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

Abstract

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.

Figure 1

Distribution of cerebral vessel disease, with and without infarcts, shown separately in subjects with and without AD dementia Legend: The distribution of cerebral vessel disease (atherosclerosis and arteriolosclerosis) is shown in the left panel for subjects without dementia, and in the right panel for subjects with AD dementia. Each wedge of the pie shows the proportion of subjects with or without atherosclerosis, arteriolosclerosis, and/or infarct(s), with percentages indicated at the periphery. Atherosclerosis and arteriolosclerosis (in color) are considered present when of moderate severity or greater. Infarcts are considered present if any infarct, whether a gross or micro-infarct, is detected on the neuropathologic evaluation. The proportion of subjects in each vessel category who also have infarcts is shown in black diagonal lines (hatch). Note the increased proportion of subjects with vessel disease among subjects with AD dementia, compared to those without.

Figure 2

Relation of cerebral vessel pathologies to AD dementia and global cognitive function Legend: Top panel (A) shows the probability of AD dementia by AD pathology, showing separate effects of infarcts and cerebral vessel pathologies. Bottom panel (B) shows the relation of AD pathology to global cognitive function, showing separate effects of infarcts and cerebral vessel pathologies.