A high frequency of apolipoprotein E4 isoprotein in Japanese patients with late-onset nonfamilial Alzheimer's disease

The clinical, psychological, and neurologic characteristics of 37 Japanese patients with early-onset Alzheimer's disease (eAD; onset before age 65 years) were compared with those of 23 patients with late-onset Alzheimer's disease (lAD; onset at age 65 years or later). This study evaluated brain atrophy using computed tomographic (CT) scans, and the behavioral and psychological differences in the two groups using the Gottfries-Bråne-Steen scale, Japanese revision (GBSS-JR). Follow-up CT scans were obtained and compared in 20 patients with eAD, 24 patients with lAD, and 23 elderly nondemented control subjects. The size of lateral cerebral ventricular dilation, measured every 6 months following admission, was significantly larger in the eAD patients than in the control subjects. The characteristics of the 37 patients with eAD were compared with those of the 23 patients with lAD by evaluating the scores on all 38 items in the five categories of the GBSS-JR. To compare the test results by duration of disease, patients were divided into subgroups according to average duration of disease: eAD1 (nine patients), 2.2 years; eAD2 (16 patients), 5.0 years; eAD3 (12 patients), 9.0 years; lAD1 (seven patients), 1.6 years; lAD2 (10 patients), 3.1 years; and lAD3 (six patients), 5.3 years. The GBSS-JR scores were compared in duration-matched pairs, that is, eAD1 versus lAD1 and eAD2 versus lAD3. The eAD1 patients showed significantly worse scores in four categories and 13 items compared with the lAD1 patients. Fewer differences in scores were found between eAD2 patients and the lAD3 patients than between the eAD1 patients and the lAD1 patients. Increasing severity of disease and rapid deterioration of patients with eAD, particularly during the first 3 years following disease onset, was recognized. The pattern of abnormalities on GBSS-JR showed no difference between the two broad groups (early versus late onset). The categorization of patients with Alzheimer's disease as early and late onset is relevant to clinical management.

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Accelerated pericyte degeneration and blood–brain barrier breakdown in apolipoprotein E4 carriers with Alzheimer’s disease

Journal of Cerebral Blood Flow & Metabolism ◽

10.1038/jcbfm.2015.44 ◽

2015 ◽

Vol 36 (1) ◽

pp. 216-227 ◽

Cited By ~ 197

Author(s):

Matthew R Halliday ◽

Sanket V Rege ◽

Qingyi Ma ◽

Zhen Zhao ◽

Carol A Miller ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Endothelial Cells ◽

Blood Brain Barrier ◽

Late Onset ◽

Density Lipoprotein ◽

Brain Barrier ◽

Lipoprotein Receptor ◽

Apolipoprotein E4 ◽

Blood Brain

The blood–brain barrier (BBB) limits the entry of neurotoxic blood-derived products and cells into the brain that is required for normal neuronal functioning and information processing. Pericytes maintain the integrity of the BBB and degenerate in Alzheimer’s disease (AD). The BBB is damaged in AD, particularly in individuals carrying apolipoprotein E4 ( APOE4) gene, which is a major genetic risk factor for late-onset AD. The mechanisms underlying the BBB breakdown in AD remain, however, elusive. Here, we show accelerated pericyte degeneration in AD APOE4 carriers >AD APOE3 carriers >non-AD controls, which correlates with the magnitude of BBB breakdown to immunoglobulin G and fibrin. We also show accumulation of the proinflammatory cytokine cyclophilin A (CypA) and matrix metalloproteinase-9 (MMP-9) in pericytes and endothelial cells in AD ( APOE4 > APOE3), previously shown to lead to BBB breakdown in transgenic APOE4 mice. The levels of the apoE lipoprotein receptor, low-density lipoprotein receptor-related protein-1 (LRP1), were similarly reduced in AD APOE4 and APOE3 carriers. Our data suggest that APOE4 leads to accelerated pericyte loss and enhanced activation of LRP1-dependent CypA–MMP-9 BBB-degrading pathway in pericytes and endothelial cells, which can mediate a greater BBB damage in AD APOE4 compared with AD APOE3 carriers.

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