Current Alzheimer Research - Volume 12, Issue 3, 2015

Aging-related major neurocognitive disorder (NCD), formerly named dementia, comprises of the different acquired diseases whose primary deficit is impairment in cognitive functions such as complex attention, executive function, learning and memory, language, perceptual/motor skills, and social cognition, and that are related to specific brain regions and/or networks. According to its etiology, the most common subtypes of major NCDs are due to Alzheimer’ s disease (AD), vascular disease (VaD), Lewy body disease (LBD), and frontotemporal lobar degeneration (FTLD). These pathologies are frequently present in mixed forms, i.e., AD plus VaD or AD plus LBD, thus diagnosed as due to multiple etiologies. In this paper, the definitions, criteria, pathologies, subtypes and genetic markers for the most common age-related major NCD subtypes are summarized. The current diagnostic criteria consider cognitive decline leading to major NCD or dementia as a progressive degenerative process with an underlying neuropathology that begins before the manifestation of symptoms. Biomarkers associated with this asymptomatic phase are being developed as accurate risk factor and biomarker assessments are fundamental to provide timely treatment since no treatments to prevent or cure NCD yet exist. Biological fluid assessment represents a safer, cheaper and less invasive method compared to contrast imaging studies to predict NCD appearance. Genetic factors particularly have a key role not only in predicting development of the disease but also the age of onset as well as the presentation of comorbidities that may contribute to the disease pathology and trigger synergistic mechanisms which may, in turn, accelerate the neurodegenerative process and its resultant behavioral and functional disorders.

Having a family history of Alzheimer’ s disease (AD) may potentiate cumulative risk associated with phenotypic expression of the ε-4 allele of the apolipoprotein E (APOE) gene. In this study, we compared the genotype distribution and allele frequencies of APOE ε-2 (rs7412) and ε -4 (rs429358) in 537 South African individuals participating in a chronic disease screening program, in order to establish whether AD family history modulates the expression of their dyslipidemic effects. Significant differences in the genotype distribution for APOE ε-2 (p=0.034) as well as APOE ε-4 (p=0.038) were found between study participants with (n=67) and without (n=470) a family history of AD. LDL cholesterol levels were inversely associated with physical activity in the study group with a positive family history of AD (p<0.001) but not in those with a negative family history of AD (p=0.257). Similar to its existing use in the diagnosis of monogenic dyslipidemias such as familial hypercholesterolemia, clinical inquiry regarding family history was identified as an important determinant of eligibility for APOE genotyping performed in the context of chronic disease risk management. To our knowledge, this is the first study to demonstrate the modulating influence of AD family history on expression of a dyslipidemic phenotype associated with the APOE ε-4 allele. Our findings provide the scientific rationale supporting a novel clinical application for APOE genotyping as a means of identifying a genetic subgroup of dyslipidemic patients set to derive the greatest benefit from early lifestyle-based interventions aimed at decreasing cumulative risk for cardiovascular disease and prevention of AD later in life.

APOE ε4 allele is a major risk factor in Late-Onset Alzheimer’s Disease (AD). Distinct phenotypes that depend on the APOE ε4 status have been demonstrated. The genetic etiology of APOE ε4 non-carriers is still elusive. Thus we investigated the genetic components of AD that is independent of APOE ε4 by combining genome association analysis with quantitative trait analyses in non-Hispanic Caucasian participants in the Alzheimer’ s Disease Neuroimaging Initiative (ADNI) cohort. Five top susceptible single nucleotide polymorphisms (SNPs) in three loci in ZNF827, KDM2B and NANP were initially identified in APOE ε4 non-carriers and four of these SNPs were confirmed in mild cognitive impairment. These SNPs and one nominally significant SNP are located in three haplotype blocks. Quantitative trait analyses of these haplotype blocks demonstrated that the haplotype block in ZNF827 was associated with CSF Aβ42 level, and the haplotype block in KDM2B with CSF p-tau181p and p-tau181p/Aβ42 ratio. The haplotype block between NANP and NINL was associated with brain atrophy. Moreover, these SNPs took additive effects on AD incidence and demonstrated the interaction with APOE ε4 status. Therefore, we conclude that these novel loci are associated with AD in APOE ε4 non-carriers. This study indicates the distinct genetic risk genes for AD non-carrying APOE ε4 and provides new insight into the molecular mechanisms of AD.

Objective: Recently, candidate genetic studies revealed the single nucleotide polymorphisms (SNPs) of CUGBP2 (rs2242451) and DNMBP (rs11190305 and rs3740058) associated with Alzheimer’s disease (AD). Due to genetic heterogeneity and different ethnic background, the purpose of our study was to confirm the association between these 3 SNPs with AD risk in the Chinese Han population. Methods: We investigated 482 sporadic AD (SAD) patients and 813 unrelated cognitive normal controls of the Chinese Han population. The genotypes of the 3 SNPs (rs2242451, rs11190305, rs3740058) were carried out by MassARRAY iPLEX system. Results: The genotype and the allele frequency of rs2242451 were significantly different between AD and control group in total subject (genotype: p=0.019, allele frequency: p=0.022, OR=0.760, 95%CI=0.601- 0.962) with A allele decreasing AD risk. After stratification by age at onset, gender, APOE ε4 carrying status and homozygous APOE ε4, the protective effect of A allele remained in female and APOE ε4ε4 non-carrying subgroups. The rs3740058 in DNMBP was significantly differently in genotype between AD and control in APOE ε4ε4 subgroup, but showed no effect on AD risk, either did rs11190305 polymorphisms in DNMBP. Meta-analysis was performed in rs11190305 and rs3740058 of DNMBP respectively. Positive relationship with AD was found in rs11190305 (OR=1.11, 95%CI=1.01-1.21), but not in rs3740058 (OR=1.05, 95%CI=0.98-1.13). Moreover, the genotypes of these 3 SNPs had no effect on age at onset of AD. Conclusion: The A allele of rs2242451 in CUGBP2 might decrease SAD risk in the Chinese Han population.

Previous studies have suggested that mild cognitive impairment (MCI) may be reflective of the early stages of neurodegenerative disorders such as Alzheimer’s disease (AD). The hypothesis was that cytokeratin (CK) 14 expression can be used as a biomarker in isolated buccal mucosa to identify individuals with MCI or AD from the Australian Imaging, Biomarkers and Lifestyle (AIBL) flagship study of aging. Visual assessment of buccal cell CK14 expression was carried out using immunofluorescence techniques. The frequency of basal buccal cells expressing CK14 was significantly lower in the MCI (P=0.0002) and AD (P<0.05) groups compared with the control group. Receiver-operating characteristic (ROC) curves were carried out for CK14 expression and yielded an area under the curve (AUC) of 0.899 for the MCI (P<0.0001) group and 0.772 for the AD (P=0.004) group. When the CK14 expression data were combined with plasma homocysteine concentration, the AUC was further improved to 0.932 and 0.788 for the MCI (P=0.0001) and AD (P=0.004) groups, respectively. APOE ε4 carriers in the control group had 21% lower CK14 expression compared with control non APOE ε4 carriers, however this difference was not statistically significant. The changes in the buccal cell CK14 expression observed in this pilot study could prove useful as a potential biomarker in identifying individuals with an increased risk of developing MCI and eventually AD. These promising results need to be replicated in a larger subset of the AIBL cohort and in cohorts of other neurodegenerative disorders to determine changes specific to AD.

Objective: Multiple lines of evidence indicate that pathological accumulation of amyloid beta (Aβ) peptide in the brain is linked to the pathophysiology of Alzheimer’s disease (AD). Removal of Aβ from the brain by binding to anti-Aβ specific antibodies is under active investigation. Vaccination with a full-length Aβ42 peptide (AN1792) successfully elicited anti-Aβ antibodies in human subjects with AD, but was associated with meningoencephalitis. To avoid this safety issue, an aminoterminal Aβ1-7 peptide conjugate, vanutide cridificar (ACC-001), was designed and is currently in clinical development. This report describes two phase 2 multiple ascending-dose studies in Japanese subjects with mild to moderate AD. Safety and immunogenicity evaluation were the primary and secondary objectives, respectively. Methods: ACC-001 was administered to three cohorts of subjects at doses of 3, 10, or 30 μg, with or without a QS-21 adjuvant in Study 1, and with a QS-21 adjuvant in Study 2; control groups consisted of QS-21 alone (both studies) and phosphate-buffered saline (Study 1 only). Results: A variety of treatment-emergent adverse events (TEAEs) were reported from most subjects during the studies; most of these were mild or moderate in intensity. Three subjects withdrew from the study because of an adverse event (in Study 2). The most common treatment-associated TEAE was injection site reactions. No deaths were observed in either study. All doses of ACC-001 + QS-21 elicited high, sustained anti-Aβ antibody titers; QS-21 was necessary for this effect. Conclusion: These data will provide valuable information on further investigation of anti-Aβ vaccine therapy for AD.

Previous studies have demonstrated that Alzheimer’s disease (AD) and amnestic mild cognitive impairment (aMCI) exhibited anatomical and functional abnormalities in the anterior cingulate cortex (ACC) and accumulating evidence supported the hypothesis that changes in the ACC predict the progression from aMCI to AD. In this study, we aimed to explore how the two functional and structural heterogeneous sub-regions of ACC, namely the dorsal ACC (dACC) and the ventral ACC (vACC), changed in aMCI and whether the structural connectivity affects the functional connectivity between the two ACC subregions. To investigate this hypothesis, we studied resting-state fMRI and DTI images in a group of 24 aMCIs and 29 healthy controls. The dACC exhibited a significantly increased functional connectivity in the Salience Network (SN) and a decreased functional connectivity with the vACC in aMCI. The DTI results showed that the bilateral cingulum fibers were the most damaged tracts in aMCI and that the fractional anisotrophy of the left anterior cingulum was significantly correlated with the functional connectivity between the two ACC sub-regions. In conclusion, this study revealed the pathological changes in the intrinsic functional connectivity of the ACC within SN, as well as the connectivity between the dACC and vACC in aMCI. Our study also revealed that disrupted white matter integrity of the anterior regions of the cingulum was associated with the alterations in subregional connectivity in the ACC.

The current study aimed to assess the relationship between the neuropsychiatric symptoms in Alzheimer’s disease (AD) and the regional grey matter (GM) volume using voxel based morphometry (VBM). Data of 85 AD patients, 208 subjects with mild cognitive impairment (MCI), and 131 healthy controls were selected from the Alzheimer’s Disease Neuroimaging Initiative. Individual VBM models across the entire sample for each items of the Neuropsychiatric Inventory Questionnaire as variables of interest were specified with four nuisance covariates, including age, sex, total intracranial volume (TIV), and Mini-Mental State Examination (MMSE) score. Agitation was related to the GM atrophy in the left inferior frontal/insula and bilateral retrosplenial cortices. Aberrant motor behavior (AMB) was related to the GM reductions in the right basal ganglia. The VBM models were recalculated by specifying three nuisance covariates (age, sex, TIV), and by excluding voxels related to AD severity by applying a MMSE mask. This procedure confirmed the first results, and additionally revealed associations between depression and GM atrophy in the left middle frontal cortex, between agitation and the GM atrophy in the left middle frontal cortex, and between AMB and GM reduction in the right inferior frontal cortex. Hierarchical multiple regression analyses using extracted mean GM value in these additional regions confirmed these associations. Finally, VBM analyses within a subgroup (85 AD patients and 41 MCI converters) largely confirmed the results. Our results suggest that specific patterns of GM atrophy within AD related neurodegeneration predispose to certain neuropsychiatric symptoms, suggesting distinct neurobiological mechanisms.

11C-Pittsburgh compound B (PiB) uptake in PET images is frequently used to analyze β amyloid (Aβ) deposition in living individuals, but its correlation with histologically determined Aβ has not been examined. Six individuals with dementia underwent PiB-PET imaging, and their brains were analyzed neuropathologically (mean interval between imaging and death: 816 days; PiB positive:negative, 3:3; male:female, 3:3; mean age: 84.0 years). PiB uptake (reported as standardized uptake value ratio [SUVR]) was analyzed in 11 cortical regions and 10 subcortical grey matter areas and compared with the Aβ load (% area [the percentage of total area positive for Aβ] and number of neuritic plaques) seen with immunohistochemical staining with an anti-Aβ 11-28 antibody. Two PiB-positive subjects had abundant neuritic plaques and were diagnosed with Alzheimer’s disease (AD). SUVR and % area were strongly correlated in the cortical regions of these subjects (subject 1: r = 0.65, p = 0.03; subject 2: r = 0.80, p = 0.003). The other PiBpositive subject (subject 3) showed focal PiB uptake. In subject 3 and the 3 PiB-negative subjects (subjects 4-6), there was no correlation between regional SUVR and % area or neuritic plaques. PiB uptake was not correlated with Aβ deposition in subcortical regions. High PiB positivity in the cerebral cortex suggests the presence of substantial Aβ deposition and neuritic plaques associated with the pathologic changes of AD. Our results suggest that high cortical SUVR is a reliable marker of AD. Subcortical PiB positivity must be interpreted more carefully.

Background: Stroke is a major cause of disability in the elderly and considerably increases the risk of dementia, which is another important source of disability. This population-based study aimed to examine the risk of dementia in patients with stroke compared with non-stroke cases with similar comorbidities. Methods: Using the Taiwan National Health Insurance databank covering the period 2001-2007, this retrospective cohort study evaluated the risk of dementia in 10,884 patients with first stroke who had no history of dementia. In this study, we performed a 1:5 case-control matched analysis, in which cases were matched to controls based on their estimated propensity scores, which were estimated with demographics and associated risk factors. This approach reduced selection bias. Cox proportional hazards regression analysis was then used to estimate the risk of dementia in stroke patients. Results: During the 5-year follow-up period, 1,487 (13.74%) stroke and 1,402 (2.59%) non-stroke patients suffered dementia. Stroke was independently associated with a 6.09 (95% confidence interval [CI], 5.66 to 6.55) times greater risk of dementia 5 years after stroke. Older age was associated with a higher incidence of dementia after stroke. Each stroke type had different impacts on the occurrence of dementia. The hazard ratio of dementia among hemorrhagic stroke patients was much higher than those of ischemic stroke and controls. Conclusion: The findings of this study suggest that stroke confers an increased risk of dementia, especially in the elderly and in patients with hemorrhagic stroke. We advocate the need for close observation and enhanced health education programs to benefit patients with stroke.