Volume 52, Number 2, 2016

Pages 391-402

Canhong Yang, Xiaomin Huang, Xiaoyu Huang, Hantao Mai, Jie Li, Tao Jiang, Xiaofeng Wang, Tianming Lü (Handling Associate Editor: Gary Arendash)
Aquaporin-4 and Alzheimer’s Disease
Abstract: Alzheimer’s disease (AD) is the most common form of dementia. Although the pathogenesis of AD remains unclear, AD is thought to result from an imbalance in the production and clearance of amyloid-β protein (Aβ). Aquaporin-4 (AQP4) is the major aquaporin in the mammalian brain, is mostly expressed on astrocytic endfeet, and functions as a water transporter. However, the distribution and expression of AQP4 are altered in both AD clinical populations and animal models. Recent studies have revealed that AQP4 is important to the clearance of Aβ in brain via lymphatic clearance, transcytotic delivery, and glial degradation, as well as to the synaptic function. Thus, AQP4 likely plays an important role in the pathogenesis of AD. Further studies would provide new targets for prevention, ultimately leading to improved treatment options for AD.

Pages 403-416

Inmaculada Cuchillo-Ibañez, Valeria Balmaceda, Trinidad Mata-Balaguer, Inmaculada López-Font, Javier Sáez-Valero
Reelin in Alzheimer’s Disease, Increased Levels but Impaired Signaling: When More is Less
Abstract: In the continuing search for proteins that play a role in Alzheimer’s disease (AD) and that are related to the pathological hallmarks, those that influence cognitive function and that constitute potential therapeutic targets deserve special interest. Reelin is a signaling protein that is involved in a cascade of cytoplasmic events that control tau phosphorylation and that regulate synaptic neurotransmission, plasticity, and memory. Both Reelin expression and glycosylation are modulated by amyloid-β (Aβ), suggesting that the activity of Reelin could be affected in AD and hence, its possible influence on this pathology should be taken into consideration. The levels of Reelin in the brain of AD patients appear to be altered and interestingly, disrupted Reelin signaling is associated with increased tau phosphorylation as well as with amyloid-β protein precursor processing. We discuss here the somewhat contradictory data regarding Reelin levels in AD and we evaluate the processing of the Reelin receptor, ApoER2, and other downstream events, such as the phosphorylation of the intracellular adapter Dab1. Together with brain Reelin levels, these changes may represent a relevant read-out of Reelin signaling in the human brain.

Pages 417-420
Short Communication

Fabrizio Piazza, Bengt Winblad
Amyloid-Related Imaging Abnormalities (ARIA) in Immunotherapy Trials for Alzheimer’s Disease: Need for Prognostic Biomarkers?
Abstract: At the 8th International Conference on Clinical Trials in Alzheimer’s Disease held November 5-7, 2015 in Barcelona, Spain, promising data were presented on two candidate Alzheimer’s disease immunotherapeutic agents, gantenerumab and aducanumab. Trial results demonstrated that the implementation of cerebrospinal fluid and Aβ-PET biomarkers improves trial enrichment and outcome, which has led to a change in targeting strategy as clinical trials would be conducted with earlier, even presymptomatic, stages of the disease. Promising findings of outcomes, as measured by Aβ-PET and cerebrospinal fluid tau and P-tau, were, nevertheless, associated with antibody dose-dependent increased risk of severe adverse effects, specifically amyloid-related imaging abnormalities (ARIA). Aducanumab was associated with concomitant time-, dose-, and APOE-related incidence of ARIA in more than one-half of the patients within the high-dose arm. The future challenge will thus be to find biomarkers more favorably balanced between effective dosing of antibody to remove Aβ versus dosing to limit deleterious side effects. Interest was shown by Roche and Biogen, which promoted high-dose phase 3 trials. However, this generated some concerns related to a reasonable expected further increase in the incidence of severe side effects. What has been learned is challenging primary industry strategies for following-up and monitoring safety and effectiveness of anti-Aβ antibodies in clinical trials. Here, we debate the issue of what is an acceptable balance of treatment side effects, i.e., therapeutic-induced ARIA, versus the positive prospects. Indeed, implementation of biomarkers for ARIA might increase value and reduce waste in the design of immunotherapy trials of Alzheimer’s disease.

Pages 421-431
Mohamad El Haj, Dimitrios Kapogiannis, Pascal Antoine
Phenomenological Reliving and Visual Imagery During Autobiographical Recall in Alzheimer’s Disease
Abstract: Multiple studies have shown compromise of autobiographical memory and phenomenological reliving in Alzheimer’s disease (AD). We investigated various phenomenological features of autobiographical memory to determine their relative vulnerability in AD. To this aim, participants with early AD and cognitively normal older adult controls were asked to retrieve an autobiographical event and rate on a five-point scale metacognitive judgments (i.e., reliving, back in time, remembering, and realness), component processes (i.e., visual imagery, auditory imagery, language, and emotion), narrative properties (i.e., rehearsal and importance), and spatiotemporal specificity (i.e., spatial details and temporal details). AD participants showed lower general autobiographical recall than controls, and poorer reliving, travel in time, remembering, realness, visual imagery, auditory imagery, language, rehearsal, and spatial detail—a decrease that was especially pronounced for visual imagery. Yet, AD participants showed high rating for emotion and importance. Early AD seems to compromise many phenomenological features, especially visual imagery, but also seems to preserve some other features.

Pages 433-449
Trine Schütt, Lone Helboe, Lars Østergaard Pedersen, Gunhild Waldemar, Mette Berendt, Jan Torleif Pedersen (Handling Associate Editor: Elizabeth Head)
Dogs with Cognitive Dysfunction as a Spontaneous Model for Early Alzheimer’s Disease: A Translational Study of Neuropathological and Inflammatory Markers
Abstract: Aged companion dogs with canine cognitive dysfunction (CCD) spontaneously develop varying degrees of progressive cognitive decline and particular neuropathological features correspondent to the changes associated with Alzheimer’s disease (AD) in humans. The aim of the present study was to characterize certain aspects of neuropathology and inflammatory markers related to aging and CCD in dogs in comparison with human AD. Fifteen brains from aged dogs with normal cognitive function, mild cognitive impairment, or CCD were investigated and compared with two control brains from young dogs and brain sections from human AD subjects. The neuropathological investigations included evaluation of amyloid-β (Aβ) plaque deposition (N-terminally truncated and pyroglutamyl-modified Aβ included), tau pathology, and inflammatory markers in prefrontal cortex. Cortical Aβ deposition was found to be only of the diffuse subtype as no dense-core or neuritic plaques were found. The Aβ deposition followed a progressive pattern in four maturation stages. Accumulation of the Aβ peptide was also observed in the vessel walls. Both immunohistochemically and biochemically measured levels of Aβ pathology in prefrontal cortex showed a consistent positive correlation to age but not to cognitive deficit severity. No evidence of neurofibrillary tau pathology was found. The level of pro-inflammatory cytokines was generally low and showed no significant association to cognitive status. The findings of the present study support the senescent dog with spontaneous cognitive dysfunction as a valuable non-transgenic model for further investigations of the molecular events involved in the neurodegenerative processes associated with aging and early stage AD, especially the Aβ-related pathology.

Pages 451-462
Brandy L. Callahan, Martine Simard, Abderazzak Mouiha, François Rousseau, Robert Jr. Laforce, Carol Hudon (Handling Associate Editor: J. Lluís Conde-Sala)
Impact of Depressive Symptoms on Memory for Emotional Words in Mild Cognitive Impairment and Late-Life Depression
Abstract: Background: Amnestic mild cognitive impairment (aMCI) and late-life depression (LLD) are associated with increased risk of Alzheimer’s disease (AD). This is also true for aMCI with concomitant depressive symptoms (aMCI/D+), but few studies have investigated this syndrome. Objectives: We aimed to clarify the association between cognitive and depressive symptoms in individuals at risk for AD by examining episodic memory for emotional stimuli in aMCI, aMCI/D+, and LLD. Methods: Participants were 34 patients with aMCI, 20 patients with aMCI/D+, 19 patients with LLD, and 28 healthy elderly adults. In an implicit encoding task, participants rated the emotional valence of 12 positive, 12 negative, and 12 neutral words. Immediately and 20 minutes later, participants recalled as many words as possible. They were also asked to identify previously presented words during a yes/no recognition trial. Results: At immediate recall, aMCI participants displayed better recall of emotional words, particularly positive words. aMCI/D+ and control participants displayed better recall of positive and negative words compared to neutral words. LLD participants recalled more negative than neutral words. At delayed recall, emotional words were generally better-remembered than neutral words by all groups. At recognition, all subjects responded more liberally to emotional than to neutral words. Conclusion: We find that the type of emotional information remembered by aMCI patients at immediate recall depends on the presence or absence of depressive symptoms. These findings contribute to identifying sources of heterogeneity in individuals at risk for AD, and suggest that the cognitive profile of aMCI/D+ is different from that of aMCI and LLD. Future studies should systematically consider the presence of depressive symptoms in elderly at-risk individuals.

Pages 463-482
Francisco M. Torres-Cruz, Fanny Rodríguez-Cruz, Jaime Escobar-Herrera, Norma Barragán-Andrade, Gustavo Basurto-Islas, Daniela Ripova, Jesús Ávila, Francisco Garcia-Sierra
Expression of Tau Produces Aberrant Plasma Membrane Blebbing in Glial Cells Through RhoA-ROCK-Dependent F-Actin Remodeling
Abstract: Abnormal aggregation of Tau in glial cells has been reported in Alzheimer’s disease (AD) and other tauopathies; however, the pathological significance of these aggregates remains unsolved to date. In this study, we evaluated whether full-length Tau (Tau441) and its aspartic acid421-truncated Tau variant (Tau421) produce alterations in the normal organization of the cytoskeleton and plasma membrane (PM) when transiently expressed in cultured C6-glial cells. Forty-eight hours post-transfection, abnormal microtubule bundling was observed in the majority of the cells, which expressed either Tau441 or Tau421. Moreover, both variants of Tau produced extensive PM blebbing associated with cortical redistribution of filamentous actin (F-Actin). These effects were reverted when Tau-expressing cells were incubated with drugs that depolymerize F-Actin. In addition, when glial cells showing Tau-induced PM blebbing were incubated with inhibitors of the Rho-associated protein kinase (ROCK) signaling pathway, both formation of abnormal PM blebs and F-Actin remodeling were avoided. All of these effects were initiated upstream by abnormal Tau-induced microtubule bundling, which may release the microtubule-bound guanine nucleotide exchange factor-H1 (GEF-H1) into the cytoplasm in order to activate its major effector RhoA-GTPase. These results may represent a new mechanism of Tau toxicity in which Tau-induced microtubule bundling produces activation of the Rho-GTPase-ROCK pathway that in turn mediates the remodeling of cortical Actin and PM blebbing. In AD and other tauopathies, these Tau-induced abnormalities may occur and contribute to the impairment of glial activity.

Pages 483-495
Dan Zhu, Nan Yang, Yan-Yong Liu, Ji Zheng, Chao Ji, Ping-Ping Zuo (Handling Associate Editor: Russell Swerdlow)
M2 Macrophage Transplantation Ameliorates Cognitive Dysfunction in Amyloid-β-Treated Rats Through Regulation of Microglial Polarization
Abstract: Alzheimer’s disease (AD) is the most common neurodegenerative disorder in the elderly population. Neuroinflammation induced by amyloid-β (Aβ) aggregation is considered to be the critical factor underlying AD pathological mechanisms. Alternatively activated (M2) macrophages/microglia have been reported to have neuroprotective effects in neurodegenerative disease. In this study, we characterized the neuroprotective effects of M2 macrophage transplantation in AD model rats and investigated the underlying mechanisms. Intracerebroventricular injection of Aβ1-42 to rats was used to model AD and resulted in cognitive impairment, neuronal damage, and inflammatory changes in the brain microenvironment. We observed an increased interferon regulatory factor (IRF) 5/IRF4 ratio, resulting in greater production of classically activated (M1) versus M2 microglia. M2 macrophage transplantation attenuated inflammation in the brain, reversed Aβ1-42-induced changes in the IRF4-IRF5 ratio, drove endogenous microglial polarization toward the M2 phenotype, and ameliorated cognitive impairment. Nerve growth factor (NGF) treatment reduced the IRF5/IRF4 ratio and induced primary microglial polarization to the M2 phenotype in vitro; these effects were prevented by tyrosine Kinase Receptor A (TrkA) inhibition. M2 macrophage transplantation restored the balance of IRF4-IRF5 by affecting the expression of NGF and inflammatory cytokines in the brains of AD model rats. This drove microglial polarization to the M2 phenotype, promoted termination of neuroinflammation, and resulted in improved cognitive abilities.

Pages 497-507
Anne M. Koivisto, Mitja I. Kurki, Irina Alafuzoff, Anna Sutela, Jaana Rummukainen, Sakari Savolainen, Ritva Vanninen, Juha E. Jääskeläinen, Hilkka Soininen, Ville Leinonen
High Risk of Dementia in Ventricular Enlargement with Normal Pressure Hydrocephalus Related Symptoms
Abstract: Background: Differential diagnosis of ventricular enlargement with normal pressure hydrocephalus (NPH) related symptoms is challenging. Patients with enlarged ventricles often manifest cognitive deterioration but their long-term outcome is not well known. Objectives: We aim to evaluate long-term cognitive outcome in patients with enlarged ventricles and clinically suspected NPH. Methods: A neurologist and a neurosurgeon clinically evaluated 468 patients with enlarged ventricles and suspected NPH using radiological methods, intraventricular pressure monitoring, and frontal cortical brain biopsy. The neurologist confirmed final diagnoses after a median follow-up interval of 4.8 years. Results: Altogether, 232 patients (50%) with enlarged ventricles did not fulfill the criteria for shunt surgery. The incidence of dementia among patients with enlarged ventricles, and at least one NPH-related symptom with adequate follow-up data (n=446) was high, varying from 77 (iNPH, shunt responders) to 141/1000 person-years (non-shunted patients with enlarged ventricles). At the end of the follow-up, 59% of all these patients were demented. The demented population comprised 73% of non-shunted patients with enlarged ventricles, 63% of shunted iNPH patients that did not respond to treatment, and 46% of iNPH patients that were initially responsive to shunting. The most common cause of dementia was Alzheimer’s disease (n=94, 36%), followed by vascular dementia (n=68, 26%). Conclusions: One-half of patients with enlarged ventricles and clinically suspected NPH were not shunted after intraventricular pressure monitoring. Dementia caused by various neurodegenerative diseases was frequently seen in patients with ventricular enlargement. Thus, careful diagnostic evaluation in collaboration with neurologists and neurosurgeons is emphasized.

Pages 509-517
Katrin Jekel, Marinella Damian, Holger Storf, Lucrezia Hausner, Lutz Frölich
Development of a Proxy-Free Objective Assessment Tool of Instrumental Activities of Daily Living in Mild Cognitive Impairment Using Smart Home Technologies
Abstract: Background: The assessment of activities of daily living (ADL) is essential for dementia diagnostics. Even in mild cognitive impairment (MCI), subtle deficits in instrumental ADL (IADL) may occur and signal a higher risk of conversion to dementia. Thus, sensitive and reliable ADL assessment tools are important. Smart homes equipped with sensor technology and video cameras may provide a proxy-free assessment tool for the detection of IADL deficits. Objective: The aim of this paper is to investigate the potential of a smart home environment for the assessment of IADL in MCI. Method: The smart home consisted of a two-room flat equipped with activity sensors and video cameras. Participants with either MCI or healthy controls (HC) had to solve a standardized set of six tasks, e.g., meal preparation, telephone use, and finding objects in the flat. Results: MCI participants needed more time (1384 versus 938 seconds, p<0.001) and scored less total points (48 versus 57 points, p<0.001) while solving the tasks than HC. Analyzing the subtasks, intergroup differences were observed for making a phone call, operating the television, and retrieving objects. MCI participants showed more searching and task-irrelevant behavior than HC. Task performance was correlated with cognitive status and IADL questionnaires but not with participants’ age. Conclusion: This pilot study showed that smart home technologies offer the chance for an objective and ecologically valid assessment of IADL. It can be analyzed not only whether a task is successfully completed but also how it is completed. Future studies should concentrate on the development of automated detection of IADL deficits.

Pages 519-528
Olivia C. Küster, Jonas Kösel, Stephanie Spohn, Niklas Schurig, Hayrettin Tumani, Christine A. F. von Arnim, Ingo Uttner *These authors contributed equally to this work.
Cognitive Reserve in Alzheimer’s Dementia: Diagnostic Accuracy of a Testing-the-Limits Paradigm
Abstract: Individuals with higher cognitive reserve are more able to cope with pathological brain alterations, potentially due to the application of more efficient cognitive strategies. The extent to which an individual’s cognitive performance can be increased by advantageous conditions differs substantially between patients with Alzheimer’s dementia (AD) and healthy older adults and can be assessed with the Testing-the-Limits (TtL) approach. Thus, TtL has been proposed as a tool for the early diagnosis of AD. Here, we report the diagnostic accuracy of a memory TtL paradigm to discriminate between AD patients and controls. The TtL paradigm was administered to 57 patients with clinically diagnosed AD and 94 controls. It consisted of a pre-test condition, representing baseline cognitive performance, the presentation of an encoding strategy, and two subsequent post-test conditions, representing learning potential. Receiver operating characteristic (ROC) curves were analyzed for each condition in order to receive optimal cutoff points along with their sensitivity and specificity and to compare the diagnostic accuracy of the conditions. Differentiation between AD patients and controls, indicated by the area under the ROC curve, increased significantly for the TtL post-test and total error scores compared to the pre-test score. The combined error score in the two post-tests could differentiate between AD patients and controls with a sensitivity of 0.93 and a specificity of 0.80. The presented approach can be carried out in 25 minutes and thus constitutes a time- and cost-effective way to diagnose AD with high accuracy.

Pages 529-538
Megan Heffernan, Karen A. Mather, Jing Xu, Amelia A. Assareh, Nicole A. Kochan, Simone Reppermund, Brian Draper, Julian N. Trollor, Perminder Sachdev, Henry Brodaty (Handling Associate Editor: Israel Ampuero)
Alcohol Consumption and Incident Dementia: Evidence from the Sydney Memory and Ageing Study
Abstract: Alcohol consumption is a potentially modifiable risk factor for dementia, but the literature is not completely consistent. This inconsistency may be partly due to an interaction with the apolipoprotein E (APOE) genotype, an established risk factor for Alzheimer’s dementia. The aim of this study was to examine whether alcohol consumption is associated with incident dementia or decline in specific cognitive domains over 4 years, and if this effect is modified by APOE ε4 status. Non-demented community dwelling older adults (70-90 years) from an ongoing longitudinal study were assessed for cognitive impairment in attention/processing speed, language, executive function, visuospatial ability, and memory. Incident dementia was diagnosed according to DSM-IV criteria. Compared to those who did not drink in the previous 12 months, neither low consumption (HR 0.64 95% CI 0.3-1.4) or risky consumption (HR 0.58 95% CI 0.2-1.5) was associated with incident dementia. Carriers of the APOE ε4 allele were more likely to develop dementia, but there was no significant interaction with alcohol consumption.

Pages 539-559
Angela L. Jefferson, Katherine A. Gifford, Lealani Mae Y. Acosta, Susan P. Bell, Manus J. Donahue, L. Taylor Davis, JoAnn Gottlieb, Deepak K. Gupta, Timothy J. Hohman, Elizabeth M. Lane, David J. Libon, Lisa A. Mendes, Kevin Niswender, Kimberly R. Pechman, Swati Rane, Frederick L. Ruberg, Yan Ru Su, Henrik Zetterberg, Dandan Liu (Handling Associate Editor: Mark Bondi)
The Vanderbilt Memory & Aging Project: Study Design and Baseline Cohort Overview
Abstract: Background: Vascular health factors frequently co-occur with Alzheimer’s disease (AD). A better understanding of how systemic vascular and cerebrovascular health intersects with clinical and pathological AD may inform prevention and treatment opportunities. Objective: To establish the Vanderbilt Memory & Aging Project, a case-control longitudinal study investigating vascular health and brain aging, and describe baseline methodology and participant characteristics. Methods: From September 2012 to November 2014, 335 participants age 60-92 were enrolled, including 168 individuals with mild cognitive impairment (MCI, 73±8 years, 41% female) and 167 age-, sex-, and race-matched cognitively normal controls (NC, 72±7 years, 41% female). At baseline, participants completed a physical and frailty examination, fasting blood draw, neuropsychological assessment, echocardiogram, cardiac MRI, and brain MRI. A subset underwent 24-hour ambulatory blood pressure monitoring and lumbar puncture for cerebrospinal fluid (CSF) collection. Results: As designed, participant groups were comparable for age (p=0.31), sex (p=0.95), and race (p=0.65). MCI participants had greater Framingham Stroke Risk Profile scores (p=0.008), systolic blood pressure values (p=0.008), and history of left ventricular hypertrophy (p=0.04) than NC participants. As expected, MCI participants performed worse on all neuropsychological measures (p-values<0.001), were more likely to be APOE ε4 carriers (p=0.02), and had enhanced CSF biomarkers, including lower Aβ42 (p=0.02), higher total tau (p=0.004), and higher p-tau (p=0.02) compared to NC participants. Conclusion: Diverse sources of baseline and longitudinal data will provide rich opportunities to investigate pathways linking vascular and cerebrovascular health, clinical and pathological AD, and neurodegeneration contributing to novel strategies to delay or prevent cognitive decline.

Pages 561-572
Sarah Westwood, Emanuela Leoni, Abdul Hye, Steven Lynham, Mizanur R. Khondoker, Nicholas J. Ashton, Steven J. Kiddle, Alison L. Baird, Ricardo Sainz-Fuertes, Rufina Leung, John Graf, Cristina Tan Hehir, David Baker, Cristina Cereda, Chantal Bazenet, Malcolm Ward, Madhav Thambisetty, Simon Lovestone (Handling Associate Editor: Audrey Gabelle)
Blood-Based Biomarker Candidates of Cerebral Amyloid Using PiB PET in Non-Demented Elderly
Abstract: Increasingly, clinical trials for Alzheimer’s disease (AD) are being conducted earlier in the disease phase and with biomarker confirmation using in vivo amyloid PET imaging or CSF tau and Aβ measures to quantify pathology. However, making such a pre-clinical AD diagnosis is relatively costly and the screening failure rate is likely to be high. Having a blood-based marker that would reduce such costs and accelerate clinical trials through identifying potential participants with likely pre-clinical AD would be a substantial advance. In order to seek such a candidate biomarker, discovery phase proteomic analyses using 2DGE and gel-free LC-MS/MS for high and low molecular weight analytes were conducted on longitudinal plasma samples collected over a 12-year period from non-demented older individuals who exhibited a range of 11C-PiB PET measures of amyloid load. We then sought to extend our discovery findings by investigating whether our candidate biomarkers were also associated with brain amyloid burden in disease, in an independent cohort. Seven plasma proteins, including A2M, Apo-A1, and multiple complement proteins, were identified as pre-clinical biomarkers of amyloid burden and were consistent across three time points (p<0.05). Five of these proteins also correlated with brain amyloid measures at different stages of the disease (q<0.1). Here we show that it is possible to detect a plasma based biomarker signature indicative of AD pathology at a stage long before the onset of clinical disease manifestation. As in previous studies, acute phase reactants and inflammatory markers dominate this signature.

Pages 573-580
Daniela I. Hirni, Sasa L. Kivisaari, Sabine Krumm, Andreas U. Monsch, Manfred Berres, Fatma Oeksuez, Julia Reinhardt, Stephan Ulmer, Reto W. Kressig, Christoph Stippich, Kirsten I. Taylor
Neuropsychological Markers of Medial Perirhinal and Entorhinal Cortex Functioning are Impaired Twelve Years Preceding Diagnosis of Alzheimer’s Dementia
Abstract: Neurofibrillary pathology in Alzheimer’s dementia (AD) is associated with cognitive impairments and cortical thinning, and begins in medial perirhinal cortex (mPRC) before entering entorhinal cortex (ERC). Thus, mPRC dysfunction (e.g., semantic object memory impairments) may predate or accompany ERC (i.e., episodic memory) dysfunction in the preclinical course of typical AD. We developed formulae estimating mPRC and ERC integrity (i.e., cortical thickness) using common neuropsychological tests in 31 healthy individuals and 58 early AD patients. These formulae estimated the longitudinal courses of mPRC and ERC functioning in independent groups of 28 optimally healthy individuals who developed AD (NC-AD) over 2.8-13.4 years and 28 pairwise-matched, stable, healthy individuals (NC-NC). Mixed models demonstrated significantly worse NC-AD than NC-NC estimated mPRC and ERC functioning at the earliest observation, 12 years preceding diagnosis, and a significant decline 4 years preceding the AD diagnosis. These findings demonstrate that specific neuropsychological impairments occur early in the course of preclinical AD and that tasks measuring mPRC functioning may serve as additional, powerful markers of preclinical AD.

Pages 581-608
Esmaeil Ebrahimie*, Seyyed Hani Moussavi-Nik*, Morgan Newman*, Mark Van Der Hoek, Michael Lardelli (Handling Associate Editor: Francesco Amenta) *These authors contributed equally to this work.
The Zebrafish Equivalent of Alzheimer’s Disease-Associated PRESENILIN Isoform PS2V Regulates Inflammatory and Other Responses to Hypoxic Stress
Abstract: Dominant mutations in the PRESENILIN genes PSEN1 and PSEN2 cause familial Alzheimer’s disease (fAD) that usually shows onset before 65 years of age. In contrast, genetic variation at the PSEN1 and PSEN2 loci does not appear to contribute to risk for the sporadic, late onset form of the disease (sAD), leading to doubts that these genes play a role in the majority of AD cases. However, a truncated isoform of PSEN2, PS2V, is upregulated in sAD brains and is induced by hypoxia and high cholesterol intake. PS2V can increase γ-secretase activity and suppress the unfolded protein response (UPR), but detailed analysis of its function has been hindered by lack of a suitable, genetically manipulable animal model since mice and rats lack this PRESENILIN isoform. We recently showed that zebrafish possess an isoform, PS1IV, that is cognate to human PS2V. Using an antisense morpholino oligonucleotide, we can block specifically the induction of PS1IV that normally occurs under hypoxia. Here, we exploit this ability to identify gene regulatory networks that are modulated by PS1IV. When PS1IV is absent under hypoxia-like conditions, we observe changes in expression of genes controlling inflammation (particularly sAD-associated IL1B and CCR5), vascular development, the UPR, protein synthesis, calcium homeostasis, catecholamine biosynthesis, TOR signaling, and cell proliferation. Our results imply an important role for PS2V in sAD as a component of a pathological mechanism that includes hypoxia/oxidative stress and support investigation of the role of PS2V in other diseases, including schizophrenia, when these are implicated in the pathology.

Pages 609-617
Jochen René Thyrian, Tilly Eichler, Bernhard Michalowsky, Diana Wucherer, Melanie Reimann, Johannes Hertel, Steffen Richter, Adina Dreier, Wolfgang Hoffmann (Handling Associate Editor: Hélène Villars)
Community-Dwelling People Screened Positive for Dementia in Primary Care: A Comprehensive, Multivariate Descriptive Analysis Using Data from the DelpHi-Study
Abstract: Background: Efficient help and care for people with dementia (PWD) is dependent on knowledge about PWD in primary care. Objective: This analysis comprehensively describes community-dwelling PWD in primary care with respect to various dementia care specific variables. Methods: The analyses are based on baseline data of the ongoing general practitioner-based, randomized, controlled intervention trial DelpHi-MV (Dementia: life- and person-centered help). 6,838 patients were screened for dementia in 136 GP practices; 17.1% were screened positive, 54.4% of those agreed to participate and data could be assessed in n=516 subjects. We assessed age, sex, living situation, cognitive status, functional status, level of impairment, comorbidities, formal diagnosis of dementia, depression, neuropsychiatric symptoms, quality of life, utilization of medical support, and pharmacological therapy. Results: Concerning clinical-, dementia-, and health-related variables, the sample under examination was on average mildly cognitively and functionally impaired (MMSE, m=22.2; BADL, m=3.7). A level of care was assigned in 38.0%. Depression was identified in 15.4% and other frequent comorbidities were high blood pressure (83.3%), coronary heart diseases (37.1%), cerebrovascular diseases (22.3%), among others. In 48.6%, neuropsychiatric symptoms were present in a clinically relevant severity. Pharmacological treatment with antidementia medication was received by 25.8% and antidepressant medication by 14.0%. Utilization of services was generally low. Conclusion: The comprehensive description of people screened positive for dementia in primary care reveals a complex and unique population of patients. They are considerably underdiagnosed and in their majority mildly to moderately affected. More in-depth analyses are needed to study relations, associations and interactions between different variables.

Pages 619-629
Tilly Eichler, Wolfgang Hoffmann, Johannes Hertel, Steffen Richter, Diana Wucherer, Bernhard Michalowsky, Adina Dreier, Jochen René Thyrian (Handling Associate Editor: Roberto Monastero)
Living Alone with Dementia: Prevalence, Correlates, and the Utilization of Health and Nursing Care Services
Abstract: Background: Little is known about the proportion and the characteristics of community-dwelling people with dementia (PWD) living alone in Germany. Objectives: To analyze the prevalence of PWD living alone (with and without the support of an informal caregiver) and socio-demographical and clinical characteristics as well as health and nursing care utilization associated with living alone. Methods: DelpHi-MV (Dementia: life- and person-centered help in Mecklenburg-Western Pomerania) is a general practitioner-based, randomized controlled intervention trial. The present analyses are based on baseline data of 511 patients (≥70 years, community-dwelling) who had screened positive for dementia (DemTect < 9). Results: N=251 (51%) of the patients lived alone. PWD living alone were statistically significantly more often female, older, and more often widowed than those not living alone. About 9% of the patients (n=24) were not supported by any informal caregiver. Regarding the clinical variables (cognitive and functional impairment, depression, falls, number of drug-related problems, malnutrition, quality of life), there were no statistically significant group differences. Patients living alone utilized professional services such as home care, help with medication, home-delivered meals, or housekeeping assistance significantly more often. Multivariate analyses confirmed these findings. Conclusion: Our results reveal the high proportion of PWD living alone in Germany. PWD living alone did not seem to be at an increased health risk. Our findings indicate that living alone with dementia is possible. In order to ensure the sufficient provision of health and nursing care services for PWD living alone, providers should consider the present results for future planning.

Pages 631-639
Yaoming Zhai, Song Yin, Dongfeng Zhang (Handling Associate Editor: Paulo Caramelli)
Association between Antipsychotic Drugs and Mortality in Older Persons with Alzheimer's Disease: A Systematic Review and Meta-Analysis
Abstract: Antipsychotic drugs have been inconsistently associated with death risk of Alzheimer’s disease (AD) patients. Herein we review and quantitatively summarize the evidence from epidemiological studies. Pertinent studies were identified by searching PubMed and Cochrane Library Register of Controlled Trials through 20 December 2015. The DerSimonian and Laird random effect model was adopted as the pooling method. Twelve studies from nine articles with 11,463 participants were included. The pooled RR of observational studies was 1.36 (95% CI, 0.83-2.24; I2= 94.9%) for antipsychotic drugs users versus individuals who were not exposed to antipsychotic drugs. When the three studies that were key contributors to the high heterogeneity were excluded, the pooled RR was 2.08 (95% CI 1.39 to 3.13). The result of one double-blind randomized clinical trial indicated that antipsychotic drugs nearly doubled the risk of death in AD patients. In conclusion, there is no evidence of absence of association between antipsychotic drugs’ use with death risk of AD patients. Careful assessments of potential benefits and risks should be made before prescribing antipsychotics for treatment of psychosis symptoms and behavioral problems of AD patients.

Pages 641-649
Jean-Sébastien Vidal, Olivier Hanon, Benoît Funalot, Nadège Brunel, Cécile Viollet, Anne-Sophie Rigaud, Marie-Laure Seux, Yves le-Bouc, Jacques Epelbaum, Emmanuelle Duron
Low Serum Insulin-Like Growth Factor-I Predicts Cognitive Decline in Alzheimer’s Disease
Abstract: Background: The relationship between the insulin-like growth factor-I (IGF-I) system and Alzheimer’s disease (AD) is mostly based on transversal studies. It remains, however, to demonstrate whether IGF-I is associated with cognitive decline over time in AD. Objective: The objective of the study was to analyze the course of cognitive decline of AD subjects over a 24-month period in relation to serum IGF-I and insulin-like growth factor binding protein-3 (IGFBP-3) measured at baseline. Methods: Data are from the SIGAL follow-up study. IGF-I and IGFBP-3 were measured in AD subjects who performed a Mini-Mental State Examination (MMSE) every 6 months for 2 years. MMSE course was analyzed using a mixed model with random intercept and slope function. Results: Among the 200 AD participants, 146 (mean age=81.1 (standard deviation (SD)=5.9) years, 62.6% of women) had at least one follow-up visit. Mean IGF-I at baseline was 147.8 (74.2) ng/mL. Hundred forty-six participants (62.6%) had at least one follow-up visit. Mean MMSE was 21.7 (4.7) and dropped on average by 2.28 points per year. MMSE decline was steeper among participants with lower IGF-I. For each decrease of 1 SD of IGF-I, subjects lost an additional 0.63 points per year in MMSE, e.g., participants with IGF-I level of 74 ng/mL lost 2.91 MMSE points per year whereas participants with IGF-I of 222 ng/mL lost 1.65 MMSE points per year. There was no association between IGFBP-3 and cognitive decline. Conclusion: Lower baseline serum IGF-I was associated with faster cognitive decline in AD over a 2-year period.

Pages 651-660
Amy Clements-Cortes, Heidi Ahonen, Michael Evans, Morris Freedman, Lee Bartel (Handling Associate Editor: George Acquaah-Mensah)
Short-Term Effects of Rhythmic Sensory Stimulation in Alzheimer’s Disease: An Exploratory Pilot Study
Abstract: This study assessed the effect of stimulating the somatosensory system of Alzheimer’s disease (AD) patients at three stages of their illness with 40 Hz sound. In this AB cross-over study design, 18 participants (6 mild, 6 moderate, 6 severe) each participated in 13 sessions: one intake and 12 treatment. Treatment A consisted of 40 Hz sound stimulation and Treatment B consisted of visual stimulation using DVDs, each provided twice a week over 6 weeks for a total of 6 times per treatment. Outcome measures included: St. Louis University Mental Status Test (SLUMS), Observed Emotion Rating Scale, and behavioral observation by the researcher. Data were submitted to regression analysis for the series of 6 SLUMS scores in treatment A and 6 scores in B with comparison by group. The slopes for the full sample and subgroups in the 40 Hz treatment were all significant beyond alpha = 0.05, while those for the DVD were not. A thematic analysis of qualitative observations supported the statistical findings. 40 Hz treatment appeared to have the strongest impact on persons with mild and moderate AD. Results are promising in terms of a potential new treatment for persons with AD, and further research is needed.

Pages 661-672
Samantha L. Gardener*, Hamid R. Sohrabi*, Kai-kai Shen, Stephanie R. Rainey-Smith, Michael Weinborn, Kristyn A. Bates, Tejal Shah, Jonathan K. Foster, Nat Lenzo, Olivier Salvado, Christoph Laske, Simon M. Laws, Kevin Taddei, Giuseppe Verdile, Ralph N. Martins (Handling Associate Editor: Ariel Graff-Guerrero) *These authors contributed equally to this work.
Cerebral Glucose Metabolism is Associated with Verbal but not Visual Memory Performance in Community-Dwelling Older Adults
Abstract: Increasing evidence suggests that Alzheimer’s disease (AD) sufferers show region-specific reductions in cerebral glucose metabolism, as measured by [18F]-fluoro-2-deoxyglucose positron emission tomography (18F-FDG PET). We investigated preclinical disease stage by cross-sectionally examining the association between global cognition, verbal and visual memory, and 18F-FDG PET standardized uptake value ratio (SUVR) in 43 healthy control individuals, subsequently focusing on differences between subjective memory complainers and non-memory complainers. The 18F-FDG PET regions of interest investigated include the hippocampus, amygdala, posterior cingulate, superior parietal, entorhinal cortices, frontal cortex, temporal cortex, and inferior parietal region. In the cohort as a whole, verbal logical memory immediate recall was positively associated with 18F-FDG PET SUVR in both the left hippocampus and right amygdala. There were no associations observed between global cognition, delayed recall in logical memory, or visual reproduction and 18F-FDG PET SUVR. Following stratification of the cohort into subjective memory complainers and non-complainers, verbal logical memory immediate recall was positively associated with 18F-FDG PET SUVR in the right amygdala in those with subjective memory complaints. There were no significant associations observed in non-memory complainers between 18F-FDG PET SUVR in regions of interest and cognitive performance. We observed subjective memory complaint-specific associations between 18F-FDG PET SUVR and immediate verbal memory performance in our cohort, however found no associations between delayed recall of verbal memory performance or visual memory performance. It is here argued that the neural mechanisms underlying verbal and visual memory performance may in fact differ in their pathways, and the characteristic reduction of 18F-FDG PET SUVR observed in this and previous studies likely reflects the pathophysiological changes in specific brain regions that occur in preclinical AD.

Pages 673-684
Harris A. Eyre, Bianca Acevedo, Hongyu Yang, Prabha Siddarth, Kathleen Van Dyk, Linda Ercoli, Amber M. Leaver, Natalie St. Cyr, Katherine Narr, Bernhard T. Baune, Dharma S. Khalsa, Helen Lavretsky
Changes in Neural Connectivity and Memory Following a Yoga Intervention for Older Adults: A Pilot Study
Abstract: Background: No study has explored the effect of yoga on cognitive decline and resting-state functional connectivity. Objectives: This study explored the relationship between performance on memory tests and resting-state functional connectivity before and after a yoga intervention versus active control for subjects with mild cognitive impairment (MCI). Methods: Participants (≥ 55 y) with MCI were randomized to receive a yoga intervention or active “gold-standard” control (i.e., memory enhancement training (MET)) for 12 weeks. Resting-state functional magnetic resonance imaging was used to map correlations between brain networks and memory performance changes over time. Default mode networks (DMN), language and superior parietal networks were chosen as networks of interest to analyze the association with changes in verbal and visuospatial memory performance. Results: Fourteen yoga and 11 MET participants completed the study. The yoga group demonstrated a statistically significant improvement in depression and visuospatial memory. We observed improved verbal memory performance correlated with increased connectivity between the DMN and frontal medial cortex, pregenual anterior cingulate cortex, right middle frontal cortex, posterior cingulate cortex, and left lateral occipital cortex. Improved verbal memory performance positively correlated with increased connectivity between the language processing network and the left inferior frontal gyrus. Improved visuospatial memory performance correlated inversely with connectivity between the superior parietal network and the medial parietal cortex. Conclusion: Yoga may be as effective as MET in improving functional connectivity in relation to verbal memory performance. These findings should be confirmed in larger prospective studies.

Pages 685-691
Emily C. Edmonds, Lisa Delano-Wood, Amy J. Jak, Douglas R. Galasko, David P. Salmon, Mark W. Bondi, for the Alzheimer’s Disease Neuroimaging Initiative <em?(Handling Associate Editor: Jason Brandt)
“Missed” Mild Cognitive Impairment: High False-Negative Error Rate Based on Conventional Diagnostic Criteria
Abstract: Mild cognitive impairment (MCI) is typically diagnosed using subjective complaints, screening measures, clinical judgment, and a single memory score. Our prior work has shown that this method is highly susceptible to false-positive diagnostic errors. We examined whether the criteria also led to “false-negative” errors by diagnostically reclassifying 520 participants using novel actuarial neuropsychological criteria. Results revealed a false-negative error rate of 7.1%. Participants’ neuropsychological performance, cerebrospinal fluid biomarkers, and rate of decline provide evidence that an MCI diagnosis is warranted. The impact of “missed” cases of MCI has direct relevance to clinical practice, research studies, and clinical trials of prodromal Alzheimer’s disease.

Pages 693-703
Qing-Fei Zhao*, Yu Wan*, Hui-Fu Wang, Fu-Rong Sun, Xiao-Ke Hao, Meng-Shan Tan, Chen-Chen Tan, Dao-Qiang Zhang, Lan Tan, Jin-Tai Yu, Alzheimer’s Disease Neuroimaging Initiative (Handling Associate Editor: Benedetta Nacmias) *These authors contributed equally to this work.
ABCA7 Genotypes Confer Alzheimer’s Disease Risk by Modulating Amyloid-β Pathology
Abstract: ABCA7 gene has been identified as a strong genetic locus for Alzheimer’s disease (AD) susceptibility in genome wide association studies (GWAS). However, the possible roles of ABCA7 variants in AD pathology were not specifically assessed. Using tagger methods, we extracted 15 targeted ABCA7 loci to investigate their associations with cerebrospinal fluid (CSF) and neuroimaging markers in Alzheimer’s Disease Neuroimaging Initiative (ADNI) dataset. Finally, although we did not detect any significant associations of previously published GWAS SNPs (rs3764650 and rs78117248) with all the CSF (Aβ1-42, T-tau, and P-tau) and neuroimaging markers, three other variants (rs3752242, rs3752240, and rs4147912) at ABCA7 loci were detected to show significant associations with amyloid deposition on AV-45 PET in brain. Moreover, haplotype and subgroup analysis confirmed these significant findings. Furthermore, there were no remarkable correlations between ABCA7 variants and neuronal degeneration biomarkers (elevated CSF tau, brain structure atrophy, and hypometabolism on imaging) in this study. Thus, our study suggested that ABCA7 genotypes contribute to the AD risk through involvement in amyloid-β deposition on in vivo imaging, but not in tau pathology, brain atrophy, or decreased glucose metabolism.

Pages 705-712
Jin-young Min, Kyoung-bok Min
The Folate-Vitamin B12 Interaction, Low Hemoglobin, and the Mortality Risk from Alzheimer’s Disease
Abstract: Abnormal hemoglobin levels are a risk factor for Alzheimer's disease (AD). Although the mechanism underlying these associations is elusive, inadequate micronutrients, particularly folate and vitamin B12, may increase the risk for anemia, cognitive impairment, and AD. In this study, we investigated whether the nutritional status of folate and vitamin B12 is involved in the association between low hemoglobin levels and the risk of AD mortality. Data were obtained from the 1999-2006 National Health and Nutrition Examination Survey (NHANES) and the NHANES (1999-2006) Linked Mortality File. A total of 4,688 participants aged ≥60 years with available baseline data were included in this study. We categorized three groups based on the quartiles of folate and vitamin B12 as follows: Group I (low folate and vitamin B12); Group II (high folate and low vitamin B12 or low folate and high vitamin B12); and Group III (high folate and vitamin B12). Of 4,688 participants, 49 subjects died due to AD. After adjusting for age, sex, ethnicity, education, smoking history, body mass index, the presence of diabetes or hypertension, and dietary intake of iron, significant increases in the AD mortality were observed in Quartile1 for hemoglobin (HR: 8.4, 95% CI: 1.4-50.8), and the overall risk of AD mortality was significantly reduced with increases in the quartile of hemoglobin (p for trend = 0.0200), in subjects with low levels of both folate and vitamin B12 at baseline. This association did not exist in subjects with at least one high level of folate and vitamin B12. Our finding shows the relationship between folate and vitamin B12 levels with respect to the association between hemoglobin levels and AD mortality.

Pages 713-717
Lisa C. Silbert, Hiroko H. Dodge, David Lahna, Nutta-on Promjunyakul, Daniel Austin, Nora Mattek, Deniz Erten-Lyons, Jeffrey A. Kaye
Less Daily Computer Use is Related to Smaller Hippocampal Volumes in Cognitively Intact Elderly
Abstract: Background: Computer use is becoming a common activity in the daily life of older individuals and declines over time in those with mild cognitive impairment (MCI). The relationship between daily computer use (DCU) and imaging markers of neurodegeneration is unknown. Objective: The objective of this study was to examine the relationship between average DCU and volumetric markers of neurodegeneration on brain MRI. Methods: Cognitively intact volunteers enrolled in the Intelligent Systems for Assessing Aging Change study underwent MRI. Total in-home computer use per day was calculated using mouse movement detection and averaged over a one-month period surrounding the MRI. Spearman’s rank order correlation (univariate analysis) and linear regression models (multivariate analysis) examined hippocampal, gray matter (GM), white matter hyperintensity (WMH), and ventricular cerebral spinal fluid (vCSF) volumes in relation to DCU. A voxel-based morphometry analysis identified relationships between regional GM density and DCU. Results: Twenty-seven cognitively intact participants used their computer for 51.3 minutes per day on average. Less DCU was associated with smaller hippocampal volumes (r = 0.48, p = 0.01), but not total GM, WMH, or vCSF volumes. After adjusting for age, education, and gender, less DCU remained associated with smaller hippocampal volume (p = 0.01). Voxel-wise analysis demonstrated that less daily computer use was associated with decreased GM density in the bilateral hippocampi and temporal lobes. Conclusions: Less daily computer use is associated with smaller brain volume in regions that are integral to memory function and known to be involved early with Alzheimer’s pathology and conversion to dementia. Continuous monitoring of daily computer use may detect signs of preclinical neurodegeneration in older individuals at risk for dementia.

Pages 719-729
Cyrus A. Raji, David A. Merrill, Harris Eyre, Sravya Mallam, Nare Torosyan, Kirk I. Erickson, Oscar L. Lopez, James T. Becker, Owen T. Carmichael, H. Michael Gach, Paul M. Thompson, W. T. Longstreth, Jr., Lewis H. Kuller
Longitudinal Relationships between Caloric Expenditure and Gray Matter in the Cardiovascular Health Study
Abstract: Background: Physical activity (PA) can be neuroprotective and reduce the risk for Alzheimer's disease (AD). In assessing physical activity, caloric expenditure is a proxy marker reflecting the sum total of multiple physical activity types conducted by an individual. Objective: To assess caloric expenditure, as a proxy marker of PA, as a predictive measure of gray matter (GM) volumes in the normal and cognitively impaired elderly persons. Methods: All subjects in this study were recruited from the Institutional Review Board approved Cardiovascular Health Study (CHS), a multisite population-based longitudinal study in persons aged 65 and older. We analyzed a sub-sample of CHS participants 876 subjects (mean age 78.3, 57.5% F, 42.5% M) who had i) energy output assessed as kilocalories (kcal) per week using the standardized Minnesota Leisure-Time Activities questionnaire, ii) cognitive assessments for clinical classification of normal cognition, mild cognitive impairment (MCI), and AD, and iii) volumetric MR imaging of the brain. Voxel-based morphometry modeled the relationship between kcal/week and GM volumes while accounting for standard covariates including head size, age, sex, white matter hyperintensity lesions, MCI or AD status, and site. Multiple comparisons were controlled using a False Discovery Rate of 5 percent. Results: Higher energy output, from a variety of physical activity types, was associated with larger GM volumes in frontal, temporal, and parietal lobes, as well as hippocampus, thalamus, and basal ganglia. High levels of caloric expenditure moderated neurodegeneration-associated volume loss in the precuneus, posterior cingulate, and cerebellar vermis. Conclusion: Increasing energy output from a variety of physical activities is related to larger gray matter volumes in the elderly, regardless of cognitive status.

Pages 731-745
Eric A. Tanifum, Ketan Ghaghada, Craig Vollert, Elizabeth Head, Jason L. Eriksen, Ananth Annapragada
A Novel Liposomal Nanoparticle for the Imaging of Amyloid Plaque by Magnetic Resonance Imaging
Abstract: Amyloid binding molecules with greater hydrophilicity than existing ligands were synthesized. The lead candidate ET6-21 bound amyloid fibrils, and amyloid deposits in dog brain and human brain tissue ex vivo. The ligand was used to prepare novel amyloid-targeted liposomal nanoparticles. The preparation was tested in the Tg2576 and TetO/APP mouse models of amyloid deposition. Gd chelates and Indocyanine green were included in the particles for visualization by MRI and near-infrared microscopy. Upon intravenous injection, the particles successfully traversed the blood-brain barrier in these mice, and bound to the plaques. Magnetic resonance imaging (T1-MRI) conducted 4 days after injection demonstrated elevated signal in the brains of mice with amyloid plaques present. No signal was observed in amyloid-negative mice, or in amyloid-positive mice injected with an untargeted version of the same agent. The MRI results were confirmed by immunohistochemical and fluorescent microscopic examination of mouse brain sections, showing colocalization of the fluorescent tags and amyloid deposits.

Pages 747-756
Qingting Hu, Wenhui Teng, Jiajia Li, Fangfang Hao, Naidong Wang
Homocysteine and Alzheimer’s Disease: Evidence for a Causal Link from Mendelian Randomization
Abstract: Background/Objective: The relationship between plasma homocysteine (Hcy) levels and Alzheimer's disease (AD) has been studied for many years, but remains controversial. While a recent meta-analysis of epidemiological studies, which included observational studies, indicated that homocysteine may be a risk factor for AD, there remains a need to further demonstrate this link due to the large degree of heterogeneity between studies. Epidemiological studies have certain limitations, as their results can be affected by confounding factors and reverse causation. In this study, we evaluated the relationship between plasma homocysteine and AD by using a Mendelian randomization method to avoid problems of confounding bias and reverse causality. Methods: We searched the PubMed and EMBASE databases for reports regarding the MTHFR C677T polymorphism (rs1801133) from the time of their inception to September 2015. These reports were combined with related observational studies, and used to evaluate the effect of MTHFR C677T (rs1801133) on the risk for AD. A recent meta-analysis of genome-wide association studies had previously suggested a relationship between homocysteine and MTHFR C677T (rs 1801133). Results: Our met-analysis included 34 studies with 9397 subjects, and demonstrated a significant relationship between plasma total homocysteine levels and the risk for AD [(OR = 3.37; 95% CI = 1.90–5.95; p =2.9 × 10-5). Conclusion: Our meta-analysis demonstrated a causal link between plasma total homocysteine and the risk for AD, and provides a new insight into the etiology and prevention of AD.

Pages 757-774
Colette M. Smart, Sidney J. Segalowitz, Bryce P. Mulligan, Jacob Koudys, Jodie R. Gawryluk (Handling Associate Editor: Katherine Gifford)
Mindfulness Training for Older Adults with Subjective Cognitive Decline: Results from a Pilot Randomized Controlled Trial
Abstract: Introduction: Subjective cognitive decline (SCD) in older adults is a condition with a complex phenomenology and diverse etiologies including (but not limited to) mood, personality, and health concerns, as well as biomarkers of preclinical Alzheimer’s disease such as amyloid-β deposition and gray matter volume loss. Approximately 60% of affected persons are estimated to decline to Alzheimer’s dementia. Regardless of etiology, persons with SCD may be optimal targets for early intervention. Objective: To ascertain the feasibility and impact of mindfulness training (MT) as an early intervention in persons with SCD. Methods: Using a single-blind, randomized controlled trial design, older adults with (n = 14) and without (n = 22) SCD were randomized to either MT or a control condition of psychoeducation (PE) on cognitive aging. EEG/ERP (specifically, the P3 component), structural MRI, and self-report measures of psychological functioning were obtained within 4 weeks prior to and within 2 weeks following intervention. Results: MT resulted in decreased reaction time intra-individual variability for all participants, with a selective increase in the P3 event-related component for those with SCD. Compared with PE, MT also resulted in an increase in percent volume brain change in structural MRI. Finally, all SCD participants reported a decrease in cognitive complaints and increase in memory self-efficacy following intervention. Discussion: Results suggest that MT is a feasible early intervention in persons with SCD. Longer-term follow-up with larger sample sizes will determine whether MT can slow the rate of decline in persons who may be at risk for Alzheimer’s dementia.