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

Authors: Llorente-Ovejero, Alberto | Manuel, Iván | Lombardero, Laura | Giralt, Maria Teresa | Ledent, Catherine | Giménez-Llort, Lydia | Rodríguez-Puertas, Rafael

Article Type: Research Article

Abstract: The endocannabinoid system, which modulates emotional learning and memory through CB1 receptors, has been found to be deregulated in Alzheimer’s disease (AD). AD is characterized by a progressive decline in memory associated with selective impairment of cholinergic neurotransmission. The functional interplay of endocannabinoid and muscarinic signaling was analyzed in seven-month-old 3xTg-AD mice following the evaluation of learning and memory of an aversive stimulus. Neurochemical correlates were simultaneously studied with both receptor and functional autoradiography for CB1 and muscarinic receptors, and regulations at the cellular level were depicted by immunofluorescence. 3xTg-AD mice exhibited increased acquisition latencies and impaired memory …retention compared to age-matched non-transgenic mice. Neurochemical analyses showed changes in CB1 receptor density and functional coupling of CB1 and muscarinic receptors to Gi/o proteins in several brain areas, highlighting that observed in the basolateral amygdala. The subchronic (seven days) stimulation of the endocannabinoid system following repeated WIN55,212-2 (1 mg/kg) or JZL184 (8 mg/kg) administration induced a CB1 receptor downregulation and CB1 -mediated signaling desensitization, normalizing acquisition latencies to control levels. However, the observed modulation of cholinergic neurotransmission in limbic areas did not modify learning and memory outcomes. A CB1 receptor-mediated decrease of GABAergic tone in the basolateral amygdala may be controlling the limbic component of learning and memory in 3xTg-AD mice. CB1 receptor desensitization may be a plausible strategy to improve behavior alterations associated with genetic risk factors for developing AD. Show more

Keywords: 3xTg-AD, Alzheimer’s disease, autoradiography, basolateral amygdala, cholinergic, endocannabinoid, learning and memory

DOI: 10.3233/JAD-180137

Citation: Journal of Alzheimer's Disease, vol. 64, no. 1, pp. 117-136, 2018

Authors: Akushevich, Igor | Yashkin, Arseniy P. | Kravchenko, Julia | Ukraintseva, Svetlana | Stallard, Eric | Yashin, Anatoliy I.

Article Type: Research Article

Abstract: Background: Trends in the prevalence of cognitive impairment (CI) based on cognitive assessment instruments are often inconsistent with those of neurocognitive disorders (ND) based on Medicare claims records. Objective: We hypothesized that improved ascertainment and resulting decrease in disease severity at the time of diagnosis are responsible for this phenomenon. Methods: Using Medicare data linked to the Health and Retirement Study (1992–2012), we performed a joint analysis of trends in CI and ND to test our hypothesis. Results: We identified two major contributors to the divergent directions in CI and ND trends: reductions in …disease severity explained more than 60% of the differences between CI and ND prevalence over the study period; the remaining 40% was explained by a decrease in the fraction of undiagnosed individuals. Discussion: Improvements in the diagnoses of ND diseases were a major contributor to reported trends in ND and CI. Recent forecasts of CI and ND trends in the U.S. may be overly pessimistic. Show more

Keywords: Alzheimer’s disease, Ascertainment, cognitive impairment, disease prevalence, Health and Retirement Study (HRS), Medicare, neurocognitive disorders, severity, Telephone Interview for Cognitive Status (TICS), time trends, underdiagnosis

DOI: 10.3233/JAD-180060

Citation: Journal of Alzheimer's Disease, vol. 64, no. 1, pp. 137-148, 2018

Authors: Wang, Qi | Guo, Lei | Thompson, Paul M. | Jack Jr., Clifford R. | Dodge, Hiroko | Zhan, Liang | Zhou, Jiayu | for the Alzheimer’s Disease Neuroimaging Initiative and National Alzheimer’s Coordinating Center

Article Type: Research Article

Abstract: T1-weighted MRI has been extensively used to extract imaging biomarkers and build classification models for differentiating Alzheimer’s disease (AD) patients from healthy controls, but only recently have brain connectome networks derived from diffusion-weighted MRI been used to model AD progression and various stages of disease such as mild cognitive impairment (MCI). MCI, as a possible prodromal stage of AD, has gained intense interest recently, since it may be used to assess risk factors for AD. Little work has been done to combine information from both white matter and gray matter, and it is unknown how much classification power the diffusion-weighted …MRI-derived structural connectome could provide beyond information available from T1-weighted MRI. In this paper, we focused on investigating whether diffusion-weighted MRI-derived structural connectome can improve differentiating healthy controls subjects from those with MCI. Specifically, we proposed a novel feature-ranking method to build classification models using the most highly ranked feature variables to classify MCI with healthy controls. We verified our method on two independent cohorts including the second stage of Alzheimer’s Disease Neuroimaging Initiative (ADNI2) database and the National Alzheimer’s Coordinating Center (NACC) database. Our results indicated that 1) diffusion-weighted MRI-derived structural connectome can complement T1-weighted MRI in the classification task; 2) the feature-rank method is effective because of the identified consistent T1-weighted MRI and network feature variables on ADNI2 and NACC. Furthermore, by comparing the top-ranked feature variables from ADNI2, NACC, and combined dataset, we concluded that cross-validation using independent cohorts is necessary and highly recommended. Show more

Keywords: Alzheimer’s disease, brain network, diffusion MRI, feature extraction, mild cognitive impairment, multiple cohorts

DOI: 10.3233/JAD-171048

Citation: Journal of Alzheimer's Disease, vol. 64, no. 1, pp. 149-169, 2018

Authors: Leinonen, Ville | Rauramaa, Tuomas | Johansson, Jarkko | Bottelbergs, Astrid | Tesseur, Ina | van der Ark, Peter | Pemberton, Darrel | Koivisto, Anne M. | Jääskeläinen, Juha E. | Hiltunen, Mikko | Herukka, Sanna-Kaisa | Blennow, Kaj | Zetterberg, Henrik | Jokinen, Pekka | Rokka, Johanna | Helin, Semi | Haaparanta-Solin, Merja | Solin, Olof | Okamura, Nobuyuki | Kolb, Hartmuth C. | Rinne, Juha O.

Article Type: Research Article

Abstract: Background: Detection of pathological tau aggregates could facilitate clinical diagnosis of Alzheimer’s disease (AD) and monitor drug effects in clinical trials. S -[18 F]THK-5117 could be a potential tracer to detect pathological tau deposits in brain. However, no previous study have correlated S -[18 F]THK-5117 uptake in PET with brain biopsy verified tau pathology in vivo . Objective: Here we aim to evaluate the association between cerebrospinal fluid (CSF) AD biomarkers, S -[18 F]THK-5117, and [11 C]PIB PET against tau and amyloid lesions in brain biopsy. Methods: Fourteen patients with idiopathic normal pressure hydrocephalus (iNPH) with …previous shunt surgery including right frontal cortical brain biopsy and CSF Aβ1 - 42 , total tau, and P-tau181 measures, underwent brain MRI, [11 C]PIB PET, and S -[18 F]THK-5117 PET imaging. Results: Seven patients had amyloid-β (Aβ, 4G8) plaques, two both Aβ and phosphorylated tau (Pτ , AT8) and one only Pτ in biopsy. As expected, increased brain biopsy Aβ was well associated with higher [11 C]PIB uptake in PET. However, S -[18 F]THK-5117 uptake did not show any statistically significant correlation with either brain biopsy Pτ or CSF P-tau181 or total tau. Conclusions: S -[18 F]THK-5117 lacked clear association with neuropathologically verified tau pathology in brain biopsy probably, at least partially, due to off-target binding. Further studies with larger samples of patients with different tau tracers are urgently needed. The detection of simultaneous Aβ and tau pathology in iNPH is important since that may indicate poorer and especially shorter response for CSF shunt surgery compared with no pathology. Show more

Keywords: Alzheimer’s disease, amyloid-beta, idiopathic normal pressure hydrocephalus, neuropathology, PIB, positron emission tomography, PTHK-5117, tau, contstartabstract

DOI: 10.3233/JAD-180071

Citation: Journal of Alzheimer's Disease, vol. 64, no. 1, pp. 171-179, 2018

Authors: Kuźma, Elżbieta | Hannon, Eilis | Zhou, Ang | Lourida, Ilianna | Bethel, Alison | Levine, Deborah A. | Lunnon, Katie | Thompson-Coon, Jo | Hyppönen, Elina | Llewellyn, David J.

Article Type: Research Article

Abstract: Background: Numerous risk factors for dementia are well established, though the causal nature of these associations remains unclear. Objective: To systematically review Mendelian randomization (MR) studies investigating causal relationships between risk factors and global cognitive function or dementia. Methods: We searched five databases from inception to February 2017 and conducted citation searches including MR studies investigating the association between any risk factor and global cognitive function, all-cause dementia or dementia subtypes. Two reviewers independently assessed titles and abstracts, full-texts, and study quality. Results: We included 18 MR studies investigating education, lifestyle factors, cardiovascular factors …and related biomarkers, diabetes related and other endocrine factors, and telomere length. Studies were of predominantly good quality, however eight received low ratings for sample size and statistical power. The most convincing causal evidence was found for an association of shorter telomeres with increased risk of Alzheimer’s disease (AD). Causal evidence was weaker for smoking quantity, vitamin D, homocysteine, systolic blood pressure, fasting glucose, insulin sensitivity, and high-density lipoprotein cholesterol. Well-replicated associations were not present for most exposures and we cannot fully discount survival and diagnostic bias, or the potential for pleiotropic effects. Conclusions: Genetic evidence supported a causal association between telomere length and AD, whereas limited evidence for other risk factors was largely inconclusive with tentative evidence for smoking quantity, vitamin D, homocysteine, and selected metabolic markers. The lack of stronger evidence for other risk factors may reflect insufficient statistical power. Larger well-designed MR studies would therefore help establish the causal status of these dementia risk factors. Show more

Keywords: Alzheimer’s disease, cognition, dementia, instrumental variable, Mendelian randomization, risk factor

DOI: 10.3233/JAD-180013

Citation: Journal of Alzheimer's Disease, vol. 64, no. 1, pp. 181-193, 2018

Authors: Thomas, Kelsey R. | Edmonds, Emily C. | Eppig, Joel | Salmon, David P. | Bondi, Mark W. | Alzheimer’s Disease Neuroimaging Initiative

Article Type: Research Article

Abstract: Background: We previously operationally-defined subtle cognitive decline (SCD) in preclinical Alzheimer’s disease (AD) using total scores on neuropsychological (NP) tests. NP process scores (i.e., provide information about how a total NP score was achieved) may be a useful tool for identifying early cognitive inefficiencies prior to objective impairment seen in mild cognitive impairment (MCI) and dementia. Objective: We aimed to integrate process scores into the SCD definition to identify stages of SCD and improve early detection of those at risk for decline. Methods: Cognitively “normal” participants from the Alzheimer’s Disease Neuroimaging Initiative were classified as …“early” SCD (E-SCD; >1 SD below norm-adjusted mean on 2 process scores or on 1 process score plus 1 NP total score), “late” SCD (L-SCD; existing SCD criteria of >1 SD below norm-adjusted mean on 2 NP total scores in different domains), or “no SCD” (NC). Process scores considered in the SCD criteria were word-list intrusion errors, retroactive interference, and learning slope. Cerebrospinal fluid AD biomarkers were used to examine pathologic burden across groups. Results: E-SCD and L-SCD progressed to MCI 2.5–3.4 times faster than the NC group. Survival curves for E-SCD and L-SCD converged at 7-8 years after baseline. The combined (E-SCD+L-SCD) group had improved sensitivity to detect progression to MCI relative to L-SCD only. AD biomarker positivity increased across NC, SCD, and MCI groups. Conclusions: Process scores can be integrated into the SCD criteria to allow for increased sensitivity and earlier identification of cognitively normal older adults at risk for decline prior to frank impairment on NP total scores. Show more

Keywords: Alzheimer’s disease, dementia, early detection, mild cognitive impairment, neuropsychology, subtle cognitive decline

DOI: 10.3233/JAD-180229

Citation: Journal of Alzheimer's Disease, vol. 64, no. 1, pp. 195-204, 2018

Authors: Li, Chuanzhou | Götz, Jürgen

Article Type: Research Article

Abstract: The protein tyrosine kinase Pyk2 is encoded by PTK2B , a novel Alzheimer’s disease (AD) susceptibility variant, with the PTK2B risk allele being associated with increased mRNA levels, suggestive of increased Pyk2 levels. However, the role of Pyk2, a member of the focal adhesion kinase (FAK) family, in AD pathology and its regulation are largely unknown. To address this, we generated mice with neuronal expression of human Pyk2. Because we had previously reported an association of Pyk2 and hyperphosphorylated tau (a hallmark feature of AD) in human tau transgenic pR5 mice, we also generated Pyk2/tau double-transgenic mice, which exhibit …increased tyrosine phosphorylation and accumulation of tau. We further demonstrated that Pyk2 colocalizes, interacts with, and phosphorylates tau in vivo and in vitro . Importantly, although Pyk2 interacts with the established tyrosine-directed tau kinase Fyn, we identified an increased Pyk2 activity in mice which constitutively overexpress Fyn (FynCA), and a decreased activity in mice lacking Fyn (FynKO). Together, our study reveals a novel role for Pyk2 as a direct tyrosine kinase of tau that is active downstream of Fyn. Our analysis may enhance the understanding of how the PTK2B risk allele contributes to tauopathy. Show more

Keywords: Alzheimer’s disease, Fyn, Pyk2, tau, tau phosphorylation, tyrosine kinase

DOI: 10.3233/JAD-180054

Citation: Journal of Alzheimer's Disease, vol. 64, no. 1, pp. 205-221, 2018

Authors: Hoffman, Alexander | Taleski, Goce | Qian, Helena | Wasek, Brandi | Arning, Erland | Bottiglieri, Teodoro | Sontag, Jean-Marie | Sontag, Estelle

Article Type: Research Article

Abstract: Deregulation of the amyloid-β protein precursor (AβPP) plays a critical role in the neurodegenerative cascade of Alzheimer’s disease (AD). Significantly, common functional polymorphisms in the 5,10-methylenetetrahydrofolate reductase (MTHFR ) gene are a risk factor for the development of late-onset AD. Reduced MTHFR activity is associated with alterations in folate and homocysteine metabolism. Here, we first show that in young MTHFR knockout mice, mild and severe MTHFR deficiency markedly increase cortical and hippocampal AβPP phosphorylation at the regulatory Thr668 site. However, the hippocampus is especially vulnerable to the effects of aging and mild MTHFR deficiency. Notably, the effects of severe …MTHFR deficiency in young mice are recapitulated by prolonged dietary folate deficiency in old mice, which leads to regional brain accumulation of cystathionine due to impaired methylation of homocysteine. The incremental AβPP phosphorylation at Thr668 mediated by severe genetic-or diet-induced impairment of the folate cycle correlates with enhanced accumulation of demethylated protein phosphatase 2A (PP2A), and activation of glycogen synthase kinase-3β (GSK-3β). Lastly, we show that severe disturbances in folate metabolism can also affect AβPP expression levels in a brain region specific manner. Together our findings identify a novel link between genetic MTHFR deficiency, activation of GSK-3β, demethylation of PP2A, and enhanced phosphorylation of AβPP at Thr668, which is known to critically influence neuronal AβPP function and pathological amyloidogenic processing. Deregulation of AβPP provides a novel mechanism by which common human MTHFR polymorphisms may interact with dietary folate deficiency to alter neuronal homeostasis and increase the risk for sporadic AD. Show more

Keywords: Alzheimer’s disease, amyloid-β protein precursor, cystathionine, folate, glycogen synthase kinase 3β, methylation, MTHFR, phosphorylation, protein phosphatase 2A

DOI: 10.3233/JAD-180032

Citation: Journal of Alzheimer's Disease, vol. 64, no. 1, pp. 223-237, 2018

Authors: Lysen, Thom S. | Wolters, Frank J. | Luik, Annemarie I. | Ikram, M. Kamran | Tiemeier, Henning | Ikram, M. Arfan

Article Type: Research Article

Abstract: Background: Poor sleep is related to higher dementia risk, but this association is more equivocal for subjective sleep quality specifically. This study investigates the link between subjective sleep quality and dementia risk in the general population. Objective: To study the role of subjective sleep quality in the risk of dementia in the general population. Methods: In the prospective population-based Rotterdam Study, 4,835 persons (mean age 72 years, 58% women) underwent a home interview (2002– 2006) that included the validated Pittsburgh Sleep Quality Index (PSQI) to assess sleep quality. Participants were followed until 2015 for incident dementia, …through in-person screening and continuous monitoring of medical records. We used Cox regression models to associate sleep quality with dementia risk, adjusting for age, sex, education, smoking, employment, coffee consumption, alcohol consumption, activities of daily living, cardiovascular risk factors, anxiety, depressive symptoms, cognition, and snoring. Results: During 41,385 person-years (8.5 years mean), 420 participants developed dementia, of whom 320 Alzheimer’s disease (AD). Poorer subjective sleep quality was not associated with the risk of all-cause dementia (hazard ratio [HR] per SD increase in PSQI score: 0.91, 95% CI 0.82– 1.02) or AD (HR 0.92, 95% CI 0.81– 1.05). Similarly, individual components of the PSQI were also not associated with dementia. Several sensitivity analyses, i.e., excluding last years of the follow-up time duration or restricting to those with best MMSE scores at baseline, did not reveal subgroups with increased risks. Conclusion: In this study, we found no association of poor subjective sleep quality with higher risk of dementia. Show more

Keywords: Alzheimer’s disease, cognition, dementia, epidemiology, sleep

DOI: 10.3233/JAD-180055

Citation: Journal of Alzheimer's Disease, vol. 64, no. 1, pp. 239-247, 2018

Authors: Durani, Lina Wati | Hamezah, Hamizah Shahirah | Ibrahim, Nor Faeizah | Yanagisawa, Daijiro | Nasaruddin, Muhammad Luqman | Mori, Masaki | Azizan, Kamalrul Azlan | Damanhuri, Hanafi Ahmad | Makpol, Suzana | Wan Ngah, Wan Zurinah | Tooyama, Ikuo

Article Type: Research Article

Abstract: We have recently shown that the tocotrienol-rich fraction (TRF) of palm oil, a mixture of vitamin E analogs, improves amyloid pathology in vitro and in vivo . However, precise mechanisms remain unknown. In this study, we examined the effects of long-term (10 months) TRF treatment on behavioral impairments and brain metabolites in (15 months old) AβPP/PS1 double transgenic (Tg) Alzheimer’s disease (AD) mice. The open field test, Morris water maze, and novel object recognition tasks revealed improved exploratory activity, spatial learning, and recognition memory, respectively, in TRF-treated Tg mice. Brain metabolite profiling of wild-type and Tg mice treated with …and without TRF was performed using ultrahigh performance liquid chromatography (UHPLC) coupled to high-resolution accurate mass (HRAM)-orbitrap tandem mass spectrometry (MS/MS). Metabolic pathway analysis found perturbed metabolic pathways that linked to AD. TRF treatment partly ameliorated metabolic perturbations in Tg mouse hippocampus. The mechanism of this pre-emptive activity may occur via modulation of metabolic pathways dependent on Aβ interaction or independent of Aβ interaction. Show more

Keywords: Alzheimer’s disease, behavioral impairments, metabolomics, pre-emptive medicine, tocotrienol

DOI: 10.3233/JAD-170880

Citation: Journal of Alzheimer's Disease, vol. 64, no. 1, pp. 249-267, 2018

Authors: Saari, Toni | Hallikainen, Ilona | Hänninen, Tuomo | Räty, Hannu | Koivisto, Anne

Article Type: Research Article

Abstract: Background: Impaired cognition and activities of daily living (ADL) are core symptoms of Alzheimer’s disease (AD), but their relationship is unclear. Objectives: To explore relationships between cognitive domains and functional ability during 5-year follow-up in persons with AD. Methods: We analyzed ALSOVA study data from 236 individuals with very mild or mild AD at baseline. The CERAD Neuropsychological Battery (CERAD-NB) was used as a cognitive measure and Alzheimer’s Disease Cooperative Study ADL (ADCS-ADL) as a functional measure, analyzing the IADL and BADL sub-scores separately. Annual regression models and linear mixed-effect models (LMMs) covering a 5-year follow-up …period were used. Results: Annually, the CERAD-NB total and especially Verbal Fluency, Clock Drawing, and Constructional Praxis were associated with the total ADCS-ADL and IADL scores increasingly yet modestly, and to a lesser extent the BADL score. In the LMMs, the same measures and MMSE were associated with ADL. Conclusion: Measures of executive function and visuoconstructive skills appear to be associated with caregiver-interview based ADL measure during the progression of AD. Show more

Keywords: Activities of daily living, Alzheimer’s disease, cognition, dementia, follow-up study, functional ability

DOI: 10.3233/JAD-171059

Citation: Journal of Alzheimer's Disease, vol. 64, no. 1, pp. 269-279, 2018

Authors: Vassilaki, Maria | Aakre, Jeremiah A. | Syrjanen, Jeremy A. | Mielke, Michelle M. | Geda, Yonas E. | Kremers, Walter K. | Machulda, Mary M. | Alhurani, Rabe E. | Staubo, Sara C. | Knopman, David S. | Petersen, Ronald C. | Lowe, Val J. | Jack Jr, Clifford R. | Roberts, Rosebud O.

Article Type: Research Article

Abstract: Background: There is accumulating evidence suggesting that diet may play a role in preventing or delaying cognitive decline and dementia, but the underlying biological mechanisms are not well understood. Objectives: To examine the cross-sectional associations of the Mediterranean diet (MeDi) and its components with 11 C-PiB-PET scan measures of amyloid-β (Aβ) deposition. Methods: The study consisted of 278 Mayo Clinic Study of Aging participants 70+ years old, who were cognitively unimpaired (CU) at the time of completion of the Food Frequency Questionnaire (FFQ) and when they underwent PET imaging. Adherence to the MeDi was assessed by …computing the MeDi score for each participant. All scans were performed after the FFQ completion; median [IQR] time between FFQ and Aβ PET was 3.5 (1.4) years. Z-scores were created for component, macro- and micronutrients measured. Linear and logistic regression models were adjusted for age, sex, education, apolipoprotein E (APOE) ɛ 4 allele carrier status, time interval between the FFQ completion and PET scan, and total energy intake. Results: Participants’ median age at FFQ was 77.7 years (55.8% men; 26.6% with an APOE ɛ 4 allele). Higher MeDi score (linear regression slope (beta):–0.035, p = 0.012; per standard deviation increase), vegetable intake (beta:–0.043, p = 0.002), intake of vitamin A (beta:–0.041, p = 0.003) or β-carotene (beta: –0.039, p = 0.005) from food sources and moderate alcohol consumption (beta: –0.074, p = 0.03) were associated with lower 11 C-PiB standardized uptake value ratio. Conclusion: Findings are consistent with previous studies suggesting that higher adherence to a MeDi pattern and higher vegetable consumption are associated with better neuroimaging biomarker profile. Prospective studies are needed to validate current findings. Show more

Keywords: Amyloid, cross-sectional study, Mediterranean diet, vegetables

DOI: 10.3233/JAD-171121

Citation: Journal of Alzheimer's Disease, vol. 64, no. 1, pp. 281-290, 2018

Authors: Li, Haitao | Jia, Jianping | Wang, Wei | Hou, Tingting | Tian, , Yuanruhua | Wu, Qiaoqi | Xu, Lingzhi | Wei, Yiping | Wang, Xiu

Article Type: Research Article

Abstract: Accumulating evidence has demonstrated that mitochondrial dysfunction is a prominent early event in the progression of Alzheimer’s disease (AD). Whether protecting mitochondrial function can reduce amyloid-β oligomer (AβO)-induced neurotoxicity in PS1V97L transgenic mice remains unknown. In this study, we examined the possible protective effects of honokiol (HKL) on mitochondrial dysfunction induced by AβOs in neurons, and cognitive function in AD PS1V97L transgenic mice. We determined that HKL increased mitochondrial sirtuin 3 (SIRT3) expression levels and activity, which in turn markedly improved ATP production and weakened mitochondrial reactive oxygen species production. We demonstrated that the enhanced energy metabolism and attenuated …oxidative stress of HKL restores AβO-mediated mitochondrial dysfunction in vitro and in vivo . Consequently, memory deficits in the PS1V97L transgenic mice were rescued by HKL in the early stages. These results suggest that HKL has therapeutic potential for delaying the onset of AD symptoms by alleviating mitochondrial impairment and increasing hyperactivation of SIRT3 in the pathogenesis of preclinical AD. Show more

Keywords: Alzheimer’s disease, amyloid-β protein, cognitive dysfunction, mitochondria, sirtuin 3 (SIRT3)

DOI: 10.3233/JAD-180126

Citation: Journal of Alzheimer's Disease, vol. 64, no. 1, pp. 291-302, 2018

Authors: Baranowski, Bradley J. | Hayward, Grant C. | Fajardo, Val A. | MacPherson, Rebecca E.K.

Article Type: Research Article

Abstract: Background/Objective: To compare Alzheimer’s disease (AD) mortality rates and coinciding risk factors in rural and urban Texas populations. Methods: 155 Texas counties were divided into 73 rural and 82 urban areas using the U.S. Census Bureau definition of rurality. Changes in age-adjusted AD mortality across these counties were calculated using a 7-year aggregation model from 2000–2006 and 2009–2015. Data pertaining to gender, race, education, obesity, diabetes, physical inactivity, and lithium concentrations in tap water were also collected from readily available databases. Results: Change in age-adjusted AD mortality was higher in rural counties (9.5±1.4) versus urban (5.9±1.1) …over the time period examined. Similarly, obesity (30.2±0.2% ), diabetes (11.0±0.1% ), and physical inactivity (29.4±0.2% ) levels were significantly higher in rural populations compared to urban (29.1±0.2%, 9.7±0.1%, and 26.7±0.3, respectively). In contrast, the percent of population with some college education (40.1±0.7% ) was lower compared to urban (29.4±0.2% and 44.4±0.9%, respectively). Lithium concentrations in tap water was significantly lower in rural counties compared to urban (63.3±8.2 and 33.4±4.7μg/L, respectively). No significant differences were observed among females and however, we did find significant differences in the percent of African American and Hispanics. Correlational analysis uncovered a negative association between education status and AD mortality over time (r  = –0.17). Further analysis controlling for physical inactivity, education, and trace lithium concentrations results in a loss of statistical significance. Conclusions: AD mortality rates are higher in rural counties when compared to urban counties, and this may be linked to greater physical inactivity, obesity, and diabetes, as well as lower trace lithium levels in tap water. Show more

Keywords: Dementia, insulin, metabolic disorders, physical activity

DOI: 10.3233/JAD-171150

Citation: Journal of Alzheimer's Disease, vol. 64, no. 1, pp. 303-308, 2018

Authors: Du, Yehong | Fu, Min | Wang, Yu Tian | Dong, Zhifang

Article Type: Research Article

Abstract: Alzheimer’s disease (AD) is a neurodegenerative disease characterized by the deposition of amyloid-β peptides (Aβ). Aβ accumulation leads to the formation of neurofibrillary tangles, inflammation, axonal injury, synapse loss, and neuronal apoptosis. Thus, reducing Aβ levels should exert a neuroprotective effect against AD. Ginsenoside Rf, an extract from Panax notoginseng, has potent anti-fatigue, anti-nociception, anti-oxidation, and anti-inflammation properties. However, it is unclear whether ginsenoside Rf is effective in the treatment of AD. Here, we reported that ginsenoside Rf could significantly attenuate Aβ-induced apoptosis in N2A cells, as reflected by a dramatic increase in mitochondrial membrane potential and decrease in Ca2 …+ concentration, reactive oxygen species, and active caspase-3 expression. Meanwhile, ginsenoside Rf could alleviate the Aβ-induced inflammation reaction, such as the decrease of interferon-gamma (IFN-γ ) and active caspase-1 expression and the increase of interleukin-13. Furthermore, we also found that Rf is able to accelerate Aβ clearance and subsequently reduces Aβ level in N2A cells stably transfected with human Swedish mutant APP695 (N2A-APP). More importantly, daily Rf treatment (20 mg/kg, i.p.) throughout the experiment dramatically improved spatial learning and memory in Aβ42 -induced mouse model of AD. Taken together, these results indicate that ginsenoside Rf may decrease Aβ-induced neurotoxicity and memory decline via anti-inflammatory response during AD development, suggesting that Rf may be a potential therapeutic agent for treating AD. Show more

Keywords: Alzheimer’s disease, amyloid-β, anti-inflammation, ginsenoside Rf, learning, memory

DOI: 10.3233/JAD-180251

Citation: Journal of Alzheimer's Disease, vol. 64, no. 1, pp. 309-322, 2018

Authors: Shea, Yat-Fung | Barker, Warren | Greig-Gusto, Maria T. | Loewenstein, David A. | Duara, Ranjan | DeKosky, Steven T.

Article Type: Research Article

Abstract: Background: Patients with cognitive impairment or dementias of uncertain etiology are frequently referred to a memory disorders specialty clinic. The impact of and role for amyloid PET imaging (Aβ -PET) may be most appropriate in this clinical setting. Objective: The primary objective of this study was to perform a systematic review and meta-analysis of the impact of Aβ -PET on etiological diagnosis and clinical management in the memory clinic setting. Methods: A search of the literature on the impact of Aβ -PET in the memory clinic setting between 1 January 2004 and 12 …February 2018 was conducted. Meta-analysis using a random effects model was performed to determine the pooled estimate of the impact of Aβ -PET in the changes of diagnoses and changes in management plan. Results: After rigorous review, results from 13 studies were extracted, involving 1,489 patients. Meta-analysis revealed a pooled effect of change in diagnoses of 35.2% (95% CI 24.6–47.5). Sub-analyses showed that the pooled effect in change in diagnoses if Aβ -PET was used under the appropriate use criteria (AUC) or non-AUC criteria were 47.8% (95% CI 25.9–70.5) and 29.6% (95% CI: 21.5–39.3), respectively. The pooled effect of a change of diagnosis from Alzheimer’s disease (AD) to non-AD and from non-AD to AD were 22.7% (95% CI: 17.1–29.5) and 25.6% (95% CI: 17.6–35.8), respectively. The pooled effect leading to a change of management was 59.6% (95% CI 39.4–77.0). Conclusions: Aβ -PET has a highly significant impact on both changes in diagnosis and management among patients being seen at a specialty memory clinic. Show more

Keywords: Alzheimer’s disease, amyloid imaging, diagnosis, management, memory clinic, positron emission tomography

DOI: 10.3233/JAD-180239

Citation: Journal of Alzheimer's Disease, vol. 64, no. 1, pp. 323-335, 2018