Volume 82, Number 4, IN PRESS

Review
David R. Elmaleh, Matthew A. Downey, Ljiljana Kundakovic, Jeremy E. Wilkinson, Ziv Neeman, Eran Segal (Handling Associate Editor: Giulio Pasinetti)
New Approaches to Profile the Microbiome for Treatment of Neurodegenerative Disease
Abstract: Progressive neurodegenerative diseases represent some of the largest growing treatment challenges for public health in modern society. These diseases mainly progress due to aging and are driven by microglial surveillance and activation in response to changes occurring in the aging brain. The lack of efficacious treatment options for Alzheimer’s disease (AD), as the focus of this review, and other neurodegenerative disorders has encouraged new approaches to address neuroinflammation for potential treatments. Here we will focus on the increasing evidence that dysbiosis of the gut microbiome is characterized by inflammation that may carry over to the central nervous system and into the brain. Neuroinflammation is the common thread associated with neurodegenerative diseases, but it is yet unknown at what point and how innate immune function turns pathogenic for an individual. This review will address extensive efforts to identify constituents of the gut microbiome and their neuroactive metabolites as a peripheral path to treatment. This approach is still in its infancy in substantive clinical trials and requires thorough human studies to elucidate the metabolic microbiome profile to design appropriate treatment strategies for early stages of neurodegenerative disease. We view that in order to address neurodegenerative mechanisms of the gut, microbiome and metabolite profiles must be determined to pre-screen AD subjects prior to the design of specific, chronic titrations of gut microbiota with low-dose antibiotics. This represents an exciting treatment strategy designed to balance inflammatory microglial involvement in disease progression with an individual’s manifestation of AD as influenced by a coercive inflammatory gut.

Hypothesis
Alberto J. Espay, Andrea Sturchio, Lon S. Schneider, Kariem Ezzat
Soluble Amyloid‐β Consumption in Alzheimer’s Disease
Abstract: Brain proteins function in their soluble, native conformation and cease to function when transformed into insoluble aggregates, also known as amyloids. Biophysically, the soluble-to-insoluble phase transformation represents a process of polymerization, similar to crystallization, dependent on such extrinsic factors as concentration, pH, and a nucleation surface. The resulting cross-β conformation of the insoluble amyloid is markedly stable, making it an unlikely source of toxicity. The spread of brain amyloidosis can be fully explained by mechanisms of spontaneous or catalyzed polymerization and phase transformation instead of active replication, which is an enzyme- and energy-requiring process dependent on a specific nucleic acid code for the transfer of biological information with high fidelity. Early neuronal toxicity in Alzheimer’s disease may therefore be mediated to a greater extent by a reduction in the pool of soluble, normal-functioning protein than its accumulation in the polymerized state. This alternative loss-of-function hypothesis of pathogenicity can be examined by assessing the clinical and neuroimaging effects of administering non-aggregating peptide analogs to replace soluble amyloid‐β levels above the threshold below which neuronal toxicity may occur. Correcting the depletion of soluble amyloid‐β, however, would only exemplify ‘rescue medicine.’ Precision medicine will necessitate identifying the pathogenic factors catalyzing the protein aggregation in each affected individual. Only then can we stratify patients for etiology-specific treatments and launch precision medicine for Alzheimer’s disease and other neurodegenerative disorders.

Hypothesis
Peter Nara, Marc Penn, Daniel Sindelar, Jan Potempa, W. Sue T. Griffin
Porphyromonas gingivalis Outer Membrane Vesicles as the Major Driver of and Explanation for Neuropathogenesis, the Cholinergic Hypothesis, Iron Dyshomeostasis, and Salivary Lactoferrin in Alzheimer’s Disease
Abstract: Porphyromonas gingivalis (Pg) is a primary oral pathogen in the widespread biofilm-induced “chronic” multi-systems inflammatory disease(s) including Alzheimer’s disease (AD). It is possibly the only second identified unique example of a biological extremophile in the human body. Having a better understanding of the key microbiological and genetic mechanisms of its pathogenesis and disease induction are central to its future diagnosis, treatment, and possible prevention. The published literature around the role of Pg in AD highlights the bacteria’s direct role within the brain to cause disease. The available evidence, although somewhat adopted, does not fully support this as the major process. There are alternative pathogenic/virulence features associated with Pg that have been overlooked and may better explain the pathogenic processes found in the “infection hypothesis” of AD. A better explanation is offered here for the discrepancy in the relatively low amounts of “Pg bacteria” residing in the brain compared to the rather florid amounts and broad distribution of one or more of its major bacterial protein toxins. Related to this, the “Gingipains Hypothesis”, AD-related iron dyshomeostasis, and the early reduced salivary lactoferrin, along with the resurrection of the Cholinergic Hypothesis may now be integrated into one working model. The current paper suggests the highly evolved and developed Type IX secretory cargo system of Pg producing outer membrane vesicles may better explain the observed diseases. Thus it is hoped that this paper can provide a unifying model for the sporadic form of AD and guide the direction of research, treatment, and possible prevention.

Short Communication
Sarang Kang*, Jungsoo Gim*, Jiwoon Lee, Tamil Iniyan Gunasekaran, Kyu Yeong Choi, Jang Jae Lee, Eun Hyun Seo, Pan-Woo Ko, Ji Yeon Chung, Seong-Min Choi, Young Min Lee, Jee Hyang Jeong, Kyung Won Park, Min Kyung Song, Ho-Won Lee, Ki Woong Kim, Seong Hye Choi, Dong Young Lee, Sang Yun Kim, Hoowon Kim, Byeong C. Kim, Takeshi Ikeuchi, Kun Ho Lee *These authors contributed equally to this work.
Potential Novel Genes for Late-Onset Alzheimer's Disease in East-Asian Descent Identified by APOE-Stratified Genome-Wide Association Study
Abstract: The present study reports two novel genome-wide significant loci for late-onset Alzheimer’s disease (LOAD) identified from APOE ε4 non-carrier subjects of East Asian origin. A genome-wide association study of Alzheimer’s disease was performed in 2,291 Korean seniors in the discovery phase, from the Gwangju Alzheimer’s and Related Dementias (GARD) cohort study. The study was replicated in a Japanese cohort of 1,956 subjects that suggested two novel susceptible SNPs in two genes: LRIG1 and CACNA1A. This study demonstrates that the discovery of AD-associated variants is feasible in non-European ethnic groups using samples comprising fewer subjects from the more homogeneous genetic background.

Short Communication
Alina Solomon, Ron Handels, Anders Wimo, Riitta Antikainen, Tiina Laatikainen, Esko Levälahti, Markku Peltonen, Hilkka Soininen, Timo Strandberg, Jaakko Tuomilehto, Miia Kivipelto, Tiia Ngandu
Effect of a Multidomain Lifestyle Intervention on Estimated Dementia Risk
Abstract: We investigated the effect of a multidomain lifestyle intervention on the risk of dementia estimated using the validated CAIDE risk score (post-hoc analysis). The Finnish Geriatric Intervention Study to Prevent Cognitive Impairment and Disability (FINGER) is a 2-year randomized controlled trial among 1,260 at-risk older adults (60-77 years). Difference in the estimated mean change in CAIDE score at 2 years in the intervention compared to the control group was -0.16 (95 % CI -0.31 to 0.00) (p=0.013), corresponding to a relative dementia risk reduction between 6.04-6.50%. This could be interpreted as a reflection of the prevention potential of the intervention.

Short Communication
Micaela Mitolo*, Michelangelo Stanzani-Maserati*, David N. Manners, Sabina Capellari, Claudia Testa, Lia Talozzi, Roberto Poda, Federico Oppi, Stefania Evangelisti, Laura L. Gramegna, Silvia Magarelli, Roberta Pantieri, Rocco Liguori, Raffaele Lodi**, Caterina Tonon** *,**These authors contributed equally
The Combination of Metabolic Posterior Cingulate Cortical Abnormalities and Structural Asymmetries Improves the Differential Diagnosis Between Primary Progressive Aphasia and Alzheimer’s Disease
Abstract: Differential diagnosis between primary progressive aphasia (PPA) and Alzheimer’s disease (AD) could be difficult if based on clinical grounds alone. We evaluated the combination of proton MR spectroscopy of posterior cingulate cortex (PCC) and quantitative structural imaging asymmetries to differentiate PPA from AD patients. A greater left-lateralized temporo-parietal atrophy (higher accuracy for the PCC, 81.4%) and metabolic neurodegenerative changes in PCC (accuracy 76.8%) was demonstrated in PPA versus AD. The combined multiparametric approach increased the accuracy to 94% in the differential diagnosis between these two neurodegenerative diseases.

Wenwen Li, Shiyuan Wang, Heng zhang, Bingqiu Li, Lingzhi Xu, Yan Li, Chaojun Kong, Haishan Jiao,Yan Wang, Yana Pang, Wei Qin, Longfei Jia, Jianping Jia (Handling Associate Editor: Jin-Tai Yu)
Honokiol Restores Microglial Phagocytosis by Reversing Metabolic Reprogramming
Abstract: Background: Dysfunction of microglia has been increasingly recognized as a causative factor in Alzheimer’s disease (AD); thus, developing medicines capable of restoring microglial functions is critically important and constitutes a promising therapeutic strategy. Honokiol is a natural neuroprotective compound extracted from Magnolia officinalis, which may play roles in AD therapy. Objective: This study aimed to evaluate the role and the underlying mechanisms of honokiol in microglial phagocytosis. Methods: MTT and flow cytometry were used to assess the cell viability and apoptosis, respectively. Phagocytic capacity, mitochondrial reactive oxygen species production, and membrane potential were evaluated using fluorescence microscopy. Seahorse XF24 extracellular flux analyzer was for cell glycolysis and oxidative phosphorylation (OXPHOS) detection. Mass spectrometry was applied for metabolites measurement. Quantitative real-time polymerase chain reaction and western blotting were performed to detect the mRNA and protein level of PPARγ and PGC1α, respectively. Results: Honokiol alleviated Aβ42-induced BV2 neurotoxicity. Honokiol promoted phagocytic efficiency of BV2 cells through reversing a metabolic switch from OXPHOS to anaerobic glycolysis and enhancing ATP production. Meanwhile, honokiol reduced mitochondrial reactive oxygen species (ROS) production and elevated mitochondrial membrane potential. Moreover, honokiol increased the expression of PPARγ and PGC1α, which might play positive roles in energy metabolism and microglial phagocytosis. Conclusion: In this study, honokiol was identified as an effect natural product capable of enhancing mitochondrial function thus promoting microglial phagocytic function.

Suman Chaudhary, Ajay Ashok, Dallas McDonald, Aaron S. Wise, Alexander E. Kritikos, Neil A. Rana, Clifford V. Harding, Neena Singh
Upregulation of Local Hepcidin Contributes to Iron Accumulation in Alzheimer’s Disease Brains
Abstract: Background: Accumulation of iron is a consistent feature of Alzheimer’s disease (AD) brains. The underlying cause, however, remains debatable. Objective: To explore whether local hepcidin synthesized by brain cells contributes to iron accumulation in AD brains. Methods: Brain tissue from the cingulate cortex of 33 cases of AD pre-assigned to Braak stage I-VI, 6 cases of non-dementia, and 15 cases of non-AD dementia were analyzed for transcriptional upregulation of hepcidin by RT-qPCR and RT-PCR. Change in the expression of ferritin, ferroportin (Fpn), microglial activation marker Iba1, IL-6, and TGFβ2 was determined by western blotting. Total tissue iron was determined by colorimetry. Results: Significant transcriptional upregulation of hepcidin was observed in Braak stage III-VI relative to Braak stage I and II, non-AD dementia, and non-dementia samples. Ferritin was increased in Braak stage V, and a significant increase in tissue iron was evident in Braak stage III-VI. The expression of Iba1 and IL-6 was also increased in Braak stage III-VI relative to Braak stage I and II and non-AD dementia samples. Amyloid-β plaques were absent in most Braak stage I and II samples, and present in Braak stage III-VI samples with few exceptions. Conclusion: These observations suggest that upregulation of brain hepcidin is mediated by IL-6, a known transcriptional activator of hepcidin. The consequent downregulation of Fpn on neuronal and other cells results in accumulation of iron in AD brains. The increase in hepcidin is disease-specific, and increases with disease progression, implicating AD-specific pathology in the accumulation of iron.

Weina Yao, Haifeng Chen, Xiaoning Sheng, Hui Zhao, Yun Xu, Feng Bai, Alzheimer’s Disease Neuroimaging Initiative
Core-Centered Connection Abnormalities Associated with Pathological Features Mediate the Progress of Cognitive Impairments in Alzheimer’s Disease Spectrum Patients
Abstract: Background: Abnormal default mode network (DMN) was associated with the progress of Alzheimer’s disease (AD). Rather than treat the DMN as a unitary network, it can be further divided into three subsystems with different functions. Objective: It remains unclear the interactions of DMN subsystems associated with the progress of cognitive impairments and AD pathological features. Methods: This study has recruited 187 participants, including test data and verification data. Firstly, an imaging analysis approach was utilized to investigate disease-related differences in the interactions of DMN subsystems in test data (n=149), including 42 cognitively normal subjects, 43 early mild cognitive impairment (EMCI), 32 late mild cognitive impairment (LMCI), and 32 AD patients. Brain-behavior-pathological relationships regarding to the interactions among DMN subsystems were then further examined. Secondly, DMN subsystems abnormalities for classifying AD spectrum population in the independent verification data (n=38). Results: This study found that the impaired cognition relates to disturbances in the interactions between DMN subsystems but preferentially in core subsystem, and the abnormal regulatory processes of core subsystem were significantly associated with the levels of cerebrospinal fluid Aβ and tau in AD-spectrum patients. Meantime, the nonlinear relationship between dysfunctional core subsystem and impaired cognition was observed as one progresses through the stages of MCI to AD. Importantly, this classification presented a higher sensitivity and specificity dependent on the core-centered connection abnormalities. Conclusion: The abnormal interaction patterns of DMN subsystems at an early stage of AD appeared and presented as core-centered connection abnormalities, which were the potential neuroimaging features for monitoring the development of AD.

Yasufumi Sakakibara, Yu Hirota, Kyoko Ibaraki, Kimi Takei, Sachie Chikamatsu, Yoko Tsubokawa, Takashi Saito, Takaomi C. Saido, Michiko Sekiya, Koichi M. Iijima
Widespread Reduced Density of Noradrenergic Locus Coeruleus Axons in the App Knock-In Mouse Model of Amyloid-β Amyloidosis
Abstract: Background: The locus coeruleus (LC), a brainstem nucleus comprising noradrenergic neurons, is one of the earliest regions affected by Alzheimer’s disease (AD). Amyloid-β (Aβ) pathology in the cortex in AD is thought to exacerbate the age-related loss of LC neurons, which may lead to cortical tau pathology. However, mechanisms underlying LC neurodegeneration remain elusive. Objective: Here, we aimed to examine how noradrenergic neurons are affected by cortical Aβ pathology in AppNL-G-F/NL-G-F knock-in mice. Methods: The density of noradrenergic axons in LC-innervated regions and the LC neuron number were analyzed by an immunohistochemical method. To explore the potential mechanisms for LC degeneration, we also examined the occurrence of tau pathology in LC neurons, the association of reactive gliosis with LC neurons, and impaired trophic support in the brains of AppNL-G-F/NL-G-F mice. Results: We observed a significant reduction in the density of noradrenergic axons from the LC in aged AppNL-G-F/NL-G-F mice without neuron loss or tau pathology, which was not limited to areas near Aβ plaques. However, none of the factors known to be related to the maintenance of LC neurons (i.e., somatostatin/somatostatin receptor 2, brain-derived neurotrophic factor, nerve growth factor, and neurotrophin-3) were significantly reduced in AppNL-G-F/NL-G-F mice. Conclusion: This study demonstrates that cortical Aβ pathology induces noradrenergic neurodegeneration, and further elucidation of the underlying mechanisms will reveal effective therapeutics to halt AD progression.

Céline Borg*, Isabelle Rouch*, Elodie Pongan, Jean Claude Getenet, Romain Bachelet, Mathieu Herrmann, Anne-Lise Bohec, Bernard Laurent, COVCARE Group, Romain Rey, Jean-Michel Dorey *These authors contributed equally to this work.
Mental Health of People with Dementia During COVID-19 Pandemic: What Have We Learned from the First Wave?
Abstract: Background: People with dementia (PWD) and their caregivers are populations highly vulnerable to COVID-19 pandemic and its consequences. A better knowledge of the living conditions during the first lockdown is necessary to prevent the risk of poor mental health (PMH) in this population. Objective: The present study aimed to compare the mental health of caregivers of PWD living at home or in nursing-homes and to identify specific factors influencing their mental health. Methods: We conducted an anonymous cross-sectional online survey in France from March 17 to May 11, 2020. Three hundred and eighty-nine caregivers accompanying a PWD living at home (HC) and 159 accompanying a PWD living in a nursing home (NHC) participated in the study. Caregivers' mental health including anxiety, depression, stress, and burden was assessed with self-reported standardized scales. Results: Half of the caregivers exhibited PMH, including depression, anxiety, or self-reported stress. Similar PMH rates were provided whatever the PWD place of residence. Regarding HC, our results also highlighted a number of risk factors for PMH, including the fact that caregiver live with PWD, to give increased support to PWD, and to feel more isolated for managing PWD since lockdown. Conclusion: PMH was observed for caregivers of PWD during lockdown, whatever PWD living place, suggesting that concern for PWD may explain more of caregiver distress than increased material tasks. In the future, it will be necessary to pay attention to caregivers after the crisis by estimating the longer-term impact on their mental health.

Linda L. Chao, Jennifer A. Lee, Steven Martinez, Cody Barlow, Margaret A. Chesney, Wolf E. Mehling, Deborah E. Barnes (Handling Associate Editor: Madeleine Hackney)
Preventing Loss of Independence through Exercise (PLIÉ): A Pilot Trial in Older Adults with Subjective Memory Decline and Mild Cognitive Impairment
Abstract: Background: Preventing Loss of Independence through Exercise (PLIÉ) is a group movement program initially developed for people with mild-to-moderate dementia that integrates principles from several well-established traditions to specifically address the needs of people with cognitive impairment. Objective: To investigate whether PLIÉ would benefit cognitive and behavioral outcomes and functional brain connectivity in older adults with milder forms of cognitive impairment. Methods: Participants (≥55 y) with subjective memory decline (SMD) or mild cognitive impairment (MCI) were assessed with tests of cognitive and physical function, self-report questionnaires, and resting state functional magnetic resonance imaging (rs-fMRI) on a 3 Tesla scanner before and after participating in twice weekly PLIÉ classes for 12 weeks at the San Francisco Veterans Affairs Medical Center. Results: Eighteen participants completed the pre-post intervention pilot trial. We observed significant improvements on the Alzheimer’s Disease Assessment Scale cognitive subscale (ADAS-cog; effect size 0.34, p=0.002) and enhanced functional connections between the medial prefrontal cortex (mPFC) and other nodes of the default mode network (DMN) after PLIÉ. Improvements (i.e., lower scores) on ADAS-cog were significantly correlated with enhanced functional connectivity between the mPFC and left lateral parietal cortex (Spearman’s ρ=-0.74, p=0.001) and between the mPFC and right hippocampus (Spearman’s ρ=-0.83, p=0.001). After completing PLIÉ, participants reported significant reductions in feelings of social isolation and improvements in well-being and interoceptive self-regulation. Conclusion: These preliminary findings of post-PLIÉ improvements in DMN functional connectivity, cognition, interoceptive self-regulation, well-being and reduced feelings of social isolation warrant larger randomized, controlled trials of PLIÉ in older adults with SMD and MCI.

Xianwen Shang, Allison M. Hodge, Edward Hill, Zhuoting Zhu, Mingguang He
Associations of Dietary Pattern and Sleep Duration with Cognitive Decline in Community-Dwelling Older Adults: A Seven-Year Follow-Up Cohort Study
Abstract: Background: A few studies have linked dietary patterns and sleep to cognitive decline. Objective: To examine the independent and joint associations of dietary patterns and sleep with cognitive decline. Methods: Our analysis included 2,307 participants aged 55-89 years at baseline from the China Health and Nutrition Survey. Dietary intake was assessed using weighing methods in combination with 24-h dietary recalls for three consecutive days. Exploratory factor analysis was applied to identify major dietary factors. Cognition was assessed in 1997, 2000, 2004, 2006, and 2015. Results: Five dietary patterns were identified: dairy-fruits-fast foods, grains-vegetables-pork, plant-based food, beans-mushroom, and beverages-nuts patterns. Beans-mushroom pattern and sleep duration of 8 h/day were defined as healthy habits. There was a positive association between the beans-mushroom pattern and change in the global cognitive Z-score over seven years (β (95% CI) for quintile 5 versus quintile 1: 0.17 (0.05, 0.30)). Compared to individuals with sleep duration of 8 h/day, those with sleep duration of ≤5 h/day (β (95% CI): -0.23 (-0.45, -0.00)) or >10 h/day (-0.52 (-0.73, -0.32)) had a greater decrease in global cognitive Z-score. Compared to individuals with no healthy patterns, those with a healthy dietary pattern only (β (95% CI): 0.18 (0.08, 0.28)), healthy sleep pattern only (0.13 (0.04, 0.23), and both healthy dietary and sleep patterns (0.19 (0.08, 0.31)) had a relative increase in global cognitive Z-score. Conclusion: Our findings highlight the importance of involving both diet and sleep as intervention priorities for the potential prevention of cognitive decline.

Katherine H. Franks, Lisa Bransby, Michael M. Saling, Matthew P. Pase (Handling Associate Editor: Shireen Sindi)
Association of Stress with Risk of Dementia and Mild Cognitive Impairment: A Systematic Review and Meta-Analysis
Abstract: Background: Although many studies have investigated the association between stress and risk of dementia, findings are inconsistent due to the variation in the measures used to assess stress. Objective: We conducted a systematic review and meta-analysis to investigate the association between psychological stress (including neuroticism, stressful life events, and perceived stress) and the risk of incident dementia and mild cognitive impairment in adults. Methods: PsycINFO, Embase, and MEDLINE were searched to October 2020 for eligible observational, prospective studies. Of the 1,607 studies screened, 26 (24 unique cohorts) were included in the qualitative analysis and 16 (15 unique cohorts) were included in the quantitative analysis. Results: Across studies, higher perceived stress was significantly associated with an increased risk of mild cognitive impairment (Cases/Total N = 207/860: hazard ratio [HR] = 1.19, 95% confidence interval [CI] = 1.03–1.38) and all-cause dementia (Cases/Total N = 203/1,882: HR = 1.44, 95% CI = 1.07–1.95). Exposure to two or more stressful life events (versus none) was significantly associated with an increased risk of all-cause dementia (Cases/Total N = 3,354/11,597: HR = 1.72, 95% CI = 1.14–2.60), while one or more stressful life events was not. Higher neuroticism was significantly associated with an increased risk of Alzheimer’s disease dementia (Cases/Total N = 497/4,771: HR = 1.07, 95% CI = 1.01–1.12), but not all-cause dementia. Conclusion: This review suggests that psychological stress in adulthood is associated with an increased risk of dementia. Further research is needed to clarify the mechanisms underlying these associations.

Jaehong Park*, Tae Jun Kim*, Joo Hye Song, Hyemin Jang, Ji Sun Kim, Sung Hoon Kang, Hang-Rai Kim, Song Hwangbo, Hee Young Shin, Duk L Na, Sang Won Seo, Hee Jin Kim7**, Jae J Kim** *,**These authors contributed equally to this work.
Helicobacter pylori Infection Is Associated with Neurodegeneration in Cognitively Normal Men
Abstract: Background: An association between Helicobacter pylori (H. pylori) infection and dementia was reported in previous studies; however, the evidence is inconsistent. Objective: In the present study, the association between H. pylori infection and brain cortical thickness as a biomarker of neurodegeneration was investigated. Methods: A cross-sectional study of 822 men who underwent a medical health check-up, including an esophagogastroduodenoscopy and 3.0 T magnetic resonance imaging, was performed. H. pylori infection status was assessed based on histology. Multiple linear regression analyses were conducted to evaluate the relationship between H. pylori infection and brain cortical thickness. Results: Men with H. pylori infection exhibited overall brain cortical thinning (p = 0.022), especially in the parietal (p = 0.008) and occipital lobes (p = 0.050) compared with non-infected men after adjusting for age, educational level, alcohol intake, smoking status, and intracranial volume. 3-dimentional topographical analysis showed that H. pylori infected men had cortical thinning in the bilateral lateral temporal, lateral frontal, and right occipital areas compared with non-infected men with the same adjustments (false discovery rate corrected, Q<0.050). The association remained significant after further adjusting for inflammatory marker (C-reactive protein) and metabolic factors (obesity, dyslipidemia, fasting glucose, and blood pressure). Conclusion: Our results indicate H. pylori infection is associated with neurodegenerative changes in cognitive normal men. H. pylori infection may play a pathophysiologic role in the neurodegeneration and further studies are needed to validate this association.

Cecilia H. Fuglsang, David Nagy, Frederikke S. Troelsen, Dora K. Farkas, Victor W. Henderson, Henrik T. Sørensen (Handling Associate Editor: M. Arfan Ikram)
Venous Thromboembolism and Risk of Cancer in Patients with Dementia: A Danish Population-Based Cohort Study
Abstract: Background: Venous thromboembolism (VTE) may be the first manifestation of occult cancer. Dementia has been linked to reduced cancer risk. Objective: We examined the risk of cancer following VTE in people with dementia in comparison to the risk in the general population. Methods: We conducted a population-based Danish registry-based cohort study following patients with a first-time VTE and a previous or concurrent diagnosis of dementia during the period 1 April 1996 – 31 December 2017. We followed the study participants from date of VTE until diagnosis of cancer, death, emigration, or end of study period, whichever came first. The absolute risk of cancer within one year after VTE was computed, treating death as a competing risk. We calculated gender, age, and calendar-period standardized incidence ratios (SIRs) of cancer based on national cancer rates. Results: We followed 3,552 people with dementia and VTE for a median of 1.3 years. Within the first year after VTE, they had a 90% increased risk of cancer in comparison with the general population [SIR: 1.9 (95% confidence interval: 1.6-2.4)]. During subsequent follow-up years, the SIR fell to 0.7 (95% confidence interval: 0.5-0.8). Findings for Alzheimer’s disease and VTE were similar. Conclusion: People with dementia have an increased risk of a cancer diagnosis during the first year following VTE, perhaps related to increased surveillance, and a lower risk thereafter. Overall risk is similar to that of the general population.

Lærke Taudorf, Ane Nørgaard, Sabrina Islamoska, Thomas Munk Laursen, Gunhild Waldemar
Causes of Death in People with Dementia from 2002 to 2015: A Nationwide Study
Abstract: Background: Dementia is associated with increased mortality. However, it is not clear whether causes of death in people with dementia have changed over time. Objective: To investigate if causes of death changed over time in people with dementia compared to the general elderly population. Methods: We included longitudinal data from nationwide registries on all Danish residents aged ≥65 years to 110 years who died between 2002 to 2015. We assessed the annual frequency of dementia-related deaths (defined as a dementia diagnosis registered as a cause of death) and of underlying causes of death in people registered with dementia compared to the general elderly population. Results: From 2002 to 2015, 621,826 people died, of whom 103,785 were diagnosed with dementia. During this period, the percentage of dementia-related deaths increased from 10.1% to 15.2% in women, and from 6.3% to 9.5% in men in the general elderly population. From 2002 to 2015, dementia became the leading, registered underlying cause of death in people with diagnosed dementia. Simultaneously, a marked decline in cardiovascular and cerebrovascular deaths was observed in people with and without dementia. Conclusion: This is the first study to investigate if the causes of death change over time in people with diagnosed dementia compared with the general elderly population. The increase in the registration of dementia as an underlying cause of death could reflect increasing awareness of dementia as a fatal condition.

Gianni Mancini, Candida Dias, Catia F. Lourenço, Joao Laranjinha, Andreza de Bem, Ana Ledo
A High Fat/Cholesterol Diet Recapitulates Some Alzheimer’s Disease-Like Features in Mice: Focus on Hippocampal Mitochondrial Dysfunction
Abstract: Background: Ample evidence from clinical and pre-clinical studies suggests mid-life hypercholesterolemia as a risk factor for developing Alzheimer’s disease (AD) at a later age. Hypercholesterolemia induced by dietary habits can lead to vascular perturbations that increase the risk of developing sporadic AD. Objective: To investigate the effects of a high fat/cholesterol diet (HFCD) as a risk factor for AD by using a rodent model of AD and its correspondent control (healthy animals). Methods: We compared the effect of a HFCD in normal mice (non-transgenic mice, NTg) and the triple transgenic mouse model of AD (3xTgAD). We evaluated cognitive performance in relation to changes in oxidative metabolism and neuron-derived nitric oxide (•NO) concentration dynamics in hippocampal slices as well as histochemical staining of markers of the neurovascular unit. Results: In NTg, the HFCD produced only moderate hypercholesterolemia but significant decline in spatial memory was observed. A tendency for decrease in •NO production was accompanied by compromised mitochondrial function with decrease in spare respiratory capacity. In 3xTgAD mice, a robust increase in plasma cholesterol levels with the HFCD did not worsen cognitive performance but did induce compromise of mitochondrial function and significantly decreased •NO production. We found increased staining of biomarkers for astrocyte endfeet and endothelial cells in 3xTgAD hippocampi, which was further increased by the HFCD. Conclusion: A short term (8 weeks) intervention with HFCD can produce an AD-like phenotype even in the absence of overt systemic hypercholesterolemia and highlights mitochondrial dysfunction as a link between hypercholesterolemia and sporadic AD.

Wen-zhi Wang*, Ming-wei Li*, Ying Chen*, Li-yuan Liu, Yong Xu, Zeng-hui Xia, Yang Yu, Xiao-dan Wang, Wei Chen, Feng Zhang, Xiao-yan Xu, Yong-feng Gao, Ji-guo Zhang, Shu-cun Qin, Hao Wang (Handling Associate Editor: Jesus Avila) *These authors contributed equally to this work.
3×Tg-AD Mice Overexpressing Phospholipid Transfer Protein Improves Cognition Through Decreasing Amyloid-β Production and Tau Hyperphosphorylation
Abstract: Background: Phospholipid transfer protein (PLTP) belongs to the lipid transfer glycoprotein family. Studies have shown that it is closely related to Alzheimer’s disease (AD); however, the exact effect and mechanism remain unknown. Objective: To observe the effect of PLTP overexpression on behavioral dysfunction and the related mechanisms in APP/PS1/Tau triple transgenic (3×Tg-AD) mice. Methods: AAV-PLTP-EGFP was injected into the lateral ventricle to induce PLTP overexpression. The memory of 3×Tg-AD mice and wild type (WT) mice aged 10 months were assessed using Morris water maze (MWM) and shuttle-box passive avoidance test (PAT). Western blotting and ELISA assays were used to quantify the protein contents. Hematoxylin and eosin, Nissl, and immunochemistry staining were utilized in observing the pathological changes in the brain. Results: 3×Tg-AD mice displayed cognitive impairment in WMW and PAT, which was ameliorated by PLTP overexpression. The histopathological hallmarks of AD, senile plaques and neurofibrillary tangles, were observed in 3×Tg-AD mice and were improved by PLTP overexpression. Besides, the increase of amyloid-β42 (Aβ42) and Aβ40 were found in the cerebral cortex and hippocampus of 3×Tg-AD mice and reversed by PLTP overexpression through inhibiting APP and PS1. PLTP overexpression also reversed tau phosphorylation at the Ser404, Thr231 and Ser199 of the hippocampus in 3×Tg-AD mice. Furthermore, PLTP overexpression induced the glycogen synthase kinase 3β (GSK3β) inactivation via upregulating GSK3β (pSer9). Conclusion: These results suggest that PLTP overexpression has neuroprotective effects. These effects are possibly achieved through the inhibition of the Aβ production and tau phosphorylation, which is related to GSK3β inactivation.

Anna Gabriel*, Carolin T. Lehner*, Chiara Höhler, Thomas Schneider, Tessa P.T. Pfeiffer, Janine Diehl-Schmid, Joachim Hermsdörfer *These authors contributed equally to this work.
Anticipatory and Reactive Grip Force Control in Patients with Alzheimer’s Disease: A Pilot Study
Abstract: Background: Alzheimer’s disease (AD) affects several cognitive functions and causes altered motor function. Fine motor deficits during object manipulation are evident in other neurological conditions, but have not been assessed in dementia patients yet. Objective: Investigate reactive and anticipatory grip force control in response to unexpected and expected load force perturbation in AD. Methods: Reactive and anticipatory grip force was investigated using a grip-device with force sensors. In this pilot study, fifteen AD patients and fourteen healthy controls performed a catching task. They held the device with one hand while a sandbag was dropped into an attached receptacle either by the experimenter or by the participant. Results: In contrast to studies of other neurological conditions, the majority of AD patients exerted lower static grip force levels than controls. Interestingly, patients who were slow in the Luria’s three-step test produced normal grip forces. The timing and magnitude of reactive grip force control were largely preserved in patients. In contrast, timing and extent of anticipatory grip forces were impaired in patients, although anticipatory control was generally preserved. These deficits were correlated with decreasing Mini-Mental State Examination scores. Apraxia scores, assessed by pantomime of tool-use, did not correlate with performance in the catching task. Conclusion: We interpreted the decreased grip force in AD in the context of loss of strength and lethargy, typical for patients with AD. The lower static grip force during object manipulation may emerge as a potential biomarker for early stages of AD, but more studies with larger sample sizes are necessary.

Julie Mouchet, Keith A. Betts, Mihaela V. Georgieva, Raluca Ionescu-Ittu, Lesley M. Butler, Xavier Teitsma, Paul Delmar, Thomas Kulalert, JingJing Zhu, Neema Lema, Urvi Desai
Classification, Prediction, and Concordance of Cognitive and Functional Progression in Patients with Mild Cognitive Impairment in the United States: A Latent Class Analysis
Abstract: Background: Progression trajectories of patients with mild cognitive impairment (MCI) are currently not well understood. Objective: To classify patients with incident MCI into different latent classes of progression and identify predictors of progression class. Methods: Participants with incident MCI were identified from the US National Alzheimer’s Coordinating Center Uniform Data Set (09/2005-02/2019). Clinical Dementia Rating (CDR®) Dementia Staging Instrument-Sum of Boxes (CDR-SB), Functional Activities Questionnaire (FAQ), and Mini-Mental State Examination (MMSE) score longitudinal trajectories from MCI diagnosis were fitted using growth mixture models. Predictors of progression class were identified using multivariate multinomial logistic regression models; odds ratios (ORs) and 95% confidence intervals (CIs) were reported. Results: In total, 21%, 22%, and 57% of participants (N=830) experienced fast, slow, and no progression on CDR-SB, respectively; for FAQ, these figures were 14%, 23%, and 64%, respectively. CDR-SB and FAQ class membership was concordant for most participants (77%). Older age (≥86 versus ≤70 years, OR [95% CI]=5.26 [1.78-15.54]), one copy of APOE ɛ4 (1.94 [1.08-3.47]), higher baseline CDR-SB (2.46 [1.56-3.88]), lower baseline MMSE (0.85 [0.75-0.97]), and higher baseline FAQ (1.13 [1.02-1.26]) scores were significant predictors of fast progression versus no progression based on CDR-SB (all p <0.05). Predictors of FAQ class membership were largely similar. Conclusion: Approximately a third of participants experienced progression based on CDR-SB or FAQ during the ~4-year follow-up period. CDR-SB and FAQ class assignment were concordant for the vast majority of participants. Identified predictors may help the selection of patients at higher risk of progression in future trials.

Tomás Barrett, Katherine A. Stangis, Takashi Saito, Takaomi Saido, Kevin H.J. Park (Handling Associate Editor: Benedict Albensi)
Neuronal Cell Cycle Re-Entry Enhances Neuropathological Features in AppNLF Knock-In Mice
Abstract: Background: Aberrant cell cycle re-entry is a well-documented process occurring early in Alzheimer’s disease (AD). This is an early feature of the disease and may contribute to disease pathogenesis. Objective: To assess the effect of forced neuronal cell cycle re-entry in mice expressing humanized Aβ, we crossed our neuronal cell cycle re-entry mouse model with AppNLF knock-in (KI) mice. Methods: Our neuronal cell cycle re-entry (NCCR) mouse model is bitransgenic mice heterozygous for both Camk2a-tTA and TRE-SV40T. The NCCR mice were crossed with AppNLF KI mice to generate NCCR-AppNLF animals. Using this tet-off system, we triggered NCCR in our animals via neuronal expression of SV40T starting at 1 month of age. The animals were examined at the following time points: 9, 12, and 18 months of age. Various neuropathological features in our mice were evaluated by image analysis and stereology on brain sections stained using either immunofluorescence or immunohistochemistry. Results: We show that neuronal cell cycle re-entry in humanized Aβ plaque producing AppNLF KI mice results in the development of additional AD-related pathologies, namely, pathological tau, neuroinflammation, brain leukocyte infiltration, DNA damage response, and neurodegeneration. Conclusion: Our findings show that neuronal cell cycle re-entry enhances AD-related neuropathological features in AppNLF mice and highlight our unique AD mouse model for studying the pathogenic role of aberrant cell cycle re-entry in AD.

Matej Kucera, Katrin Wolfova, Pavla Cermakova
Association Between Season of Birth and Cognitive Aging in Older Adults: Pan-European Population-Based Study on 70,000 Individuals
Abstract: Background: Several early-life factors have been associated with higher risk of developing dementia. It is unclear whether season of birth (SOB) can affect cognitive aging in older adults or not. Objective: We aimed to study the association of SOB with the level of cognitive performance as well as with the rate of cognitive decline. Methods: We studied 70,203 individuals who participated in the Survey of Health, Aging and Retirement in Europe. Cognition was measured with tests on verbal fluency and immediate and delayed recall. We assessed the association of SOB with the level of cognitive performance using multiple linear regression and with the rate of cognitive decline using linear mixed-effects models. Results: When compared to individuals born in winter and adjusted for sociodemographic and health-related characteristics, being born in summer was associated with a higher level of delayed recall (B 0.05; 95% CI 0.01 to 0.09) and verbal fluency (B 0.15; 95% CI 0.00 to 0.29) and being born in fall with a higher level of immediate recall (B 0.04; 95% CI 0.01 to 0.08) and verbal fluency (B 0.15; 95% CI 0.01 to 0.29). Individuals born in summer had a higher yearly decline in delayed recall (B -0.005; 95% CI -0.009 to 0.000), while the scores in delayed recall in participants born in spring showed an inverse trend (B 0.005; 95% CI 0.000 to 0.010). Conclusion: Individuals born in winter seem to carry a life-long disadvantage in a lower level of cognitive performance; however, being born in winter does not seem to affect the rate of cognitive decline.

Mirjam Frank, Jonas Hensel, Lisa Baak, Sara Schramm, Nico Dragano, Christian Weimar, Per Hoffmann, Markus M. Nöthen, Raimund Erbel, Karl-Heinz Jöckel, Martha Jokisch, Börge Schmidt
Interaction of Alzheimer’s Disease-Associated Genetic Risk with Indicators of Socioeconomic Position on Mild Cognitive Impairment in the Heinz Nixdorf Recall Study
Abstract: Background: The apolipoprotein E (APOE) ε4 allele is reported to be a strong genetic risk factor for mild cognitive impairment (MCI) and Alzheimer’s disease (AD). Additional genetic loci have been detected that influence the risk for late-onset AD. As socioeconomic position (SEP) is also strongly related to cognitive decline, SEP has been suggested to be a possible modifier of the genetic effect on MCI. Objective: To investigate whether APOE ε4 and a genetic sum score of AD-associated risk alleles (GRSAD) interact with SEP indicators to affect MCI in a population-based cohort. Methods: Using data of 3,834 participants of the Heinz Nixdorf Recall Study, APOE ε4 and GRSAD by SEP interactions were assessed using logistic regression models, as well as SEP-stratified genetic association analysis. Interaction on additive scale was calculated using the relative excess risk due to interaction (RERI). All analysis were additionally stratified by sex. Results: Indication for interaction on the additive scale was found between APOE ε4 and low education on MCI (RERI: 0.52 [95%-confidence interval (CI): 0.01; 1.03]). The strongest genetic effects of the APOE ε4 genotype on MCI were observed in groups of low education (Odds ratio (OR): 1.46 [95%-CI: 0.79; 2.63] for ≤10 years of education versus OR: 1.00 [95%-CI: 0.43; 2.14] for ≥18 years of education). Sex stratified results showed stronger effects in women. No indication for interaction between the GRSAD and SEP indicators on MCI was observed. Conclusion: Results indicate that low education may have an impact on APOE ε4 expression on MCI, especially among women.

Brian Downer, Lin-Na Chou, Soham Al Snih, Cheyanne Barba, Yong-Fang Kuo, Mukaila Raji, Kyriakos S. Markides, Kenneth J. Ottenbacher (Handling Associate Editor: Mayra Estrella)
Documentation of Dementia as a Cause of Death Among Mexican-American Decedents Diagnosed with Dementia
Abstract:Background: Hispanic older adults are a high-risk population for Alzheimer’s disease and related dementias (ADRD) but are less likely than non-Hispanic White older adults to have ADRD documented as a cause of death on a death certificate. Objective: To investigate characteristics associated with ADRD as a cause of death among Mexican-American decedents diagnosed with ADRD. Methods: Data came from the Hispanic Established Populations for the Epidemiologic Study of the Elderly, Medicare claims, and National Death Index. Results: The final sample included 853 decedents diagnosed with ADRD of which 242 had ADRD documented as a cause of death. More health comorbidities (OR=0.40, 95% CI=0.28-0.58), older age at death (OR=1.18, 95% CI=1.03-1.36), and longer ADRD duration (OR=1.08, 95% CI=1.03-1.14) were associated with ADRD as a cause of death. In the last year of life, any ER admission without a hospitalization (OR=0.45, 95% CI=0.22-0.92), more physician visits (OR=0.96, 95% CI=0.93-0.98), and seeing a medical specialist (OR=0.46, 95% CI=0.29-0.75) were associated with lower odds for ADRD as a cause of death. In the last 30 days of life, any hospitalization with an ICU stay (OR=0.55, 95% CI=0.36-0.82) and ER admission with a hospitalization (OR=0.67, 95% CI=0.48-0.94) were associated with lower odds for ADRD as a cause of death. Receiving hospice care in the last 30 days of life was associated with 1.98 (95% CI=1.37-2.87) higher odds for ADRD as a cause of death. Conclusion: Under-documentation of ADRD as a cause of death may reflect an underestimation of resource needs for Mexican-Americans with ADRD.

Hiroaki Mori, Yu Funahashi, Yuta Yoshino, Hiroshi Kumon, Yuki Ozaki, Kiyohiro Yamazaki, Shinichiro Ochi, Ayumi Tachibana, Taku Yoshida, Hideaki Shimizu, Takaaki Mori, Jun-ichi Iga, Shu-ichi Ueno
Blood CDKN2A Gene Expression in Aging and Neurodegenerative Diseases
Abstract: Background: Cyclin-dependent kinase inhibitor 2A (CDKN2A) is an important gene in cellular senescence and aging. Objective: This study assessed the utility of blood CDKN2A mRNA expression levels and methylation status as a potential biomarker for aging and the pathogenesis of Alzheimer’s disease (AD). Methods: The correlation between CDKN2A mRNA expression levels and age was examined in 45 healthy subjects, after which mRNA expression levels were compared among 46 AD patients, 20 mild cognitive impairment due to AD patients, 21 Parkinson’s disease patients, 21 dementia with Lewy bodies patients, and 55 older healthy controls. The methylation rates of the second exon of the CDKN2A gene, known to influence its expression levels, was also examined. Results: A significant correlation between CDKN2A mRNA expression levels and age was found (Spearman’s rank correlation coefficient: r = 0.407, p = 0.005). CDKN2A mRNA expression levels in blood were significantly decreased in AD patients, although those of healthy controls were significantly increased with age. Further, only in AD patients were CDKN2A mRNA expression levels significantly and positively correlated with methylation rates. Conclusion: Although further research with a larger sample size is needed to elucidate the relationships between CDKN2A gene expression in blood and the development of other neurodegenerative diseases, CDKN2A mRNA expression in blood may be a biomarker for differentiating AD from normal aging and other neurodegenerative diseases.

Louis Jacob, Karel Kostev, Lee Smith, Hans Oh, Guillermo F. López-Sánchez, Jae Il Shin, Adel S. Abduljabbar, Josep Maria Haro, Ai Koyanagi (Handling Associate Editor: Paulo Caramelli)
Sarcopenia and Mild Cognitive Impairment in Older Adults from Six Low- and Middle-Income Countries
Abstract: Background: Little is known about the relationship between sarcopenia and mild cognitive impairment (MCI) in low- and middle-income countries (LMICs). Objective: This study aimed to investigate this association among community-dwelling adults aged ≥65 years from six LMICs. Methods: Cross-sectional, nationally representative data from the Study on Global Ageing and Adult Health (SAGE) were analyzed. These data were obtained in China, Ghana, India, Mexico, Russia, and South Africa in 2007-2010. Participants were considered to have sarcopenia if they had low skeletal muscle mass (i.e., lower skeletal mass index) and a weak handgrip strength. MCI was defined using the National Institute on Aging-Alzheimer’s Association criteria. Multivariable logistic regression analysis was conducted to assess associations. Results: The final analytical sample consisted of 12,912 individuals aged ≥65 years with preservation in functional abilities without stroke (mean [standard deviation] age 72.2 [10.8] years; 45.2% males). The overall prevalence of sarcopenia and MCI were 11.3% and 18.1%, respectively. After adjusting for potential confounders, there was a positive association between sarcopenia and MCI in all countries (i.e., odds ratio [OR]>1) with the exception of South Africa, and the overall estimate was OR=1.60 (95% confidence interval [CI]=1.32-1.93) with a low level of between-country heterogeneity (I2=0.0%). Conclusion: There was a positive association between sarcopenia and MCI in this sample of older adults living in LMICs. Causality should be assessed in future longitudinal research, while the utility of sarcopenia as a marker of MCI should also be investigated.

Magdalena I. Tolea, Jaeyeong Heo, Stephanie Chrisphonte, James E. Galvin
A Modified CAIDE Risk Score as a Screening Tool for Cognitive Impairment in Older Adults
Abstract: Background: Although an efficacious dementia-risk score system, Cardiovascular Risk Factors, Aging, and Dementia (CAIDE) was derived using midlife risk factors in a population with low educational attainment that does not reflect today’s US population, and requires laboratory biomarkers, which are not always available. Objective: Develop and validate a modified CAIDE (mCAIDE) system and test its ability to predict presence, severity, and etiology of cognitive impairment in older adults. Methods: Population consisted of 449 participants in dementia research (N=230; community sample; 67.9±10.0 years old, 29.6% male, 13.7±4.1 years education) or receiving dementia clinical services (N=219; clinical sample; 74.3±9.8 years old, 50.2% male, 15.5±2.6 years education). The mCAIDE, which includes self-reported and performance-based rather than blood-derived measures, was developed in the community sample and tested in the independent clinical sample. Validity against Framingham, Hachinski, and CAIDE risk scores was assessed. Results: Higher mCAIDE quartiles were associated with lower performance on global and domain-specific cognitive tests. Each one-point increase in mCAIDE increased the odds of mild cognitive impairment (MCI) by up to 65%, those of AD by 69%, and those for non-AD dementia by >85%, with highest scores in cases with vascular etiologies. Being in the highest mCAIDE risk group improved ability to discriminate dementia from MCI and controls and MCI from controls, with a cut-off of ≥7 points offering the highest sensitivity, specificity, and positive and negative predictive values. Conclusion: mCAIDE is a robust indicator of cognitive impairment in community-dwelling seniors, which can discriminate well between dementia severity including MCI versus controls. The mCAIDE may be a valuable tool for case ascertainment in research studies, helping flag primary care patients for cognitive testing, and identify those in need of lifestyle interventions for symptomatic control.

Ram Kuwar, Andrew Rolfe, Long Di, Hallie Blevins, Yiming Xu, Xuehan Sun, George S. Bloom, Shijun Zhang, Dong Sun
A Novel Inhibitor Targeting NLRP3 Inflammasome Reduces Neuropathology and Improves Cognitive Function in Alzheimer’s Disease Transgenic Mice
Abstract: Background: Alzheimer’s disease (AD) is a progressive neurodegenerative disorder, and the most common type of dementia. A growing body of evidence has implicated neuroinflammation as an essential player in the etiology of AD. Inflammasomes are intracellular multiprotein complexes and essential components of innate immunity in response to pathogen- and danger-associated molecular patterns. Among the known inflammasomes, the NOD-like receptor family pyrin domain containing 3 (NLRP3) inflammasome plays a critical role in the pathogenesis of AD. Objective: We recently developed a novel class of small molecule inhibitors that selectively target the NLRP3 inflammasome. One of the lead compounds, JC124, has shown therapeutic efficacy in a transgenic animal model of AD. In this study we tested the preventative efficacy of JC124 in another strain of transgenic AD mice. Methods: In this study, 5-month-old female APP/PS1 and matched wild type mice were treated orally with JC124 for 3 months. After completion of treatment, cognitive functions and AD pathologies, as well as protein expression levels of synaptic proteins, were assessed. Results: We found that inhibition of NLRP3 inflammasome with JC124 significantly decreased multiple AD pathologies in APP/PS1 mice, including amyloid-β (Aβ) load, neuroinflammation, and neuronal cell cycle re-entry, accompanied by preserved synaptic plasticity with higher expression of pre- and post-synaptic proteins, increased hippocampal neurogenesis, and improved cognitive functions. Conclusion: Our study demonstrates the importance of the NLRP3 inflammasome in AD pathological development, and pharmacological inhibition of NLRP3 inflammasome with small molecule inhibitors represents a potential therapy for AD.

Roni Lotan, Ithamar Ganmore, Abigail Livny, Nofar Itzhaki, Mark Waserman, Shahar Shelly, Moran Zacharia, Erin Moshier, Jaime Uribarri, Paul Beisswenger, Weijing Cai, Aron M. Troen, Michal Schnaider Beeri
Effect of Advanced Glycation End Products on Cognition in Older Adults with Type 2 Diabetes: Results from a Pilot Clinical Trial
Abstract: Background: Dietary advanced glycation end-products (AGEs) are linked to cognitive decline. However, clinical trials have not tested the effect of AGEs on cognition in older adults. Objective: The aim of the current pilot trial was to examine the feasibility of an intervention to reduce dietary AGEs on cognition and on cerebral blood flow (CBF). Methods: The design is a pilot randomized controlled trial of dietary AGEs reduction in older adults with type 2 diabetes. Seventy-five participants were randomized to two arms. The control arm received standard of care (SOC) guidelines for good glycemic control; the intervention arm, in addition to SOC guidelines, were instructed to reduce their dietary AGEs intake. Global cognition and CBF were assessed at baseline and after 6 months of intervention. Results: At baseline, we found a reverse association between AGEs and cognitive functioning, possibly reflecting the long-term toxicity of AGEs on the brain. There was a significant improvement in global cognition at 6 months in both the intervention and SOC groups which was more prominent in participants with mild cognitive impairment. We also found that at baseline, higher AGEs were associated with increased CBF in the left inferior parietal cortex; however, 6 months of the AGEs lowering intervention did not affect CBF levels, despite lowering AGEs exposure in blood. Conclusion: The current pilot trial focused on the feasibility and methodology of intervening through diet to reduce AGEs in older adults with type 2 diabetes. Our results suggest that participants with mild cognitive impairment may benefit from an intensive dietary intervention.

Giulia Quattrini, Moira Marizzoni, Francesca B. Pizzini, Ilaria Boscolo Galazzo, Marco Aiello, Mira Didic, Andrea Soricelli, Diego Albani, Melissa Romano, Olivier Blin, Gianluigi Forloni, Xavier Golay, Jorge Jovicich, Pradeep J. Nathan, Jill C. Richardson, Marco Salvatore, Giovanni B. Frisoni, Michela Pievani, on behalf of the PharmaCog Consortium
Convergent and Discriminant Validity of Default Mode Network and Limbic Network Perfusion in Amnestic Mild Cognitive Impairment Patients
Abstract: Background: Previous studies reported default mode network (DMN) and limbic network (LIN) brain perfusion deficits in patients with amnestic mild cognitive impairment (aMCI), frequently a prodromal stage of Alzheimer’s disease (AD). However, the validity of these measures as AD markers has not yet been tested using MRI arterial spin labeling (ASL). Objective: To investigate the convergent and discriminant validity of DMN and LIN perfusion in aMCI. Methods: We collected core AD markers (amyloid-β 42 [Aβ42], phosphorylated tau 181 levels in cerebrospinal fluid [CSF]), neurodegenerative (hippocampal volumes and CSF total tau), vascular (white matter hyperintensities), genetic (apolipoprotein E [APOE] status), and cognitive features (memory functioning on Paired Associate Learning test [PAL]) in 14 aMCI patients. Cerebral blood flow (CBF) was extracted from DMN and LIN using ASL and correlated with AD features to assess convergent validity. Discriminant validity was assessed carrying out the same analysis with AD-unrelated features, i.e., somatomotor and visual networks’ perfusion, cerebellar volume, and processing speed. Results: Perfusion was reduced in the DMN (F=5.486, p=0.039) and LIN (F=12.678, p=0.004) in APOE ε4 carriers compared to non-carriers. LIN perfusion correlated with CSF Aβ42 levels (r=0.678, p=0.022) and memory impairment (PAL, number of errors, r=-0.779, p=0.002). No significant correlation was detected with tau, neurodegeneration, and vascular features, nor with AD-unrelated features. Conclusion: Our results support the validity of DMN and LIN ASL perfusion as AD markers in aMCI, indicating a significant correlation between CBF and amyloidosis, APOE ε4, and memory impairment.

Ana Baena, Yamile Bocanegra, Valeria Torres, Clara Vila-Castelar, Edmarie Guzmán-Vélez, Joshua T. Fox-Fuller, Jennifer R. Gatchel, Justin Sánchez, Celina F. Pluim, Liliana Ramirez-Gómez, Jairo Martínez, David Pineda, Francisco Lopera, Yakeel T. Quiroz
Neuroticism Is Associated with Tau Pathology in Cognitively Unimpaired Individuals with Autosomal Dominant Alzheimer’s Disease
Abstract: Background: Greater neuroticism has been associated with higher risk for Alzheimer’s disease (AD) dementia. However, the directionality of this association is unclear. We examined whether personality traits differ between cognitively-unimpaired carriers of autosomal-dominant AD (ADAD) and non-carriers, and are associated with in vivo AD pathology. Objective: To determine whether personality traits differ between cognitively unimpaired ADAD mutation carriers and non-carriers, and whether the traits are related to age and AD biomarkers. Methods: A total of 33 cognitively-unimpaired Presenilin-1 E280A mutation carriers and 41 non-carriers (ages 27-46) completed neuropsychological testing and the NEO Five-Factor Personality Inventory. A subsample (n = 46; 20 carriers) also underwent tau and amyloid PET imaging. Results: Carriers reported higher neuroticism relative to non-carriers, although this difference was not significant after controlling for sex. Neuroticism was positively correlated with entorhinal tau levels only in carriers, but not with amyloid levels. Conclusion: The finding of higher neuroticism in carriers and the association of this trait with tau pathology in preclinical stages of AD highlights the importance of including personality measures in the evaluation of individuals at increased risk for cognitive impairment and dementia. Further research is needed to characterize the mechanisms of these relationships.

Fangyu Li, Wei Qin, Min Zhu, Jianping Jia
Model-Based Projection of Dementia Prevalence in China and Worldwide: 2020-2050
Abstract: Background: Current and future incidence and prevalence estimates of dementia are essential for public health planning. Objective: The objective was to establish prediction model of incidence and estimate the prevalence of dementia in the Chinese and worldwide population from 2020 to 2050. Methods: A model-based method was used to project the dementia prevalence from 2020 to 2050 in China, which required incidence, the mortality rate for individual without dementia, and the relative risk of death. Furthermore, we detected the impact of intervention on the prevalence projection for dementia using a simulation method. We applied the same method to other projections worldwide. Results: In 2020, the model predicted 16.25 million (95% confidence interval 11.55−21.18) persons with dementia in China. By 2050, this number would increase by approximately three-fold to 48.98 million (38.02-61.73). Through data simulation, if the incidence of dementia decreased by 10% every 10 years from 2020 after intervention and prevention, the number of dementia cases by 2050 was reduced by 11.96 million. This would reduce the economic burden by US $639.04 billion. In addition, using this model, dementia cases grew relatively slowly over the next few decades in the United States of America, the United Kingdom, and Japan, with percentage changes of 100.88%, 65.93%, and 16.20%, respectively. Conclusion: The number of people with dementia in China is large and will continue to increase rapidly. Effective interventions could reduce the number of patients drastically. Therefore, prevention and control strategies must be formulated urgently to reduce the occurrence of dementia.

Melissa Lamar, Deborah Drabick, Elizabeth A. Boots, Puja Agarwal, Sheina Emrani, Lisa Delano-Wood, Mark W. Bondi, Lisa L. Barnes, David J. Libon
Latent Profile Analysis of Cognition in a Non-Demented Diverse Cohort: A Focus on Modifiable Cardiovascular and Lifestyle Factors
Abstract: Background: Cognitively-defined subgroups are well-documented within neurodegeneration. Objective: We examined such profiles in diverse non-demented older adults and considered how resulting subgroups relate to modifiable factors associated with neurodegeneration. Methods: 121 non-demented (MMSE=28.62) diverse (46% non-Latino Black, 40% non-Latino White, 15% Latino) community-dwelling adults (age=67.7 years) completed cognitive, cardiovascular, physical activity, and diet evaluations. Latent profile analyses (LPA) employed six cognitive scores (letter fluency, letter-number sequencing, confrontational naming, ‘animal’ fluency, list-learning delayed recall, and recognition discriminability) to characterize cognitively-defined subgroups. Differences between resulting subgroups on cardiovascular (composite scores of overall health; specific health components including fasting blood levels) and lifestyle (sedentary behavior; moderate-to-vigorous physical activity; Mediterranean diet consumption) factors were examined using ANCOVAs adjusting for relevant confounders. Results: Based on sample means across cognitive scores, LPA resulted in the following cognitive subgroups: 1) high-average cognition, 55% non-Latino White and 64% female participants; 2) average cognition, 58% non-Latino Black and 68% male participants; 3) lower memory, 58% non-Latino Black participants; and 4) lower executive functioning, 70% Latinos. The high-average subgroup reported significantly higher Mediterranean diet consumption than the average subgroup (p=0.001). The lower executive functioning group had higher fasting glucose and hemoglobin A1c than all other subgroups (p-values<0.001). Conclusion: LPA revealed two average subgroups reflecting level differences in cognition previously reported between non-Latino White and Black adults, and two lower cognition subgroups in domains similar to those documented in neurodegeneration. These subgroups, and their differences, suggest the importance of considering social determinants of health in cognitive aging and modifiable risk.

Juyoung Park, James E. Galvin
Pre-Loss Grief in Caregivers of Older Adults with Dementia with Lewy Bodies
Abstract: Background: Pre-loss grief increases as dementia advances. Caregivers who experience pre-loss grief face risks to their own physical and psychological health. Objective: The study examined factors associated with pre-loss grief in caregivers of older adults with dementia with Lewy bodies (DLB) to determine whether overall caregiver experiences differ based on the stages of DLB in care recipients. The study also compared pre-loss grief in caregivers of DLB patients with that in caregivers of patients with Alzheimer’s disease (AD) and other dementias. Method: Using a cross-sectional design, 714 caregivers of older adults with dementia (488 DLB, 81 AD, 145 other dementia) completed an online survey on pre-loss grief. Multivariate linear regression identified risk factors associated with pre-loss grief and analysis of variance examined whether pre-loss grief in caregivers differed significantly based on type of dementia or stage of DLB. Results: Being the caregiver of a spouse, lower level of caregiver well-being, lower psychological well-being of the caregiver, and higher level of burden were associated (p < 0.005) with increased pre-loss grief in caregivers of older adults with DLB. There was no significant difference in caregiver burden, well-being, or depression according to the various stages of DLB (mild, moderate, severe, deceased) in the care recipients. There was no significant difference in pre-loss grief in caregivers of DLB care recipients compared to caregivers of patients with other dementias. Conclusion: Assessment of DLB caregivers and appropriate interventions should be conducted to reduce their burden and emotional distress to decrease the incidence of pre-loss grief.