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Volume 58, Number 1, IN PRESS

Review
Chunmei Jiang, Guangning Li, Pengru Huang, Zhou Liu, Bin Zhao
The Gut Microbiota and Alzheimer’s Disease
Abstract: The gut microbiota comprises a complex community of microorganism species that resides in our gastrointestinal ecosystem and whose alterations influence not only various gut disorders but also central nervous system disorders such as Alzheimer’s disease (AD). AD, the most common form of dementia, is a neurodegenerative disorder associated with impaired cognition and cerebral accumulation of amyloid-β peptides (Aβ). Most notably, the microbiota-gut-brain axis is a bidirectional communication system that is not fully understood, but includes neural, immune, endocrine, and metabolic pathways. Studies in germ-free animals and in animals exposed to pathogenic microbial infections, antibiotics, probiotics, or fecal microbiota transplantation suggest a role for the gut microbiota in host cognition or AD-related pathogenesis. The increased permeability of the gut and blood-brain barrier induced by microbiota dysbiosis may mediate or affect AD pathogenesis and other neurodegenerative disorders, especially those associated with aging. In addition, bacteria populating the gut microbiota can secrete large amounts of amyloids and lipopolysaccharides, which might contribute to the modulation of signaling pathways and the production of proinflammatory cytokines associated with the pathogenesis of AD. Moreover, imbalances in the gut microbiota can induce inflammation that is associated with the pathogenesis of obesity, type 2 diabetes mellitus, and AD. The purpose of this review is to summarize and discuss the current findings that may elucidate the role of the gut microbiota in the development of AD. Understanding the underlying mechanisms may provide new insights into novel therapeutic strategies for AD.

Short Communication
Erin M. Shellington, Matthew Heath, Dawn P. Gill, Robert J. Petrella
Long-Term Maintenance of Executive-Related Oculomotor Improvements in Older Adults with Self-Reported Cognitive Complaints Following a 24-Week Multiple Modality Exercise Program
Abstract: Adults (55 years) with self-reported cognitive complaints (sCC) were randomized to: multiple-modality exercise (M2), or multiple-modality plus mind-motor exercise (M4), for 24-weeks. Participants (n=58) were assessed on antisaccade reaction time (RT) to examine executive-related oculomotor control and self-reported physical activity (PA) at pre-intervention (V0), post-intervention (V1), and 52-weeks follow-up (V2). We previously reported significant improvements in antisaccade RT of 23 ms at V1, in both groups. We now report maintenance of antisaccade RT improvement from V1 to V2, t(57)=0.8, p=0.45, and improved PA from V1 to V2, t(56)=-2.4, p=0.02. Improvements in executive-related oculomotor control attained at V1 were maintained at V2.

Stephanie M. Williams, Philip Schulz, Terrone L. Rosenberry, Richard J. Caselli, Michael R. Sierks (Handling Associate Editor: Gary Arendash)
Blood-Based Oligomeric and Other Protein Variant Biomarkers to Facilitate Pre-Symptomatic Diagnosis and Staging of Alzheimer’s Disease
Abstract: Oligomeric forms of amyloid-β (Aβ), tau, and TDP-43 play important roles in Alzheimer’s disease (AD), and therefore are promising biomarkers. We previously generated single chain antibody fragments (scFvs) that selectively bind disease-related variants of these proteins including A4, C6T, and E1, which bind different oligomeric Aβ variants; D11C, which binds oligomeric tau; and AD-TDP1 and AD-TDP2, which bind disease related TDP-43 variants. To determine the utility of these disease-related variants as early biomarkers, we first analyzed 11 human sera samples obtained ~2 years prior to an initial mild cognitive impairment (MCI) diagnosis. While the subsequent diagnoses for the cases covered several different conditions, all samples had elevated protein variant levels relative to the plasma controls although with different individual biomarker profiles. We then analyzed a set of longitudinal human plasma samples from four AD (encompassing time points prior to MCI diagnosis and continuing until after conversion to AD) and two control cases. Pre-MCI samples were characterized by high TDP-43 variant levels, MCI samples by high Aβ variant levels, and AD samples by high Aβ and tau variant levels. Sample time points ranged from ~7 years pre-MCI to ~9 years after AD conversion. Bivariate correlations showed a negative correlation with TDP-43 levels and positive correlations with cumulative Aβ and oligomeric tau levels indicating an increase in neurodegenerative processes with time in AD. Detection of disease related protein variants not only readily selects AD cases from controls, but also stages progression of AD and holds promise for a pre-symptomatic blood-based biomarker profile for AD.

Jens Bohlken, Louis Jacob, Karel Kostev
Association between Anti-Dementia Treatment Persistence and Daily Dosage of the First Prescription: A Retrospective Analysis in Neuropsychiatric Practices in Germany
Abstract:Background: High adherence and persistence are important for the efficacy of anti-dementia treatments. Objective: The goal of this study was to analyze the association between anti-dementia treatment persistence and daily dosage of the first prescription in patients treated in neuropsychiatric practices in Germany. Methods: This study included patients aged 60 years or over who were diagnosed with Alzheimer’s disease and received anti-dementia prescriptions (galantamine, donepezil, memantine, and rivastigmine) for the first time between 2005 and 2014. The main outcome measure was the treatment persistence rate within 12 months after the index date as a function of the first dose. Cox proportional hazards regression models were used to estimate the relation between persistence and daily dosages after adjusting for age, gender, and residence in nursing homes. Results: In this study, 2,442, 5,669, 4,416, 642, and 2,334 patients received galantamine, donepezil, memantine, oral rivastigmine, and patch rivastigmine, respectively. After 12 months of follow-up, continuation rates were similar for individuals using different doses of galantamine, donepezil, oral rivastigmine, and patch rivastigmine, but were significantly different for those taking memantine. Patients using 20 mg of memantine were less likely to discontinue their treatment than patients using 10 mg (HR=0.88, 95% CI: 0.80-0.96). There was no significant association between daily dosages and persistence for the other drugs (HRs ranging from 0.86 to 1.15). Conclusions: There was no significant association between treatment persistence and daily dosages in patients with Alzheimer’s disease in Germany who were treated with galantamine, donepezil, or rivastigmine.

Naaheed Mukadam, Andrew Sommerlad, Gill Livingston
The Relationship of Bilingualism Compared to Monolingualism to the Risk of Cognitive Decline or Dementia: A Systematic Review and Meta-Analysis
Abstract: Background: Bilingualism may contribute to cognitive reserve, protect against cognitive decline, and delay the onset of dementia. Objective: We systematically reviewed evidence about the effect of bilingualism on subsequent cognitive decline or dementia. Methods: We searched electronic databases and references for longitudinal studies comparing cognitive decline in people who were bilingual with those who were monolingual and evaluated study quality. We conducted meta-analyses using random effects models to calculate pooled odds ratio of incident dementia. Results: We included 13/1,156 eligible articles. Meta-analysis of prospective studies of the effects of bilingualism on future dementia gave a combined Odds Ratio of dementia of 0.96 (95% CI 0.74-1.23) in bilingual participants (n = 5,527) compared to monolinguals. Most retrospective studies found that bilingual people were reported to develop symptoms of cognitive decline at a later age than monolingual participants. Conclusion: We did not find that bilingualism protects from cognitive decline or dementia from prospective studies. Retrospective studies are more prone to confounding by education, or cultural differences in presentation to dementia services and are therefore not suited to establishing causative links between risk factors and outcomes.

Ruth Alonso, Diana Pisa, Begoña Aguado, Luis Carrasco
Identification of Fungal Species in Brain Tissue from Alzheimer’s Disease by Next-Generation Sequencing
Abstract: The possibility that patients diagnosed with Alzheimer’s disease (AD) have disseminated fungal infection has been recently advanced by the demonstration of fungal proteins and DNA in nervous tissue from AD patients. In the present study, next-generation sequencing (NGS) was used to identify fungal species present in the central nervous system (CNS) of AD patients. Initially, DNA was extracted from frozen tissue from four different CNS regions of one AD patient and the fungi in each region were identified by NGS. Notably, whereas a great variety of species were identified using the Illumina platform, Botrytis cinerea and Cryptococcus curvatus were common to all four CNS regions analyzed. Further analysis of entorhinal/cortex hippocampus samples from an additional eight AD patients revealed a variety of fungal species, although some were more prominent than others. Five genera were common to all nine patients: Alternaria, Botrytis, Candida, Cladosporium, and Malassezia. These observations could be used to guide targeted antifungal therapy for AD patients. Moreover, the differences found between the fungal species in each patient may constitute a basis to understand the evolution and severity of clinical symptoms in AD.

Catherine Robb*, Chinedu Udeh-Momoh*, Stefan Wagenpfeil, Jakob Schöpe, Panagiotis Alexopoulos**, Robert Perneczky** for the Alzheimer's Disease Neuroimaging Initiative *,**These authors contributed equally to this work.
Biomarkers and Functional Decline in Prodromal Alzheimer’s Disease
Abstract: Background: Little is known of possible associations between Alzheimer’s disease (AD) biomarkers and instrumental activities of daily living (IADL) change over time. Objective: The present study seeks to identify relationships between baseline imaging and fluid biomarker profiles, and decline in IADL utilizing data collated from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) cohort. Methods: Generalized estimating equations analysis, adjusted for cognitive deterioration, was applied to a cohort of 509 individuals from all stages of ADNI, including 156 healthy controls, 189 early mild cognitive impairment (MCI) patients and 164 MCI patients. Results: A significant correlation was found between baseline biomarkers, specifically CSF Aβ and FDG PET, and IADL change over a 3-year period in individuals with MCI. Importantly, comparable correlations between presence of pathological biomarker levels and temporal decline in both functional and cognitive performance were also noted. Discussion: We show that distinct baseline biomarkers may predict latent changes in IADL. Our results necessitate a revision of the commonly held view upholding cognitive changes as the predominant endpoint measure associated with presence of abnormal baseline biomarkers.

Tong Wang, Yili Wu, Yongye Sun, Long Zhai, Dongfeng Zhang (Handling Associate Editor: Paulo Caramelli)
A Prospective Study on the Association between Uric Acid and Cognitive Function among Middle-Aged and Older Chinese
Abstract: Background: Uric acid (UA) is a powerful antioxidant that may have neuroprotective properties, yet it is also a risk factor of vascular disease that predisposes individuals to cognitive impairment. Results from longitudinal studies on UA and cognitive decline remain controversial. Objective: We examined the associations of baseline plasma UA level with follow-up cognitive function as well as cognitive decline over time among a large sample of middle-aged and older Chinese. Methods: Data from China Health and Retirement Longitudinal Study (CHARLS) were used. Cognitive function, including episodic memory, mental intactness, and global cognition, were tested twice with 2-year interval. Plasma UA was measured at baseline. Basic demographics, life habits, and health status were considered as potential confounders. Multiple linear regression models and mixed-effects regression models were fitted. Results: A total of 12,798 individuals aged above 45 years were eligible with the follow-up time ranging from 1.33 to 2.42 years. Both global cognitive function and mental intactness declined, while episodic memory remained stable over time. In multiple linear regression models, compared with the lowest baseline UA level, 3rd baseline UA quartile was associated with better follow-up global cognitive function (b=0.425, p=0.041) and episodic memory (b=0.413, p=0.004), and highest baseline UA quartile was associated with better follow-up mental intactness (b=0.253, p=0.041) in males; highest baseline UA level was associated with better follow-up cognition for each measure (b=0.281~0.768, p≤0.046) in females. Mixed-effects regression models suggested no significant baseline UA-by-time interactions on any cognitive measure. Conclusion: Higher baseline UA level was associated with better cognition in later life but not with rates of cognitive decline among middle-aged and older Chinese.

Karim Bennys, Audrey Gabelle, Claudine Berr, Delphine De Verbizier, Sandrine Andrieu, Bruno Vellas, Jacques Touchon; MAPT-DSA Study group
Cognitive Event-Related Potential, an Early Diagnosis Biomarker in Frail Elderly Subjects: The ERP-MAPT-PLUS Ancillary Study
Abstract: Background: By analyzing brain synaptic function, cognitive event-related potentials (ERPs) could provide powerful and innovative tools for early Alzheimer's disease (AD) diagnosis. Objective: We investigated the relevance of the ERP-P300 component as a potential diagnosis marker in elderly subjects at risk of developing AD. Methods: ERP-P300 was analyzed on 85 subjects recruited from the Multidomain Alzheimer Preventive Trial (MAPT). PET-AV45 brain imaging was available from 36 subjects. Results: Two ERP-P300 subgroups were identified according to their PET-AV45 status: PET-Aβ positive (n=15) and PET-Aβ negative (n=21). In the amyloid positive group, we observed a highly significant increase in P3b latency in parietal brain regions (p=0.0052). P3b in parietal regions correctly categorized 69.4% elderly subjects from the P300-PET Aβ positive group. Combined analysis of parietal P3b latencies and category fluency correctly classified 75% subjects from the P300-PET Aβ positive group. Conclusions: The P300 ERP presents good predictive measure of brain amyloid load and has the potential to be used as a screening instrument for preclinical AD. The incorporation of P3b latency may be used as an adjunctive tool with neuropsychological assessment (i.e., verbal category fluency) as a specific and sensitive method for preclinical assessment of AD.

Mizanur Khondoker, Snorri Bjorn Rafnsson, Stephen Morris, Martin Orrell, Andrew Steptoe
Positive and Negative Experiences of Social Support and Risk of Dementia in Later Life: An Investigation Using the English Longitudinal Study of Ageing
Abstract: Background: Having a network of close relationships may reduce the risk of developing dementia. However, social exchange theory suggests that social interaction entails both rewards and costs. The effects of quality of close social relationships in later life on the risk of developing dementia are not well understood. Objective: To investigate the effects of positive and negative experiences of social support within key relationships (spouse or partner, children, other immediate family, and friends) on the risk of developing dementia in later life. Methods: We analyzed 10-year follow up data (2003/4 to 2012/13) in a cohort of 10,055 dementia free (at baseline) core participants aged 50 years and over from the English Longitudinal Study of Ageing (ELSA). Incidence of dementia was identified from participant or informant reported physician diagnosed dementia or overall score of informant-completed IQCODE questionnaire. Effects of positive and negative experiences of social support measured at baseline on risk of developing dementia were investigated using proportional hazards regression accommodating interval censoring of time-to-dementia. Results: There were 340 (3.4%) incident dementia cases during the follow-up. Positive social support from children significantly reduced the risk of dementia (hazard ratio, HR=0.83, p=0.042, 95% CI: 0.69 to 0.99). Negative support from other immediate family (HR=1.26, p=0.011, CI: 1.05 to 1.50); combined negative scores from spouse and children (HR=1.23, p=0.046, CI: 1.004 to 1.51); spouse, children, and other family (HR=1.27, p=0.021, CI=1.04 to 1.56); other family & friends (HR=1.25, p=0.033, CI: 1.02 to 1.55); and the overall negative scores (HR=1.31, p=0.019, CI: 1.05 to 1.64) all were significantly associated with increased risk of dementia. Conclusion: Positive social support from children is associated with reduced risk of developing dementia whereas experiences of negative social support from children and other immediate family increase the risk. Further research is needed to better understand the causal mechanisms that drive these associations.

Arnaud Adrait, Xavier Perrot, Marie-France Nguyen, Marine Gueugnon, Charles Petitot, Lionel Collet, Adeline Roux, Marc Bonnefoy, on behalf of the ADPHA study group
Do Hearing Aids Influence Behavioral and Psychological Symptoms of Dementia and Quality of Life in Hearing Impaired Alzheimer’s Disease Patients and Their Caregivers?
Abstract: Background: It has been suggested that age-related hearing loss (ARHL) and Alzheimer’s disease (AD) are commonly associated. Objective: The Alzheimer Disease, Presbycusis and Hearing Aids (ADPHA) clinical trial assessed the influence of hearing aids (HAs) on patients affected by ARHL and AD, as judged by behavioral symptoms and functional abilities, as well as patient and caregiver quality of life (QoL). Methods: A multicenter double-blind randomized placebo-controlled trial, with a semi-crossover procedure over 12 months, was conducted from 2006 to 2012. For the first 6 months, the active group was treated with active HAs and the placebo group with inactive HAs. For the last 6 months, HAs in the placebo group were activated. Assessment was conducted at baseline, 6 months, and 12 months. We performed intergroup and intragroup comparisons. Behavioral symptoms were assessed by neuropsychiatric inventory (NPI), functional abilities by instrumental activities of daily living, and QoL by Zarit, Alzheimer’s disease related quality of life, and simplified Duke scales. Results: Fifty-one patients were included and randomized: 22 in active group (mean NPI 17.6; mean age 83±6.2) and 26 in placebo group (mean NPI 25.8; mean age 82.3 ±7.2) were fitted with HAs. At 6-month follow-up, all scores worsened without significant difference between the two groups. In placebo group, activation of HAs had no effect on the change of these scores. Conclusion: These findings do not provide evidence of improvement in behavioral symptoms, functional status, or QoL of hearing impaired AD patients and their caregivers after 6 months of HA use. However, we cannot exclude that HAs may have a positive effect in patients aged less than 75 years.

Marie-France Nguyen, Marc Bonnefoy, Arnaud Adrait, Marine Gueugnon, Charles Petitot, Lionel Collet, Adeline Roux, Xavier Perrot, on behalf of the ADPHA study group
Efficacy of Hearing Aids on the Cognitive Status of Patients with Alzheimer’s Disease and Hearing Loss: A Multicenter Controlled Randomized Trial
Abstract: Background/Objective: This study evaluated the cognitive benefit of hearing aids (HA) in older patients with Alzheimer's disease (AD) and hearing loss (HL) after a 6- and 12-month period of utilization. Methods: A multicenter double-blind randomized placebo-controlled trial was conducted in patients aged more than 65 years. A group was equipped with active HA for 6 months (active group) and a second group had placebo HA for 6 months (placebo group) followed by a secondary activation phase for a further 6 months (semi crossover procedure). Both groups were retested after a 12-month period. The primary endpoint was the change from baseline of the Alzheimer’s Disease Assessment Scale-Cognitive subscale (ADAS Cog) after a 6-month period in both groups and after 6 months of secondary HA activation in the placebo group. A smaller cognitive decline should be obtained with HA use; an increase in ADAS Cog score of less than 6 points was defined a success. Results: Fifty-one patients aged 68 to 99 years were included; 38 attended the 6-month visit: 18 in the active group and 20 in the placebo group. At 6 months, 14 (82.4%) successes were noticed in the active group, and 15 (88.2%) in the placebo group (p=1.0); delta ADAS Cog in the active group was 1.8 ±5.3 and 1.3 ±5.3 in the placebo group (p=0.8). In the placebo group, after the secondary HA activation, no significant improvement was observed. Conclusion: No significant effect of HA use was observed after 6 months of follow-up in patients with AD and HL.

Angeles Garcia, Shubha Mathur, Maria Carmela Kalaw, Elizabeth McAvoy, James Anderson, Angela Luedke, Justine Itorralba, Sabine Mai
Quantitative 3D Telomeric Imaging of Buccal Cells Reveals Alzheimer’s Disease-Specific Signatures
Abstract: This study validates and expands on our previous work that assessed three-dimensional (3D) nuclear telomere profiling in buccal cells of Alzheimer’s disease (AD) patients and non-AD controls (Mathur et al., J Alzheimers Dis 39, 35-48, 2014). While the previous study used age- and gender-matched caregiver controls, the current study consented a new cohort of 44 age- and gender-matched healthy non-caregiver controls and 44 AD study participants. 3D telomeric profiles of buccal cells of AD patients and their non-AD controls were examined with participant information blinded to the analysis. In agreement with our previous study, we demonstrate that 3D telomeric profiles allow for the distinction between AD and non-AD individuals. This validation cohort provides an indication that the total number of 3D telomeric signals and their telomere lengths may be a suitable biomarker to differentiate between AD and non-AD and between mild, moderate, and severe AD. Further studies with larger sample sizes are required to move this technology further toward the clinic.

P. Hemachandra Reddy, Maria Manczak, XiangLing Yin
Mitochondria-Division Inhibitor 1 Protects Against Amyloid-β induced Mitochondrial Fragmentation and Synaptic Damage in Alzheimer’s Disease
Abstract: The purpose our study was to determine the protective effects of mitochondria division inhibitor 1 (Mdivi1) in Alzheimer’s disease (AD). Mdivi1 is hypothesized to reduce excessive fragmentation of mitochondria and mitochondrial dysfunction in AD neurons. Very little is known about whether Mdivi1 can confer protective effects in AD. In the present study, we sought to determine the protective effects of Mdivi1 against amyloid- (A)- and mitochondrial fission protein, dynamin-related protein 1 (Drp1)-induced excessive fragmentation of mitochondria in AD progression. We also studied preventive (Mdivi1+A42) and intervention (A42+Mdivi1) effects against A42 in N2a cells. Using real-time RT-PCR and immunoblotting analysis, we measured mRNA and protein levels of mitochondrial dynamics, mitochondrial biogenesis, and synaptic genes. We also assessed mitochondrial function by measuring H2O2, lipid peroxidation, cytochrome oxidase activity, and mitochondrial ATP. MTT assays were used to assess the cell viability. A42 was found to impair mitochondrial dynamics, lower mitochondrial biogenesis, lower synaptic activity, and lower mitochondrial function. On the contrary, Mdivi1 enhanced mitochondrial fusion activity, lowered fission machinery, and increased biogenesis and synaptic proteins. Mitochondrial function and cell viability were elevated in Mdivi1-treated cells. Interestingly, Mdivi1 pre- and post-treated cells treated with A showed reduced mitochondrial dysfunction, and maintained cell viability, mitochondrial dynamics, mitochondrial biogenesis, and synaptic activity. The protective effects of Mdivi1 were stronger in N2a+A42 pre-treated with Mdivi1, than in N2a+A42 cells than Mdivi1 post-treated cells, indicating that Mdivi1 works better in prevention than treatment in AD like neurons.

Tim Van Langenhove, Olivier Piguet, James R. Burrell, Cristian Leyton, David Foxe, Melissa Abela, Lauren Bartley, Woojin S. Kim, Eve Jary, Yue Huang, Carol Dobson-Stone, John B. Kwok, Glenda M. Halliday, John R. Hodges
Predicting Development of Amyotrophic Lateral Sclerosis in Frontotemporal Dementia
Abstract: Background: A proportion of patients with frontotemporal dementia (FTD) also develop amyotrophic lateral sclerosis (ALS). Objective: We aimed to establish the risk of developing ALS in patients presenting with FTD and to identify the relevant clinical variables associated with progression from FTD to FTD-ALS. Methods: Of 218 consecutive patients with FTD, 10.1% had a dual FTD-ALS diagnosis at presentation. The remaining 152 FTD patients with follow-up of at least 12 months were included in the present study. We calculated the rate of progression to FTD-ALS and compared the baseline characteristics of FTD patients who developed ALS to those who did not develop ALS. Results: Five percent of FTD patients developed ALS. The incidence rate of ALS was 6.7/100 patient-years in patients with FTD symptoms since 1 year, which declined with duration of FTD symptoms. No FTD patients developed ALS after 5 years. Five out of 8 FTD patients who developed ALS had presented with a mixed behavioral variant FTD and progressive non-fluent aphasia (bvFTD+PNFA) phenotype, 2 with bvFTD, and 1 with PNFA. Progression to FTD-ALS was significantly more frequent in patients with bvFTD+PNFA compared to those without this phenotype (p<0.0001, OR 38.3, 95%CI: 7.3 to 199.2), and in FTD patients who carried the C9orf72 repeat expansion compared to those without the repeat expansion (p=0.02, OR 8.0, 95%CI: 1.7 to 38.6). Conclusions: FTD patients with a mixed bvFTD+PNFA phenotype and a C9orf72 repeat expansion should be closely monitored for the possible development of ALS. The risk of developing ALS in FTD appears to decline with the duration of FTD symptoms.

Laura Serra, Michela Bruschini, Carlotta Di Domenico, Giulia Bechi Gabrielli, Camillo Marra, Carlo Caltagirone, Mara Cercignani, Marco Bozzali (Handling Associate Editor: Daniela Galimberti)
Memory is Not Enough: The Neurobiological Substrates of Dynamic Cognitive Reserve
Abstract: Changes in the residual memory variance are considered as a dynamic aspect of cognitive reserve (d-CR). We aimed to investigate for the first time the neural substrate associated with changes in the residual memory variance overtime in patients with amnestic mild cognitive impairment (aMCI). Thirty-four aMCI patients followed-up for 36 months and 48 healthy elderly individuals (HE) were recruited. All participants underwent 3T MRI, collecting T1-weighted images for voxel-based morphometry (VBM). They underwent an extensive neuropsychological battery, including six episodic memory tests. In patients and controls, factor analyses were used on the episodic memory scores to obtain a composite memory score (C-MS). Partial Least Square analyses were used to decompose the variance of C-MS in latent variables (LT scores), accounting for demographic variables and for the general cognitive efficiency level; linear regressions were applied on LT scores, striping off any contribution of general cognitive abilities, to obtain the residual value of memory variance, considered as an index of d-CR. LT scores and d-CR were used in discriminant analysis, in patients only. Finally, LT scores and d-CR were used as variable of interest in VBM analysis. The d-CR score was not able to correctly classify patients. In both aMCI patients and HE, LT1st and d-CR scores showed correlations with grey matter volumes in common and in specific brain areas. Using CR measures limited to assess memory function is likely less sensitive to detect the cognitive decline and predict the evolution of Alzheimer’s disease. In conclusion, d-CR needs a measure of general cognition to identify conversion to Alzheimer’s disease efficiently.

Beatriz García, Carla Martín, Olivia García-Suárez, Bárbara Muñiz-Alonso, Helena Ordiales, Santiago Fernández-Menéndez, Jorge Santos-Juanes, Laura Lorente-Gea, Sonia Castañón, Ikerne Vicente-Etxenausia, Kelvin Manuel Piña Batista, Irune Ruiz- Díaz, María Cristina Caballero-Martínez, Jesús Merayo-Lloves, Isabel Guerra-Merino, Luis M. Quirós, Iván Fernández-Vega (Handling Associate Editor: Bing Zhang)
Upregulated Expression of Heparanase and Heparanase 2 in the Brains of Alzheimer’s Disease
Abstract: Background: Heparan sulfate proteoglycans (HSPGs) promote amyloid-β peptide and tau fibrillization in Alzheimer’s disease (AD) and provide resistance against proteolytic breakdown. Heparanase (HPSE) is the only enzyme that cleaves heparan sulfate (HS). Heparanase 2 (HPSE2) lacks HS-degrading activity, although it is able to interact with HS with high affinity. Objective: To analyze HPSE and HPSE2 expressions at different stages of AD. Methods: RT-PCR was used to analyze transcription levels of both heparanases at different stages of AD, and immunohistochemistry was performed to localize each one in different parts of the brain. Results: Both proteins appeared overexpressed at different stages of AD. Immunohistochemistry indicated that the presence of the heparanases was related to AD pathology, with intracellular deposits found in degenerated neurons. At the extracellular level, HPSE was observed only in neuritic plaques with a fragmented core, while HPSE2 appeared in those with compact cores as well. Conclusion: Given the involvement of HSPGs in AD pathology, there would seem to be a relationship between the regulation of heparanase expression, the features of the disease, and a possible therapeutic alternative.

Samantha L. Gardener, Stephanie R. Rainey-Smith, Hamid R. Sohrabi, Michael Weinborn, Giuseppe Verdile, W.M.A.D. Binosha Fernando, Yen Ying Lim, Karra Harrington, Samantha Burnham, Kevin Taddei, Colin L. Masters, Stuart L. Macaulay, Christopher C. Rowe, David Ames, Paul Maruff, Ralph N. Martins; for the AIBL Research Group (Handling Associate Editor: Sid O'Bryant)
Increased Carbohydrate Intake is Associated with Poorer Performance in Verbal Memory and Attention in an APOE Genotype-Dependent Manner
Abstract: Evidence suggests that a diet low in carbohydrates can impact on cognitive performance among those with Alzheimer’s disease (AD). However, there is a lack of data assessing this relationship among cognitively normal (CN) older adults at increased future risk of developing AD due to carriage of the apolipoprotein E (APOE) ε4 allele. We assessed the cross-sectional association between carbohydrate intake, cognitive performance, and cerebral amyloid-β (Aβ) load in CN older adults, genotyped for APOE ɛ4 allele carrier status. Greater carbohydrate intake was associated with poorer performance in verbal memory in APOE ɛ4 allele non-carriers, and poorer performance in attention in APOE ɛ4 allele carriers. There were no associations between carbohydrate intake and cerebral Aβ load. These results provide support to the idea that decreasing carbohydrate intake may offer neurocognitive benefits, with specific cognitive domains affected in an APOE genotype-dependent manner. These findings warrant further investigation utilizing a longitudinal study design.

Patrick Gavin Kehoe, Elliott Hibbs, Laura E. Palmer, J. Scott Miners
Angiotensin-III is Increased in Alzheimer’s Disease in Association with Amyloid-β and Tau Pathology
Abstract: Hyperactivity of the renin-angiotensin system (RAS) is associated with the pathogenesis of Alzheimer’s disease (AD) believed to be mediated by angiotensin-II (Ang-II) activation of the angiotensin type 1 receptor (AT1R). We previously showed that angiotensin-converting enzyme-1 (ACE-1) activity, the rate-limiting enzyme in the production of Ang-II, is increased in human postmortem brain tissue in AD. Angiotensin-III (Ang-III) activates the AT1R and angiotensin type-2 receptor (AT2R), but its potential role in the pathophysiology of AD remains unexplored. We measured Ang-II and Ang-III levels by ELISA, and the levels and activities of aminopeptidase-A (AP-A) and aminopeptidase-N (AP-N) (responsible for the production and metabolism of Ang-III, respectively) in human postmortem brain tissue in the mid-frontal cortex (Brodmann area 9) in a cohort of AD (n=90) and age-matched non-demented controls (n=59), for which we had previous measurements of ACE-1 activity, Aβ level, and tau pathology (also in the mid-frontal cortex). We found that both Ang-II and Ang-III levels were significantly higher in AD compared to age-matched controls and that Ang-III, rather than Ang-II, was strongly associated with Aβ load and tau load. Levels of AP-A were significantly reduced in AD but AP-A enzyme activity was unchanged whereas AP-N activity was reduced in AD but AP-N protein level was unchanged. Together, these data indicate that the APA/Ang-III/APN/Ang-IV/AT4R pathway is dysregulated and that elevated Ang-III could contribute to the pathogenesis of AD.

Narjes Baazaoui, Khalid Iqbal
Prevention of Amyloid-β and Tau Pathologies, Associated Neurodegeneration, and Cognitive Deficit by Early Treatment with a Neurotrophic Compound
Abstract: To date, neither any effective treatment nor prevention of Alzheimer’s disease (AD), a major dementia causing disorder, are available. Herein, we investigated the secondary prevention of neurodegeneration, amyloid-β (Aβ) and tau pathologies with a neurotrophic compound P021 in 3xTg-AD mice. Previous work found that P021 can rescue at mild to moderate stages Aβ and tau pathologies in 3xTg-AD mice. To determine its potential clinical application, we sought to test the preventive effect of P021 on Aβ and tau pathologies by starting the treatment during the period of synaptic compensation several months before the appearance of any overt pathology in 3xTg-AD mice. We started a continuous treatment with P021 in 3-month-old female animals and followed its effect at 9-, 15- and 18-months post-treatment. Neurodegeneration at the above time points was studied using Fluorojade C staining, and tau and Aβ pathologies both immunohistochemically and by western blots. Cognitive performance was studied by assessing episodic memory with Novel Object Recognition task at 16-17-months post-treatment. We found that P021 treatment initiated during the synaptic compensation period can prevent neurodegeneration, Aβ and tau pathologies, rescue episodic memory impairment, and markedly reduce mortality rate. These findings for the first time show effective prevention of AD changes with a neurotrophic compound that targets neurogenesis and synaptic plasticity, suggesting that improving the health of the neuronal network can prevent AD.

Judith Godin, Joshua J. Armstrong, Kenneth Rockwood, Melissa K. Andrew
Dynamics of Frailty and Cognition After Age 50: Why It Matters that Cognitive Decline is Mostly Seen in Old Age
Abstract: Background: Frailty has been considered an antecedent and, to a lesser extent, an outcome of cognitive impairment. Both frailty and cognitive impairment are multiply determined and each is strongly related to age, making it likely that the two interact, especially as people age. In consequence, understanding their interaction and co-occurrence can offer insight into pathophysiology, prevention, and management. Objective: To examine the nature of the relationship between frailty and cognitive impairment using longitudinal data from the Survey of Health Aging and Retirement in Europe (SHARE), assessing for bidirectionality. Methods: We conducted secondary analyses using data from the first two waves of SHARE. The sample (N=11,941) was randomly split into two halves: one half for model development and one half for model confirmation. We used a 65 deficit Frailty Index and combined 5 cognitive deficits into a global cognitive impairment index. Cross-lagged path analysis within a structural equation modelling framework was used to examine the bi-directional relationship between the two measures. Results: After controlling for age, sex, social vulnerability, education, and initial cognitive impairment, each 0.10 increase in baseline frailty was associated with a 0.01 increase in cognitive impairment at follow-up (p<0.001). Likewise, each 0.1 increase in baseline cognitive impairment was associated with a 0.003 increase frailty at follow-up (p<0.01). Conclusion: Our findings underscore the importance of considering cognitive impairment in the context of overall health. Many people with dementia are likely to have other health problems, which need to be considered in concert to achieve optimal health outcomes.

Ralf Kunschmann*, Stefan Busse*, Thomas Frodl, Mandy Busse *These authors contributed equally to this work.
Psychotic Symptoms Associated with Poor Renal Function in Mild Cognitive Impairment and Dementias
Abstract: Patients suffering from cognitive decline such as mild cognitive impairment or neurodegenerative disorders including Alzheimer’s dementia, vascular dementia, frontotemporal dementia, and Lewy body dementia are often accompanied by symptoms like psychosis, depression, agitation, and apathy. Aging increases not only the prevalence of dementia but also the development of kidney disorders, which had emerged as possible risk factor of cognitive impairment and dementia. However, a contribution of renal dysfunction to psychosis associated with cognitive decline remains to be investigated. We addressed the question whether patients diagnosed with mild cognitive impairment or dementia and co-symptoms show alterations in serum parameters. Analyzing 309 patients in total, we detected a positive correlation between the occurrence of psychotic symptoms and increased retention parameters in serum, including creatinine and urea levels and the estimated glomerular filtration rates. This was in particular detected in female patients. In male patients, psychotic symptoms were associated with an increased number of leukocytes in blood. We propose that clinicians should be aware of psychotic symptoms in patients with reduced cognitive functions that could be associated with changes in the retention parameters.

Hoyoung An*, Mi-Hyang Cho*, Dong-Hou Kim, Seockhoon Chung, Seung-Yong Yoon *These authors contributed equally to this work.
Orexin Impairs the Phagocytosis and Degradation of Amyloid-β Fibrils by Microglial Cells
Abstract: Background: Intracranial accumulation of amyloid-β (Aβ) is a characteristic finding of Alzheimer’s disease (AD). It is thought to be the result of Aβ overproduction by neurons and impaired clearance by several systems, including degradation by microglia. Sleep disturbance is now considered a risk factor for AD, but studies focusing on how sleep modulates microglial handling of Aβ have been scarce. Objective: To determine whether phagocytosis and degradation of extracellular Aβ fibrils by BV2 microglial cells were impaired by treatment with orexin-A/B, a major modulator of the sleep-wake cycle, which may mimic sleep deprivation conditions. Methods: BV2 cells were treated with orexin and Aβ for various durations and phagocytic and autophagic processes for degradation of extracellular Aβ were examined. Results: After treatment with orexin, the formation of actin filaments around Aβ fibrils, which is needed for phagocytosis, was impaired, and phagocytosis regulating molecules such as PI3K, Akt, and p38-MAPK were downregulated in BV2 cells. Orexin also suppressed autophagic flux, through disruption of the autophagosome-lysosome fusion process, resulting in impaired Aβ degradation in BV2 cells. Conclusions: Our results demonstrate that orexin can hinder clearance of Aβ through the suppression of phagocytosis and autophagic flux in microglia. This is a novel mechanism linking AD and sleep, and suggests that attenuated microglial function, due to sleep deprivation, may increase Aβ accumulation in the brain.

Bing Xie*, Zanchao Liu*, Wenxuan Liu, Lei Jiang, Rui Zhang, Dongsheng Cui, Qingfu Zhang, Shunjiang Xu (Handling Associate Editor: Ling-Qiang Zhu) *These authors contributed equally to this work.
DNA Methylation and Tag SNPs of the BDNF Gene in Conversion of Amnestic Mild Cognitive Impairment into Alzheimer’s Disease: A Cross-Sectional Cohort Study
Abstract: Alzheimer's disease (AD) is a complex multifactorial disease influenced by both genetic and epigenetic factors. This study was aimed to evaluate the interaction between brain-derived neurotrophic factor (BDNF) promoter methylation status and tag single nucleotide polymorphisms (tag SNPs) on amnestic mild cognitive impairment (aMCI) and its conversion to AD. A total of 506 aMCI patients and 728 cognitive normal controls were included in the cross-sectional analysis. Patients (n = 458) from aMCI cohort were selected in the 5-year longitudinal study and classified into two groups: aMCI-stable group (n = 330) and AD-conversion group (n = 128). BDNF promoter methylation was detected by bisulfite-PCR amplification and pyrosequencing. Seven tag SNPs were genotyped by matrix-assisted laser desorption ionization time-of-flight mass spectrometry (MALDI-TOF MS). Elevation of BDNF promoter methylation status was associated with aMCI and AD conversion. The higher methylation levels at CpG5 site showed significant main interactive effects between group and time (F = 8.827, p = 0.005). Genetic analysis revealed rs2030324 and rs6265 were associated with aMCI and rs6265 was associated with AD conversion. The interaction between DNA methylation of CpG5 and AA genotype of rs6265 had a risk role in the development of aMCI (p = 0.019, OR = 1.233, 95% CI: 1.117 - 1.303) and its progression to AD (p = 0.003, OR = 1.399, 95% CI: 1.198 - 1.477). The interactions between DNA methylation (CpG5) of the BDNF gene promoter and the tag SNP (rs6265) play important roles in the etiology of aMCI and its conversion to AD.

Simin Mahinrad*, Annelotte E. Vriend*, J. Wouter Jukema, Diana van Heemst, Naveed Sattar, Gerard Jan Blauw, Peter W. Macfarlane, Elaine N. Clark, Anton J.M. de Craen, Behnam Sabayan (Handling Associate Editor: Philip Scheltens) *These authors contributed equally to this work.
Left Ventricular Hypertrophy and Cognitive Decline in Old Age
Abstract: Background: Patients with advanced heart failure run a greater risk of dementia. Whether early cardiac structural changes also associate with cognitive decline is yet to be determined. Objective: We tested whether left ventricular hypertrophy (LVH) derived from electrocardiogram associates with cognitive decline in older subjects at risk of cardiovascular disease. Methods: We included 4,233 participants (mean age 75.2 years, 47.8% male) from PROSPER (PROspective Study of Pravastatin in the Elderly at Risk). LVH was assessed from baseline electrocardiograms by measuring the Sokolow-Lyon index. Higher levels of Sokolow-Lyon index indicate higher degrees of LVH. Cognitive domains involving selective attention, processing speed, and immediate and delayed memory were measured at baseline and repeated during a mean follow-up of 3.2 years. Results: At baseline, LVH was not associated with worse cognitive function. During follow-up, participants with higher levels of LVH had a steeper decline in cognitive function including in selective attention (p = 0.009), processing speed (p = 0.010), immediate memory (p< 0.001), and delayed memory (p = 0.002). These associations were independent of cardiovascular risk factors, co-morbidities, and medications. Conclusion: LVH assessed by electrocardiogram associates with steeper decline in cognitive function of older subjects independent of cardiovascular risk factors and co-morbidities. This study provides further evidence on the link between subclinical cardiac structural changes and cognitive decline in older subjects.

Commentary
Jodi D. Edwards
The Importance of Identifying Early Changes in Cardiac Structure and Function for the Prevention of Cognitive Impairment and Dementia
Abstract: Multiple cardiac pathologies have been shown to contribute to progressive cognitive decline and dementia in elderly populations, including left ventricular hypertrophy (LVH), a marker of prolonged exposure to hypertension. Although associations between chronic hypertension and cognitive function are thought to be mediated primarily by these end organ effects, there is increasing evidence that early changes in cardiac structure and function, such as LVH, may independently contribute to cognitive decline and impairment. In the current issue of the Journal of Alzheimer’s Disease, Mahinrad and colleagues report important new findings on the association between LVH and cognitive function that are incremental to cardiovascular risk and co-morbidity, including hypertension. Emerging evidence that early changes in cardiac structure and function may independently contribute to cognitive decline in elderly populations has resulted in an increased interest in these preclinical substrates as potential treatment targets for the prevention of cognitive decline and in their putative contributions to the pathogenesis of dementia.