Risk factors and global cognitive status related to brain arteriolosclerosis in elderly individuals

Abstract

Risk factors and cognitive sequelae of brain arteriolosclerosis pathology are not fully understood. To address this, we used multimodal data from the National Alzheimer's Coordinating Center and Alzheimer's Disease Neuroimaging Initiative data sets. Previous studies showed evidence of distinct neurodegenerative disease outcomes and clinical-pathological correlations in the "oldest-old" compared to younger cohorts. Therefore, using the National Alzheimer's Coordinating Center data set, we analyzed clinical and neuropathological data from two groups according to ages at death: < 80 years (n = 1008) and ≥80 years (n = 1382). In both age groups, severe brain arteriolosclerosis was associated with worse performances on global cognition tests. Hypertension (but not diabetes) was a brain arteriolosclerosis risk factor in the younger group. In the ≥ 80 years age at death group, an ABCC9 gene variant (rs704180), previously associated with aging-related hippocampal sclerosis, was also associated with brain arteriolosclerosis. A post-hoc arterial spin labeling neuroimaging experiment indicated that ABCC9 genotype is associated with cerebral blood flow impairment; in a convenience sample from Alzheimer's Disease Neuroimaging Initiative (n = 15, homozygous individuals), non-risk genotype carriers showed higher global cerebral blood flow compared to risk genotype carriers. We conclude that brain arteriolosclerosis is associated with altered cognitive status and a novel vascular genetic risk factor.

Keywords: Arteriosclerosis; CVD; HS-Aging; TDP-43; VCID.

Figure 1.

Exclusion/inclusion criteria and frequency of brain arteriolosclerosis (B-ASC) pathology in autopsied cases from the National Alzheimer's Coordinating Center (NACC) data set. (a) Living cases and autopsied cases with missing information which would preclude making an assessment of B-ASC status were excluded from analysis. (b) The percentage of cases with any B-ASC pathology (mild, moderate or severe) in the NACC data set. Asterisk (*) indicates that 64 cases with age at death <50 years or > 100 years were not plotted. (c) A stacked bar graph showing that B-ASC severity increases with age at death, Chi-square p-value < 0.0001.

Figure 2.

Semi-quantitative severity grading of B-ASC pathology and its non-association with APOE ɛ4 allele in the NACC data set. (a, b, c, d) Photomicrographs of hematoxylin- and eosin-stained blood vessels. (a) What we assume to be a normal arteriole (green arrow). (b) mild B-ASC with relatively mild thickening of vessel wall. (c) moderate B-ASC severity grade 2 with increased thickening of vessel wall. (d) severe B-ASC with prominent thickening of vessel wall and partly occluded vessel lumen. Scale bars = 100 µm. (e) The association between APOE ɛ4 genotypes and any degree of CAA (mild, moderate, severe) combining both age at death groups: *Chi-square p-value < 0.0001 among 1883 individuals for whom APOE genotype data and CAA diagnosis were available. Those with ɛ2/ɛ3 and ɛ2/ɛ2 genotypes were combined into one category. There were no statistically significant associations that could be determined between B-ASC severity and APOE genotype. B-ASC: brain arteriolosclerosis; CAA: cerebral amyloid angiopathy.

Figure 3.

Relationship between any degree of brain arteriolosclerosis (B-ASC) pathology in NACC and HS-Aging risk genotypes. (a) The association between ABCC9 HS-Aging risk genotype (rs704180 A_A, as determined previously)^, and B-ASC pathology, stratifying by age of death. *Chi-square p-value = 0.032. By contrast, as shown in (b,c), neither the TMEM106B (rs1990622 A_A or A_G) nor GRN (rs5848 T_T) risk genotypes are associated with B-ASC pathology.

Figure 4.

Arterial Spin labeling (ASL) neuroimaging indicates that ABCC9 HS-Aging risk genotype is associated with decreased cerebral blood flow (CBF), compatible with a novel pathogenetic mechanism. (a) A representative scan of a 77-year-old female with the ABCC9 HS-Aging non-risk genotype: rs704180 G_G. (b) A representative scan from a 76-year-old male with rs704180 A_A. (c) Individuals with the rs704180 G_G genotype showed significantly higher global CBF compared to those with the rs704180 A_A genotype, group level relative difference in CBF is 28%, p < 0.001. Neither other scans nor SNPs were analyzed from the ADNI data set. (d) An interpretation of the results presented in this paper. We hypothesize that an ABCC9 gene variant increases risk for B-ASC and/or decreased CBF, which, in turn, may cause or exacerbate hippocampal TDP-43 pathology and HS-Aging. All of these pathologies have been associated with cognitive impairment. Other variants in GRN and TMEM106B genes are not associated with B-ASC pathology and thus may represent downstream factors, perhaps more directly related to risk of hippocampal TDP-43 pathology. Presumed non-cerebrovascular pathologies (e.g. frontotemporal lobar degeneration (FTLD), brain trauma, and Alzheimer's disease) also are associated with hippocampal TDP-43 pathology, indicating that hippocampal TDP-43 pathology is a common downstream pathological phenomenon.