Relation of cerebral vessel disease to Alzheimer's disease dementia and cognitive function in elderly people: a cross-sectional study

Summary

Background

Few data on the pathology of cerebral vessel disease, dementia, and cognition are available. We examined the association of cerebral atherosclerosis and arteriolosclerosis neuropathology with probable and possible Alzheimer's disease dementia and cognitive function.

Methods

This cross-sectional study included men and women aged 65 years or older who had yearly clinical assessments and had agreed to brain autopsy at the time of death, as part of one of two cohort studies of ageing (The Religious Orders Study and the Rush Memory and Aging Project). Individuals without dementia or with Alzheimer's disease dementia, and with complete neuropathological data, are included in our analyses. We used neuropsychological data proximate to death to create summary measures of global cognition and cognitive domains. Clinical data recorded between 1994 and 2015 were used to determine presence of Alzheimer's disease dementia. Systematic neuropathological assessments documented the severity of cerebral large vessel (atherosclerosis) and small vessel (arteriolosclerosis) disease. By use of regression analyses adjusted for demographics, gross and microscopic infarcts, and Alzheimer's disease pathology, we examined associations of vessel disease severity (mild, moderate, and severe) with odds of probable and possible Alzheimer's disease dementia and cognitive function.

Findings

Study enrolment began in January, 1994, and two cohort studies are ongoing. 1143 individuals were included in our analyses (median age at death 88·8 years; 478 [42%] with Alzheimer's disease dementia). Moderate-to-severe atherosclerosis was present in 445 (39%) individuals, and arteriolosclerosis in 401 (35%) individuals. Each level increase in the severity of atherosclerosis or arteriolosclerosis was associated with significantly higher odds of Alzheimer's disease dementia (odds ratio [OR] for atherosclerosis 1·33, 95% CI 1·11–1·58; OR for arteriolosclerosis 1·20, 1·04–1·40). Atherosclerosis was associated with lower scores for global cognition (estimate −0·10 [SE 0·04], p=0·0096) and four cognitive domains (episodic memory −0·10 [0·04], p=0·017; semantic memory −0·11 [0·05], p=0·018; perceptual speed −0·14 [0·04], p=0·00080; and visuospatial abilities −0·13 [0·04], p=0·0080), but not working memory (−0·05 [0·04], p=0·21). Arteriolosclerosis was associated with lower scores for global cognition (estimate −0·10 [0·03], p=0·0015) and four domains (episodic memory −0·12 [0·04], p=0·00090; semantic memory −0·10 [0·04], p=0·013; working memory −0·07 [0·03], p=0·045; perceptual speed −0·12 [0·04], p=0·0012), and a non-significant association was noted for visuospatial abilities (−0·07 [0·03], p=0·052). Findings were unchanged in analyses controlling for the presence of APOE ε4 allele or vascular risk factors.

Interpretation

Cerebral atherosclerosis and arteriolosclerosis are associated with Alzheimer's disease dementia, and are also associated with low scores in most cognitive domains. Cerebral vessel pathology might be an under-recognised risk factor for Alzheimer's disease dementia.

Funding

US National Institutes of Health.

Introduction

Cerebral vascular disease is common in elderly people and is associated with poor health outcomes, and stroke was identified as the second leading cause of death worldwide in 2012.¹ Research has consistently shown that cerebral vascular disease, as identified by use of neuroimaging and neuropathology, lowers the threshold for the clinical expression of dementia.² Indeed, stroke and its major cause, cerebral infarction, are established risk factors for dementia and cognitive impairment, and a relation between both gross and microscopic infarcts and dementia has been reported in pathological studies.² Less is known about the role of other cerebral vascular diseases, specifically atherosclerosis (large vessel disease) and arteriolosclerosis (small vessel disease). Data suggest that large vessel diseases, especially atherosclerosis, might increase the risk of dementia, particularly Alzheimer's disease;³ however, the focus in previous studies of atherosclerosis was largely on in-vivo data that do not enable control for the mediating or confounding effects of microinfarcts and Alzheimer's disease pathology. Furthermore, previous studies have focused on imaging of extracranial vessel disease and therefore cannot clarify a potential role of intracranial vessels, particularly small vessels, in dementia. Also, there are few data on the association between vessel disease and cognitive domains. Similar to studies on infarcts, in-vivo studies of atherosclerosis suggested that executive function and processing speed are particularly affected, by contrast with memory.4, 5 Additionally, we are not aware of any studies of arteriolosclerosis and cognitive domains.

Research in context

Evidence before this study

We searched PubMed for articles published up to January, 2016, with the terms “atherosclerosis” and (“arteriolosclerosis” or “lipohyalinosis”) and “dementia”. No restrictions were set for language or any other filter. This search yielded 16 citations, all of which were reviewed. After exclusion of six review articles, one case report, and four studies with a small number of participants (n<75), five studies remained. None of the five studies directly examined cognition or dementia in relation to both atherosclerosis and arteriolosclerosis. Our search suggested that little is known about the relation of intracranial cerebral vessel disease to cognition and dementia. Furthermore, there are few pathological studies on intracranial vascular disease and dementia. Yet, pathological studies are able to capture data not only on large but also small vessel pathology, which can only be indirectly assessed by use of in-vivo imaging. Moreover, since cerebral vessel disease is related to infarcts and arguably Alzheimer's disease pathology (the most common underlying dementia pathologies), pathological studies can control for infarcts, as well as Alzheimer's disease pathology, to assess the independent effect of both atherosclerosis and arteriolosclerosis separate from these other common pathologies.

Added value of this study

This clinical-pathological study examined the association of cerebral large vessel (atherosclerosis) and small vessel (arteriolosclerosis) neuropathology with Alzheimer's disease dementia and with cognitive function proximate to death in more than 1100 community-dwelling elderly individuals, who had yearly clinical assessments until death and had an autopsy. Our results show that atherosclerosis and arteriolosclerosis are related to each other, but each separately contributes to the odds of Alzheimer's disease dementia by 20–30% per level increase in vessel disease severity. Atherosclerosis and arteriolosclerosis are associated with lower scores in perceptual speed, which is the hallmark of vascular pathology, and also in episodic memory, which is typically regarded as the hallmark of Alzheimer's disease. The results are independent of the effects of infarcts (both gross and microscopic infarcts) and Alzheimer's disease pathology, and are not modified by age at death, infarcts, or Alzheimer's disease pathologies. Additionally, the results are essentially unchanged when taking presence of APOE ε4 or vascular risk factors into account. Our data add important information to current knowledge of intracranial vessel disease and cognitive function and dementia.

Implications of all the available evidence

Cerebral vessel diseases, specifically intracranial atherosclerosis and arteriolosclerosis, are common, under-recognised, and independently associated with Alzheimer's disease dementia. Our study lays the foundation for future research to examine pathophysiological mechanisms by which vessel disease leads to dementia, to differentiate cognitive impairment from Alzheimer's disease versus vascular pathology, and to detect and treat the cognitive impairment caused by vessel disease in the early phases.

Cerebral vessels are difficult to assess in vivo and examination of post-mortem tissue in elderly people who were followed up prospectively is useful to directly assess cerebral vessel diseases and determine their relation to dementia.6, 7, 8, 9, 10 A few studies have examined cerebral vessel disease and cognition,⁵ but we are not aware of any reported studies of the associations of these diseases with performance-based measures of specific cognitive domains.

We examined whether two common cerebral vessel diseases in ageing, atherosclerosis and arteriolosclerosis, are associated with risk of Alzheimer's disease dementia and with cognitive function before death. We also examined whether associations were independent of Alzheimer's disease and vascular pathologies, or affected by the presence of an apolipoprotein E (APO E) ε4 allele or vascular risk factors.