Journal of Alzheimer's Disease - Volume 64, issue 1

Authors: Kaminari, Archontia | Tsilibary, Effie C. | Tzinia, Athina

Article Type: Review Article

Abstract: Matrix metalloprotease 9 (MMP-9) is a 92 kDa type IV collagenase and a member of the family of endopeptidases. MMP-9 is involved in the degradation of extracellular matrix components, tissue remodeling, cellular receptor stripping, and processing of various signaling molecules. In the CNS, the effects of MMP-9 are quite complex, since it exerts beneficial effects including neurogenesis, angiogenesis, myelogenesis, axonal growth, and inhibition of apoptosis, or destructive effects including apoptosis, blood-brain barrier disorder, and demyelination. Likewise, in the periphery, physiological events, as the involvement of MMP-9 in angiogenesis, for instance in wound healing, can be turned into pathological, such as …in tumor metastasis, depending on the state of the organism. Alzheimer’s disease is a neurodegenerative disorder, characterized by amyloid accumulation and deposition in the brain. Amyloidogenesis, however, also occurs in diseases of the periphery, such as type II diabetes mellitus, where an analogous type of amyloid, is deposited in the pancreas. Interestingly, both diseases exhibit similar pathology and disease progression, with insulin resistance being a major common denominator. Hence, combinatorial strategies searching new or existing molecules to apply for therapeutic use for both diseases are gaining momentum. MMP-9 is extensively studied due to its association with a variety of physiological and pathological processes. Consequently, meticulous design could render MMP-9 into a potential therapeutic target for Alzheimer’s disease and type 2 diabetes mellitus; two seemingly unrelated diseases. Show more

Keywords: Alzheimer’s disease, amyloidogenesis, insulin resistance, MMP-9, type 2 diabetes mellitus

DOI: 10.3233/JAD-180035

Citation: Journal of Alzheimer's Disease, vol. 64, no. 1, pp. 1-16, 2018

Authors: Reuben, Aaron

Article Type: Review Article

Abstract: Millions of Americans now entering midlife and old age were exposed to high levels of lead, a neurotoxin, as children. Evidence from animal-model and human observational studies suggest that childhood lead exposure may raise the risk of adult neurodegenerative disease, particularly dementia, through a variety of possible mechanisms including epigenetic modification, delayed cardiovascular and kidney disease, direct degenerative CNS injury from lead remobilized from bone, and lowered neural and cognitive reserve. Within the next ten years, the generation of children with the highest historical lead exposures, those born in the 1960s, 1970s, and 1980s, will begin to enter the age …at which dementia symptoms tend to emerge. Many will also enter the age in which lead stored in the skeleton may be remobilized at greater rates, particularly for women entering menopause and men and women experiencing osteoporosis. Should childhood lead exposure prove pro-degenerative, the next twenty years will provide the last opportunities for possible early intervention to forestall greater degenerative disease burden across the aging lead-exposed population. More evidence is needed now to characterize the nature and magnitude of the degenerative risks facing adults exposed to lead as children and to identify interventions to limit long-term harm. Show more

Keywords: Aging, development, epigenetics, lead, neurodegeneration

DOI: 10.3233/JAD-180267

Citation: Journal of Alzheimer's Disease, vol. 64, no. 1, pp. 17-42, 2018

Authors: Kishi, Taro | Matsuda, Yuki | Iwata, Nakao

Article Type: Short Communication

Abstract: We performed a meta-analysis to determine whether combination therapy with serotonin reuptake inhibitors (SRIs) and memantine (MEM) was beneficial for the treatment of obsessive– compulsive disorder. This study included three double-blind, randomized, placebo-controlled trials. MEM+SRI was superior to placebo+SRI with regard to response rate [primary outcome, n = 97; risk ratio = 0.22; 95% confidence intervals (CI) = 0.12–0.42; p < 0.00001; I2 = 0%; number needed to treat = 2], the Yale– Brown Obsessive– Compulsive Scale total [standardized mean difference (SMD) = – 4.56; 95% CI = – 8.50, – 0.62; p = 0.02], obsession …subscale (SMD = – 4.39; 95% CI = – 5.94, – 2.85; p < 0.00001), and compulsion subscale score (SMD = – 4.60; 95% CI = – 7.64, – 1.55; p = 0.003). No significant differences in any safety outcome were found between the groups. Show more

Keywords: Memantine, meta-analysis, obsessive–compulsive disorder, response rate, Yale–Brown Obsessive–Compulsive Scale score

DOI: 10.3233/JAD-180237

Citation: Journal of Alzheimer's Disease, vol. 64, no. 1, pp. 43-48, 2018

Authors: Lupton, Michelle K. | Medland, Sarah E. | Gordon, Scott D. | Goncalves, Tabatha | MacGregor, Stuart | Mackey, David A. | Young, Terri L. | Duffy, David L. | Visscher, Peter M. | Wray, Naomi R. | Nyholt, Dale R. | Bain, Lisa | Ferreira, Manuel A. | Henders, Anjali K. | Wallace, Leanne | Montgomery, Grant W. | Wright, Margaret J. | Martin, Nicholas G.

Article Type: Short Communication

Abstract: Cohort studies investigating aging and dementia require APOE genotyping. We compared directly measured APOE genotypes to ‘hard-call’ genotypes derived from imputing genome-wide genotyping data from a range of platforms using several imputation panels. Older GWAS arrays imputed to 1000 Genomes Project (1KGP) phases and the Haplotype Reference Consortium (HRC) reference panels were able to achieve concordance rates of over 98% with stringent quality control (hard-call-threshold 0.8). However, this resulted in high levels of missingness (>12% with 1KGP and 5% with HRC). With recent GWAS arrays, concordance of 99% could be obtained with relatively lenient QC, resulting in no …missingness. Show more

Keywords: Alzheimer’s disease, ApoE receptor, cohort studies, computational biology, genetic association studies

DOI: 10.3233/JAD-171104

Citation: Journal of Alzheimer's Disease, vol. 64, no. 1, pp. 49-54, 2018

Authors: Tan, Meng-Shan | Zhu, Jun-Xia | Cao, Xi-Peng | Yu, Jin-Tai | Tan, Lan

Article Type: Short Communication

Abstract: Next-generation sequencing studies had reported that a rare coding variant p.V232M in PLD3 was associated with Alzheimer’s disease (AD) and a two-fold increased AD risk in European cohorts. To test whether coding region variants of PLD3 were associated with AD in a large Han Chinese cohort, we performed sequencing to analyze all exons of PLD3 , and demonstrated that rare variants p.I163M and c.1020-8G>A conferred considerable risk of late-onset AD (LOAD) in our cohort. Meanwhile, the previously reported p.V232M variant was identified in our AD group. These findings indicate that rare variants of PLD3 may play an …important role in LOAD in northern Han Chinese. Show more

Keywords: Alzheimer’s disease, Han Chinese, PLD3, rare variants

DOI: 10.3233/JAD-180205

Citation: Journal of Alzheimer's Disease, vol. 64, no. 1, pp. 55-59, 2018

Authors: Wang, Jin | Qiao, Fan | Shang, Suhang | Li, Pei | Chen, Chen | Dang, Liangjun | Jiang, Yu | Huo, Kang | Deng, Meiying | Wang, Jingyi | Qu, Qiumin

Article Type: Research Article

Abstract: Background: Aggregation and deposition of amyloid-β (Aβ) in the brain is the main pathological change of Alzheimer’s disease (AD). Decreased Aβ42 in the cerebrospinal fluid has been confirmed as a biomarker of AD; however, the relationship between plasma Aβ and cognitive impairment is currently unclear. Objective: The aim was to explore the relationship between plasma Aβ and cognitive impairment in a cross-sectional study. Methods: A total of 1,314 subjects (age above 40) from a village in the suburbs of Xi’an, China were enrolled between October 8, 2014 and March 30, 2015. A validated Chinese version …of the Mini-Mental State Examination and neuropsychological battery were used to assess cognition. Levels of plasma Aβ42 and Aβ40 were tested using commercial enzyme-linked immunosorbent assay. Relationship of plasma Aβ and cognitive impairment was analyzed using logistic regression analysis. Results: Of the enrolled subjects, 1,180 (89.80%) had normal cognition, 85 (6.47%) had possible cognitive impairment and 49 (3.73%) had probable cognitive impairment. Logistic regression analysis showed that the Aβ42 /Aβ40 ratio (OR = 4.042, 95% CI: 1.248–11.098, p = 0.012) and plasma Aβ42 (OR = 1.036, 95% CI: 1.003–1.071, p = 0.031) was higher in the possible cognitive impairment than that in the normal cognition group. Furthermore, the plasma Aβ42 /Aβ40 ratio was higher in the possible cognitive impairment group than that in the probable cognitive impairment group (OR = 0.029, 95% CI: 0.002–0.450, p = 0.011). Conclusions: Levels of plasma Aβ42 and Aβ42 /Aβ40 ratio were elevated in patients with possible cognitive impairment, indicating that plasma Aβ42 and Aβ42 /Aβ40 ratio increases may be more pronounced in early stage of cognitive impairment. Show more

Keywords: Alzheimer’s disease, amyloid-β, cognitive impairment, plasma

DOI: 10.3233/JAD-180140

Citation: Journal of Alzheimer's Disease, vol. 64, no. 1, pp. 61-69, 2018

Authors: Chhetri, Jagadish K. | de Souto Barreto, Philipe | Cantet, Christelle | Pothier, Kristell | Cesari, Matteo | Andrieu, Sandrine | Coley, Nicola | Vellas, Bruno

Article Type: Research Article

Abstract: Findings from recent Alzheimer’s disease prevention trials have shown subjects with increased dementia score based upon mid-life cardiovascular risk factors, to benefit from multi-domain intervention strategies to some extent. The effects of such interventions on cognitive functions remains yet to be well-established. This study is a secondary analysis of the MAPT study, 1,293 older subjects (mean age 75 years) with high CAIDE score (i.e., ≥6) were classified according to the four intervention groups: 1) multi-domain intervention plus placebo, 2) isolated supplementation with Omega-3 polyunsaturated fatty acid (n-3 PUFA), 3) combination of the two interventions, and 4) placebo alone. Linear mixed-model …repeated-measures analyses were used to assess the cognitive changes according to various neuropsychological test scores between intervention groups compared to the placebo at 36 months from baseline. Compared to the placebo, group with multi-domain intervention in combination withn-3PUFA was found to show significant improvement in the delayed total recall test of the free and cued selective reminding test (FCSRT) (mean±standard error(SE) = 0.20±0.10) and MMSE orientation test (mean±SE = 0.15±0.06) at 36 months. Isolated multi-domain intervention group showed significant less decline in the MMSE orientation test (mean±SE = 0.12±0.06) compared to the placebo. There was significant less improvement (mean±SE = – 1.01±0.46) in the FCSRT free recall test in the n-3 PUFA intervention group compared to the placebo at 36 months. Our findings show high-risk subjects for dementia screened with CAIDE dementia score might benefit from multi-domain intervention strategies as in the MAPT study, particularly in the orientation and delayed recall domain. Show more

Keywords: Alzheimer’s disease, CAIDE, cognitive decline, cognitive functions, MAPT study, multi-domain intervention, n-3 PUFA, neuropsychological tests, omega-3, prevention

DOI: 10.3233/JAD-180209

Citation: Journal of Alzheimer's Disease, vol. 64, no. 1, pp. 71-78, 2018

Authors: Caldwell, Jessica Z.K. | Berg, Jody-Lynn | Shan, Guogen | Cummings, Jeffrey L. | Banks, Sarah J. | Alzheimer’s Disease Neuroimaging Initiative

Article Type: Research Article

Abstract: We examined moderation effects of sex and diagnosis on the effect of positive florbetapir positron emission tomography (PET) amyloid-β (Aβ) scan (A+) on hippocampus subfield volumes in 526 normal control (NC) and early mild cognitive impairment (eMCI) participants from the Alzheimer’s Disease Neuroimaging Initiative (ADNI2; ADNI-GO). Regression moderation models showed that women— but not men— with NC designation did not show reduced subiculum volumes despite A+. At the eMCI stage, A+ was detrimental across sexes. Findings were significant while accounting for the effects of age, cognition at screening, education, and APOE4 carrier status. These findings suggest that women with A+ …have early neural resistance to Alzheimer’s disease-related amyloid burden. Show more

Keywords: Alzheimer’s disease, amyloid, magnetic resonance imaging, memory, mild cognitive impairment, positron emission tomography

DOI: 10.3233/JAD-180028

Citation: Journal of Alzheimer's Disease, vol. 64, no. 1, pp. 79-89, 2018

Authors: Flatt, Jason D. | Johnson, Julene K. | Karpiak, Stephen E. | Seidel, Liz | Larson, Britta | Brennan-Ing, Mark

Article Type: Research Article

Abstract: Background: Little is known about subjective cognitive decline (SCD) in lesbian, gay, bisexual, and transgender (LGBT) older adults. Objectives: To examine SCD and its association with dementia risk factors, other physical and psychosocial health factors in LGBT older adults. Methods: A cross-sectional study of SCD was conducted with LGBT older adults, aged 50 and older (n = 210). SCD was categorized based on endorsement of memory problems and one other cognitive domain. Hierarchical logistic regression examined the associations between demographic factors, dementia risk factors, other health and psychosocial factors, and SCD. Results: Nearly …25% of LGBT older adults were classified as having SCD. LGBT older adults who were people of color (OR = 2.5; 95% CI = 1.1– 7.8), depressed (OR = 2.9; 95% CI = 1.3– 6.9), or reported having functional impairment (OR = 2.6; 95% CI = 1.1– 6.5) were significantly more likely to be classified as having SCD (Nagelkerke pseudo R2 = 0.27). Conclusion: Depression and functional impairment should be considered when screening LGBT older adults for cognitive impairment and dementia. Future research on the cognitive impairment and dementia risk in LGBT older adults is needed. Show more

Keywords: Dementia, depression, risk factors, sexual minorities, subjective cognitive decline, subjective memory impairment

DOI: 10.3233/JAD-171061

Citation: Journal of Alzheimer's Disease, vol. 64, no. 1, pp. 91-102, 2018

Authors: Ruan, Yang | Guo, Shi-Jie | Wang, Xu | Dong, Dong | Shen, Dong-Hui | Zhu, Jie | Zheng, Xiang-Yu

Article Type: Research Article

Abstract: Kainic acid (KA) was recently identified as an epileptogenic and neuroexcitotoxic agent that is responsible for inducing learning and memory deficits in various neurodegenerative diseases, such as Alzheimer’s disease (AD). However, the mechanism by which KA acts upon AD remains unclear. To this end, we presently investigated the roles of KA in processing amyloid-β protein precursor (AβPP) and amyloid-β protein (Aβ) loads during the course of AD development and progression. Specifically, KA treatment clearly caused the upregulation of tumor necrosis factor α (TNF-α) via activation of the PI3-K/AKT, ERK1/2, and p65 pathways in glial cells. TNF-α secreted from glial cells …was then found to be responsible for stimulating the expression of BACE-1 and PS1/2, which resulted in the production and deposition of Aβ in neurons. Finally, the accumulation and aggregation of Aβ lead to the cognitive decline of APP23 mice. These results indicate that KA accelerates the progression of AD by inducing the crosstalk between glial cells and neurons. Show more

Keywords: Alzheimer’s disease, BACE-1, kainic acid, presenilin, tumor necrosis factor α

DOI: 10.3233/JAD-171137

Citation: Journal of Alzheimer's Disease, vol. 64, no. 1, pp. 103-116, 2018