Volume 73, Number 2, 2020

Pages 431-442
Ethics Review

Rachel K.B. Hamilton, Cynthia H. Phelan, Nathaniel A. Chin, Mary F. Wyman, Nickolas Lambrou, Nichelle Cobb, Lisa Wilson, Amy J.H. Kind, Hanna Blazel, Sanjay Asthana, Carey E. Gleason
The U-ARE Protocol: A Pragmatic Approach to Decisional Capacity Assessment for Clinical Research
Abstract: With increased longevity and growth in the number of older adults comes rising rates of individuals with cognitive impairment and dementia. The expansion of this population has important implications for research on aging and dementia syndromes, namely increased enrollment of older individuals in clinical research. Ethical prerogatives, as well as historical underrepresentation of persons with dementia in research studies due to the perceived burden of traditional decisional capacity evaluations, necessitates the development of pragmatic approaches to ascertain decisional abilities in research settings. We outline a protocol used in the Wisconsin Alzheimer's Disease Research Center (ADRC) that adopts a stepped approach to the evaluation of decisional capacity meant to maximize study visit efficiency while preserving participant safety and autonomy. The protocol specifies the structure of the consent process and incorporates a brief semi-structured interview based on Appelbaum & Grisso’s theoretical model for evaluating a patient’s decisional capacity to provide informed consent to participate in research. This protocol is easily implemented in a research study visit and is designed to minimize participant burden and ensure reliable assessment of decisional capacity in older adults across a wide range of research protocols. The protocol emphasizes capacity optimization, using memory aids and other compensatory strategies to preserve participant autonomy while protecting welfare.

Pages 443-454

Nicole K. Rogers, Cesar Romero, Carol D. SanMartín, Daniela P. Ponce, Felipe Salech, Mercedes N. López, Alejandra Gleisner, Fabián Tempio, María I. Behrens
Inverse Relationship Between Alzheimer’s Disease and Cancer: How Immune Checkpoints Might Explain the Mechanisms Underlying Age-Related Diseases
Abstract: Alzheimer’s disease (AD) is the most prevalent neurodegenerative disease in the adult population. There is evidence of an inverse epidemiological relationship between AD and cancer, another prevalent age-related disease. This has led to hypothesize that there could be a common biological mechanism, deregulated in opposite directions that might explain the phenomenon of mutual protection. The immunological system and its regulatory checkpoints are good candidates to explain why having survived a cancer could protect from developing AD. During cancerous growth, the neoplastic cells induce immune tolerance to block the host’s immunity system that would prevent tumor growth. This has led to the development of drugs that block distinct immune checkpoints, such as Programmed Death 1 (PD-1) and its major ligand PD-L1, that have shown great promise in treating diverse types of cancer. We propose that in those individuals who survived a cancer, the immune system is left in a state of diminished tolerance or proinflammatory systemic milieu, after its successful attempt to fight the cancer, that protects them from developing AD.

Pages 455-459

Esme Fuller-Thomson, ZhiDi Deng
Could Lifetime Lead Exposure Play a Role in Limbic-predominant Age-related TDP-43 Encephalopathy (LATE)?
Abstract: Limbic-predominant Age-related TDP-43 Encephalopathy (LATE) is a disease whose clinical presentation mimics that of Alzheimer’s disease. TDP-43 proteinopathy associated with LATE has been identified in more than 20% of autopsies of community-dwelling adults over the age of 80. It is believed to contribute significantly toward tau-negative dementia. Heavy metals such as lead has also been linked to TDP-43 proteinopathy. In particular, lead triggers TDP-43 accumulation and disrupts TDP-43 homeostasis. However, the specific relationship between LATE and lead remains unknown. Before leaded gasoline was phased out during the 1970s and 1980s, average blood lead levels were 15 times what they are today. Thus, each successive birth cohort entering old age has had less cumulative life exposure to lead. Lifetime exposure can be tracked in the tibia bone, where the half-life of lead is many decades. We hypothesize that lead plays a role in the development of LATE. There are two ways to explore the validity of this hypothesis. Generational differences in lead exposure should result in a steady decline in the prevalence of LATE among older adults. We propose the use of tibia bone lead levels be examined in brain autopsies from different birth cohorts to examine the link between lead exposure and LATE prevalence, holding age constant. Furthermore, individuals with genetic polymorphisms that confer a greater lead absorption phenotype should display a higher degree of TDP-43 accumulation in autopsies. The results of such studies could provide insight into gene by environment interactions relevant to the development of LATE.

Pages 461-466
Short Communication

Philippos Koulousakis, Daniel van den Hove, Veerle Visser-Vandewalle, Thibaut Sesia
Cognitive Improvements After Intermittent Deep Brain Stimulation of the Nucleus Basalis of Meynert in a Transgenic Rat Model for Alzheimer’s Disease: A Preliminary Approach
Abstract: Deep brain stimulation (DBS) of the nucleus basalis of Meynert (NBM) has been shown to exert promising therapeutical effects in a pilot study with patients suffering from Alzheimer’s disease (AD). We aimed at comparing the cognitive effects of intermittent and continuous NBM stimulation paradigms in an animal model for AD. In this exploratory study, aged Tgf344-AD rats were behaviorally tested pre-, and post implantation, while being stimulated with unilateral- or bilateral-intermittent and bilateral-continuous patterns. Bilateral-intermittent NBM DBS lead to supernormal performance in a spatial memory task. These findings suggest that NBM DBS could be further refined, thereby improving patient care.

Pages 467-476
Marc Bouji, Anthony Lecomte, Christelle Gamez, Kelly Blazy, Anne-Sophie Villégier
Impact of Cerebral Radiofrequency Exposures on Oxidative Stress and Corticosterone in a Rat Model of Alzheimer’s Disease
Abstract: Background: Alzheimer's disease (AD) is the most common type of neurodegenerative disease leading to dementia. Several studies suggested that mobile phone radiofrequency electromagnetic field (RF-EMF) exposures modified AD memory deficits in rodent models. Objective: Here we aimed to test the hypothesis that RF-EMF exposure may modify memory through corticosterone and oxidative stress in the Samaritan rat model of AD. Methods: Long-Evans male rats received intracerebroventricular infusion with ferrous sulphate, amyloid-beta 1-42 peptide, and buthionine-sufloximine (AD rats) or with vehicle (control rats). To mimic cell phone use, RF-EMF were exposed to the head for 1 month (5 days/week, in restraint). To look for hazard thresholds, high brain averaged specific absorption rates (BASAR) were tested: 1.5 W/Kg (15 min), 6 W/Kg (15 min), and 6 W/Kg (45 min). The sham group was in restraint for 45 min. Endpoints were spatial memory in the radial maze, plasmatic corticosterone, heme oxygenase-1 (HO1), and amyloid plaques. Results: Results indicated similar corticosterone levels but impaired memory performances and increased cerebral staining of thioflavine and of HO1 in the sham AD rats compared to the controls. A correlative increase of cortical HO1 staining was the only effect of RF-EMF in control rats. In AD rats, RF-EMF exposures induced a correlative increase of hippocampal HO1 staining and reduced corticosterone. Discussion: According to our data, neither AD nor control rats showed modified memory after RF-EMF exposures. Unlike control rats, AD rats showed higher hippocampal oxidative stress and reduced corticosterone with the higher BASAR. This data suggests more fragility related to neurodegenerative disease toward RF-EMF exposures.

Pages 477-487
Monique J. Brown, Robert Patterson
Subjective Cognitive Decline Among Sexual and Gender Minorities: Results from a U.S. Population-Based Sample
Abstract: The risk of dementia and mild cognitive impairment between older adults in same-sex relationships and those in opposite-sex relationships have been found to be statistically not different. However, studies examining subjective cognitive decline (SCD) among sexual and gender minority populations (SGM) are lacking. The primary objective was to determine if SGM report greater SCD compared to non-SGM populations in a U.S. population-based sample of non-institutionalized adults aged 45 and older. The secondary objective was to assess the association between gender and SCD. Cross-sectional data were obtained from the 2016 Behavioral Risk Factor Surveillance System (n=36,734). There were 1,094 SGM adults in the sample. Descriptive statistics examined sociodemographic characteristics and their distribution by SCD and SGM status. Crude and multivariable logistic regression models were used to determine the association between SGM status, gender, and SCD. Adjusted models controlled for age, race/ethnicity, income, education, employment, marital status, depression, and diabetes. Statistically significant differences in SGM status and SCD existed by age, race/ethnicity, education, employment, marital status, and depression. Differences in SCD also existed by income and diabetes status. There was no statistically significant association between SGM status and SCD (OR: 0.88; 95% CI: 0.63–1.24). However, men had 64% higher odds (OR: 1.64; 95%CI: 1.44–1.88) of reporting SCD compared to women. Future studies examining the potential reasons for this null association, including resilience and/or premature aging are warranted. Future research assessing potential reasons for gender differences in SCD, whether physiological or environmental, is also needed.

Pages 489-501
Takashi Tarumi, Binu P. Thomas, Benjamin Y. Tseng, Ciwen Wang, Kyle B. Womack, Linda Hynan, Hanzhang Lu, C. Munro Cullum, Rong Zhang
Cerebral White Matter Integrity in Amnestic Mild Cognitive Impairment: A 1-Year Randomized Controlled Trial of Aerobic Exercise Training
Abstract: Cerebral white matter (WM) represents the structural substrate of neuronal communications which is damaged by Alzheimer’s disease (AD). Aerobic exercise training (AET) may improve WM integrity in cognitively normal older adults, but its efficacy remains unknown in patients with amnestic mild cognitive impairment (MCI), a prodromal phase of AD dementia. Therefore, we conducted a proof-of-concept study that randomized 70 amnestic MCI patients to a 1-year program of AET or a non-aerobic stretching and toning (SAT), active control group. Thirty-six patients completed both baseline and follow-up MRI scans, and cerebral WM integrity was measured by WM lesion volume and diffusion characteristics using fluid-attenuated-inversion-recovery and diffusion tensor imaging respectively. Peak oxygen uptake (VO2peak) and neuropsychological function were also measured. At baseline and 1-year follow-up, WM lesion volume and diffusion characteristics were similar between the AET and SAT groups, although VO2peak significantly improved after AET. The AET group showed slight improvement in neuropsychological performance. When analyzing individual data, tract-based spatial statistics demonstrated that VO2peak improvements are associated with attenuated elevations in mean and axial diffusivities, particularly the anterior WM fiber tracts (e.g., genu of corpus callosum). In patients with amnestic MCI, we found that although AET intervention did not improve WM integrity at group level analysis, individual cardiorespiratory fitness gains were associated with improved WM tract integrity of the prefrontal cortex.

Pages 503-515
Ping Yin*, Shuang Wang*, Yafen Wei, Xu Wang, Jingdian Zhang, Xiang Yin, Jiachun Feng*, Mingqin Zhu* *These authors contributed equally to this work.
Maresin1 Decreased Microglial Chemotaxis and Ameliorated Inflammation Induced by Amyloid-β42 in Neuron-Microglia Co-Culture Models
Abstract: Inflammation resolution is regulated by specialized pro-resolving lipid mediators (SPMs) and the levels of SPMs are found decreased in Alzheimer’s disease (AD) brain. We have previously found that one of the SPMs, Maresin1 (MaR1), improved neuronal survival and increase microglial phagocytosis of amyloid-β 1-42 (Aβ42); however, the mechanisms underlying the protective mechanism remain further investigation. We aim to investigate the effects of MaR1 on microglial chemotaxis and activation in this study. Both indirect and direct primary neuron and microglia co-culture system was used in this study. Our results showed MaR1 downregulated the increased microglial chemotaxis induced by Aβ42. The microglial inactivation marker CD200R was downregulated by Aβ42 and upregulated by MaR1. Pro-inflammatory cytokines secretion such as tumor necrosis factor (TNF)-α were increased by Aβ42 and these changes were revised by MaR1 treatment. In addition, the levels of chemokine monocyte chemoattractant protein (MCP)-1 were increased while the levels of anti-inflammatory factor IL-10 secretion were decreased by Aβ42, and these changes were abolished by MaR1 treatment. Moreover, by proteomics analysis, we identified cell signaling pathways affected by MaR1 were not only limited to inflammation-related pathways such as P38, but also in pathways involved in cell survival, autophagy, axon formation, and apoptosis, including PI3K/AKT, mTOR, ERK, caspase3, Cdc42, and p75NTR. In conclusion, MaR1 promoted inflammation resolution by inhibiting chemotaxis and regulating activation of microglia. MaR1 played a neuroprotective role by affecting cell signaling pathways involving inflammation, cell survival, autophagy, axon formation, and apoptosis inhibition.

Pages 517-528
Maoxiao Feng, Donghai Cui, Yi Li, Jian Shi, Lan Xiang, Hong Bian, Zhiyong Ma, Wen Xia, Guangwei Wei
Carnosic Acid Reverses the Inhibition of ApoE4 on Cell Surface Level of ApoER2 and Reelin Signaling Pathway
Abstract: The cell surface level of apolipoprotein E receptor 2 (ApoER2) increases by cyclic transport of ApoER2 and then activates Reelin signaling pathway to exert neuroprotective function in AD. ApoER2 ligand Apolipoprotein E4 (ApoE4) inhibits the recycling of ApoER2 to the cell surface rendering neurons unresponsive to Reelin. Carnosic acid (CA) is proven to possess neuroprotective and neurotrophic functions in Alzheimer’s disease (AD) mouse model. However, there are no reports about how ApoE4 impairs the recycling of ApoER2 and if CA can affect the cyclic transport of ApoER2. In this study, we demonstrated that ApoE4 attenuates the binding of sorting nexin 17 (SNX17) to ApoER2 and inhibits the recycling of ApoER2, resulting in decreased cell surface level of ApoER2. Further, we found that CA enhances the binding of SNX17 to ApoER2, counteracts the negative effects of ApoE4 on the cell surface level of ApoER2 to reverse the ApoE4-induced reduction in Reelin signaling activation by increasing the phosphorylation of the N-methyl-D-aspartate receptor (NMDAR) and cAMP-response element-binding protein (CREB) and the expression of Gria2. Thus, CA promotes neurite growth inhibited by ApoE4. Our work suggests that CA may be a potential approach to attenuate the risk of ApoE4-associated AD.

Pages 529-541
Cansu Agca, Diana Klakotskaia, Edward G. Stopa, Todd R. Schachtman, Yuksel Agca
Ovariectomy Influences Cognition and Markers of Alzheimer’s Disease
Abstract: Alzheimer’s disease (AD) is one of the most devastating and costly diseases, and prevalence of AD increases with age. Furthermore, females are twice as likely to suffer from AD compared to males. The cessation of reproductive steroid hormone production during menopause is hypothesized to cause this difference. Two rodent AD models, APP21 and APP+PS1, and wild type (WT) rats underwent an ovariectomy or sham surgery. Changes in learning and memory, brain histology, amyloid-β (Aβ) deposition, levels of mRNAs involved in Aβ production and clearance, and synaptic and cognitive function were determined. Barnes maze results showed that regardless of ovariectomy status, APP+PS1 rats learned slower and had poor memory retention. Ovariectomy caused learning impairment only in the APP21 rats. High levels of Aβ42 and very low levels of Aβ40 were observed in the brain cortices of APP+PS1 rats indicating limited endogenous PS1. The APP+PS1 rats had 43-fold greater formic acid soluble Aβ42 than Aβ40 at 17 months. Furthermore, levels of formic acid soluble Aβ42 increased 57-fold in ovariectomized APP+PS1 rats between 12 and 17 months of age. The mRNA encoding Grin1 significantly decreased due to ovariectomy whereas levels of Bace1, Chat, and Prkcb all decreased with age. The expression levels of mRNAs involved in Aβ degradation and AβPP cleavage (Neprilysin, Ide, Adam9, and Psenen) were found to be highly correlated with each other as well as hippocampal Aβ deposition. Taken together, these results indicate that both ovariectomy and genotype influence AD markers in a complex manner.

Pages 543-557
Felix Carbonell, Alex P. Zijdenbos, Barry J. Bedell, for the Alzheimer’s Disease Neuroimaging Initiative (Handling Associate Editor: Miguel Castelo-Branco)
Spatially Distributed Amyloid-β Reduces Glucose Metabolism in Mild Cognitive Impairment
Abstract: Background: Several positron emission tomography (PET) studies have explored the relationship between amyloid-β (Aβ), glucose metabolism, and the APOE ε4 genotype. It has been reported that APOE ε4, and not aggregated Aβ, contributes to glucose hypometabolism in pre-clinical stages of Alzheimer’s disease (AD) pathology. Objective: We hypothesize that typical measurements of Aβ taken either from composite regions-of-interest with relatively high burden actually cover significant patterns of the relationship with glucose metabolism. In contrast, spatially weighted measures of Aβ are more related to glucose metabolism in cognitively normal (CN) aging and mild cognitive impairment (MCI). Methods: We have generated a score of amyloid burden based on a joint singular value decomposition (SVD) of the cross-correlation structure between glucose metabolism, as measured by [18F]2-fluoro-2-deoxyglucose (FDG) PET, and Aβ, as measured by [18F]florbetapir PET, from the Alzheimer’s Disease Neuroimaging Initiative study. This SVD-based score reveals cortical regions where a reduced glucose metabolism is maximally correlated with distributed patterns of Aβ. Results: From an older population of CN and MCI subjects, we found that the SVD-based Aβ score was significantly correlated with glucose metabolism in several cortical regions. Additionally, the corresponding Aβ network has hubs that contribute to distributed glucose hypometabolism, which, in turn, are not necessarily foci of Aβ deposition. Conclusions: Our approach uncovered hidden patterns of the glucose metabolism-Aβ relationship. We showed that the SVD-based Aβ score produces a stronger relationship with decreasing glucose metabolism than either APOE ε4 genotype or global measures of Aβ burden.

Pages 559-569
Juhan Reimand, Colin Groot, Charlotte E. Teunissen, Albert D. Windhorst, Ronald Boellaard, Frederik Barkhof, Sergei Nazarenko, Wiesje M. van der Flier, Bart N.M. van Berckel, Philip Scheltens, Rik Ossenkoppel, Femke Bouwman
Why Is Amyloid-β PET Requested After Performing Cerebrospinal Fluid Biomarkers?
Abstract: Background: Amyloid-β PET and cerebrospinal fluid (CSF) Aβ42 are considered interchangeable for clinical diagnosis of Alzheimer’s disease. Objective: To explore the clinical reasoning for requesting additional amyloid-β PET after performing CSF biomarkers. Methods: We retrospectively identified 72 memory clinic patients who underwent amyloid-β PET after CSF biomarkers analysis for clinical diagnostic evaluation between 2011 and 2019. We performed patient chart reviews to identify factors which led to additional amyloid-β PET. Additionally, we assessed accordance with appropriate-use-criteria (AUC) for amyloid-β PET. Results: Mean patient age was 62.0 (SD=8.1) and mean Mini-Mental State Exam score was 23.6 (SD=3.8). CSF analysis conflicting with the clinical diagnosis was the most frequent reason for requesting an amyloid-β PET scan (n=53, 74%), followed by incongruent MRI (n=16, 22%), unusual clinical presentation (n=11, 15%) and young age (n=8, 11%). An amyloid-β PET scan was rarely (n=5, 7%) requested in patients with a CSF Aβ+/tau+ status. Fifteen (47%) patients with a post-PET diagnosis of AD had a predominantly non-amnestic presentation. In n=11 (15%) cases, the reason that the clinician requested amyloid-β was not covered by AUC. This happened most often (n=7) when previous CSF analysis did not support current clinical diagnosis, which led to requesting amyloid-β PET. Conclusion: In this single-center study, the main reason for requesting an amyloid-β PET scan after performing CSF biomarkers was the occurrence of a mismatch between the primary clinical diagnosis and CSF Aβ/tau results.

Pages 571-584
Sharon L. Naismith, Shantel L. Duffy, Nathan Cross, Ron Grunstein, Zoe Terpening, Camilla Hoyos, Angela D’Rozario, Jim Lagopoulos, Ricardo S. Osorio, James M. Shine, Andrew C. McKinnon (Handling Associate Editor: Michael Hornberger)
Nocturnal Hypoxemia Is Associated with Altered Parahippocampal Functional Brain Connectivity in Older Adults at Risk for Dementia
Abstract: Background: Obstructive sleep apnea is associated with an increased risk of developing mild cognitive impairment and dementia. Intermittent nocturnal hypoxemia in obstructive sleep apnea is associated with brain changes in key regions that underpin memory. Objective: To determine whether older adults with severe nocturnal hypoxemia would exhibit reduced functional connectivity within these regions, with associated deficits in memory. Methods: Seventy-two participants 51 years and over underwent polysomnography with continuous blood oxygen saturation recorded via oximetry. The oxygen desaturation index (ODI, 3% dips in oxygen levels per hour) was the primary outcome measure. ODI was split into tertiles, with analyses comparing the lowest and highest tertiles (N=48). Thirty-five of the 48 participants from these two tertiles had mild cognitive impairment. Participants also underwent resting-state fMRI and comprehensive neuropsychological, medical, and psychiatric assessment. Results: The highest ODI tertile group demonstrated significantly reduced connectivity between the left and right parahippocampal cortex, relative to the lowest ODI tertile group (t(42) = -3.26, p = 0.041, beta = -1.99).The highest ODI tertile group also had poorer working memory performance. In the highest ODI tertile group only, higher left-right parahippocampal functional connectivity was associated with poorer visual memory recall (between-groups z = -2.93, p = 0.0034). Conclusions: Older adults with severe nocturnal hypoxemia demonstrate impaired functional connectivity in medial temporal structures, key regions involved in sleep memory processing and implicated in dementia pathophysiology. Oxygen desaturation and functional connectivity in these individuals each relate to cognitive performance. Research is now required to further elucidate these findings.

Pages 585-596
Jade de Oliveira, Daiane F. Engel, Gabriela C. de Paula, Helen M. Melo, Samantha C. Lopes, Camila Tiefensee Ribeiro, Eslen Delanogare, José Claudio Fonseca Moreira, Daniel Pens Gelain, Rui D. Prediger, Nelson H. Gabilan, Eduardo Luiz G. Moreira, Sergio T. Ferreira, Andreza F. de Bem
LDL Receptor Deficiency Does not Alter Brain Amyloid-β Levels but Causes an Exacerbation of Apoptosis
Abstract: Familial hypercholesterolemia (FH) is a genetic disorder caused by dysfunction of low density lipoprotein receptors (LDLr), resulting in elevated plasma cholesterol levels. FH patients frequently exhibit cognitive impairment, a finding recapitulated in LDLr deficient mice (LDLr-/-), an animal model of FH. In addition, LDLr-/- mice are more vulnerable to the deleterious memory impact of amyloid-β (Aβ), a peptide linked to Alzheimer’s disease. Here, we investigated whether the expression of proteins involved in Aβ metabolism are altered in the brains of adult or middle-aged LDLr-/- mice. After spatial memory assessment, Aβ levels and gene expression of LDLr related-protein 1, proteins involved in Aβ synthesis, and apoptosis-related proteins were evaluated in prefrontal cortex and hippocampus. Moreover, the location and cell-specificity of apoptosis signals were evaluated. LDLr-/- mice presented memory impairment, which was more severe in middle-aged animals. Memory deficit in LDLr-/- mice was not associated with altered expression of proteins involved in Aβ processing or changes in Aβ levels in either hippocampus or prefrontal cortex. We further found that the expression of Bcl-2 was reduced while the expression of Bax was increased in both prefrontal cortex and hippocampus in 3- and 14-month-old LDLr-/-mice Finally, LDLr-/- mice presented increased immunoreactivity for activated caspase-3 in the prefrontal cortex and hippocampus. The activation of caspase 3 was predominantly associated with neurons in LDLr-/- mice. Cognitive impairment in LDLr-/- mice is thus accompanied by an exacerbation of neuronal apoptosis in brain regions related to memory formation, but not by changes in Aβ processing or levels.

Pages 597-607
Carl Eckerström, Marie Eckerström, Mattias Göthlin, Anna Molinder, Michael Jonsson, Petronella Kettunen, Johan Svensson, Sindre Rolstad, Anders Wallin
Characteristic Biomarker and Cognitive Profile in Incipient Mixed Dementia
Abstract: Background: Research has shown that mixed dementia is more common than previously believed but little is known of its early stages. Objective: To examine if incipient mixed dementia can be differentiated from incipient Alzheimer’s disease (AD) and subcortical ischemic vascular dementia (SVD) using neuropsychological tests, cerebrospinal fluid (CSF) markers, and magnetic resonance imaging markers. Methods: We included 493 patients and controls from the Gothenburg MCI study and used the dementia groups for marker selection (CSF total-tau (T-tau), phospho-tau (P-tau), and amyloid-β42 (Aβ42), 11 neuropsychological tests, and 92 regional brain volumes) and to obtain cut-off values which were then applied to the MCI groups. Results: Incipient mixed dementia was best differentiated from incipient AD by the Word fluency F-A-S test and the Trail making test A. CSF T-tau, P-tau, and Aβ42 differentiated incipient mixed dementia from incipient SVD. Conclusion: Incipient mixed dementia is characterized by an AD-like biomarker profile and an SVD-like cognitive profile. Incipient mixed dementia can be separated from incipient AD and incipient SVD using CSF markers and cognitive testing.

Pages 609-618
Longcai Wang*, Yanchun Qiao*, Haihua Zhang, Yan Zhang, Jiao Hua, Shuilin Jin, Guiyou Liu (Handling Associate Editor: Jin-Tai Yu) *These authors contributed equally to this work.
Circulating Vitamin D Levels and Alzheimer’s Disease: A Mendelian Randomization Study in the IGAP and UK Biobank
Abstract: Observational studies strongly supported the association of low levels of circulating 25-hydroxyvitamin D (25OHD) and cognitive impairment or dementia in aging populations. However, randomized controlled trials have not shown clear evidence that vitamin D supplementation could improve cognitive outcomes. In fact, some studies reported the association between vitamin D and cognitive impairment based on individuals aged 60 years and over. However, it is still unclear that whether vitamin D levels are causally associated with Alzheimer’s disease (AD) risk in individuals aged 60 years and over. Here, we performed a Mendelian randomization (MR) study to investigate the causal association between vitamin D levels and AD using a large-scale vitamin D genome-wide association study (GWAS) dataset and two large-scale AD GWAS datasets from the IGAP and UK Biobank with individuals aged 60 years and over. Our results showed that genetically increased 25OHD levels were significantly associated with reduced AD risk in individuals aged 60 years and over. Hence, our findings in combination with previous literature indicate that maintaining adequate vitamin D status in older people especially aged 60 years and over, may contribute to slow down cognitive decline and forestall AD. Long-term randomized controlled trials are required to test whether vitamin D supplementation may prevent AD in older people especially those aged 60 years and may be recommended as preventive agents.

Pages 619-632
Andrew C. Robinson, Stephen Chew-Graham, Yvonne S. Davidson, Michael A. Horan, Federico Roncaroli, James Minshull, Daniel du Plessis, Piyali Pal, Antony Payton, Neil Pendleton, David M.A. Mann (Handling Associate Editor: Brittany Dugger)
A Comparative Study of Pathological Outcomes in The University of Manchester Longitudinal Study of Cognition in Normal Healthy Old Age and Brains for Dementia Research Cohorts
Abstract: In the present study, we have characterized and compared individuals whose brains were donated as part of The University of Manchester Longitudinal Study of Cognition in Normal Healthy Old Age (UoM) with those donated through the Manchester arm of the UK Brains for Dementia Research (BDR) program. The aim of this study was to investigate how differences in study recruitment may affect final pathological composition of cohort studies. The UoM cohort was established as a longitudinal study of aging and cognition whereas the BDR program was established, prima facie, to collect brains from both demented and non-demented individuals for the purpose of building a tissue research resource. Consequently, the differences in recruitment patterns generated differences in demographic, clinical, and neuropathological characteristics. There was a higher proportion of recruits with dementia [mostly Alzheimer’s disease (AD)] within the BDR cohort than in the UoM cohort. In pathological terms, the BDR cohort was more ‘polarized’, being more composed of demented cases with high Braak pathology scores and non-demented cases with low Braak scores, and fewer non-AD pathology cases, than the UoM cohort. In both cohorts, cerebral amyloid angiopathy tended to be greater in demented than non-demented individuals. Such observations partly reflect the recruitment of demented and non-demented individuals into the BDR cohort, and also that insufficient study time may have elapsed for disease onset and development in non-demented individuals to take place. Conversely, in the UoM cohort, where there had been nearly 30 years of study time, a broader spread of AD-type pathological changes had ‘naturally’ evolved in the brains of both demented and non-demented participants.

Pages 633-644
Bora Yoon, Seong Hye Choi, Jee Hyang Jeong, Kyung Won Park, Eun-Joo Kim, Jihye Hwang, Jae-Won Jang, Hee Jin Kim, Jin Yong Hong, Jong-Min Lee, Ju-Hee Kang, Soo Jin Yoon (Handling Associate Editor: Sang Won Seo)
Balance and Mobility Performance Along the Alzheimer’s Disease Spectrum
Abstract: Background: Balance impairments are common in patients with Alzheimer’s disease (AD) dementia. Objective: We sought to determine the stage along the AD spectrum during which balance impairments appear and identify factors associated with a decline in balance function. Methods: Our cross-sectional study included 295 participants; 71 were cognitively normal (CN), 96 reported subjective cognitive decline (SCD), 72 had amnestic mild cognitive impairment (MCI), and 56 had AD dementia. The balance and mobility function was assessed using the Timed Up and Go test (TUG) and the One-Leg Standing Test (OLST). Results: Participants in the MCI and AD dementia groups were older than those in the cognitively normal and SCD groups. TUG and OLST test scores were linearly correlated with Mini-Mental Status Examination-Korean Version score (MMSE-KC). TUG score increased with greater AD spectrum severity (all p < 0.001), whereas OLST score showed a precipitous impairment starting in the SCD group (all p < 0.001), even after adjusting for age, sex, MMSE-KC, Geriatric depression scale, and body mass index. Based on subgroup analyses, in females and apolipoprotein E (APOE) ɛ4 carriers, there was significant balance/mobility impairment in the SCD group when compared to the CN group. Conclusion: Our results suggest that balance/mobility is related to cognitive function and that balance/mobility impairment can be observed beginning in the SCD stage. Furthermore, CN females and APOE ɛ4 carriers had better balance and mobility when compared to females and APOE ɛ4 carriers along the ADD spectrum/with cognitive impairment respectively.

Pages 645-655
Peter D. Fransquet, Karen Ritchie, Vania Januar, Richard Saffery, Marie-Laure Ancelin, Joanne Ryan (Handling Associate Editor: Elizabeta Mukaetova-Ladinska)
Is Peripheral BDNF Promoter Methylation a Preclinical Biomarker of Dementia?
Abstract: Brain-derived neurotrophic factor (BDNF) has been implicated in dementia. Preliminary evidence suggests that BDNF DNA methylation may be a diagnostic biomarker of dementia, but the potential pre-clinical utility remains unclear. Participants in the ESPRIT study were assessed for cognitive function and dementia (DSM-IV criteria) over 14 years. BDNF exon 1 promoter methylation was measured in blood at baseline (n=769) and buccal samples during follow-up (n=1062). Genotyping was carried out for several common BDNF SNPs, including Val66Met (rs6265) and APOE ɛ4. Multivariable logistic regression analyses determined the association between BDNF methylation and both prevalent and incident dementia. Adjustment for gender, age, education, APOE ε4 genotype, body mass index, depression, and type 2 diabetes, as well as possible effect modification by gender and genetic variation were also investigated. Weak evidence of an association between lower blood methylation and dementia was observed at one of 11 sites investigated (Δ-0.5%, 95%CI:-0.9,-0.04, p=0.03, p=0.22 adjusted for multiple comparisons). Buccal methylation at two other sites was associated with 14-year incident dementia cases prior to adjustment for multiple comparisons only, and the effect sizes were small (Δ+0.3%, OR:1.57, SE:0.30, p=0.02, p=0.14 adjusted and Δ-1.5%, OR:0.85, SE:0.06, p=0.03, p=0.14 adjusted). Genetic variation in the BDNF gene did not modify these associations, and no gender-specific effects were observed. There was only a weak correlation between blood and buccal BDNF log-methylation at two sites (both r=-0.11). There was no strong evidence that blood or buccal BDNF exon 1 promoter DNA methylation is associated with prevalent or incident dementia, and reported associations would not remain after adjustment for multiple testing.

Pages 657-670
Shuo Xiao*, Lin-Lin Song*, Jiang-Tao Li*, He Wang, Na Yu, Zi-Qi Wang, Ying Zhang, Jin-Sheng He, Tao Hung *These authors contributed equally to this work.
Intraperitoneal Administration of Monoclonal Antibody Against Pathologic Aβ42 Aggregates Alleviated Cognitive Deficits and Synaptic Lesions in APP/PS1 Mice
Abstract: Alzheimer’s disease (AD) is the most common form of dementia, characterized by amyloid-β peptide (Aβ) aggregates, phosphorylated tau protein (p-tau), and progressive neurodegeneration. Amyloid-β peptide 42 (Aβ42) is considered an early trigger of AD pathogenesis. We have previously reported that Aβ N-terminus monoclonal antibody (mAb) A8 alleviated cognitive dysfunction and reduced the abundance of soluble Aβ in brain of the senescence-accelerated mouse prone 8 (SAMP8) mouse model. To confirm the efficacy of mAb A8 in the double-transgenic APPswe/PS1ΔE9 (APP/PS1) mice, here we reported the related findings. The Morris water maze (MWM) data showed that the A8 treatment group had a shorter escape latency than the control groups in the place navigation test and the probe trial (p < 0.05). Moreover, immunohistochemistry showed decreased levels of both Aβ and p-tau in the brains of APP/PS1 mice. Regarding Aβ levels, western blot results showed that Aβ42 oligomer (p < 0.01) but not Aβ40 levels were diminished in brains of A8-treated APP/PS1 mice. Western blot results showed that phospho-tau (pSer231) (p < 0.01) but not tau levels were reduced in A8-treated mouse brains. Furthermore, transmission electron microscopy images indicated ultrastructural improvements, including an increased (p < 0.01) density of synapses and a reduction of abnormally enlarged mitochondria (p < 0.01), in the brains of A8-treated mice. Taken together, our data showed that mAb A8 is highly efficacious in APP/PS1 mice as a treatment for AD, and the underlying mechanism may target synaptic pathology by inhibiting the amyloid cascade.

Pages 671-682
Megan Zuelsdorff, Ozioma C. Okonkwo, Derek Norton, Lisa L. Barnes, Karen L. Graham, Lindsay R. Clark, Mary F. Wyman, Susan F. Benton, Alexander Gee, Nickolas Lambrou, Sterling C. Johnson, Carey E. Gleason (Handling Associate Editor: Laura Zahodne)
Stressful Life Events and Racial Disparities in Cognition Among Middle-Aged and Older Adults
Abstract: Background: It is well-documented that African Americans have elevated risk for cognitive impairment and dementia in late life, but reasons for the racial disparities remain unknown. Stress processes have been linked to premature age-related morbidity, including Alzheimer’s and related dementias (ADRD), and plausibly contribute to social disparities in cognitive aging. Objective: We examined the relationship between stressful life events and cognitive decline among African American and White participants enrolled in the Wisconsin Registry for Alzheimer’s Prevention (WRAP). Methods: Linear mixed models including demographic, literacy, and health-related covariates were used to estimate (1) relationships between a life event index score and decline in cognitive test performance in two domains of executive function (Speed & Flexibility, Working Memory) and one domain of episodic memory (Verbal Learning & Memory) among 1,241 WRAP enrollees, stratified by race, and (2) contributions of stressful life events to racial differences in cognition within the full sample. Results: African Americans (N=50) reported more stressful life events than Whites (N=1,191). Higher stress scores associated with poorer Speed & Flexibility performance in both groups, though not with declines across time, and partially explained racial differentials in this domain. Among African Americans only, stressor exposure also associated with age-related decline in Verbal Learning & Memory. Stressor-cognition relationships were independent of literacy and health-related variables. Conclusions: Greater lifetime stress predicted poorer later-life cognition, and, in a small sample of African Americans, faster declines in a key domain of episodic memory. These preliminary findings suggest that future work in large minority aging cohorts should explore stress as an important source of modifiable, socially-rooted risk for impairment and ADRD in African Americans, who are disproportionately exposed to adverse experiences across the life course.

Pages 683-693
Zoe van Havre, Paul Maruff, Victor Villemagne, Kerrie Mengersen, Judith Rousseau, Nicole White, James D. Doecke
Identification of Pre-Clinical Alzheimer’s Disease in a Population of Elderly Cognitively Normal Participants
Abstract: Alzheimer’s disease (AD) has a long pathological process, with an approximate lead-time of 20 years. During the early stages of the disease process, little evidence of the building pathology is identifiable without cerebrospinal fluid and/or imaging analyses. Clinical manifestations of AD do not present until irreversible pathological changes have occurred. Given an opportunity to provide treatment prior to irreversible pathological change, this study aims to identify a subgroup of cognitively normal (CN) participants from the Australian Imaging, Biomarker & Lifestyle Flagship Study of Ageing (AIBL), where subtle changes in cognition are indicative of early AD-related pathology. Using a Bayesian method for unsupervised clustering via mixture models, we define an aggregate measure of posterior probabilities (AMPP score) establishing the likelihood of pre-clinical AD. From Baseline through to 54 months, visuo-spatial function had the greatest contribution to the AMPP score, followed by attention and processing speed and visual memory. Participants with the highest AMPP scores had both increasing neo-cortical amyloid burden and decreasing hippocampus volume over 54 months, compared to those in the lowest category with stable amyloid burden and hippocampus volume. The identification of a possible pre-clinical stage in CN participants via this method, without the aid of disease specific biomarkers, represents an important step in utilizing the strength of cognitive composite scores for the early detection of AD pathology.

Pages 695-705
Rajnish Kumar, Pavel F. Pavlov, Bengt Winblad
Metal Binding by GMP-1 and Its Pyrimido[1,2]benzimidazole Analogs Confirms Protection Against Amyloid-β Associated Neurotoxicity
Abstract: Alzheimer’s disease (AD) represents a major public health threat and, unfortunately, available therapeutics provide only temporary symptomatic relief. AD is a complex multifactorial disease and failure of single target therapeutics targeting amyloid-β (Aβ) in recent clinical trials suggests that future AD drug development should be focused on simultaneous targeting of several pathological hallmarks of the disease. Recently, we have shown that GMP-1, a 2-(methoxymethyl)pyrimido[1,2-a] benzimidazol-4-ol, protects mitochondrial function in drosophila and mice models of AD, and improved memory and behavior indicating neuroprotective effect of GMP‐1 treatment. Here, we have found that GMP-1 specifically binds to copper and zinc, metals that are dysregulated in AD brain. Addition of GMP-1 does not inhibit metal-dependent enzymatic reactions. Also, binding of Zn(II) and Cu(II) by GMP-1 is weaker than the 8-hydroxyquinoline scaffold compound clioquinol previously tested in AD clinical trials. However, GMP-1 affects Cu(II)-dependent Aβ fibrillization as well as oxidative damage and viability of SH-SY5Y cells upon addition of Cu(II) and Aβ. Our data provide new insight on GMP-1 as a Zn(II) and Cu(II) specific metal chelator of moderate affinity that can be responsible for some of its neuroprotective effects observed in AD animal models.

Pages 707-714
Lana Fani, Saima Hilal, Sanaz Sedaghat, Linda Broer, Silvan Licher, Pascal P. Arp, Joyce B.J. van Meurs, M. Kamran Ikram, M. Arfan Ikram
Telomere Length and the Risk of Alzheimer’s Disease: The Rotterdam Study
Abstract: There is a wide interest in biomarkers that capture the burden of detrimental factors as these accumulate with the passage of time, i.e., increasing age. Telomere length has received considerable attention as such a marker, because it is easily quantified and it may aid in disentangling the etiology of dementia or serve as predictive marker. We determined the association of telomere length with risk of Alzheimer’s disease and all-cause dementia in a population-based setting. Within the Rotterdam Study, we performed quantitative PCR to measure mean leukocyte telomere length in blood. We determined the association of telomere length with risk of Alzheimer’s disease until 2016, using Cox regression models. Of 1,961 participants (mean age 71.4±9.3 years, 57.1% women) with a median follow-up of 8.3 years, 237 individuals were diagnosed with Alzheimer’s disease. We found a U-shaped association between telomere length and risk of Alzheimer’s disease: compared to the middle tertile the adjusted hazard ratio was 1.59 (95% confidence interval (CI), 1.13-2.23) for the lowest tertile and 1.47 (1.03-2.10) for the highest tertile. Results were similarly U-shaped but slightly attenuated for all-cause dementia. In conclusion, shorter and longer telomere length are both associated with an increased risk of Alzheimer’s disease in the general population.

Pages 715-721
Marco Canevelli, Valerio Zaccaria, Eleonora Lacorte, Ilaria Cova, Giulia Remoli, Ilaria Bacigalupo, Silvia Cascini, Anna Maria Bargagli, Simone Pomati, Leonardo Pantoni, Nicola Vanacore (Handling Associate Editor: Carlo Abbate)
Mild Cognitive Impairment in the Migrant Population Living in Europe: An Epidemiological Estimation of the Phenomenon
Abstract: Background: The construct of mild cognitive impairment (MCI) is triggering growing clinical and research interest. The detection of MCI may be affected by diverse ethno-cultural determinants possibly influencing the personal and social perception of the individual cognitive functioning as well as the reliability of objective cognitive assessment. These challenges may acquire special relevance in subjects with a migration background and composing ethnic minority groups. Objective: The present study is aimed at providing an estimate of the number of MCI cases occurring in the migrant population living in the extended European Union (EU) in 2018. Methods: The number of MCI cases in older migrants living in Europe and in each of the 32 considered countries was estimated by multiplying the number of migrants, provided by Eurostat, with the age-specific prevalence rates, derived by the harmonized data produced by the COSMIC collaboration and based on different operational definitions of MCI. Results: Nearly 686,000 cases of MCI were estimated in the extended EU by applying age-specific prevalence rates based on the International Working Group criteria. Higher figures were obtained when the Clinical Dementia Rating- and the Mini Mental State Examination-based criteria were applied. The proportion of MCI cases in migrant subjects ranged from 1.1% (Romania) to 54.1% (Liechtenstein) (median: 8.4%; IQR: 4.7%-14.2%). Conclusions: MCI represents and will increasingly constitute a relevant issue in the migrant population living in Europe. The present data reinforce the need of developing approaches and models of care that may be diversity-sensitive and inclusive for a culturally variegated population.

Pages 723-739
Edward N. Wilson, Sonia Do Carmo, Lindsay A. Welikovitch, Hélène Hall, Lisi Flores Aguilar, Morgan K. Foret, M. Florencia Iulita, Dan Tong Jia, Adam R. Marks, Simon Allard, Joshua T. Emmerson, Adriana Ducatenzeiler, A. Claudio Cuello
NP03, a Microdose Lithium Formulation, Blunts Early Amyloid Post-Plaque Neuropathology in McGill-R-Thy1-APP Alzheimer-Like Transgenic Rats
Abstract: Epidemiological, preclinical, and clinical studies have suggested a role for microdose lithium in reducing Alzheimer’s disease (AD) risk by modulating key mechanisms associated with AD pathology. The novel microdose lithium formulation, NP03, has disease-modifying effects in the McGill-R-Thy1-APP transgenic rat model of AD-like amyloidosis at pre-plaque stages, before frank amyloid-β (Aβ) plaque deposition, during which Aβ is primarily intraneuronal. Here, we are interested in determining whether the positive effects of microdose lithium extend into early Aβ post-plaque stages. We administered NP03 (40 µg Li/kg; 1 ml/kg body weight) to McGill-R-Thy1-APP transgenic rats for 12 weeks spanning the transition phase from plaque-free to plaque-bearing. The effect of NP03 on remote working memory was assessed using the novel object recognition task. Levels of human Aβ38, Aβ40, and Aβ42 as well as levels of pro-inflammatory mediators were measured in brain-extracts and plasma using electrochemiluminescent assays. Mature Aβ plaques were visualized with a thioflavin-S staining. Vesicular acetylcholine transporter (VAChT) bouton density and levels of chemokine (C-X-C motif) ligand 1 (CXCL1), interleukin-6 (IL-6), and 4-hydroxynonenal (4-HNE) were probed using quantitative immunohistochemistry. During the early Aβ post-plaque stage, we find that NP03 rescues functional deficits in object recognition, reduces loss of cholinergic boutons in the hippocampus, reduces levels of soluble and insoluble cortical Aβ42 and reduces hippocampal Aβ plaque number. In addition, NP03 reduces markers of neuroinflammation and cellular oxidative stress. Together these results indicate that microdose lithium NP03 is effective at later stages of amyloid pathology, after appearance of Aβ plaques.

Pages 741-749
Ane Miren Crespo-Cuevas, Elena López-Cancio, Cynthia Cáceres, Anna González, Lourdes Ispierto, María Hernández-Pérez, María Mataró, Anna Planas, Tamara Canento, Lorena Martín, Juan Francisco Arenillas, Ramiro Alvarez, Dolores Vilas
Third Ventricle Width Assessed by Transcranial Sonography as Predictor of Long-Term Cognitive Impairment
Abstract: Background: Non-invasive biomarkers of cognitive impairment are needed. We aim to evaluate transcranial sonographic markers as predictors of cognitive impairment in a prospective cohort. Objective: To study the changes in the third ventricle diameter and the SN echogenicity between the baseline and the control visit, as well as its association with cognitive performance and the diagnosis of cognitive impairment in a prospective cohort. Methods: From the longitudinal population-based Asymptomatic Intracranial Atherosclerosis Study, we selected those subjects that received a complete transcranial sonography (TCS) and extensive cognitive testing, both at baseline and follow-up. We evaluated third ventricle (IIIv) width, echogenicity of substantia nigra (SN), and temporal changes of these parameters. Results: We included 289 participants with a median follow-up time of 7.16 years. Those subjects who developed cognitive decline (n=23, 7.96%) had a larger IIIv at baseline than those who did not (0.54±0.14 cm versus 0.41±0.15 cm; p=0.001). A cut-off point of 0.465 cm for the IIIv width was identified as an independent predictor of long-term cognitive impairment after adjustment for age, gender, educational level, and vascular risk score. Change in IIIv diameter after follow-up was not associated with diagnosis of cognitive impairment. The area of SN and the presence of hyperechogenicity of the SN remained stable over time and was not associated with the diagnosis of cognitive impairment. Conclusion: IIIv width assessed by TCS emerged as an independent predictor of long-term cognitive impairment.

Pages 751-758
Wanqing Wu, Ding Ding, Qianhua Zhao, Ruru Wang, Xiaoniu Liang, Zhenxu Xiao, Jianfeng Luo, Qihao Guo, Zhen Hong
Medium-to-High Late-Life Physical Activity Is Associated with Lower Risk of Incident Dementia: The Shanghai Aging Study
Abstract: Background: There is significant evidence that physical activity has profound effects on the neurochemistry and plasticity of the brain and may prevent cognitive decline. Objective: This study aimed to determine the association between physical activity and incident dementia among older Chinese adults. Methods: In the prospective phase of the Shanghai Aging Study, 1,648 community-dwellers aged 60 years or older were followed for an average of 5 years. Their physical activity was assessed based on questionnaires. The physical activities were further transformed into metabolic equivalent values. A consensus diagnosis of incident dementia was ascertained based on medical, neurological, and neuropsychological data and the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition. Results: We identified 166 incident dementia cases; the incidence rate was 19.4 per 1000 person-years. A multivariate Cox regression model indicated that compared to low levels of physical activity, medium-to-high levels of physical activity were associated with a reduced risk of dementia (hazard ratio, 95% confidence interval = 0.62, 0.44-0.89) after adjusting for age, sex, years of education, apolipoprotein E ε4, and other confounders. Conclusion: Our findings demonstrate that medium-to-high level of physical activity is protective against dementia in older adults.

Pages 759-768
Yan-Li Wang*, Wei Chen*, Wen-Jie Cai*, Hao Hu, Wei Xu, Zuo-Teng Wang, Xi-Peng Cao, Lan Tan, Jin-Tai Yu, Alzheimer’s Disease Neuroimaging Initiative (Handling Associate Editor: Yong Liu) *These authors contributed equally to this work.
Associations of White Matter Hyperintensities with Cognitive Decline: A Longitudinal Study
Abstract: White matter hyperintensities (WMHs), mainly caused by cerebrovascular injury, may lead to cognitive impairment. In order to identify whether the volume of WMHs is associated with cognitive decline over years, this longitudinal study involved 818 individuals from the ADNI-2 dataset from August 2010 to May 2017. Cross-sectional and longitudinal associations of WMHs with 8 cognitive domains were explored, using Mini-Mental State Examination (MMSE), Montreal Cognitive Assessment (MoCA), Clinical Dementia Rating Sum of Boxes (CDRSB), Alzheimer Disease Assessment Scale-Cognitive (ADAS-Cog13), Rey Auditory Verbal Learning Test (RAVLT), Functional Assessment Questionnaire (FAQ), executive function (ADNI-EF), and memory function (ADNI-Mem). The association analyses were performed using multiple linear regression models, linear mixed models, Spearman rank correlation, and Kaplan-Meier survival curves. The volumes of WMHs were greater in patients with Alzheimer’s disease (AD) dementia compared with controls (p<0.001) and mild cognitive impairment (p=0.006) patients at baseline. The bigger volumes of WMHs correlated with worse performances on ADAS-Cog13 and ADNI-EF (p=0.029; p=0.003) at baseline and MMSE, MoCA, CDRSB, ADAS-Cog13, FAQ, and ADNI-Mem (overall p<0.05) longitudinally, after adjusting for age, sex, educational level, apolipoprotein E ε4 genotype, hypertension, hyperlipidemia, diabetes, smoking, infarction, and diagnosis. Additionally, the correlations between the change rate of WMHs and change rates of MMSE, MoCA, CDRSB, FAQ, ADNI-EF, and ADNI-Mem were statistically significant. Furthermore, patients with high WMH volumes showed an increased likelihood of dementia. The results of the study suggest that WMH volume is associated with cognitive decline, and it contributes to the conversion to AD.

Pages 769-783
Marta Bisbe, Andrea Fuente-Vidal, Elisabet López, Marta Moreno, Marian Naya, Claudio de Benetti, Raimon Milà, Olga Bruna, Mercè Boada, Montserrat Alegret
Comparative Cognitive Effects of Choreographed Exercise and Multimodal Physical Therapy in Older Adults with Amnestic Mild Cognitive Impairment: Randomized Clinical Trial
Abstract: Background: Recent research on mild cognitive impairment (MCI) has primarily focused on searching for measures to prevent or delay the progression of MCI to dementia. Physical exercise has shown to be effective in the prevention of age-related cognitive decline in elderly adults with MCI. However, the most effective type and dose of exercise for the improvement of cognition are yet to be determined. Objective: To compare the cognitive effects of choreographed exercise (Choreography group) with a multimodal physical therapy program (Physical Therapy group) in elderly adults with amnestic MCI, a population with an increased risk of developing dementia. Methods: We conducted a randomized clinical trial with two parallel groups under allocation concealment and assessor blinding. Participants were allocated into Choreography or Physical Therapy group and performed exercises twice per week in 60-minute sessions during 12 weeks. Results: Thirty-six participants with amnestic MCI, ages 65 to 85, were assessed at baseline and after 12 weeks of intervention, by comprehensive validated neuropsychological and physical assessments. A Repeated measures General Lineal Model showed statistically significant differences in cognitive and physical outcomes. Both groups significantly improved in visual delayed recall. The Choreography group exhibited significantly more benefits on verbal recognition memory than the Physical Therapy group. Conclusion: Greater cognitive benefits were achieved in the choreographic intervention than in the multimodal physical therapy, mainly in those functions more related to the risk of conversion to dementia. Additional studies are needed to confirm whether the observed effects are related to delayed onset of Alzheimer’s disease in elderly adults with amnestic MCI.

Pages 785-790
Kimberly E. Capp, Rosie E. Curiel Cid, Elizabeth A. Crocco, Ashley Stripling, Marcela Kitaigorodsky, Luis A. Sierra, Jose G. Melo, David A. Loewenstein
Semantic Intrusion Error Ratio Distinguishes Between Cognitively Impaired and Cognitively Intact African American Older Adults
Abstract: Background: Semantic intrusion errors on memory tests may represent very early cognitive changes associated with elevated Alzheimer’s disease pathology within the brain, including amyloid-β (Aβ). Subscales that measure proactive semantic interference (PSI) and intrusions related to PSI on the Loewenstein Acevedo Scales of Semantic Interference and Learning (LASSI-L) have been associated with high levels of brain amyloid load, structural changes on brain MRI in Hispanic and non-Hispanic groups. It is presently unknown whether intrusion errors or other measures of the LASSI-L can differentiate between African-American (AA) older adults diagnosed with amnestic mild cognitive impairment (aMCI) or classified as cognitively normal (CN). Objective: This study examined the extent to which a high percentage of semantic intrusion errors on LASSI-L subscales susceptible to PSI and other LASSI-L measures could differentiate between AA aMCI and CN groups. Methods: Forty-eight AA older adults were recruited (27 CN and 21 aMCI) and received a through clinical and neuropsychological evaluation. The LASSI-L was administered independent of diagnostic classification. Results: With and without statistical adjustment for literacy, AA aMCI participants scored lower on all LASSI-L measures. ROC analyses revealed an area under the curve exceeding 90% and correctly classified 86% of AA aMCI with 82% specificity for AA CN participants. Conclusions: Percentage of intrusion errors on the LASSI-L subscales susceptible to PSI differentiated AA aMCI from AA CN. This adds to emerging evidence indicating that the LASSI-L may be culturally appropriate and can differentiate between aMCI and CN in diverse ethnic/cultural groups.

Pages 791-799
Anne Wohlgemuth, Bernhard Michalowsky, Diana Wucherer, Tilly Eichler, Jochen René Thyrian, Ina Zwingmann, Anika Rädke, Wolfgang Hoffmann
Drug-Related Problems Increase Healthcare Costs for People Living with Dementia
Abstract: Background: Drug-related problems (DRP) are common in the elderly population, especially in people living with dementia (PwD). DRP are associated with adverse outcomes that could result in increased costs. Objective: The objective of the study was to analyze the association between DRP and healthcare costs in PwD. Methods: The analysis was based on the cross-sectional data of 424 PwD. Compliance, adverse effects, and drug administration of prescribed and over-the-counter drugs taken were assessed. DRP were identified and classified by pharmacists using an adapted German version of “PIE-Doc®”. Healthcare utilization was assessed retrospectively used to calculated costs from a public payer perspective using standardized unit costs. The associations between DRP and healthcare costs were analyzed using multiple linear regression models. Results: 394 PwD (93%) had at least one DRP. An inappropriate drug choice was significantly associated with increased total costs (b=2,718€; CI95% 1,448-3,988) due to significantly higher costs for hospitalization (b=1,936€; 670-3,202) and for medications (b=417€; 68 to 765). Problems with medication dosage and drug interactions were significantly associated with higher medication costs (b=679€; 31-1,328; and b=630€; 259-1,001, respectively). Conclusions: DRP could significantly lead to adverse outcomes for PwD and healthcare payers, reflected by a higher hospitalization and costs, respectively. Further research is needed to clarify on interventions and approaches efficiently avoiding DRP and on the effect on patient-reported and economic outcomes.

Pages 801-809
Guillaume Albaret, Elodie Sifré, Pauline Floch, Sophie Laye, Agnès Aubert, Pierre Dubus, Lamia Azzi-Martin, Alban Giese, Nathalie Salles, Francis Mégraud, Christine Varon, Philippe Lehours, Claire Roubaud-Baudron (Handling Associate Editor: Sim Singhrao)
Alzheimer’s Disease and Helicobacter pylori Infection: Inflammation from Stomach to Brain?
Abstract: Despite extensive research, the origin of Alzheimer’s disease (AD) remains unknown. The role of infectious pathogens has recently emerged. Epidemiological studies have shown that Helicobacter pylori infection increases the risk of developing AD. We hypothesized that H. pylori-induced gastritis may be associated with a systemic inflammation and finally neuroinflammation. C57BL/6 mice were infected with H. pylori (n=15) or Helicobacter felis (n=13) or left uninfected (n=9) during 18 months. Gastritis, amyloid deposition, astroglial and microglial cell area, and systemic and brain cytokines were assessed. The infection (H. felis > H. pylori) induced a severe gastritis and an increased neuroinflammation but without brain amyloid deposition or systemic inflammation.

Pages 811-818
Yanxing Chen*, Caixiu Lin*, Zhangyu Guo, Shuai Zhao, Yueli Zhu, Fude Huang, Guanghou Shui, Sin Man Lam, Jiali Pu, Yaping Yan, Zhirong Liu, Baorong Zhang Handling Associate Editor: Xiaochuan Wang) *These authors contributed equally to this work.
Altered Expression Profile of Phosphatidylinositols in Erythrocytes of Alzheimer’s Disease and Amnestic Mild Cognitive Impairment Patients
Abstract: Background: Studies have demonstrated that the levels of phospholipids, including phosphatidylinositols (PIs), were decreased in Alzheimer’s disease (AD) brain, presenting as a potential biomarker for AD. The plasma phospholipids levels have also been discovered to predict the conversion of cognitively normal elderly adults to amnestic mild cognitive impairment (aMCI) or demented patients. Objective: To investigate the expression profile of PIs in erythrocytes of AD and aMCI patients, which would serve as a blood-based method to distinguish AD and aMCI patients from normal controls (NC). Methods: In this study, we used anion-exchange high-performance liquid chromatography to analyze PIs alterations in erythrocytes from a total of 86 prospectively recruited subjects (including 24 NC, 21 aMCI patients, and 41 AD patients). Results: We found that the levels of PI40:4, PI3/5P, and PI(3,4)P2 in aMCI patients, and the levels of PI4P, PI(3,4)P2, and PI3/5P in AD patients were significantly decreased compared to NC. The changed expression profile of PIs could effectively discriminate AD and aMCI patients from NC (AUC=0.964, 0.938, respectively). Conclusion: The altered expression profile of erythrocytes PIs might be a potential blood-based biomarker for AD and aMCI. This alteration of PIs probably reflected the impaired deformability and oxygen-carrying capacity of erythrocytes in AD and aMCI patients.