The effects of human leukocyte antigen DRB1*13 and apolipoprotein E on age-related variability of synchronous neural interactions in healthy women

Abstract

Background Age-related brain changes are well-documented and influenced by genetics. Extensive research links apolipoprotein E (apoE) to brain function, with the E4 allele serving as a risk factor for brain disease, including Alzheimer's disease, and the E2 allele conferring protection. Recent evidence also supports protective effects of another gene, human leukocyte antigen (HLA) DRB1*13, on brain disease and age-related brain atrophy in cognitively healthy adults. Here we investigated the effects of apoE and HLA DRB1*13 on brain function by examining changes in neural network properties with age in healthy adults. Methods One hundred seventy-eight cognitively healthy women (28–99 y old) underwent a magnetoencephalography scan and provided a blood sample for genetic analysis. Age-related changes in neural network variability in genetic subgroups of DRB1*13 × apoE genotype combinations were assessed using linear regression of network variability against age. Findings For individuals lacking a DRB1*13 allele and/or carrying an apoE4 allele, network variability increased significantly with age. In contrast, no such increase was observed in the presence of DRB1*13 and/or apoE2. Interpretation These findings extend previous research documenting the protective effect of DRB1*13 on brain structure to include protection against age-related changes in brain function, and demonstrate similar protective effects on neural network variability for either DRB1*13 or apoE2. These protective effects could be due to reduction or elimination of factors known to disrupt brain function, including neuroinflammation and amyloid beta protein. Funding U.S. Department of Veterans Affairs, and University of Minnesota.

Human Leukocyte Antigen as a Key Factor in Preventing Dementia and Associated Apolipoprotein E4 Risk

“…A search of the Immune Epitope Database (www.iedb.org) indicates that 78 human herpes virus 1 epitopes match with HLA class I proteins and 72 epitopes match with HLA class II proteins. Furthermore, 23 human herpes virus 1 epitopes were found to bind with DRB1 * 13:02, the same genes that we have found to protect against age-related brain changes (James et al, 2018a,b), with high affinity using the Sturniolo et al (1999) method. These results support the hypothesis that several HLA proteins are effective for elimination of human herpes virus 1 either through apoptosis (Class I) or antibody production (Class II).…”

“…For example, HLA-DRB1 * 13:02 has been shown to confer protection against various illnesses ranging from hepatitis B and C (Singh et al, 2007), influenza (Posteraro et al, 2014), HIV (Pereyra et al, 2010), malaria (Hill et al, 1991), and numerous autoimmune disorders (Bettencourt et al, 2015). Perhaps the most relevant in this case is recent evidence of HLA-protection against structural and functional age-related brain changes (James et al, 2018a,b). Notably, DRB1 * 13:02, has been shown to not only protect against age-related deterioration in neural network functioning, but also to negate the deleterious effects of apoE4 on neural network functioning (James et al, 2018b; Figure 1, top), suggesting a common pathway.…”

“…Perhaps the most relevant in this case is recent evidence of HLA-protection against structural and functional age-related brain changes (James et al, 2018a,b). Notably, DRB1 * 13:02, has been shown to not only protect against age-related deterioration in neural network functioning, but also to negate the deleterious effects of apoE4 on neural network functioning (James et al, 2018b; Figure 1, top), suggesting a common pathway.…”

“…HLA DRB1*13 and ApoE effects on brain health. (Top) HLA protection against age-related increases in neural network variability in apoE4 carriers (adapted from James et al, 2018b). (Bottom) Hypothesized neuroimmune cascade in which persistent antigens cause initial neuronal damage, stimulating apoE synthesis.…”

Persistent Antigens Hypothesis: The Human Leukocyte Antigen (HLA) Connection

“…To that end, protective HLA alleles have been observed in conditions including autoimmune disorders 6,16 , HIV 17,18 , Hepatitis B and C 19 , malaria 20 , and Gulf War Illness 15,21 , among others. Furthermore, certain HLA alleles have been shown to exert protective effects in healthy individuals, minimizing age-related brain changes typically attributed to "normal" aging 22,23 (see below).…”