to medical attention, reasons for providing autopsy consent, and criteria for including the autopsy cases for study. In general, limited information regarding vascular risk factors is available on autopsy samples, and the focus of these studies is on cross-sectional pathology measures of atherosclerosis and AD (Table 7). Th e methods of assessing atherosclerosis severity vary widely among studies, including gross visual inspection of the Circle of Willis [41], cross-sectional measurements of arterial lumen narrowing [42], and microscopic evalu ation of major branches of the Circle of Willis [20].
Th ree groups of investigators have reported asso ciations between atherosclerosis and AD pathology (either NPs or NFTs) among cases drawn from AD brain banks. In a study from Sun Health Research Institute, which focuses on cognitive impairment in late life, Roher and colleagues [42] fi rst called attention to correlations between atherosclerosis in the Circle of Willis and tangle and plaque scores in a sample composed of ten AD and ten normal controls. In this small sample, the correlations between atherosclerosis and AD pathology appear to be driven by the absence of either type of pathology in the normal controls. In a larger and more heterogeneous sample from the same center (n = 397) [41], athero sclerosis was signifi cantly greater in VaD (n = 30) and AD (n = 215), compared to non-AD (n = 60) and normal controls (n = 92). In a logistic regression analysis, adjusted for age, gender and APOE ε4 genotype, the odds ratios for increasing severity of AD pathology per unit increase in atherosclerosis were signifi cantly elevated: NP score >1 (OR = 1.30, 95% CI 1.07 to 1.57); Braak Stage >4 (OR = 1.27, 95% CI 1.06 to 1.52). In a study of 99 cases drawn from the Mount Sinai Dementia Brain Bank [43] (81 AD and 18 controls), atherosclerosis in coronary arteries and the aorta were correlated with NP and NFT scores, particu larly among APOE ε4 carriers. In a large conven ience autopsy sample from the National Alzheimer's Co ordinating Center, severity of atherosclerosis was asso ciated with frequency of NP, but not Braak and Braak Stage, among 921 AD and 133 neuropathologically normal controls [44].
On the other hand, other autopsy studies drawn from non-dementia settings have not shown positive associations between atherosclerosis and AD pathology. From cases autopsied at a Geriatric Hospital in Japan, Itoh and colleagues [45] noted lower atherosclerosis scores in AD (n = 48) than non-AD patients (n = 99) (P < 0.05). No signifi cant associations were noted between severities of atherosclerosis in the aorta, coronary, or cerebral arteries and hippocampal plaques or tangles. In a study of medico-legal (coroner) cases over age 50 years (n = 466) unselected for either athero sclerosis or AD [46], amyloid plaque percentage area in the frontal lobe was associated with age (P < 0.0001) and APOE ε4 allele (P < 0.0001), but not with atherosclerosis in the Circle of Willis. Similarly, hippocampal tangle counts were associated with age, but not cerebral atherosclerosis score. In a study focused on patients with stroke, Aβ load, Aβ40, and Aβ42 aggregates in the cortex and thalamus increased with age, but not with atherosclerosis in the Circle of Willis. Finally, in a retrospective autopsy study, no diff erences in severity of AD pathology were found among 49 cases with diabetes compared to 52 age-matched normal controls [47].
Th us, in autopsy studies drawn from convenience samples, the relationship between atherosclerosis and AD pathology diff ers depending on the settings from which the sample is drawn. Associations between intracranial atherosclerosis and severity of plaques and sometimes tangles are reported from AD brain banks, but not from stroke banks, or from cases unselected for atherosclerosis or AD. Th ese level C fi ndings are inconclusive, due to sample selection, relative crudeness of the pathology measures, and to a variable sample size.

Conclusion
A few representative, prospective studies with autopsy (evidence level A) fail to show a positive association between vascular risk factors and AD pathology. Not surprisingly, vascular risk factors increased the likelihood of cerebral infarcts. No associations have been demonstrated between diabetes and AD pathology or between intracranial atherosclerosis and AD pathology. Some pros pective, representative, epidemiologic studies (evidence level B) show associations between diabetes, hypertension, hyperlipidemia, and aggregate vascular risk factors and incident AD; these studies have attracted considerable attention in the literature. However, when relative risk has been reported by subgroup, the strength of association diminished in the following order: VaD > AD + VaD > AD. Th e declining trends across dementia subgroups is more consistent with the hypothesis that atherosclerosis promotes subclinical vascular brain injury that increases the likelihood of dementia. Convenience autopsy studies from AD brain banks (evidence level C) report positive associations between intracranial atherosclerosis and severity of plaques and sometimes tangles. However, these associations are not confi rmed when samples are drawn from other non-dementia brain bank settings. We conclude that, at the present time, there is no level A or B evidence that the vascular risk factors reviewed here increase AD pathology.