The Emerging Role of the Apolipoproteins APOE and APOJ in the Interaction Between Diabetes and Alzheimer Disease
Naoyuki Sato · The Journal of Clinical Endocrinology & Metabolism · 2020
Genetic risk factors, nongenetic risk factors, and lifestyle factors contribute to the development of dementia. Epidemiological studies suggest that diabetes is associated with Alzheimer disease (AD) and neurodegeneration (1), although the mechanisms underlying these associations remain unclear. Various genome-wide association studies have identified apolipoprotein J, APOJ (clusterin, CLU) as a strong genetic locus for AD (2), while apolipoprotein E (APOE) is the strongest genetic risk factor for this devastating disease. Previous reports from the Australian Imaging, Biomarkers, and Lifestyle Study of Ageing (AIBL) have shown that plasma clusterin is a potential biomarker for AD (3). Clusterin has recently been reported to be associated with cardiometabolic risk (4). However, it remains uncertain how plasma clusterin levels are associated with diabetes and AD in the same individual. In this issue of the Journal of Clinical Endocrinology and Metabolism, Ha et al from the Yonsei University College of Medicine, Republic of Korea, demonstrate that plasma clusterin is a promising biomarker for diabetes and AD and that clusterin mediates a link between these 2 diseases (5). Ha and colleagues classified 80 participants from a university-affiliated general hospital and local dementia center by severity of cognitive and metabolic impairments. They performed neuropsychological assessments, brain magnetic resonance imaging, and various blood tests to explore potential relationships between cognitive and metabolic impairments and plasma clusterin levels. They found that participants with AD had higher plasma clusterin levels than patients with mild cognitive impairment (MCI) or normal cognition. On the other hand, plasma clusterin levels were higher in participants with either prediabetes or diabetes than in healthy controls. Consistent with this observation, plasma clusterin levels were highly correlated with reliable indicators of insulin resistance such as fasting C-peptide levels and the homeostatic model assessment for insulin resistance (HOMA-IR). Interestingly, clusterin has been reported to impair hepatic insulin sensitivity and adipocyte clusterin is associated with cardiometabolic risk (4), indicating that plasma clusterin might be involved in worsening of insulin resistance. Clinical studies have reported that diabetes is associated with reduced white-matter volume as well as hippocampal volume and gray-matter volume. Diabetes is associated with aberrant functional connectivity between the posterior cingulate cortex and the temporal and frontal gyri, suggesting both white-matter and gray-matter functional abnormalities in diabetes (6). Ha et al found that plasma clusterin levels are also correlated with medial temporal atrophy and periventricular white-matter lesions. In a mediation analysis, they found that plasma clusterin is a potential mediator between diabetes and AD. When they set HOMA-IR or fasting C-peptide as a mediator, they did not find any significant effects. An intriguing question is how plasma clusterin mediates the interaction between diabetes and AD. Gene and protein expression of clusterin are upregulated in adipocytes in people with obesity; clusterin causes insulin resistance through its receptor, low-density lipoprotein-related protein 2 (LRP2, also known as megalin) in hepatocytes (4). In addition to being a ligand, clusterin is an extracellular chaperone protein that is part of the defense machinery acting against disease-associated misfolding of extracellular proteins such as amyloid (7). Therefore, increased levels of plasma clusterin, partly derived from adipocytes, might cause insulin resistance in peripheral tissues and interact with cerebral amyloid angiopathy to modify amyloid deposition and inflammation in the vascular walls of brains with AD. Indeed, Ha and colleagues also found that increased levels of clusterin in patients with prediabetes and diabetes are associated with more periventricular white-matter lesions. From these observations, however, it is not possible to determine whether increased levels of clusterin in prediabetes and diabetes are protective against or promote cerebrovascular damage or neurodegeneration. Interestingly, recent studies have shown an association between diabetes and AD via another apolipoprotein, APOE, in a genotype-dependent manner. Diabetes is associated with earlier cognitive decline during aging in APOE2 and APOE3 carriers, but not in APOE4 carriers (8). Moreover, the AIBL research group reported that APOE4 has a significant impact on the association between plasma clusterin and brain Aβ levels (3). In healthy participants, APOE4 carriers with severe amyloid deposition have higher plasma clusterin levels than APOE4 carriers with less amyloid deposition, whereas this relationship is reversed in APOE4 noncarriers (3), suggesting a compensatory or other type of biological mechanism exerted by the chaperone activity of clusterin in plasma. Another explanation for APOE genotype–dependent clusterin levels may be related to the fact that APOE and clusterin (APOJ) share receptors in the low-density lipoprotein receptor family such as megalin. One major difference between this study by Ha et al and the AIBL study is that plasma clusterin levels were significantly higher in participants with MCI compared to control individuals in the AIBL study, whereas there was no significant difference in the study by Ha et al, probably because of the difference in age and the ratio of APOE4 carriers to total participants with MCI between the 2 studies. Therefore, further clinical investigation of the APOE genotype–dependent effect of plasma clusterin on the interaction between diabetes and AD with larger numbers of participants is needed. In addition, laboratory investigation of the impact of conditional clusterin depletion from an AD model with diabetes on cognitive function or other outcomes such as lifespan would be especially interesting for assessing the role of clusterin in the interaction between these devastating diseases. These investigations might also identify clusterin as a potential therapeutic target or biomarker for AD and diabetes. Alzheimer disease Australian Imaging Biomarkers and Lifestyle Study of Ageing apolipoprotein E homeostatic model assessment for insulin resistance mild cognitive impairment I apologize to the many scientists whose work I could not cite because of space limitations. Financial Support: This work was supported in part by Research Funding for Longevity Sciences from the National Center for Geriatrics and Gerontology (Grants 28-45, 19-3, and 19-9); Grants-in-Aid from the Japan Promotion of Science; and the Japanese Ministry of Education, Culture, Sports, Science and Technology (Grants MEXT26293167, MEXT15K15272, and MEXT17H04154). Disclosure Summary: The author has nothing to disclose. Data sharing is not applicable to this article because no data sets were generated or analyzed during the present study.