Structural Dynamics of Amyloid-ß Protofibrils and Actions of Anti-Amyloid-ß Antibodies as Observed by High-Speed Atomic Force Microscopy.

Amyloid-ß (Aß) aggregation intermediates, including oligomers and protofibrils (PFs), have attracted attention as neurotoxic aggregates in Alzheimer's disease. However, due to the complexity of the aggregation pathway, the structural dynamics of aggregation intermediates and how drugs act on them have not been clarified. Here we used high-speed atomic force microscopy to observe the structural dynamics of Aß42 PF at the single-molecule level and the effect of lecanemab, an anti-Aß PF antibody with the positive results from Phase 3 Clarity AD. PF was found to be a curved nodal structure with stable binding angle between individual nodes. PF was also a dynamic structure that associates with other PF molecules and undergoes intramolecular cleavage. Lecanemab remained stable in binding to PFs and to globular oligomers, inhibiting the formation of large aggregates. These results provide direct evidence for a mechanism by which antibody drugs interfere with the Aß aggregation process.

The Mechanisms of the Roles of α-Synuclein, Amyloid-ß, and Tau Protein in the Lewy Body Diseases: Pathogenesis, Early Detection, and Therapeutics.

Lewy body diseases (LBD) are pathologically defined as the accumulation of Lewy bodies composed of an aggregation of α-synuclein (αSyn). In LBD, not only the sole aggregation of αSyn but also the co-aggregation of amyloidogenic proteins, such as amyloid-ß (Aß) and tau, has been reported. In this review, the pathophysiology of co-aggregation of αSyn, Aß, and tau protein and the advancement in imaging and fluid biomarkers that can detect αSyn and co-occurring Aß and/or tau pathologies are discussed. Additionally, the αSyn-targeted disease-modifying therapies in clinical trials are summarized.

Higher-resolution quantification of white matter hypointensities by large-scale transfer learning from 2D images on the JPSC-AD cohort.

White matter lesions (WML) commonly occur in older brains and are quantifiable on MRI, often used as a biomarker in Aging research. Although algorithms are regularly proposed that identify these lesions from T2-fluid-attenuated inversion recovery (FLAIR) sequences, none so far can estimate lesions directly from T1-weighted images with acceptable accuracy. Since 3D T1 is a polyvalent and higher-resolution sequence, it could be beneficial to obtain the distribution of WML directly from it. However a serious difficulty, both for algorithms and human, can be found in the ambiguities of brain signal intensity in T1 images. This manuscript shows that a cross-domain ConvNet (Convolutional Neural Network) approach can help solve this problem. Still, this is non-trivial, as it would appear to require a large and varied dataset (for robustness) labelled at the same high resolution (for spatial accuracy). Instead, our model was taught from two-dimensional FLAIR images with a loss function designed to handle the super-resolution need. And crucially, we leveraged a very large training set for this task, the recently assembled, multi-sites Japan Prospective Studies Collaboration for Aging and Dementia (JPSC-AD) cohort. We describe the two-step procedure that we followed to handle such a large number of imperfectly labeled samples. A large-scale accuracy evaluation conducted against FreeSurfer 7, and a further visual expert rating revealed that WML segmentation from our ConvNet was consistently better. Finally, we made a directly usable software program based on that trained ConvNet model, available at https://github.com/bthyreau/deep-T1-WMH.

Cerebrospinal fluid cytokines and metalloproteinases in cerebral amyloid angiopathy-related inflammation.

OBJECTIVES: To clarify pathomechanisms of cerebral amyloid angiopathy-related inflammation/vasculitis (CAA-ri). METHODS: We collected cerebrospinal fluid (CSF) samples of nine patients with CAA-ri of before (acute CAA-ri group) and after treatment (post-treatment CAA-ri group) and nine patients with CAA (CAA without inflammation group). We examined anti-amyloid ß protein (Aß) antibody titer by ELISA, and measured 27 Cytokines, nine matrix metalloproteinases (MMPs), and four tissue inhibitors of MMPs (TIMPs) by multiplexed fluorescent bead-based immunoassay. RESULTS: We demonstrated TIMP-2 (median) in CSF of the acute CAA-ri group (30,994.49 pg/ml, p = 0.007) and the post-treatment CAA-ri group (36,430.97 pg/ml, p = 0.001) was significantly elevated compared to that of the CAA without inflammation group (22,013.58 pg/ml). TIMP-1 was also higher in the post-treatment CAA-ri group than that in the CAA without inflammation group (58,167.75 pg/ml vs. 45,770.03 pg/ml, p = 0.005). There was a significant positive correlation between TIMP-1 and anti-Aß antibodies in CAA-ri (rs  = 0.900, p = 0.037). Median MMP-2 tended to be higher in the acute and post-treatment CAA-ri groups (10,619.82 pg/ml and 8396.98 pg/ml, respectively) than in the CAA without inflammation group (4436.34 pg/ml). Platelet-derived growth factor (PDGF)-BB levels before treatment were higher than those after treatment (median, 12.66 pg/ml vs. 6.39 pg/ml; p = 0.011) and correlated with the titer of anti-Aß antibodies (rs  =0.900, p = 0.037). CONCLUSIONS: Elevated levels of MMP-2, TIMP-1, and TIMP-2 might be related to the development of CAA-ri. Elevation of PDGF-BB could be a useful marker for clinical diagnosis of CAA-ri.

Contiguous and symmetrical disease expansion and massive necrosis of the cerebral white matter in a patient with neuromyelitis optica.

The present report discusses the case of a woman with neuromyelitis optica (NMO) who exhibited bilateral optic neuritis, longitudinally extensive myelitis, serum anti-aquaporin-4 antibodies, and a unique pattern of white matter involvement. The disease duration was 26 years, and the patient died at the age of 65 years. Sequential magnetic resonance images obtained during the last 6 years of life revealed leukoencephalopathy-like lesions extending symmetrically and contiguously from the periventricular regions, which had begun to transform into multiple cavities with semi-annular partitions. This unique pattern of white matter abnormalities should thus be considered among those associated with NMO.

Natural Phenolic Compounds as Therapeutic and Preventive Agents for Cerebral Amyloidosis.

Epidemiological studies have suggested that diets rich in phenolic compounds may have preventive effects on the development of dementia or Alzheimer's disease (AD). We investigated the effects of natural phenolic compounds, such as myricetin (Myr), rosmarinic acid (RA), ferulic acid (FA), curcumin (Cur) and nordihydroguaiaretic acid (NDGA) on the aggregation of amyloid ß-protein (Aß), using in vitro and in vivo models of cerebral Aß amyloidosis. The in vitro studies revealed that these phenolic compounds efficiently inhibit oligomerization as well as fibril formation of Aß through differential binding, whilst reducing Aß oligomer-induced synaptic and neuronal toxicity. Furthermore, a transgenic mouse model fed orally with such phenolic compounds showed significant reduction of soluble Aß oligomers as well as of insoluble Aß deposition in the brain. These data, together with an updated review of the literature, indicate that natural phenolic compounds have anti-amyloidogenic effects on Aß in addition to well-known anti-oxidative and anti-inflammatory effects, hence suggesting their potential as therapeutic and/or preventive agents for cerebral Aß amyloidosis, including AD and cerebral amyloid angiopathy (CAA). Well-designed clinical trials or preventive interventions with natural phenolic compounds are necessary to establish their efficacy as disease-modifying agents.

Lutein from Chicken Eggs Prevents Amyloid ß-Peptide Aggregation In Vitro and Amyloid ß-Induced Inflammation in Human Macrophages (THP-1).

Epidemiological studies predict that chicken eggs contain constituents other than proteins that prevent Alzheimer's disease. This study screened for constituents that inhibit the aggregation of amyloid ß peptide (Aß)1-42 and elucidated their mechanisms to explore the active components of chicken eggs. Thioflavin T assays and transmission electron microscopy observations showed that arachidonic acid (ARA), lysophosphatidylcholine, lutein (LTN), palmitoleic acid, and zeaxanthin inhibited Aß aggregation. Among these, ARA and LTN showed the highest activity. Photoinduced cross-linking of unmodified protein assays and infrared absorption spectrometry measurements showed that LTN strongly inhibited highly toxic Aß1-42 protofibril formation. Furthermore, LTN suppressed Aß1-42-induced IL 1B and TNF expression in human macrophage-like cells. In summary, LTN plays a crucial role in the AD-preventive effect of chicken eggs by suppressing Aß1-42 aggregation and Aß1-42-induced inflammation.

Brain atrophy in normal older adult links tooth loss and diet changes to future cognitive decline.

Several studies have found associations between poor oral health, particularly tooth loss and cognitive decline. However, the specific brain regions affected by tooth loss and the probable causes remain unclear. We conducted a population-based longitudinal cohort study in Nakajima, Nanao City, Japan. Between 2016 and 2018, 2454 residents aged ≥60 participated, covering 92.9% of the local age demographics. This study used comprehensive approach by combining detailed dental examinations, dietary assessments, magnetic resonance imaging (MRI) analysis, and cognitive evaluations. Tooth loss, even in cognitively normal individuals, is associated with parahippocampal gyrus atrophy and increased WMH volume, both of which are characteristics of dementia. Tooth loss was associated with altered dietary patterns, notably a reduction in plant-based food intake and an increase in fatty, processed food intake. This study highlights a possible preventative pathway where oral health may play a significant role in preventing the early neuropathological shifts associated with dementia.

Insight into the frequent occurrence of dura mater graft-associated Creutzfeldt-Jakob disease in Japan.

OBJECTIVE: More than 60% of patients worldwide with Creutzfeldt-Jakob disease (CJD) associated with dura mater graft (dCJD) have been diagnosed in Japan. The remarkable frequency of dura mater grafts in Japan may possibly contribute to the elevated incidence of dCJD, but reasons for the disproportionate use of this procedure in Japan remain unclear. We investigated differences between dCJD patients in Japan and those elsewhere to help explain the more frequent use of cadaveric dura mater and the high incidence of dCJD in Japan. METHODS: We obtained data on dCJD patients in Japan from the Japanese national CJD surveillance programme and on dCJD patients in other countries from the extant literature. We compared the demographic, clinical and pathological features of dCJD patients in Japan with those from other countries. RESULTS: Data were obtained for 142 dCJD patients in Japan and 53 dCJD patients elsewhere. The medical conditions preceding dura mater graft transplantation were significantly different between Japan and other countries (p<0.001); in Japan, there were more cases of cerebrovascular disease and hemifacial spasm or trigeminal neuralgia. Patients with dCJD in Japan received dura mater graft more often for non-life-threatening conditions, such as meningioma, hemifacial spasm and trigeminal neuralgia, than in other countries. CONCLUSIONS: Differences in the medical conditions precipitating dura mater graft may contribute to the frequent use of cadaveric dura mater and the higher incidence of dCJD in Japan.

Exercise program to reduce the risk of cognitive decline and physical frailty in older adults: study protocol for an open label double-arm clinical trial.

Objective: It is a big problem that many older adults are physically inactive. Well-known benefits of physical exercise include a decrease in the risk of cognitive decline and physical frailty. Therefore, this study aims to examine whether our proposed exercise program can prevent cognitive decline and improve physical function in the elderly. Methods: This study will include nondemented older adults (n = 103) without regular exercise habits. The trial will include a physical exercise training program (once a week) and nutritional lectures (once a month) over 5 months and follow-up for ≥1 year. The primary endpoint is the program's efficacy in preventing cognitive decline, as assessed by changes in the memory performance index of the mild cognitive impairment (MCI) screen; the secondary endpoints are the incidence of MCI and dementia, physical testing, and frailty proportion. In the exploratory phase of the study, we will elucidate the underlying diseases causing MCI in community-dwelling older adults by neuroimaging. Discussion: This double-arm trial that aims to assess the impact of physical exercise on nondemented older adults' cognitive and physical function. Furthermore, our newly developed exercise program will be easy for older adults to undertake.Clinical Trial Registration: https://clinicaltrials.gov/, identifier [jRCT 1040220140].

Effects of Melissa officinalis Extract Containing Rosmarinic Acid on Cognition in Older Adults Without Dementia: A Randomized Controlled Trial.

BACKGROUND: Previous in vitro and in vivo studies on Alzheimer's disease (AD) models have reported that rosmarinic acid (RA) can inhibit the formation of amyloid-ß fibrils as well as the oligomerization and deposition of amyloid-ß protein. Melissa officinalis (M. officinalis) extract containing 500 mg of RA is tolerable and safe in healthy individuals and patients with mild AD dementia. OBJECTIVE: This randomized placebo-controlled double-blind trial aimed to assess the effects of M. officinalis extract on cognition in older adults without dementia. METHODS: This study included individuals who were diagnosed with subjective or mild cognitive impairment (n = 323). The trial involved M. officinalis extract supplementation (500 mg of RA per day) period of 96 weeks followed by a washout period of 24 weeks. The primary endpoint was the Alzheimer's Disease Assessment Scale-cognitive subscale score, and the secondary endpoints were other cognitive measure results as well as safety and tolerability. RESULTS: There were no significant differences in cognitive measures between the placebo and M. officinalis groups from baseline to 96 weeks. However, based on the analysis of Clinical Dementia Rating Sum of Boxes scores in participants without hypertension, the score was found to be increased by 0.006 and decreased by 0.085 in the M. officinalis and placebo groups, respectively; this difference was statistically significant (p = 0.036). Furthermore, there were no differences in vital signs, physical and neurological measures, or hippocampal volume between the two groups. CONCLUSION: These results indicate that M. officinalis extract may help prevent cognitive decline in older adults without hypertension.

Cerebrospinal Fluid Biomarkers and Amyloid-ß Elimination from the Brain in Cerebral Amyloid Angiopathy-Related Inflammation.

BACKGROUND: Cerebrospinal fluid (CSF) biomarkers in patients with cerebral amyloid angiopathy-related inflammation (CAA-ri) have demonstrated inconsistent results. OBJECTIVE: We investigated the relationship between CSF amyloid-ß protein (Aß) and vascular pathological findings to elucidate the mechanisms of Aß elimination from the brain in CAA-ri. METHODS: We examined Aß40 and Aß42 levels in CSF samples in 15 patients with CAA-ri and 15 patients with Alzheimer's disease and cerebral amyloid angiopathy (AD-CAA) using ELISA as a cross-sectional study. Furthermore, we pathologically examined Aß40 and Aß42 depositions on the leptomeningeal blood vessels (arteries, arterioles, and veins) using brain biopsy samples from six patients with acute CAA-ri and brain tissues of two autopsied patients with CAA-ri. RESULTS: The median Aß40 and Aß42 levels in the CSF showed no significant difference between pre-treatment CAA-ri (Aß40, 6837 pg/ml; Aß42, 324 pg/ml) and AD-CAA (Aß40, 7669 pg/ml, p = 0.345; Aß42, 355 pg/ml, p = 0.760). Aß40 and Aß42 levels in patients with post-treatment CAA-ri (Aß40, 1770 pg/ml, p = 0.056; Aß42, 167 pg/ml, p = 0.006) were lower than those in patients with pre-treatment CAA-ri. Regarding Aß40 and Aß42 positive arteries, acute CAA-ri cases showed a higher frequency of partially Aß-deposited blood vessels than postmortem CAA-ri cases (Aß40, 20.8% versus 3.9%, p = 0.0714; Aß42, 27.4% versus 2.0%, p = 0.0714, respectively). CONCLUSION: Lower levels of CSF Aß40 and Aß42 could be biomarkers for the cessation of inflammation in CAA-ri reflecting the recovery of the intramural periarterial drainage pathway and vascular function.

Plasma amyloid-ß biomarkers are associated with Alzheimer's disease comorbidity in Lewy body disease.

No blood biomarkers which can identify Alzheimer's disease pathology in Lewy body disease (LBD) have ever been established. We showed that the plasma amyloid-ß (Aß) 1-42/Aß1-40 ratio was significantly decreased in patients with Aß+ LBD compared with those with Aß- LBD and it might be a useful biomarker.

Association of the prefrailty with global brain atrophy and white matter lesions among cognitively unimpaired older adults: the Nakajima study.

Physical frailty has been associated with adverse outcomes such as dementia. However, the underlying structural brain abnormalities of physical frailty are unclear. We investigated the relationship between physical frailty and structural brain abnormalities in 670 cognitively unimpaired individuals (mean age 70.1 years). Total brain volume (TBV), hippocampal volume (HV), total white matter hypointensities volume (WMHV), and estimated total intracranial volume (eTIV) on the 3D T1-weighted images were automatically computed using FreeSurfer software. Participants were divided into two states of physical frailty (robust vs. prefrail) based on the revised Japanese version of the Cardiovascular Health Study criteria. The multivariable-adjusted mean values of the TBV-to-eTIV ratio was significantly decreased, whereas that of the WMHV-to-eTIV ratio was significantly increased in the prefrail group compared with the robust group. Slowness, one of the components of physical frailty, was significantly associated with reduced TBV-to-eTIV and HV-to-eTIV ratios, and slowness and weakness were significantly associated with an increased WMHV-to-eTIV ratio. Our results suggest that the prefrail state is significantly associated with global brain atrophy and white matter hypointensities. Furthermore, slowness was significantly associated with hippocampal atrophy.

Diabetes Mellitus, Elevated Hemoglobin A1c, and Glycated Albumin Are Associated with the Presence of All-Cause Dementia and Alzheimer's Disease: The JPSC-AD Study.

BACKGROUND: Glucose dysmetabolism is an important risk factor for dementia. OBJECTIVE: We investigated the associations of diabetes mellitus, the levels of glycemic measures, and insulin resistance and secretion measures with dementia and its subtypes in a cross-sectional study. METHODS: In this study, 10,214 community-dwelling participants were enrolled. Hemoglobin A1c (HbA1c), the homeostasis model assessment (HOMA) for insulin resistance (HOMA-IR), the HOMA of percent ß-cell function (HOMA-ß), and the glycated albumin (GA) was evaluated. The associations of each measure with Alzheimer's disease (AD) and vascular dementia (VaD) were investigated. RESULTS: The multivariable-adjusted odds ratios (ORs) of AD were significantly higher in participants with diabetes mellitus than in those without diabetes (1.46 [95% CI: 1.08-1.97]). Higher HbA1c levels were significantly associated with AD at diabetes (≥6.5%) and even at prediabetes (5.7 %-6.4 %) levels; multivariable-adjusted ORs for AD in participants at the diabetes level were 1.72 (95% CI: 1.19-2.49), and those in participants at the prediabetes level were 1.30 (95% CI: 1.00-1.68), compared with those in normal participants. Moreover, higher GA levels were associated with AD. No associations were observed between the diabetic status or the levels of glycemic measures and VaD. In addition, no significant relationships were observed between insulin resistance and secretion measurements and AD and VaD. CONCLUSION: Our findings indicate that diabetes mellitus and hyperglycemia are significantly associated with AD, even in individuals at the prediabetes level.

Prospective 10-year surveillance of human prion diseases in Japan.

We analysed the epidemiological data and clinical features of patients with prion diseases that had been registered by the Creutzfeldt-Jakob Disease Surveillance Committee, Japan, over the past 10 years, since 1999. We obtained information on 1685 Japanese patients suspected as having prion diseases and judged that 1222 patients had prion diseases, consisting of definite (n=180, 14.7%) and probable (n=1029, 84.2%) cases, except for dura mater graft-associated Creutzfeldt-Jakob disease which also included possible cases (n=13, 1.1%). They were classified into 922 (75.5%) with sporadic Creutzfeldt-Jakob disease, 216 (17.7%) with genetic prion diseases, 81 (6.6%) with acquired prion diseases, including 80 cases of dura mater graft-associated Creutzfeldt-Jakob disease and one case of variant Creutzfeldt-Jakob disease, and three cases of unclassified Creutzfeldt-Jakob disease (0.2%). The annual incidence rate of prion disease ranged from 0.65 in 1999 to 1.10 in 2006, with an average of 0.85, similar to European countries. Although methionine homozygosity at codon 129 polymorphism of the prion protein gene was reported to be very common (93%) in the general Japanese population, sporadic Creutzfeldt-Jakob disease in Japan was significantly associated with codon 129 homozygosity (97.5%), as reported in western countries. In sporadic Creutzfeldt-Jakob disease, MM1 type (Parchi's classification) is the most common, as in western countries. Among atypical sporadic Creutzfeldt-Jakob disease cases, the MM2 type appeared most common, probably related to the very high proportion of methionine allele in the Japanese population. As for iatrogenic Creutzfeldt-Jakob disease, only dura mater graft-associated Creutzfeldt-Jakob disease cases were reported in Japan and, combined with the data from previous surveillance systems, the total number of dura mater graft-associated Creutzfeldt-Jakob disease was 138, comprising the majority of worldwide dura mater graft-associated Creutzfeldt-Jakob disease patients. Regarding genetic prion diseases, the most common mutation of prion protein gene was V180I (41.2%), followed by P102L (18.1%), E200K (17.1%) and M232R (15.3%), and this distribution was quite different from that in Europe. In particular, V180I and M232R were quite rare mutations worldwide. Patients with V180I or M232R mutations rarely had a family history of prion diseases, indicating that a genetic test for sporadic cases is necessary to distinguish these from sporadic Creutzfeldt-Jakob disease. In conclusion, our prospective 10-year surveillance revealed a frequent occurrence of dura mater graft-associated Creutzfeldt-Jakob disease, and unique phenotypes of sporadic Creutzfeldt-Jakob disease and genetic prion diseases related to the characteristic distribution of prion protein gene mutations and polymorphisms in Japan, compared with those in western countries.

Rosmarinic acid suppresses tau phosphorylation and cognitive decline by downregulating the JNK signaling pathway.

Rosmarinic acid (RA), a polyphenol found in Lamiaceae herbs, is a candidate of preventive ingredients against Alzheimer's disease (AD) as it potently suppresses the aggregation of amyloid ß (Aß); however, the effect of RA on tau phosphorylation and cognitive dysfunction remains unclear. The present study revealed that RA intake inhibited the pathological hallmarks of AD, including Aß and phosphorylated tau accumulation, and improved cognitive function in the 3 × Tg-AD mouse model. Additionally, RA intake suppressed hippocampal inflammation and led to the downregulation of the JNK signaling pathway that induces tau phosphorylation. Feeding with RA exerted an anti-inflammatory effect not only in the central nervous system but also in the periphery. Downregulation of the JNK signaling pathway in hippocampus may be a potential mechanism underlying the inhibition of progression of pathology and cognitive deficit by RA feeding.

MEG activity of the dorsolateral prefrontal cortex during optic flow stimulations detects mild cognitive impairment due to Alzheimer's disease.

Dorsal stream, which has a neuronal connection with dorsolateral prefrontal cortex (DLPFC), is known to be responsible for detection of motion including optic flow perception. Using magnetoencephalography (MEG), this study aimed to examine neural responses to optic flow stimuli with looming motion in the DLPFC in patients with mild cognitive impairment due to Alzheimer's disease (AD-MCI) compared with cognitively unimpaired participants (CU). We analyzed the neural responses by evaluating maximum source-localized power for the AD-MCI group (n = 11) and CU (n = 20), focusing on six regions of interest (ROIs) that form the DLPFC: right and left dorsal Brodmann area 9/46 (A9/46d), Brodmann area 46 (A46) and ventral Brodmann area 9/46 (A9/46v). We found significant differences in the maximum power between the groups in the left A46 and A9/46v. Moreover, in the left A9/46v, the maximum power significantly correlated with the Wechsler Memory Scale-Revised general memory score and delayed recall score. The maximum power in the left A9/46v also revealed high performance in AD-MCI versus CU classification with the area under the ROC curve of 0.90. This study demonstrated that MEG during the optic flow task can be useful in discriminating AD-MCI from CU.

[Factors Associated with Self-reported Medication Adherence in Japanese Community-dwelling Elderly Individuals: The Nakajima Study].

Medication non-adherence in the elderly population is a major problem, preventing them from obtaining optimal therapeutic effects. Identifying the factors affecting medication adherence is crucial for improving and maintaining health among the elderly population and enhance healthcare economy. The purpose of this study was to examine the prevalence of self-reported medication adherence, and identify the associated factors and the influence of health-related quality of life (HRQOL) in the Japanese community-dwelling elderly population. This cross-sectional study was part of the Nakajima study and targeted inhabitants aged ≥60 years who underwent health examinations in 2017. Data regarding medication adherence were acquired through interviews and self-administered questionnaires. Medication adherence were assessed using a visual analog scale, and HRQOL was assessed by EuroQol five-dimensional questionnaire with 3 levels. Among the 455 participants, low and high medication adherence were seen in 9.7% and 66.2% of the participants, respectively (visual analog scores <80% and ≥95%, respectively). Medication adherence was significantly lower in participants taking medications ≥3 times daily than in those taking medications once or twice daily; a regimen involving drug administration ≥3 times daily had significantly lower odds of medication adherence. The use of a drug profile book and HRQOL had significant positive association with medication adherence. Our results suggest that low dosing frequency and using a drug profile book was positively associated with medication adherence among elderly persons, which in turn could enhance their QOL.

Effects of functional variants of vitamin C transporter genes on apolipoprotein E E4-associated risk of cognitive decline: The Nakajima study.

Apolipoprotein E E4 (APOE4) is a risk factor for cognitive decline. A high blood vitamin C (VC) level reduces APOE4-associated risk of developing cognitive decline in women. In the present study, we aimed to examine the effects of functional variants of VC transporter genes expressed in the brain (SLC2A1, SLC2A3, and SLC23A2) on APOE4-associated risk of developing cognitive decline. This case-control study involved 393 Japanese subjects: 252 cognitively normal and 141 cognitively impaired individuals (87 mild cognitive impairment and 54 dementia). Database searches revealed that rs1279683 of SLC23A2, and rs710218 and rs841851 of SLC2A1 are functional variants that are significantly associated with the altered expression of the respective genes and genotyped as three single nucleotide variants (SNVs). When stratified by SNV genotype, we found a significant association between APOE4 and cognitive decline in minor allele carriers of rs1279683 (odds ratio [OR] 2.02, 95% CI, 1.05-3.87, p = 0.035) but not in the homozygote carriers of the major allele. Significant associations between APOE4 and cognitive decline were also observed in participants with major allele homozygotes of rs710218 (OR 2.35, 95% CI, 1.05-5.23, p = 0.037) and rs841851 (OR 3.2, 95% CI, 1.58-6.46, p = 0.0012), but not in minor allele carriers of the respective SNVs. In contrast, the three functional SNVs showed no significant effect on cognitive decline. Our results imply that functional SNVs of VC transporter genes can affect APOE4-associated risk of developing cognitive decline via altered VC levels in the brain.