Volume 91, Number 1, 2023

Pages 1-23

Mahdieh Golzari-Sorkheh, Donald F. Weaver, Mark A. Reed
COVID-19 as a Risk Factor for Alzheimer’s Disease
Abstract: Severe acute respiratory disease coronavirus 2 (SARS-CoV-2) is responsible for the coronavirus disease 2019 (COVID-19) pandemic. Although a primarily respiratory disease, recent reports indicate that it also affects the central nervous system (CNS). Over 25% of COVID-19 patients report neurological symptoms such as memory loss, anosmia, hyposmia, confusion, and headaches. The neurological outcomes may be a result of viral entry into the CNS and/or resulting neuroinflammation, both of which underlie an elevated risk for Alzheimer’s disease (AD). Herein, we ask: Is COVID-19 a risk factor for AD? To answer, we identify the literature and review mechanisms by which COVID-19-mediated neuroinflammation can contribute to the development of AD, evaluate the effects of acute versus chronic phases of infection, and lastly, discuss potential therapeutics to address the rising rates of COVID-19 neurological sequelae.

Pages 25-31

Nuria Carcavilla-González, Sara Torres-Castro, Teresa Álvarez-Cisneros, Juan José García-Meilán (Handling Associate Editor: Madeleine Hackney)
Therapeutic Lying as a Non-Pharmacological and Person-Centered Approach in Dementia for Behavioral and Psychological Symptoms of Dementia
Abstract:The acceptance and ethics behind therapeutic lying (TL) as a non-pharmacological intervention for behavioral and psychological symptoms of dementia (BPSD) among persons with dementia continues to generate heated debates. This article presents a discussion of the ethical and cultural challenges on the perception of TL by people with dementia, their families, and health care professionals. Additionally, decision-making before TL was analyzed, including the types of TL, its efficacy and implications, alternatives to TL, and the ethical principles behind it. The results from this analysis show that TL is a common practice for BPSD. Its benefits include the reduction of these symptoms as well as the use of physical or chemical restraints. However, there is no consensus on its suitability as an approach, nor on the appropriate way it should be used. More experimental studies are needed to create legal and clinical intervention protocols that respect the fundamental rights of people with dementia promoting coherence, good ethical practices, and guidelines for person-centered care.

Pages 33-42

Ziyu Liu, Haotian Zhang, Shiji Liu, Yi Hou, Guangfan Chi
The Dual Role of Astrocyte-Derived Exosomes and Their Contents in the Process of Alzheimer’s Disease
Abstract: Millions of patients worldwide are affected by Alzheimer's disease (AD), and the number of patients with AD is increasing. However, current treatment can only improve symptoms but cannot cure the disease. Astrocytes, glial cells in the central nervous system, play important roles in support, nutrition, protection, and information transmission in the nervous system. Pathological changes in astrocytes are closely associated with the development and progression of AD. As carriers for material and information exchange between astrocytes and other neural cells, astrocyte-derived exosomes (ADEs) have been widely studied in recent years, and ADE secretion has been shown to be increased in patients with AD and animal models of AD. ADEs contain a variety of substances, including nucleic acids, proteins, and lipids. The contents of ADEs can effectively control oxidative stress and detoxification during the early development of AD, thereby playing positive and negative roles in the occurrence and development of AD. In this review, we elaborate on the functions of ADEs and their components in AD and discuss their applications in AD research and clinical practice.

Pages 43-70

Corlia Grobler, Marvi van Tongeren, Jan Gettemans, Douglas B. Kell, Etheresia Pretorius
Alzheimer’s Disease: A Systems View Provides a Unifying Explanation of Its Development
Abstract: Alzheimer’s disease (AD) is a debilitating neurodegenerative disorder affecting 50 million people globally. It is characterized by the presence of extracellular senile plaques and intracellular neurofibrillary tangles, consisting of amyloid-β and hyperphosphorylated tau proteins, respectively. Despite global research efforts, there is currently no cure available, due in part to an incomplete understanding of the disease pathogenesis. Numerous possible mechanisms, or hypotheses, explaining the origins of sporadic or late-onset AD have been proposed, including the amyloid-β, inflammatory, vascular, and infectious hypotheses. However, despite ample evidence, the failure of multiple trial drugs at the clinical stage illuminates the possible pitfalls of these hypotheses. Systems biology is a strategy which aims to elucidate the interactions between parts of a whole. Using this approach, the current paper shows how the four previously mentioned hypotheses of AD pathogenesis can be intricately connected. This approach allows for seemingly contradictory evidence to be unified in a system-focused explanation of sporadic AD development. Within this view, it is seen that infectious agents, such as P. gingivalis, may play a central role. The data presented here shows that when present, P. gingivalis or its virulence factors, such as gingipains, may induce or exacerbate pathologies underlying sporadic AD. This evidence supports the view that infectious agents, and specifically P. gingivalis, may be suitable treatment targets in AD.

Pages 71-90

Mohammad Rafi Khezri, Morteza Ghasemnejad-Berenji
The Role of Caspases in Alzheimer’s Disease: Pathophysiology Implications and Pharmacologic Modulation
Abstract: Alzheimer’s disease (AD) is the most common neurodegenerative disorder worldwide. Although the main cause of the onset and development of AD is not known yet, neuronal death due to pathologic changes such as amyloid-β (Aβ) deposition, tau aggregation, neuroinflammation, oxidative stress, and calcium dyshomeostasis are considered to be the main cause. At the present, there is no cure for this insidious disorder. However, accurate identification of molecular changes in AD can help provide new therapeutic goals. Caspases are a group of proteases which are known because of their role in cellular apoptosis. In addition, different caspases are involved in other cellular responses to the environment, such as induction of inflammation. Emerging evidence suggest that these proteases play a central role in AD pathophysiology due to their role in the processing of amyloid-β protein precursor, tau cleavage, and neuroinflammation. Therefore, it seems that targeting caspases may be a suitable therapeutic option to slow the progression of AD. This review focuses on the role of caspases in AD pathophysiology and introduce results from studies targeted caspases in different models of AD.

Pages 91-103
Systematic Review

Kay T. Kyaw, Alec Levine, Amanda Jin Zhao
Topical Review of Hobbies and Cognitive Health
Background: Establishing preventive measures to improve cognitive health of the growing older adult population is a public health priority. Though, the links between low-cost non-pharmacologist interventions that target activities like hobbies and cognitive health remain unclear. Objective: We conducted a topical review of extant literature to characterize prior findings in context and identify potential research opportunities. Methods: Search criteria was conducted with search terms “Hobbies and Dementia”, “Hobbies and Cognitive Health," "Leisure Activities and Dementia," and "Leisure Activities and Cognitive Health”. From the initial 383 articles, 25 articles were selected for review by using broad inclusion and exclusion criteria. Results: Of the 25 articles included in this review, 19 were longitudinal cohort, 1 was a retrospective cohort, 2 were case–control, and 3 were cross-sectional. These studies classified hobbies as leisure activities that were cognitive/intellectual, cultural, religious, social, gardening, traveling, or physical. These studies were conducted in the United States (9), United Kingdom (3), Sweden (3), France (5), Finland (1), Korea (1), Japan (2), and China (1). The associations of different types of hobbies with dementia from these studies were not consistent. Inconsistencies could be due to limitations of study design, lack of standardized methods, sample diversity, and differences in factors like social/cultural environment across the study populations. Conclusion: This review examined existing evidence for the association between engagement in different types of hobbies and dementia and identified key knowledge gaps and promising approaches for future research.

Pages 105-114
Systematic Review

Joost D. Wammes, Joffre D. Swait, Esther W. de Bekker-Grob, Joan K. Monin, Nanon H.M. Labrie, Janet L. MacNeil Vroomen
Dyadic Discrete Choice Experiments Enable Persons with Dementia and Informal Caregivers to Participate in Health Care Decision Making: A Mixed Methods Study
Abstract: Background: Discrete choice experiments (DCEs) may facilitate persons with dementia and informal caregivers to state care preferences. DCEs can be cognitively challenging for persons with dementia. Objective: This study aims to design a dementia friendly dyadic DCE that enables persons with dementia and informal caregivers to provide input individually and jointly, by testing the number of attributes and choice tasks persons with dementia can complete and providing insight in their DCE decision-making process. Methods: This study included three DCE rounds: 1) persons with dementia, 2) informal caregivers, and 3) persons with dementia and informal caregivers together. A flexible DCE design was employed, with increasing choice task complexity to explore cognitive limitations in decision-making. Summary statistics and bivariate comparisons were calculated. A qualitative think-aloud approach was used to gain insight in the DCE decision-making processes. Transcripts were analyzed using thematic analysis. Results: Fifteen person with dementia, 15 informal caregiver, and 14 dyadic DCEs were conducted. In the individual DCE, persons with dementia completed six choice tasks (median), and 80% could complete a choice task with least three attributes. In the dyadic DCE persons with dementia completed eight choice tasks (median) and could handle slightly more attributes. Qualitative results included themes of core components in DCE decision-making such as: understanding the choice task, attribute and level perception, option attractiveness evaluation, decision rule selection, and preference adaptation. Conclusion: Persons with dementia can use simple DCE designs. The dyadic DCE was promising for dyads to identify overlapping and discrepant care preferences while reaching consensus.

Pages 115-128
Systematic Review

Angeladine Kenne Malaha, Clémence Thébaut, Dayna Achille, Pierre-Marie Preux, Maëlenn Guerchet (Handling Associate Editor: Sophie Vandepitte)
Costs of Dementia in Low- And Middle-Income Countries: A Systematic Review
Abstract: Background: The proportion of people living with dementia in low- and middle-income countries (LMICs) is expected to reach 71% by 2050. Appraising the economic burden of the disease may contribute to strategic policy planning. Objective: To review studies conducted on the costs of dementia in LMICs, describe their methodology and summarize available costs estimates. Methods: Systematic review, including a search of health, economics, and social science bibliographic databases. No date or language restrictions were applied. All studies with a direct measure of the costs of dementia care were included. Results: Of the 6,843 publications reviewed, 17 studies from 11 LMICs were included. Costs of dementia tended to increase with the severity of the disease. Medical costs were greater in the mild stage, while social and informal care costs were highest in the moderate and severe stages. Annual cost estimates per patient ranged from PPP$131.0 to PPP$31,188.8 for medical costs; from PPP$16.1 to PPP$10,581.7 for social care services and from PPP$140.0 to PPP$25,798 for informal care. Overall, dementia care can cost from PPP$479.0 to PPP$66,143.6 per year for a single patient. Conclusion: Few studies have been conducted on the costs of dementia in LMICs, and none so far in Africa. There seems to be a need to provide accurate data on the burden of disease in these countries to guide public health policies in the coming decades.

Pages 129-150
Systematic Review

Sixin Liu, Stuart G. Dashper, Rui Zhao (Handling Associate Editor: Jin-Tai Yu)
Association Between Oral Bacteria and Alzheimer’s Disease: A Systematic Review and Meta-Analysis
Abstract: Background: Pre-clinical evidence implicates oral bacteria in the pathogenesis of Alzheimer’s disease (AD), while clinical studies show diverse results. Objective: To comprehensively assess the association between oral bacteria and AD with clinical evidence. Methods: Studies investigating the association between oral bacteria and AD were identified through a systematic search of six databases PubMed, Embase, Cochrane Central Library, Scopus, ScienceDirect, and Web of Science. Methodological quality ratings of the included studies were performed. A best evidence synthesis was employed to integrate the results. When applicable, a meta-analysis was conducted using a random-effect model. Results: Of the 16 studies included, ten investigated periodontal pathobionts and six were microbiome-wide association studies. Samples from the brain, serum, and oral cavity were tested. We found over a ten-fold and six-fold increased risk of AD when there were oral bacteria (OR=10.68 95% CI: 4.48–25.43; p<0.00001, I2=0%) and Porphyromonas gingivalis (OR=6.84 95% CI: 2.70–17.31; p<0.0001, I2=0%) respectively in the brain. While AD patients exhibited lower alpha diversity of oral microbiota than healthy controls, the findings of bacterial communities were inconsistent among studies. The best evidence synthesis suggested a moderate level of evidence for an overall association between oral bacteria and AD and for oral bacteria being a risk factor for AD. Conclusion: Current evidence moderately supports the association between oral bacteria and AD, while the association was strong when oral bacteria were detectable in the brain. Further evidence is needed to clarify the interrelationship between both individual species and bacterial communities and the development of AD.

Pages 151-167
Systematic Review

Maria João Garcia, Regina Leadley, Shona Lang, Janine Ross, Elizabeth Vinand, Clive Ballard, Sandro Gsteiger (Handling Associate Editor: Elzbieta Kuzma)
Real-World Use of Symptomatic Treatments in Early Alzheimer’s Disease
Abstract: Background: Alzheimer’s disease (AD) is the most common type of dementia, causing progressive decline of memory, thinking, and behavior, impairing daily functioning. Early AD (eAD) includes mild cognitive impairment (MCI) due to AD and mild AD dementia. Objective: The aim of this study was to investigate symptomatic treatment prevalence and treatment patterns in eAD. Methods: Embase, MEDLINE, and EBM Reviews were searched in November 2021 for observational studies reporting symptomatic treatment patterns in eAD. The range of patients receiving treatment was collated. Risk of bias was assessed using the Joanna Briggs Institute (JBI) prevalence tool. Two independent reviewers screened the records, one performed data extraction and quality assessment while a second checked. Results: Twenty-one studies (prospective and retrospective cohorts, cross-sectional studies, and a survey) were included. Population size ranged from 23 to 2,028. Worldwide, 18 to 35% of patients diagnosed with MCI due to AD received any AChE inhibitor (three studies; n=631), 7 to 8% memantine (two studies; n=229), and 9% combination therapy (one study; n=402). Patients receiving no treatment ranged from 41 to 54% (two studies; n=733). Worldwide, in mild AD dementia patients, 13 to 89% received any AChE inhibitor (six studies; n=3,715), 1 to 21% memantine (five studies, n=3,527), and 0.4 to 39% combination therapy (four studies, n=3,018). Patients receiving no treatment ranged from 9 to 26% (five studies, n=4,073). Conclusion: Limitations in reporting led to unclear risk of bias. The results reveal a pattern of use of symptomatic treatment in eAD beyond approved labels and highlights the opportunity for new consensus guidelines to inform clinical practice.

Pages 169-182
Systematic Review
Anne R. Carlew, Alyssa Kaser, Jeff Schaffert, William Goette, Laura Lacritz, Heidi Rossetti
A Critical Review of Neuropsychological Actuarial Criteria for Mild Cognitive Impairment
Abstract: Background: The concept of mild cognitive impairment (MCI) has evolved since its original conception. So, too, have MCI diagnostic methods, all of which have varying degrees of success in identifying individuals at risk of conversion to dementia. The neuropsychological actuarial method is a straightforward diagnostic approach that has shown promise in large datasets in identifying individuals with MCI who are likely to have progressive courses. This method has been increasingly applied in various iterations and samples, raising questions of how best to apply this method and when caution should be used. Objective: Our objective was to review the literature investigating use of the neuropsychological actuarial method to diagnose MCI to identify strengths and weaknesses of this approach, as well as highlight areas for further research. Methods: Databases PubMed and PsychInfo were systematically searched for studies that compared the neuropsychological actuarial method to some other diagnostic method. Results: We identified 13 articles and extracted relevant study characteristics and findings. Existing literature was reviewed and integrated, with focus on the neuropsychological actuarial method’s performance relative to existing diagnostic methods/criteria as well as associations with longitudinal outcomes and biomarkers. Tables with pertinent methodological information and general findings are also provided. Conclusion: The neuropsychological actuarial method to diagnose MCI has shown utility some in large-scale homogenous databases compared to research criteria. However, its standing relative to consensus diagnostic methods is unclear, and emerging evidence suggests the neuropsychological actuarial method may be more prone to diagnostic errors in more demographically diverse populations.

Pages 183-189
Short Communication

Adrienne L. Johnson, Elaina Seep, Derek L. Norton, Marlon P. Mundt, Mary F. Wyman, Taryn T. James, Megan Zuelsdorff, Nickolas H. Lambrou, Lauren W.Y. McLester-Davis, Emre Umucu, Carey E. Gleason (Handling Associate Editor: Suzanne Tyas)
Wisconsin Healthcare Utilization Cost Among American Indians/Alaska Natives with and without Alzheimer’s Disease and Related Dementias
Abstract: Individuals with Alzheimer’s disease and related dementias (ADRD) accrue higher healthcare utilization costs than peers without ADRD, but incremental costs of ADRD among American Indians/Alaska Natives (AI/AN) is unknown. State-wide paid electronic health record data were retrospectively analyzed using percentile-based bootstrapped 95% confidence intervals of the weighted mean difference of total 5-year billed costs to compare total accrued for non-Tribal and Indian Health Service utilization costs among Medicaid and state program eligible AI/AN, >40 years, based on the presence/absence of ADRD (matching by demographic and medical factors). AI/AN individuals with ADRD accrued double the costs compared to those without ADRD, costing an additional $880.45 million to $1.91 billion/year.

Pages 191-201
Liang Chen*, Jun Xue*, Qianhua Zhao, Xiaoniu Liang, Li Zheng, Zhen Fan, Ibrahima Sory Jnr Souare, Yuanzhen Suo, Xunbin Wei, Ding Ding, Ying Mao (Handling Associate Editor: Ling-Qiang Zhu) *These authors contributed equally to this work.
A Pilot Study of Near-Infrared Light Treatment for Alzheimer’s Disease
Abstract: Background: Laboratory investigations have demonstrated that near-infrared (NIR) light treatment can reduce amyloid-β burden in models of Alzheimer’s disease (AD). However, previous clinical studies are rather insufficient. Objective: Before starting a large-scale clinical trial, we performed a pilot study to characterize the efficacy of NIR light for AD patients. Methods: Twenty participants with mild to moderate AD were assigned randomly to the intervention (1060-1080 nm and 800-820 nm NIR light treatment for 12 weeks) or control group (without sham treatment). Safety and efficacy were evaluated at baseline, week 4, 8, and 12, and 4 weeks after treatment. Results: In the intervention and control groups at week 12, mean changes from baseline on the Alzheimer’s Disease Assessment Scale-Cognitive (ADAS-Cog) were -3.1 and -1.3 (p = 0.5689). Mean changes from baseline on the Activities of Daily Living (ADL) were -3.6 versus 3.1 (p = 0.0437). Mean changes from baseline on the Mini-Mental State Examination (MMSE) were 4.4 versus 1.0 (p = 0.0253). The percentage of participants who exhibited a change larger than 4 points from baseline to week 12 was determined for the intervention and control groups on the ADAS-Cog (57% versus 29%), ADL (29% versus 0%), and MMSE (57% versus 14%). Treatment with NIR light did not increase the incidence of adverse events in participants. Conclusion: NIR light treatment appears to be safe and potentially beneficial for AD patients. It improved cognitive function and activities of daily living. The preliminary data encouraged us to launch a large-sample, multicenter, double-blind clinical trial.

Pages 203-214
Alison Cowley, Vicky Booth, Claudio Di Lorito, Pooja Chandria, Olivia Chadwick, Catherine Stanislas, Marianne Dunlop, Louise Howe, Rowan H Harwood, Pip Logan
A Qualitative Study on the Experiences of Therapists Delivering the Promoting Activity, Independence and Stability in Early Dementia (PrAISED) Intervention During the COVID-19 Pandemic
Abstract: Background: The Promoting Activity, Independence and Stability in Early Dementia (PrAISED) intervention is a programme of physical activity and exercise designed to maintain participation in activities of daily living, mobility, and quality of life for people living with dementia. During the COVID-19 pandemic first national lockdown in England, the PrAISED physiotherapists, occupational therapists, and rehabilitation support workers adapted to delivering the intervention remotely via telephone or video conferencing. Objective: The aim of this study was to explore therapists’ experience of delivering the PrAISED intervention during the COVID-19 pandemic and derive implications for clinical practice. Methods: Qualitative semi-structured interviews were conducted with 16 therapists using purposive sampling. Thematic analysis was used to analyze the transcripts. Results: Therapists reported a change in the relationship between themselves, the person with dementia and the caregiver, with an increased reliance on the caregiver and a loss of autonomy for the person living with dementia. There was concern that this would increase the burden on the caregiver. The therapists reported using creativity to adapt to different modes of delivery. They felt their sessions were mostly focused on providing social and emotional support, and that assessing, progressing, and tailoring the intervention was difficult. Conclusion: It is possible to deliver some elements of a physical intervention using remote delivery, but a dual modal approach including remote and face-to-face delivery would optimize treatment efficacy. Educational support would be required to enable people living with dementia and their caregivers to overcome barriers relating to digital literacy.

Pages 215-223
Jenna I. Rajczyk, Amy Ferketich, Jeffrey J. Wing
Relation Between Smoking Status and Subjective Cognitive Decline in Middle Age and Older Adults: A Cross-Sectional Analysis of 2019 Behavioral Risk Factor Surveillance System Data
Abstract: Background: Smoking status may influence subjective cognitive decline (SCD); however, few studies have evaluated this association. Objective: To assess whether smoking status is associated with SCD among middle age and older adults, and to determine if this association is modified by sex at birth. Methods: A cross-sectional analysis was conducted using data from the 2019 Behavioral Risk Factor Surveillance System (BRFSS) survey to analyze the relationship between SCD and smoking status (current, recent former, and remote former). Eligible respondents included participants 45 years of age or older who responded to the SCD and tobacco questions of interest. Survey-weighted Poisson regression models were employed to estimate the crude and adjusted prevalence ratios (cPR/aPR) and corresponding 95% confidence intervals (CI) of the association between smoking status and SCD. A Wald test was computed to determine the significance of the interaction term between smoking status and sex (α=0.05). Results: There were 136,018 eligible respondents, of which approximately 10% had SCD. There was a graded association between smoking and SCD, with the greatest prevalence of SCD among current smokers (aPR=1.87; CI: 1.54, 2.28), followed by recent former smokers (aPR=1.47; 95% CI: 1.02, 2.12), and remote former smokers (aPR=1.11; 95% CI: 0.93, 1.33) each compared to never smokers. There was no evidence of effect modification by sex (p interaction=0.73). Conclusion: The consistency of smoking as a risk factor for objective and subjective cognitive decline supports the need for future studies to further the evidence on whether changes to smoking status impacts cognition in middle age.

Pages 225-232
Helmi Soppela, Johanna Krüger, Päivi Hartikainen, Anne Koivisto, Annakaisa Haapasalo, Barbara Borroni, Anne M. Remes, Kasper Katisko, Eino Solje
Traumatic Brain Injury Associates with an Earlier Onset in Sporadic Frontotemporal Dementia
Abstract: Background: Currently, there are few studies considering possible modifiable risk factors of frontotemporal dementia (FTD). Objective: In this retrospective case-control study, we evaluated whether a history of traumatic brain injury (TBI) associates with a diagnosis of FTD or modulates the clinical phenotype or onset age in FTD patients. Methods: We compared the prevalence of prior TBI between individuals with FTD (N=218) and age and sex-matched AD patients (N=214) or healthy controls (HC; N=100). Based on the patient records, an individual was categorized to the TBI+ group if they were reported to have suffered from TBI during lifetime. The possible associations of TBI with age of onset and disease duration were also evaluated in the whole FTD patient group or separately in the sporadic and genetic FTD groups. Results: The prevalence of previous TBI was the highest in the FTD group (19.3%) when compared to the AD group (13.1%, p=0.050) or HC group (12%, p=0.108, not significant). Preceding TBI was more often associated with the sporadic FTD cases than the C9orf72 repeat expansion-carrying FTD cases (p=0.003). Furthermore, comparison of the TBI+ and TBI- FTD groups indicated that previous TBI was associated with an earlier onset age in the FTD patients (B=3.066, p=0.010). Conclusion: A preceding TBI associates especially with sporadic FTD and with earlier onset of symptoms. The results of this study suggest that TBI may be a triggering factor for the neurodegenerative processes in FTD. However, understanding the precise underlying mechanisms still needs further studies.

Pages 233-243
Sreevani Katabathula, Pamela B. Davis, Rong Xu for the Alzheimer’s Disease Neuroimaging Initiative
Sex-Specific Heterogeneity of Mild Cognitive Impairment Identified Based on Multi-Modal Data Analysis
Abstract: Background: Mild cognitive impairment (MCI), a prodromal phase of Alzheimer’s disease (AD), is heterogeneous with different rates and risks of progression to AD. There are significant gender disparities in the susceptibility, prognosis, and outcomes in patients with MCI, with female being disproportionately negatively impacted. Objective: The aim of this study was to identify sex-specific heterogeneity of MCI using multi-modality data and examine the differences in the respective MCI subtypes with different prognostic outcomes or different risks for MCI to AD conversion. Methods: A total of 325 MCI subjects (146 women, 179 men) and 30 relevant features were considered. Mixed-data clustering was applied to women and men separately to discover gender-specific MCI subtypes. Gender differences were compared in the respective subtypes of MCI by examining their MCI to AD disease prognosis, descriptive statistics, and conversion rates. Results: We identified three MCI subtypes: poor-, good-, and best-prognosis for women and for men, separately. The subtype-wise comparison (for example, poor-prognosis subtype in women versus poor-prognosis subtype in men) showed significantly different means for brain volumetric, cognitive test-related, also for the proportion of comorbidities. Also, there were substantial gender differences in the proportions of participants who reverted to normal function, remained stable, or converted to AD. Conclusion: Analyzing sex-specific heterogeneity of MCI offers the opportunity to advance the understanding of the pathophysiology of both MCI and AD, allows stratification of risk in clinical trials of interventions, and suggests gender-based early intervention with targeted treatment for patients at risk of developing AD.

Pages 245-261
Mary Dover, Taylor Moseley, Adrienne Biskaduros, Mousumi Paulchakrabarti, Sung Hee Hwang, Bruce Hammock, Biswa Choudhury, Karolina Elżbieta Kaczor- Urbanowicz, Andrzej Urbanowicz, Marco Morselli, Johnny Dang, Matteo Pellegrini, Ketema Paul, Laurent A. Bentolila, Milan Fiala (Handling Associate Editor: Giulio Pasinetti)
Polyunsaturated Fatty Acids Mend Macrophage Transcriptome, Glycome, and Phenotype in the Patients with Neurodegenerative Diseases, Including Alzheimer’s Disease
Abstract: Background: Macrophages of healthy subjects have a pro-resolution phenotype, upload amyloid-β (Aβ) into endosomes, and degrade Aβ, whereas macrophages of patients with Alzheimer’s disease (AD) generally have a pro-inflammatory phenotype and lack energy for brain clearance of Aβ. Objective: To clarify the pathogenesis of sporadic AD and therapeutic effects of polyunsaturated fatty acids (PUFA) with vitamins B and D and antioxidants on monocyte/macrophage (MM) migration in the AD brain, MM transcripts in energy and Aβ degradation, MM glycome, and macrophage clearance of Aβ. Methods: We followed for 31.3 months (mean) ten PUFA-supplemented neurodegenerative patients: 3 with subjective cognitive impairment (SCI), 2 with mild cognitive impairment (MCI), 3 MCI/vascular cognitive impairment, 2 with dementia with Lewy bodies, and 7 non-supplemented caregivers. We examined: monocyte migration in the brain and a blood-brain barrier model by immunochemistry and electron microscopy; macrophage transcriptome by RNAseq; macrophage glycome by N-glycan profiling and LTQ-Orbitrap mass spectrometry; and macrophage phenotype and phagocytosis by immunofluorescence. Results: MM invade Aβ plaques, upload but do not degrade Aβ, and release Aβ into vessels, which develop cerebrovascular amyloid angiopathy; PUFA upregulate energy and Aβ degradation enzyme transcripts in macrophages; PUFA enhance sialylated N-glycans in macrophages; PUFA reduce oxidative stress and increase pro-resolution MM phenotype, mitochondrial membrane potential, and Aβ phagocytosis (p<0.001). Conclusion: Macrophages of SCI, MCI, and AD patients have interrelated defects in the transcriptome, glycome, Aβ phagocytosis, and Aβ degradation. PUFA mend macrophage transcriptome, enrich glycome, enhance Aβ clearance, and benefit the cognition of early-stage AD patients.

Pages 263-272
Yu Kong*, Zhongyun Chen*, Qi Shi, Ya Zuo, Jing Zhang *These authors contributed equally to this work.
Clinical Correlates of Cerebrospinal Fluid 14-3-3 Protein in Non-Prion Rapid Progressive Dementia
Abstract: Background: The 14-3-3 protein in cerebrospinal fluid (CSF) is a suitable biomarker for the diagnosis of Creutzfeldt-Jakob disease (CJD). However, it has also been detected in various non-prion-related rapidly progressive dementia (RPD), which affected its diagnostic performance and clinical utilization. Objective: To investigate the general disease distribution with positive 14-3-3 result and to evaluate the association between CSF 14-3-3 protein and the clinical features in patients with non-prion RPD. Methods: A total of 150 patients with non-prion RPD were enrolled. The clinical data were collected and CSF 14-3-3 test was performed for all patients. The distribution of various diseases with a positive 14-3-3 result was analyzed and the association of CSF 14-3-3 with clinical features was tested. Results: The CSF 14-3-3 protein was detected in 23.3% of non-prion RPD patients, and the most frequent diagnoses were autoimmune encephalitis (22.9%) and neurodegenerative disease (22.9%). CSF 14-3-3 protein was more common in older patients (p=0.028) and those presenting myoclonus (p=0.008). In subgroup analysis, the positive 14-3-3 test was more common in neurodegenerative disease with a long time from the symptom onset to CSF 14-3-3 test (p=0.014). Conclusion: CSF 14-3-3 protein could be detected in a broad spectrum of non-prion RPD. In particular, patients with autoimmune encephalitis and rapidly progressive neurodegenerative diseases and those with myoclonus have a greater likelihood of a positive 14-3-3 result. These results could help clinicians interpret the results of CSF 14-3-3 protein more reasonably.

Pages 273-290
Alyssa L. Wiseman, Clark A. Briggs, Ariel Peritt, Nicolas Kapecki, Daniel A. Peterson, Seong S. Shim, Grace E. Stutzmann
Lithium Provides Broad Therapeutic Benefits in an Alzheimer’s Disease Mouse Model
Abstract: Background: Alzheimer’s disease (AD) is a chronic neurodegenerative disorder with a progressive loss of cognitive function. Currently, no effective treatment regimen is available. Lithium, a mood stabilizer for bipolar disorder, exerts broad neuroprotective and neurotrophic actions and improves cognitive function. Objective: The study investigated if lithium stabilizes Ca2+ signaling abnormalities in hippocampal neurons and subsequently normalize downstream effects on AD neuropathology and synaptic plasticity in young AD mice. Methods: Four-month-old 3xTg-AD mice were treated with a LiCl diet chow for 30 days. At the end of the lithium treatment, a combination of two-photon Ca2+ imaging, electrophysiology, and immunohistochemistry assays were used to assess the effects of the LiCl treatment on inositol trisphosphate receptor (IP3R)-dependent endoplasmic reticulum (ER) Ca2+ and voltage-gated Ca2+ channel (VGCC)-mediated Ca2+ signaling in CA1 neurons, neuronal nitric oxide synthase (nNOS) and hyperphosphorylated tau (p-tau) levels and synaptic plasticity in the hippocampus and overlying cortex from 3xTg-AD mice. Results: Thirty-day LiCl treatment reduced aberrant IP3R-dependent ER Ca2+ and VGCC-mediated Ca2+ signaling in CA1 pyramidal neurons from 3xTg-AD mice and restored neuronal nitric oxide synthase (nNOS) and hyperphosphorylated tau (p-tau) levels to control levels in the hippocampal subfields and overlying cortex. The LiCl treatment enhanced post-tetanic potentiation (PTP), a form of short-term plasticity in the hippocampus. Conclusion: The study found that lithium exerts therapeutic effects across several AD-associated early neuronal signaling abnormalities including aberrant Ca2+ signaling, nNOS, and p-tau formation and enhances short-term synaptic plasticity. Lithium could serve as an effective treatment or co-therapeutic for AD.

Pages 291-303
Maya Arvidsson Rådestig, Johan Skoog, Henrik Zetterberg, Tobias Skillbäck, Anna Zettergren, Therese Rydberg Sterner, Madeleine Mellqvist Fässberg, Simona Sacuiu, Margda Waern, Hanna Wetterberg, Kaj Blennow, Ingmar Skoog*, Silke Kern* *These authors share last authorship.
Subtle Differences in Cognition in 70-Year-Olds with Elevated Cerebrospinal Fluid Neurofilament Light and Neurogranin: A H70 Cross-Sectional Study
Abstract: Background: Most research on cerebrospinal fluid (CSF) neurofilament light protein (NfL) as a marker for neurodegeneration and neurogranin (Ng) for synaptic dysfunction has largely focused on clinical cohorts rather than population-based samples. Objective: We hypothesized that increased CSF levels of NfL and Ng are associated with subtle cognitive deficits in cognitively unimpaired (CU) older adults. Methods: The sample was derived from the Gothenburg H70 Birth Cohort Studies and comprised 258 CU 70-year-olds, with a Clinical Dementia Rating score of zero. All participants underwent extensive cognitive testing. CSF levels of NfL and Ng, as well as amyloid 1-42, total tau, and phosphorylated tau, were measured. Results: Participants with high CSF NfL performed worse in one memory-based test (Immediate recall, p=0.013) and a language test (FAS, p=0.016). Individuals with high CSF Ng performed worse on the memory-based test Supra Span (p=0.035). When stratified according to CSF tau and Aβ42 concentrations, participants with high NfL and increased tau performed worse on a memory test than participants normal tau concentrations (Delayed recall, p=0.003). In participants with high NfL, those with pathologic Aβ42 concentrations performed worse on the Delayed recall memory (p=0.044). In the high Ng group, participants with pathological Aβ42 concentrations had lower MMSE scores (p=0.027). However, in regression analysis we found no linear correlations between CSF NfL or CSF Ng in relation to cognitive tests when controlled for important co-variates. Conclusion: Markers of neurodegeneration and synaptic pathology might be associated with subtle signs of cognitive decline in a population-based sample of 70-year-olds.

Pages 305-319
Heikki Lukkarinen, Aleksi Vanninen, Ina Tesseur, Darrel Pemberton, Peter Van Der Ark, Tarja Kokkola, Sanna-Kaisa Herukka, Tuomas Rauramaa, Mikko Hiltunen, Kaj Blennow, Henrik Zetterberg, Ville Leinonen
Concordance of Alzheimer’s Disease-Related Biomarkers Between Intraventricular and Lumbar Cerebrospinal Fluid in Idiopathic Normal Pressure Hydrocephalus
Abstract: Background: Alzheimer’s disease cerebrospinal fluid (CSF) biomarkers amyloid-β 1-42 (Aβ42), total tau (T-tau), and phosphorylated tau 181 (P-tau181) are widely used. However, concentration gradient of these biomarkers between intraventricular (V-CSF) and lumbar CSF (L-CSF) has been demonstrated in idiopathic normal pressure hydrocephalus (iNPH), potentially affecting clinical utility. Objective: Here we aim to provide conversion factors for clinical and research use between V-CSF and L-CSF. Methods: Altogether 138 iNPH patients participated. L-CSF samples were obtained prior to shunt surgery. Intraoperative V-CSF samples were obtained from 97 patients. Post-operative follow-up L- and V-CSF (shunt reservoir) samples of 41 patients were obtained 1-73 months after surgery and then after 3, 6, and 18 months. CSF concentrations of Aβ42, T-tau, and P-tau181 were analyzed using commercial ELISA assays. Results: Preoperative L-CSF Aβ42, T-tau, and P-tau181 correlated to intraoperative V-CSF (ρ=0.34-0.55, p<0.001). Strong correlations were seen between postoperative L- and V-CSF for all biomarkers in every follow-up sampling point (ρs Aβ42: 0.77-0.88, T-tau: 0.91-0.94, P-tau181: 0.94-0.96, p<0.0001). Regression equations were determined for intraoperative V- and preoperative L-CSF (Aβ42: V-CSF=185+0.34*L-CSF, T-tau: Ln(V-CSF)=3.11+0.49*Ln(L-CSF), P-tau181: V-CSF=8.2+0.51*L-CSF), and for postoperative V- and L-CSF (Aβ42: V-CSF=86.7+0.75*L-CSF, T-tau: V-CSF=86.9+0.62*L-CSF, P-tau181: V-CSF=2.6+0.74*L-CSF). Conclusion: Aβ42, T-tau, and P-tau181 correlate linearly in-between V- and L-CSF, even stronger after CSF shunt surgery. Equations presented here, provide a novel tool to use V-CSF for diagnostic and prognostic entities relying on the L-CSF concentrations and can be applicable to clinical use when L-CSF samples are not available or less invasively obtained shunt reservoir samples should be interpreted.

Pages 321-343
Jørgen Wagle, Geir Selbæk, Jūratė Šaltytė Benth, Linda Gjøra, Thale Kinne Rønqvist, Peter Bekkhus-Wetterberg, Karin Persson, Knut Engedal (Handling Associate Editor: Anne Fink)
The CERAD Word List Memory Test: Normative Data Based on a Norwegian Population-Based Sample of Healthy Older Adults 70 Years and Above. The HUNT Study
Abstract: Background: The CERAD Word List Memory Test (WLMT) is widely used in the assessment of older adults with suspected dementia. Although normative data of the WLMT exist in many different regions of the world, normative data based on large population-based cohorts from the Scandinavian countries are lacking. Objective: To develop normative data for the WLMT based on a large population-based Norwegian sample of healthy older adults aged 70 years and above, stratified by age, gender, and education. Methods: A total of 6,356 older adults from two population-based studies in Norway, HUNT4 70+ and HUNT4 Trondheim 70+, were administered the WLMT. Only persons with normal cognitive function were included. We excluded persons with a diagnosis of mild cognitive impairment (MCI) and dementia, and persons with a history of stroke and/or depression. This resulted in 3,951 persons aged between 70 and 90 years, of whom 56.2% were females. Regression-based normative data were developed for this sample. Results: Age, gender, and education were significant predictors of performance on the WLMT list-learning subtests and the delayed recall subtest, i.e., participants of younger age, female sex, and higher education level attained higher scores compared to participants of older age, male sex, and lower level of education. Conclusion: Regression-based normative data from the WMLT, stratified by age, gender, and education from a large population-based Norwegian sample of cognitively healthy older adults aged 70 to 90 years are presented. An online norm calculator is available to facilitate scoring of the subtests (in percentiles and z-scores).

Pages 345-354
Jinhee Kim, Hyemin Jang, Yu-hyun Park, Jinyoung Youn, Sang Won Seo, Hee Jin Kim, Duk L. Na
Motor Symptoms in Early- versus Late-Onset Alzheimer’s Disease
Abstract: Background: Age at onset was suggested as one possible risk factor for motor dysfunction in Alzheimer’s disease (AD). Objective: We investigated the association of motor symptoms with cognition or neurodegeneration in patients with AD, and whether this association differs by the age at onset. Methods: We included 113 amyloid positive AD patients and divided them into early-onset AD (EOAD) and late-onset AD (LOAD), who underwent the Unified Parkinson’s Disease Rating Scale (UPDRS)-Part III (=UPDRS) scoring, Mini-Mental State Examination (MMSE)/Clinical Deterioration Rating Sum-of-Boxes (CDR-SOB), and magnetic resonance image (MRI). Multiple linear regression was used to evaluate the association of UPDRS and MMSE/CDR-SOB or MRI neurodegeneration measures, and whether the association differs according to the group. Results: The prevalence of motor symptoms and their severity did not differ between the groups. Lower MMSE (β=-1.1, p<0.001) and higher CDR-SOB (β=2.0, p<0.001) were significantly associated with higher UPDRS. There was no interaction effect between MMSE/CDR-SOB and AD group on UPDRS. Global or all regional cortical thickness and putaminal volume were negatively associated with UPDRS score, but the interaction effect of neurodegeneration and AD group on UPDRS score was significant only in parietal lobe (p for interaction=0.035), which showed EOAD to have a more pronounced association between parietal thinning and motor symptoms. Conclusion: Our study suggested that the severity of motor deterioration in AD is related to the severity of cognitive impairment itself rather than age at onset, and motor symptoms might occur through multiple mechanisms including cortical and subcortical atrophy.

Pages 355-362
Neal R. Swerdlow, Yash B. Joshi, Joyce Sprock, Jo Talledo, Juan L. Molina, Lisa Delano-Wood, Dylan Iwanaga, Juliana E. Kotz, Steven Huege, Gabriel Leger, Gregory A. Light
Preliminary Evidence that Memantine Enhances Prepulse Effects on Startle Magnitude and Latency in Patients with Alzheimer’s Disease
Abstract: Background: The uncompetitive NMDA antagonist, memantine (MEM), enhances prepulse inhibition of startle (PPI) across species. MEM is used to treat Alzheimer’s disease (AD); conceivably, its acute impact on PPI might be used to predict a patient’s sensitivity to MEM’s therapeutic effects. Objective: To begin to test this possibility, we studied MEM effects on PPI and related measures in AD patients. Methods: 18 carefully screened individuals with AD (mean age=72.8 y; M:F=9:9) completed double-blind order-balanced testing with MEM (placebo versus 20 mg), assessing acoustic startle magnitude, habituation, PPI, and latency. Results: Fifteen out of 18 participants exhibited reliable startle responses. MEM did not significantly impact startle magnitude or habituation. Compared to placebo responses, PPI was significantly increased after MEM (p<0.04; d=0.40); this comparison reached a large effect size for the 60 ms interval (d=0.62), where maximal MEM effects on PPI were previously detected. Prepulses reduced peak startle latency (“latency facilitation”) and this effect was amplified after MEM (p=0.03; d=0.41; for 60 ms intervals, d=0.69). No effects of MEM were detected on cognition, nor were MEM effects on startle associated with cognitive or clinical measures. Conclusion: MEM enhances prepulse effects on startle magnitude and latency in AD; these changes in PPI and latency facilitation with MEM suggest that these measures can be used to detect an AD patient’s neural sensitivity to acute MEM challenge. Studies in progress will determine whether such a “biomarker” measured at the outset on treatment can predict sensitivity to MEM’s therapeutic effects.

Pages 363-388
Carlo Abbate, Pietro D. Trimarchi, Giorgio G. Fumagalli, Alessia Gallucci, Emanuele Tomasini, Stefania Fracchia, Isabella Rebecchi, Elisabetta Morello, Anna Fontanella, Paola M.R. Parisi, Federica Tartarone, Fabrizio Giunco, Simona Ciccone, Paola Nicolini, Tiziano Lucchi, Beatrice Arosio, Silvia Inglese, Paolo D. Rossi
Diencephalic versus Hippocampal Amnesia in Alzheimer’s Disease: The Possible Confabulation-Misidentification Phenotype
Abstract: Background: Alzheimer’s disease (AD) is clinically heterogeneous, including the classical-amnesic (CA-) phenotype and some variants. Objective: We aim to describe a further presentation we (re)named confabulation-misidentification (CM-) phenotype. Methods: We performed a retrospective longitudinal case-series study of 17 AD outpatients with the possible CM-phenotype (CM-ADs). Then, in a cross-sectional study, we compared the CM-ADs to a sample of 30 AD patients with the CA-phenotype (CA-ADs). The primary outcome was the frequency of cognitive and behavioral features. Data were analyzed as differences in percentage by non-parametric Chi Square and mean differences by parametric T-test. Results: Anterograde amnesia (100%) with early confabulation (88.2%), disorientation (88.2%) and non-infrequently retrograde amnesia (64.7%) associated with reduced insight (88.2%), moderate prefrontal executive impairment (94.1%) and attention deficits (82.3%) dominated the CM-phenotype. Neuropsychiatric features with striking misidentification (52.9%), other less-structured delusions (70.6%), and brief hallucinations (64.7%) were present. Marked behavioral disturbances were present early in some patients and very common at later stages. At the baseline, the CM-ADs showed more confabulation (p<0.001), temporal disorientation (p<0.02), misidentification (p=0.013), other delusions (p=0.002), and logorrhea (p=0.004) than the CA-ADs. In addition, more social disinhibition (p=0.018), reduction of insight (p=0.029), and hallucination (p=0.03) persisted at 12 months from baseline. Both the CA- and CM-ADs showed anterior and medial temporal atrophy. Compared to HCs, the CM-ADs showed more right fronto-insular atrophy, while the CA-ADs showed more dorsal parietal, precuneus, and right parietal atrophy. Conclusion: We described an AD phenotype resembling diencephalic rather than hippocampal amnesia and overlapping the past-century description of presbyophrenia.

Pages 389-406
Maria Maćkowiak, Agnieszka Libura, Lyn Phillipson, Dorota Szcześniak, Joanna Rymaszewska
Understanding of Dementia in the Polish Language: A Frame Semantic Approach
Abstract: Background: With the increasing incidences of dementia in aging societies, attention should be paid to the social context in which people with dementia live. One of its aspects is language transmitting beliefs, perceptions, and behavioral patterns. An analysis of understanding the diagnostic label of dementia may reveal the role of semantics in the process of social cognition of this disease. Objective: The overall aim of this study was to investigate the understanding of the word dementia (otępienie) in the Polish language. Methods: Frame semantics approach was applied. The structure of semantic information was uncovered with the concept of frame utilizing The National Corpus of Polish (the biggest corpus of contemporary Polish language of 1,500 million words). Additional data was collected from Polish speaking adults in Poland. Results: The analyses allowed to identify the otępienie frame for Polish and verify how its elements are filled in by the general population, indicating the selectivity of colloquial knowledge about dementia. Dementia deviates from the prototypical disease. Need to care for the person with dementia outweighs treatment options. The cognitive symptoms and characteristics of the subject are salient. The perceptions of people with dementia embedded in semantics of the diagnostic label might create a basis for prejudicial attitudes among lay part of the society. Conclusion: Findings give foundation to further studies on relationship between semantics and social cognition of dementia which has a real impact on the social and clinical situation of people with dementia and may facilitate formulation of tailored messages aimed at building dementia-friendly society.

Pages 407-426
Li-Tian Hu, Xiao-Yong Xie, Gui-Feng Zhou, Qi-Xin Wen, Li Song, Biao Luo, Xiao-Juan Deng, Qiu-Ling Pan, Guo-Jun Chen
HMGCS2-Induced Autophagic Degradation of Tau Involves Ketone Body and ANKRD2
Abstract: Background: Accumulation of hyperphosphorylated Tau (pTau) contributes to the formation of neurofibrillary tangles in Alzheimer’s disease (AD), and targeting Tau/pTau metabolism has emerged as a therapeutic approach. We have previously reported that mitochondrial 3-hydroxy-3-methylglutaryl-COA synthase 2 (HMGCS2) is involved in AD by promoting autophagic clearance of amyloid-β protein precursor via ketone body-associated mechanism, whether HMGCS2 may also regulate Tau metabolism remains elusive. Objective: The present study was to investigate the role of HMGCS2 in Tau/p degradation. Methods: The protein levels of Tau and pTau including pT217 and pT181, as well as autophagic markers LAMP1 and LC3-II were assessed by western blotting. The differentially regulated genes by HMGCS2 were analyzed by RNA sequencing. Autophagosomes were assessed by transmission electron microscopy. Results: HMGCS2 significantly decreased Tau/pTau levels, which was paralleled by enhanced formation of autophagic vacuoles and prevented by autophagic regulators chloroquine, bafilomycin A1, 3-methyladenine, and rapamycin. Moreover, HMGCS2-induced alterations of LAMP1/LC3-II and Tau/pTau levels were mimicked by ketone body acetoacetate or β-hydroxybutyrate. Further RNA-sequencing identified ankyrin repeat domain 24 (ANKRD24) as a target gene of HMGCS2, and silencing of ANKRD24 reduced LAMP1/LC3-II levels, which was accompanied by the altered formation of autophagic vacuoles, and diminished the effect of HMGCS2 on Tau/pTau. Conclusion: HMGCS2 promoted autophagic clearance of Tau/pTau, in which ketone body and ANKRD24 played an important role.

Pages 427-436
Alina Königsberg, Matthias H. Belau, Leonie Ascone, Jürgen Gallinat, Simone Kühn, Märit Jensen, Christian Gerloff, Bastian Cheng, Götz Thomalla
Subjective Cognitive Decline Is Associated with Health-Related Quality of Life in the Middle-Aged to Elderly Population
Abstract: Background: Subjective cognitive decline (SCD) is considered to be a preliminary stage of dementia, and its prevalence is increasing with age. Objective: We aimed to study the association of SCD with health-related quality of life (HRQoL) in a large population-based sample. Methods: We analyzed data of the first 10,000 participants from the Hamburg City Health Study in Germany, a single center prospective cohort study, aged between 45 and 74 years that scored higher than 25 points in the Mini-Mental State Examination and had no known pre-existing dementia. HRQoL was assessed by the EQ-5D-5L index, as well as the mental (MCS) and physical component summary (PCS) score of the Short Form-8. We computed linear regression analyses with 99% bias-corrected and accelerated (BCa) confidence intervals (CI) from 10,000 bootstrap samples to investigate the association between SCD and different indicators of HRQoL, while controlling for depression (PHQ-9), age, sex, and education as potential confounders. Results: Of 7,799 eligible participants (mean (SD) age 62.01 (8.41) years, 51.1% female), 3,708 (47.5%) reported SCD. Participants with SCD were older (62.7 versus 61.4 years) and more frequently female (54.2% versus 48.2%). SCD was independently associated with a lower EQ-5D-5L index (β = -0.01, 99% BCa CI = [-0.020, -0.003], p<0.001) and PCS (β = -1.00, 99% BCa CI = [-1.48, -0.51], p<0.001) but not with MCS score. Conclusion: In a population of middle-aged to elderly participants, there is a significant negative association between SCD and HRQoL across different instruments of HRQoL measurement independent of depression, demographics, and education.

Pages 437-447
Bang-Sheng Wu, Ya-Ru Zhang, Liu Yang, Wei Zhang, Yue-Ting Deng, Shi-Dong Chen, Jian-Feng Feng, Wei Cheng, Jin-Tai Yu
Polygenic Liability to Alzheimer’s Disease Is Associated with a Wide Range of Chronic Diseases: A Cohort Study of 312,305 Participants
Abstract: Background: Alzheimer’s disease (AD) patients rank among the highest levels of comorbidities compared to persons with other diseases. However, it is unclear whether the conditions are caused by shared pathophysiology due to the genetic pleiotropy for AD risk genes. Objective: To figure out the genetic pleiotropy for AD risk genes in a wide range of diseases. Methods: We estimated the polygenic risk score (PRS) for AD and tested the association between PRS and 16 ICD10 main chapters, 136 ICD10 level-1 chapters, and 377 diseases with cases more than 1,000 in 312,305 individuals without AD diagnosis from the UK Biobank. Results: After correction for multiple testing, AD PRS was associated with two main ICD10 chapters: Chapter IV (endocrine, nutritional and metabolic diseases) and Chapter VII (eye and adnexa disorders). When narrowing the definition of the phenotypes, positive associations were observed between AD PRS and other types of dementia (OR = 1.39, 95%CI [1.34, 1.45], p = 1.96E-59) and other degenerative diseases of the nervous system (OR = 1.18, 95%CI [1.13, 1.24], p = 7.74E-10). In contrast, we detected negative associations between AD PRS and diabetes mellitus, obesity, chronic bronchitis, other retinal disorders, pancreas diseases, and cholecystitis without cholelithiasis (ORs range from 0.94 to 0.97, FDR < 0.05). Conclusion: Our study confirms several associations reported previously and finds some novel results, which extends the knowledge of genetic pleiotropy for AD in a range of diseases. Further mechanistic studies are necessary to illustrate the molecular mechanisms behind these associations.

Pages 449-461
Wei Ying Tan, Carol Hargreaves, Christopher Chen, Saima Hilal
A Machine Learning Approach for Early Diagnosis of Cognitive Impairment Using Population-Based Data
Abstract: Background: The major mechanisms of dementia and cognitive impairment are vascular and neurodegenerative processes. Early diagnosis of cognitive impairment can facilitate timely interventions to mitigate progression. Objective: This study aims to develop a reliable machine learning (ML) model using socio-demographics, vascular risk factors, and structural neuroimaging markers for early diagnosis of cognitive impairment in a multi-ethnic Asian population. Methods: The study consisted of 911 participants from the Epidemiology of Dementia in Singapore study (aged 60-88 years, 49.6% male). Three ML classifiers, logistic regression, support vector machine, and gradient boosting machine, were developed. Prediction results of independent classifiers were combined in a final ensemble model. Model performances were evaluated on test data using F1 score and area under the receiver operating curve (AUC) methods. Post modelling, SHapely Additive exPlanation (SHAP) was applied on the prediction results to identify the predictors that contribute most to the cognitive impairment prediction. Findings: The final ensemble model achieved a F1 score and AUC of 0.87 and 0.80 respectively. Accuracy (0.83), sensitivity (0.86), specificity (0.74) and predictive values (positive 0.88 negative 0.72) of the ensemble model were higher compared to the independent classifiers. Age, ethnicity, highest education attainment and neuroimaging markers were identified as important predictors of cognitive impairment. Conclusion: This study demonstrates the feasibility of using ML tools to integrate multiple domains of data for reliable diagnosis of early cognitive impairment. The ML model uses easy-to-obtain variables and is scalable for screening individuals with a high risk of developing dementia in a population-based setting.

Pages 463-469
Jian-Guo Li, Benjamin E. Blass, Domenico Praticὸ
Beneficial Effect of a Small Pharmacologic Chaperone on the Established Alzheimer’s Disease Phenotype
Abstract: Background: The endosomal retromer complex system is a key controller for trafficking of proteins. Downregulation of its recognition core proteins, such as VPS35, is present in Alzheimer’s disease (AD) brain, whereas its normalization prevents the development of AD pathology in a transgenic model with amyloid-β deposits and tau tangles. Objective: Assess the effect of targeting VPS35 after the AD pathology and memory impairments have developed. Methods: Twelve-month-old triple transgenic mice were treated with a small pharmacological chaperone, TPT-172, or vehicle for 14 weeks. At the end of this period, the effect of the drug on their phenotype was evaluated. Results: While control mice had a decline of learning and memory, the group receiving the chaperone did not. Moreover, when compared with controls the treated mice had significantly less amyloid-β peptides and phosphorylated tau, elevation of post-synaptic protein, and reduction in astrocytes activation. Conclusion: Taken together, our findings demonstrate that pharmacologic stabilization of the retromer recognition core is beneficial also after the AD-like pathologic phenotype is established.

Pages 471-481
Domingo J. Quintana-Hernández, Jaime Rojas-Hernández, Angelo Santana-del Pino, Carmen Céspedes Suárez, Mónica Pellejero Silva, María Teresa Miró-Barrachina, Ignacio Ibáñez Fernández, José Antonio Estupiñán López, Lucas F. Borkel
Mindfulness Prevents Depression and Psychopathology in Elderly People with Mild to Moderate Alzheimer's Disease: A Randomized Clinical Trial
Abstract: Background: This longitudinal study addressed whether mindfulness practice prevents psychological and behavioral symptoms, especially mood disorders, in Alzheimer's disease (AD). Objective: To assess the incidence of depression in the course of AD and to determine which non-pharmacological treatment (NPT) is most effective in preventing psychopathological symptoms. Methods: We conducted a longitudinal, non-inferiority and equivalence randomized clinical trial, repeated-measures design, with a control group and three experimental treatments: mindfulness, cognitive stimulation, and relaxation. Each experimental group performed three weekly sessions for two years. The pharmacological treatment of all participants was donepezil (10 mg). Participants were patients with probable AD without diagnosed depression from the public neurology services of the Canary Health Service, Spain. Psychological evaluation was performed using the Geriatric Depression Scale (GDS), Hamilton Depression Rating Scale (HDRS), and Neuropsychiatric Inventory (NPI-Q). The statistical analysis included only patients who attended at least 75% of the sessions. A nonparametric, repeated-measures analysis was performed with Kruskal-Wallis H test and between-group differences with Mann-Whitney U test with Bonferroni correction (p<0.008). Effect size was calculated with partial eta-squared. Results: The results showed significant differences with large effect sizes (η²p>0.14) between mindfulness and the rest of the experimental groups as well as the control in the GDS, HDRS, and NPI-Q scales. Conclusion: Compared to the other experimental groups, only mindfulness prevented the onset of depression and other psychopathologies in early-stage AD. Based on its effectiveness in maintaining cognitive functions and preventing psychopathology, we recommend mindfulness as the first-choice NPT for mild to moderate AD.

Pages 483-494
Jeffrey R. Petrella, Andrew M. Michael, Min Qian, Adaora Nwosu, Joel Sneed, Terry E. Goldberg, Davangere P. Devanand, P. Murali Doraiswamy
Impact of Computerized Cognitive Training on Default Mode Network Connectivity in Subjects at Risk for Alzheimer’s Disease: A 78-week Randomized Controlled Trial
Abstract: Background: Mild cognitive impairment (MCI) represents a high risk group for Alzheimer’s disease (AD). Computerized Cognitive Games Training (CCT) is an investigational strategy to improve targeted functions in MCI through the modulation of cognitive networks. Objective: The goal of this study was to examine the effect of CCT versus a non-targeted active brain exercise on functional cognitive networks. Methods: 107 patients with MCI were randomized to CCT or web-based crossword puzzles. Resting-state functional MRI (fMRI) was obtained at baseline and 18 months to evaluate differences in fMRI measured within- and between-network functional connectivity (FC) of the default mode network (DMN) and other large-scale brain networks: the executive control, salience, and sensorimotor networks. Results: There were no differences between crosswords and games in the primary FC outcome. However, secondary analyses suggest differential effects on between-network connectivity involving the DMN and SLN, and within-network connectivity of the DMN in subjects with late MCI. Paradoxically, in both cases, there was a decrease in FC for games and an increase for the crosswords control (p < 0.05), accompanied by lesser cognitive decline in the crosswords group. Conclusion: There were no differences between crosswords and games in the primary outcome, within-network DMN FC across all subjects. However, crossword puzzles might nonspecifically engage multiple specialized cognitive networks at a low level, resulting in cognitively beneficial remodeling between the DMN and other networks, and within the DMN in subjects at higher risk of dementia.

Pages 495-506
E. Valerie Daniel, Michael J. Kleiman, James E. Galvin
Exploring Reasons for Differential Vulnerability and Alzheimer’s Disease Risk in Racial and Ethnic Minorities
Abstract: Background: African American and Hispanic older adults are reported to have up to a 2-fold higher risk of Alzheimer’s disease and related disorders (ADRD), but the reasons for this increased vulnerability have not been fully explored. The Vulnerability Index (VI) was designed to identify individuals who are at risk of developing cognitive impairment in the future, capturing 12 sociodemographic variables and modifiable medical comorbidities associated with higher ADRD risk. However, a prior limitation of the VI was that the original study cohort had limited diversity. We examined the association of the VI within and between non-Hispanic White, African American, and Hispanic older adults with and without cognitive impairment and different socioeconomic strata enrolled in a community-based dementia screening study. Objective: To explore reasons for reported higher ADRD vulnerability in African Americans and Hispanics. Methods: In a cross-sectional study of 300 non-Hispanic White, African American, and Hispanic older adults with and without cognitive impairment, we studied the association between cognitive status, the VI, and socioeconomic status (SES). Results: When considering race/ethnicity, the presence of more vascular comorbidities drove greater vulnerability. When considering SES, vascular comorbidities played a less prominent role suggesting resources and access to care drives risk. The VI had differential effects on cognitive performance with the greatest effect in the earlier stages of impairment. Conclusion: Findings from this study provide a deeper understanding of the differential risk of ADRD in multicultural older adults captured by the VI and how barriers to healthcare access may increase vulnerability in racial/ethnic minorities.