Volume 100, Number 2, IN PRESS

Announcement
2024 Alzheimer Award Winner

Review
David A. Loeffler (Handling Associate Editor: Masafumi Ihara)
Approaches for Increasing Cerebral Efflux of Amyloid-β in Experimental Systems
Abstract: Amyloid protein-β (Aβ) concentrations are increased in the brain in both early onset and late onset Alzheimer’s disease (AD). In early onset AD, cerebral Aβ production is increased and its clearance is decreased, while increased Aβ burden in late onset AD is due to impaired clearance. Aβ has been the focus of AD therapeutics since development of the amyloid hypothesis, but efforts to slow AD progression by lowering brain Aβ failed until phase 3 trials with the monoclonal antibodies lecanemab and donanemab. In addition to promoting phagocytic clearance of Aβ, antibodies lower cerebral Aβ by efflux of Aβ-antibody complexes across the capillary endothelia, dissolving Aβ aggregates, and a “peripheral sink” mechanism. Although the blood-brain barrier is the main route by which soluble Aβ leaves the brain (facilitated by low-density lipoprotein receptor-related protein-1 and ATP-binding cassette sub-family B member 1), Aβ can also be removed via the blood-cerebrospinal fluid barrier, glymphatic drainage, and intramural periarterial drainage. This review discusses experimental approaches to increase cerebral Aβ efflux via these mechanisms, clinical applications of these approaches, and findings in clinical trials with these approaches in patients with AD or mild cognitive impairment. Based on negative findings in clinical trials with previous approaches targeting monomeric Aβ, increasing the cerebral efflux of soluble Aβ is unlikely to slow AD progression if used as monotherapy. But if used as an adjunct to treatment with lecanemab or donanemab, this approach might allow greater slowing of AD progression than treatment with either antibody alone.

Review
Emanuel Candeias, Ana Raquel Pereira-Santos, Nuno Empadinhas, Sandra Morais Cardoso, Ana Raquel Fernandes Esteves
The Gut-Brain Axis in Alzheimer’s and Parkinson’s Diseases: The Catalytic Role of Mitochondria
Abstract: Accumulating evidence suggests that gut inflammation is implicated in neuroinflammation in Alzheimer's and Parkinson's diseases. Despite the numerous connections it remains unclear how the gut and the brain communicate and whether gut dysbiosis is the cause or consequence of these pathologies. Importantly, several reports highlight the importance of mitochondria in the gut-brain axis, as well as in mechanisms like gut epithelium self-renewal, differentiation, and homeostasis. Herein we comprehensively address the important role of mitochondria as a cellular hub in infection and inflammation and as a link between inflammation and neurodegeneration in the gut-brain axis. The role of mitochondria in gut homeostasis and as well the crosstalk between mitochondria and gut microbiota is discussed. Significantly, we also review studies highlighting how gut microbiota can ultimately affect the central nervous system. Overall, this review summarizes novel findings regarding this cross-talk where the mitochondria has a main role in the pathophysiology of both Alzheimer’s and Parkinson’s disease strengthen by cellular, animal and clinical studies.

Systematic Review
Nikolai S. Sjaelland, Mathias H. Gramkow, Steen G. Hasselbalch, Kristian Steen Frederiksen (Handling Associate Editor: João Duraes)
Digital Biomarkers for the Assessment of Non-Cognitive Symptoms in Patients with Dementia with Lewy Bodies: A Systematic Review
Abstract: Background: Portable digital health technologies (DHTs) could help evaluate non-cognitive symptoms, but evidence to support their use in patients with dementia with Lewy bodies (DLB) is uncertain. Objectives: 1) To describe portable or wearable DHTs used to obtain digital biomarkers in patients with DLB, 2) to assess the digital biomarkers’ ability to evaluate non-cognitive symptoms, and 3) to assess the feasibility of applying digital biomarkers in patients with DLB. Methods: We systematically searched databases MEDLINE, Embase, and Web of Science from inception through February 28, 2023. Studies assessing digital biomarkers obtained by portable or wearable DHTs and related to non-cognitive symptoms were eligible if including patients with DLB. The quality of studies was assessed using a modified check list based on the NIH Quality assessment tool for Observational Cohort and Cross-sectional Studies. A narrative synthesis of data was carried out. Results: We screened 4,295 records and included 20 studies. Seventeen different DHTs were identified for assessment of most non-cognitive symptoms related to DLB. No thorough validation of digital biomarkers for measurement of non-cognitive symptoms in DLB was reported. Studies did not report on aspects of feasibility in a systematic way. Conclusions: Knowledge about feasibility and validity of individual digital biomarkers remains extremely limited. Study heterogeneity is a barrier for establishing a broad evidence base for application of digital biomarkers in DLB. Researchers should conform to recommended standards for systematic evaluation of digital biomarkers. Other: The present study was not funded. A protocol was registered at PROSPERO: CRD42023400196

Systematic Review
Brenda Chino, David López-Sanz, Sandra Doval, Lucía Torres-Simón, Jaisalmer de Frutos Lucas, Lydia Giménez-Llort, Jonathan Zegarra-Valdivia, Fernando Maestú
Resting State Electrophysiological Profiles and Their Relationship with Cognitive Performance in Cognitively Unimpaired Older Adults: A Systematic Review
Abstract: Background: Aging is a complex and natural process. The physiological decline related to aging is accompanied by a slowdown in cognitive processes, which begins shortly after individuals reach maturity. These changes have been sometimes interpreted as a compensatory sign and others as a fingerprint of deterioration. Objective: In this context, our aim is to uncover the mechanisms that underlie and support normal cognitive functioning in the brain during the later stages of life. Methods: With this purpose, a systematic literature search was conducted using PubMed, Scopus, and Web of Science databases, which identified 781 potential articles. After applying inclusion and exclusion criteria, we selected 12 studies that examined the brain oscillations patterns in resting-state conditions associated with cognitive performance in cognitively unimpaired older adults. Results: Although cognitive healthy aging was characterized differently across studies, and various approaches to analyzing brain activity were employed, our review indicates a relationship between alpha peak frequency (APF) and improved performance in neuropsychological scores among cognitively unimpaired older adults. Conclusions: A higher APF is linked with a higher score in intelligence, executive function, and general cognitive performance, and could be considered an optimal, and easy-to-assess, electrophysiological marker of cognitive health in older adults.

Commentary
Lucía Jiménez-Gonzalo, Isabel Bermejo-Gómez
What Has the Pandemic Taught Us About Caregiving? Mental Health in Family Caregivers of People with Dementia One Year After the Lock-Down Due to COVID-19 Pandemic
Abstract: Caregiving for a person with dementia is considered a situation of chronic stress, with consequences on caregivers’ physical and psychological health. The usual challenges of dementia care were intensified during the pandemic due to the risk of contagion, social isolation measures, and decrease in healthcare resources. The COVID-19 pandemic increased the stress both in the persons with dementia and their caregivers. This commentary reflects on the long-term effects of the pandemic on caregivers’ mental health, focusing on the study by Olavarría and colleagues and drawing future research lines for culturally diverse family caregivers.

Anas Shamsi, Mohammad Furkan, Mohd Shahnawaz Khan, Dharmendra Kumar Yadav, Moyad Shahwan
Computational Screening of Repurposed Drugs for HMG-CoA Synthase 2 in Alzheimer’s Disease
Abstract: Background: HMGCS2 (mitochondrial 3-hydroxy-3-methylglutaryl-COA synthase 2) plays a pivotal role as a control enzyme in ketogenesis, and its association with the amyloid-β protein precursor (AβPP) in mitochondria implicates a potential involvement in Alzheimer's disease (AD) pathophysiology. Objective: Our study aimed at identifying repurposed drugs using the DrugBank database capable of inhibiting HMGCS2 activity. Methods: Exploiting the power of drug repurposing in conjunction with virtual screening and molecular dynamic (MD) simulations against HMGCS2, we present new in-silico insight into structure-based drug repurposing. Results: The initial molecules were screened for their binding affinity to HMGCS2. Subsequent interaction analyses and extensive 300 ns MD simulations were conducted to explore the conformational dynamics and stability of HMGCS2 in complex with the screened molecules, particularly Penfluridol and Lurasidone. Conclusions: The study revealed that HMGCS2 forms stable protein-ligand complexes with Penfluridol and Lurasidone. Our findings indicate that Penfluridol and Lurasidone competitively bind to HMGCS2 and warrant their further exploration as potential repurposed molecules for anti-Alzheimer’s drug development.

Jaime Ramos-Cejudo, Matthew R. Scott, Jeremy A. Tanner, Matthew P. Pase, Emer R. McGrath, Saptaparni Ghosh, Ricardo S. Osorio, Emma Thibault, Georges El Fakhri, Keith A. Johnson, Alexa Beiser, Sudha Seshadri
Associations of Plasma Tau with Amyloid and Tau PET: Results from the Community-Based Framingham Heart Study
Abstract: Background: Associations of plasma total tau levels with future risk of AD have been described. Objective: To examine the extent to which plasma tau reflects underlying AD brain pathology in cognitively healthy individuals. Methods: We examined cross-sectional associations of plasma total tau with 11C-Pittsburgh Compound-B (PiB)-PET and 18F-Flortaucipir (FTP)-PET in middle-aged participants at the community-based Framingham Heart Study. Results: Our final sample included 425 participants (mean age 57.6±9.9, 50% F). Plasma total tau levels were positively associated with amyloid-β deposition in the precuneus region (β±SE, 0.11±0.05; p=0.025). A positive association between plasma total tau and tau PET in the rhinal cortex was suggested in participants with higher amyloid-PET burden and in APOE ε4 carriers. Conclusions: Our study highlights that plasma total tau is a marker of amyloid deposition as early as in middle-age.

Nela Krizanovic, Martha Jokisch, Karl-Heinz Jöckel, Börge Schmidt, Andreas Stang, Sara Schramm
Sex-Specific Differences in Serum Kallikrein-8 (KLK8): An Exploratory Study
Abstract: Background: There are indications for sex-specific differences regarding the association between kallikrein-8 (KLK8) and cognitive impairment in early stages of Alzheimer’s disease for which KLK8 may be an early blood-based biomarker. These may be due to different levels of sex hormones. To correctly interpret KLK8 blood concentrations, sex-specific analyses are needed. Objective: The aim of our exploratory study was to investigate sex-specific differences in blood-based KLK8 in participants of the population-based Heinz Nixdorf Recall study with different cognitive status and the association between KLK8 and sex hormones. Methods: In 290 participants (45% women, 69.7±7.4 years (mean±SD)) we investigated sex-specific serum KLK8 differences between cognitively unimpaired (CU, 43%) and cognitively impaired (CI) participants and the association between KLK8 and dehydroepiandrosteronsulfate (DHEAS), estradiol and testosterone, using adjusted multiple linear regression. Results: The mean±SD KLK8 was similar for CU men (808.1±729.6 pg/ml) and women (795.9±577.7 pg/ml); adjusted mean-difference [95%-CI]: -95.3 [-324.1;133.5] pg/ml. KLK8 was lower in CI women (783.5±498.7 pg/ml) than men (1048.4±829 pg/ml); -261 [-493.1;-29] pg/ml. In men but not women, there was a weak indication for a positive slope between estradiol (11.9 [-0.4;24.3] pg/ml) and DHEAS (1.4 [-0.5;3.3] pg/ml) with KLK8, while testosterone had no impact. Conclusions: The results suggested a different role for KLK8 in the development of cognitive impairment in men and women, potentially influenced by sex hormones. To use blood KLK8 as an early biomarker, further research on hormonal regulation of KLK8 expression is needed as a part of the investigation of the KLK8 involvement in cognitive impairment and Alzheimer´s disease pathology.

James E. Galvin, Lun-Ching Chang, Paul Estes, Heather M. Harris, Ernest Fung
Cognitive Assessment with Cognivue Clarity®: Psychometric Properties and Normative Ranges in a Diverse Population
Abstract: Background: Detecting cognitive impairment in clinical practice is challenging as most instruments do not perform well in diverse samples of older adults. These same instruments are often used for eligibility into clinical trials making it difficult to recruit minoritized adults into Alzheimer’s disease (AD) studies. Cognivue Clarity® is an FDA-cleared computerized 10-minute cognitive screening platform using adaptive psychophysics to detect cognitive impairment. Objective: Test the ability of Cognivue Clarity to measure cognitive performance in a diverse community sample compared with the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS). Methods: This study enrolled 452 participants across 6 US study sites and completed both Cognivue Clarity device and RBANS. Psychometric properties and exploratory factor analysis of Cognivue Clarity were explored and comparisons against RBANS across different age, sex, education, and ethnoracial groups were conducted. Results: Participants had a mean age of 47.9±16.1 years (range: 18-85), 63.6% were female, 45.9% had ≤12 years of education, 31.2% were African American and 9.2% were Hispanic. Cognivue Clarity had strong internal consistency, test-retest and minimal practice effects. A 4-factor structure (Memory, Attention, Visuomotor, and Discrimination) had excellent goodness-of-fit. Normalizing age effects improved performance. Race and education effects were similar to those seen with RBANS. Cognivue Clarity had strong correlations with RBANS. Conclusions: Our study supports the use of Cognivue Clarity as an easy-to-use, brief, and valid cognitive assessment that measures cognitive performance. In the correct clinical setting, Cognivue Clarity may identify individuals with likely cognitive impairment who could be candidates for AD research studies.

Shunji Toya, Mamoru Hashimoto, Yuta Manabe, Hajime Yamakage, Manabu Ikeda (Handling Associate Editor: Akihiko Nunomura)
Factors Associated with Quality of Life in Patients with Dementia with Lewy Bodies: Additional Analysis of a Cross-Sectional Study
Abstract: Background: Quality of life (QOL) and treatment needs of patients with dementia with Lewy bodies (DLB) and their caregivers are important factors to consider when developing treatment strategies. Objective: To investigate factors associated with QOL in patients with DLB, and to examine factors associated with activities of daily living (ADL) if ADL was associated with QOL. Methods: We previously conducted a questionnaire survey study to investigate the treatment needs of patients with DLB and their caregivers. This pre-specified additional analysis evaluated the Physical Component Score (PCS) and Mental Component Score (MCS) of the Short Form-8 for QOL, and the Movement Disorder Society-Unified Parkinson’s Disease Rating Scale (MDS-UPDRS) Part II total score for ADL. Results: In total, 231 patient–caregiver pairs and 38 physicians were included. Multivariable analysis of QOL showed that the MDS-UPDRS Part II total score (standard regression coefficient [β], −0.432) was associated with the PCS, and presence of depression (β, −0.330) was associated with the MCS. The severity of postural instability/gait disorder (PIGD) (β, 0.337) and rigidity (β, 0.266), presence of hallucinations (β, 0.165), male sex (β, 0.157), and use of “short stay” or “small-scale, multifunctional home care” (β, 0.156) were associated with worsened ADL. Conclusions: In patients with DLB, QOL was negatively impacted by severity of ADL disability and depression, and ADL was negatively impacted by severity of PIGD and rigidity, hallucinations, male sex, and use of “short stay” or “small-scale, multifunctional home care.”

Erica Howard, Jena N. Moody, Sarah Prieto, Jasmeet P. Hayes for the Alzheimer’s Disease Neuroimaging Initiative
Higher Cerebrospinal Fluid Levels of Amyloid-β40 Following Traumatic Brain Injury Relate to Confrontation Naming Performance
Abstract: Background: Traumatic brain injury (TBI) may confer risk for Alzheimer’s disease (AD) through amyloid-β (Aβ) overproduction. However, the relationship between TBI and Aβ levels in cerebrospinal fluid (CSF) remains unclear. Objective: To explore whether Aβ overproduction is implicated in the relationship between TBI and AD, we compared CSF levels of Aβ in individuals with a TBI history versus controls (CTRLs) and related CSF Aβ levels to cognitive markers associated with preclinical AD. Methods: Participants were 112 non-impaired Veterans (TBI=56, CTRL=56) from the Alzheimer’s Disease Neuroimaging Initiative-Department of Defense database with available cognitive data (Boston Naming Test [BNT], Rey Auditory Verbal Learning Test [AVLT]) and CSF measures of Aβ42, Aβ40, and Aβ38. Mediation models explored relationships between TBI history and BNT scores with Aβ peptides as mediators. Results: The TBI group had higher CSF Aβ40 (t=-2.43, p=0.017) and Aβ38 (t=-2.10, p=0.038) levels than the CTRL group, but groups did not differ in CSF Aβ42 levels or Aβ42/Aβ40 ratios (p>0.05). Both Aβ peptides negatively correlated with BNT (Aβ40: rho=-0.20, p=0.032; Aβ38: rho=-0.19, p=0.048) but not AVLT (p>0.05). Aβ40 had a significant indirect effect on the relationship between TBI and BNT performance (β=-0.16, 95% CI [-0.393, -0.004], pM=0.54). Conclusions: TBI may increase AD risk and cognitive vulnerability through Aβ overproduction. Biomarker models incorporating multiple Aβ peptides may help identify AD risk among those with TBI.

Senli Deng*, Ruikun He*, Zhongbao Yue, Benchao Li, Fengping Li, Qing Xiao, Xiaoge Wang, Yuanyuan Li, Ruilin Chen, Shuang Rong *These authors contributed equally to this work.
Association of Advanced Glycation End Products with Cognitive Function: HealthyDance Study
Abstract: Background: The current research on advanced glycosylation end products (AGEs) and cognitive function is limited. Objective: We aimed to investigate the relationship between multiple plasma AGEs and cognitive function and mild cognitive impairment (MCI). Methods: Baseline data from The Lifestyle and Healthy Aging of Chinese Square Dancer Study was used in this cross-sectional study. Ultra-high-performance liquid chromatography tandem mass spectrometry was used to determine plasma levels of carboxymethyl lysine (CML), carboxyethyl lysine (CEL), and methyl imidazolinone (MG-H1). Four cognitive tests were used to obtain the four cognitive domain scores and the composite z scores. The Petersen criteria were used to diagnose MCI. The data were analyzed by multivariable linear and logistic regression models. Results: This study included 1,018 participants (median age 61.0 years, 87.3% female). After multivariate adjustment, the βs of the highest quartile of CML and CEL compared to the lowest quartile were -0.28 (-0.38, -0.17) and -0.13 (-0.23, -0.03), respectively, for the composite z score. For the four cognitive domains, CML was negatively correlated with memory, attention, and executive function, and CEL was negatively associated with memory and language function. In addition, higher CML was associated with a higher odd of MCI. MG-H1 was not associated with cognitive function. Conclusions: High plasma AGE levels were correlated with poorer cognitive function, particularly CML and CEL, higher levels of CML were also associated with higher odds of MCI. To clarify the effects of different AGEs on cognitive function and the underlying mechanisms, further longitudinal and experimental studies are needed.

Julie M. Chandler, Wenyu Ye, Xiaojuan Mi, Erin G. Doty, Joseph A. Johnston
Potential Impact of Slowing Disease Progression in Early Symptomatic Alzheimer’s Disease on Patient Quality of Life, Caregiver Time, and Total Societal Costs: Estimates Based on Findings from GERAS-US Study
Abstract: Background: Impact of Alzheimer’s disease (AD) progression on patient health-related quality of life (HRQoL), caregiver time, and societal costs is not well characterized in early AD. Objective: To assess the association of change in cognition with HRQoL, caregiver time, and societal costs over 36 months, and estimate the impact of slowing disease progression on these outcomes. Methods: This post-hoc analysis included patients with amyloid-positive mild cognitive impairment (MCI) and mild AD dementia (MILD AD) from the 36-month GERAS-US study. Disease progression was assessed using the Mini-Mental State Examination score. Change in outcomes associated with slowing AD progression was estimated using coefficients from generalized linear models. Results: At baseline, 300 patients had MCI and 317 had MILD AD. Observed natural progression over 36 months was associated with: 5.1 point decline in the Bath Assessment of Subjective Quality of Life in Dementia (BASQID) score (for HRQoL), increase in 1,050 hours of total caregiver time, and $8,504 total societal costs for MCI; 6.6 point decline in the BASQID score, increase in 1,929 hours of total caregiver time, and $12,795 total societal costs for MILD AD per person. Slowing AD progression by 30% could result in per person savings in HRQoL decline, total caregiver time, and total societal costs: for MCI: 1.5 points, 315 hours, and $2,638; for MILD AD: 2.0 points, 579 hours, and $3,974. Conclusions: Slowing AD progression over 36 months could slow decline in HRQoL and save caregiver time and societal cost in patients with MCI and MILD AD.

H. Sebastian Caballero, G. Peggy McFall, Myrlene Gee, Stuart MacDonald, Natalie A. Phillips, Jennifer Fogarty, Manuel Montero-Odasso, Richard Camicioli, Roger A. Dixon
Cognitive Speed in Neurodegenerative Disease: Comparing Mean Rate and Inconsistency Within and Across the Alzheimer’s and Lewy Body Spectra in the COMPASS-ND Study
Abstract: Background: Alzheimer’s disease (AD) and Lewy body disease (LBD) are characterized by early and gradual worsening perturbations in speeded cognitive responses. Objective: Using simple and choice reaction time tasks, we compared two indicators of cognitive speed within and across the AD and LBD spectra: mean rate (average reaction time across trials) and inconsistency (within person variability). Methods: The AD spectrum cohorts included subjective cognitive impairment (SCI, n = 28), mild cognitive impairment (MCI, n = 121), and AD (n = 45) participants. The LBD spectrum included Parkinson’s disease (PD, n = 32), mild cognitive impairment in PD (PD-MCI, n = 21), and LBD (n = 18) participants. A cognitively unimpaired (CU, n = 39) cohort served as common benchmark. We conducted multivariate analyses of variance and discrimination analyses. Results: Within the AD spectrum, the AD cohort was slower and more inconsistent than the CU, SCI, and MCI cohorts. The MCI cohort was slower than the CU cohort. Within the LBD spectrum, the LBD cohort was slower and more inconsistent than the CU, PD, and PD-MCI cohorts. The PD-MCI cohort was slower than the CU and PD cohorts. In cross-spectra (corresponding cohort) comparisons, the LBD cohort was slower and more inconsistent than the AD cohort. The PD-MCI cohort was slower than the MCI cohort. Discrimination analyses clarified the group difference patterns. Conclusions: For both speed tasks, mean rate and inconsistency demonstrated similar sensitivity to spectra-related comparisons. Both dementia cohorts were slower and more inconsistent than each of their respective non-dementia cohorts.

Qiang He, Wenjing Wang, Yang Xiong, Chuanyuan Tao, Lu Ma, Chao You
Potential Biomarkers in Cerebrospinal Fluid and Plasma for Dementia
Abstract: Background: The identification of biomarkers for different dementias in plasma and cerebrospinal fluid (CSF) has made substantial progress. However, they are observational studies, and there remains a lack of research on dementias with low incidence rates. Objective: We performed a comprehensive Mendelian randomization to identify potential biomarkers for different dementia type. Methods: The summary-level datasets encompassed 734 plasma and 154 cerebrospinal fluid proteins sourced from recently published genome-wide association studies (GWAS). Summary statistics for different dementias, including any dementia (refering to any type of dementia symptoms, 218,792 samples), Alzheimer’s disease (AD, 63,926 samples), vascular dementia (212,389 samples), frontotemporal dementia (3,024 samples), dementia with Lewy bodies (DLB, 6,618 samples), and dementia in Parkinson's disease (216,895 samples), were collected from large GWAS. The primary method is inverse variance weighting, with additional sensitivity analyses conducted to ensure the robustness of the findings. Results: The molecules released into CSF, namely APOE2 for any dementia, APOE2 and Siglec-3 for AD, APOE2 for vascular dementia, and APOE2 for DLB, might be potential biomarkers. CD33 for AD and SNCA for DLB in plasma could be promising biomarkers. Conclusions: This is the first study to integrate plasma and CSF proteins to identify potential biomarkers for different dementias.

Shivum Desai*, Ivy Y. Chen*, Christy Hom, Eric Doran, Dana D. Nguyen, Ruth Benca, Ira T. Lott, Bryce A. Mander (Handling Associate Editor: Barbara Bendlin) *These authors contributed equally to this work.
Insomnia Symptoms Are Associated with Measures of Functional Deterioration and Dementia Status in Adults with Down Syndrome at High Risk for Alzheimer’s Disease
Abstract: Background: While obstructive sleep apnea (OSA) and insomnia symptoms in neurotypical populations are associated with Alzheimer’s disease (AD), their association with dementia in adults with Down syndrome (DS) remains less clear, even though these symptoms are prevalent and treatable in DS. Understanding their associations with AD-related dementia status, cognitive impairment, and functional deterioration may lead to interventions to slow decline or disease progression in adults with DS. Objective: To characterize differences in OSA and insomnia symptom expression by dementia status, and to determine which sleep factors support dementia diagnosis. Methods: Multimodal consensus conference was used to determine dementia status in 52 adults with DS (52.2±6.4 years, 21 women). Cognitive impairment, adaptive behavior skills, and symptoms of OSA and insomnia were quantified using validated assessments for adults with DS and their primary informants. Results: A sex by dementia status interaction demonstrated that older women with DS and dementia had more severe terminal insomnia but not OSA symptoms relative to older women with DS who were cognitively stable (CS). Greater insomnia symptom severity was associated with greater functional impairments in social and self-care domains adjusting for age, sex, premorbid intellectual impairment, and dementia status. Conclusions: Insomnia symptoms are more severe in women with DS with dementia than in women with DS and no dementia, and regardless of dementia status or sex, more severe insomnia symptoms are associated with greater impairment in activities of daily living. These findings underscore the potential importance of early insomnia symptom evaluation and treatment in women with DS at risk of developing AD.

Daman Preet Kaur, Magda Bucholc, David P. Finn, Stephen Todd, KongFatt Wong-Lin, Paula L. McClean (Handling Associate Editor: Suzanne Tyas)
Impact of Different Diagnostic Measures on Drug Class Association with Dementia Progression Risk: A Longitudinal Prospective Cohort Study
Abstract: Background: The Clinical Dementia Rating Scale Sum of Boxes (CDRSOB) score is known to be highly indicative of cognitive-functional status and is regularly employed for clinical and research purposes. Objective: Our aim is to determine whether CDRSOB is consistent with clinical diagnosis in evaluating drug class associations with risk of progression to mild cognitive impairment (MCI) and dementia. Methods: We employed weighted Cox regression analysis on longitudinal NACC data, to identify drug classes associated with disease progression risk, using clinical diagnosis and CDRSOB as the outcome. Results: Aspirin (antiplatelet/NSAID), angiotensin II inhibitors (antihypertensive), and Parkinson’s disease medications were significantly associated with reduced risk of progression to MCI/dementia and Alzheimer’s disease medications were associated with increased MCI-to-Dementia progression risk with both clinical diagnosis and CDRSOB as the outcome. However, certain drug classes/subcategories, like anxiolytics, antiadrenergics, calcium (Ca2+) channel blockers, and diuretics (antihypertensives) were associated with reduced risk of disease progression, and SSRIs (antidepressant) were associated with increased progression risk only with CDRSOB. Additionally, metformin (antidiabetic medication) was associated with reduced MCI-to-Dementia progression risk only with clinical diagnosis as the outcome. Conclusions: Although the magnitude and direction of the effect were primarily similar for both diagnostic outcomes, we demonstrate that choice of diagnostic measure can influence the significance of risk/protection attributed to drug classes and consequently the conclusion of findings. A consensus must be reached within the research community with respect to the most accurate diagnostic outcome to identify risk and improve reproducibility.

Javier Mar, Uxue Zubiagirre, Igor Larrañaga, Myriam Soto-Gordoa, Lorea Mar-Barrutia, Ana González-Pinto, Oliver Ibarrondo (Handling Associate Editor: Bernhard Michalowsky)
Disparities by Socioeconomic Status and Diagnosis of Dementia in the Prescribing of Antipsychotics in a Real-World Data Population Over 60 Years of Age
Abstract: Background: Antipsychotics are widely used in the elderly due to the high prevalence of neuropsychiatric associated with dementia. Objective: To analyze potential disparities in antipsychotic use in the general population of Gipuzkoa by socioeconomic status (SES) and diagnosis of Alzheimer’s disease and related dementia (ADRD) adjusting for somatic and psychiatric comorbidities, age, and sex. Methods: A retrospective observational study was carried out in all the 221,777 individuals over 60 years of age (Gipuzkoa, Spain) to collect diagnosis of ADRD, the Charlson Comorbidity Index, and psychiatric comorbidities considering all primary, outpatient, emergency and inpatient care episodes and first- and second-generation antipsychotics, and sociodemographic variables, namely, age, sex, SES and living in a nursing home. Logistic regression was used for multivariate statistical analysis. Results: Use of any antipsychotic was greater in women, individuals over 80 years old, living in a nursing home, with a diagnosis of dementia, somatic and psychiatric comorbidities, and low SES. Quetiapine was the most used drug. The likelihood of any antipsychotic use was significantly associated with low SES (odds ratio [OR]: 1.60; confidence interval [CI]: 1.52-1.68), age over 80 years (OR: 1.56; CI: 1.47-1.65), institutionalization (OR: 12.61; CI: 11.64-13.65), diagnosis of dementia (OR: 10.18; CI: 9.55-10.85) and the comorbidities of depression (OR: 3.79; CI: 3.58-4.01) and psychosis (OR: 4.96; CI: 4.64-5.30). Conclusions: The greater levels of antipsychotic use and institutionalization in people of low SES indicate inequity in the management of neuropsychiatric symptoms. Increasing the offer of non-pharmacological treatments in the health system might help reduce inequity.

Yufei Hu, Xupeng Wang, Zijun Zhao, Menglin Liu, Xiaoqin Ren, Xiaohui Xian, Chunxiao Liu, Qiujun Wang
The Downregulation of ITGAX Exacerbates Amyloid-β Plaque Deposition in Alzheimer’s Disease by Increasing Polarization of M1 Microglia
Abstract: Background: Alzheimer's disease (AD) is the most common sort of neurodegenerative dementia, characterized by its challenging, diverse, and progressive nature. Despite significant progress in neuroscience, the current treatment strategies remain suboptimal. Objective: Identifying a more accurate molecular target for the involvement of microglia in the pathogenic process of AD and exploring potential mechanisms via which it could influence disease. Methods: We utilized single-cell RNA sequencing (scRNA-seq) analysis in conjunction with APP/PS1 mouse models to find out the molecular mechanism of AD. With the goal of investigating the cellular heterogeneity of AD, we downloaded the scRNA-seq data from the Gene Expression Omnibus (GEO) database and identified differentially expressed genes (DEGs). Additionally, we evaluated learning and memory capacity using the behavioral experiment. We also examined the expression of proteins associated with memory using western blotting. Immunofluorescence was employed to investigate alterations in amyloid plaques and microglia. Results: Our findings revealed an upregulation of ITGAX expression in APP/PS1 transgenic mice, which coincided with a downregulation of synaptic plasticity-related proteins, an increase in amyloid-β (Aβ) plaques, and an elevation in the number of M1 microglia. Interestingly, deletion of ITGAX resulted in increased Aβ plaque deposition, a rise in the M1 microglial phenotype, and decreased production of synaptic plasticity-related proteins, all of which contributed to a decline in learning and memory. Conclusions: This research suggested that ITGAX may have a beneficial impact on the APP/PS1 mice model, as its decreased expression could exacerbate the impairment of synaptic plasticity and worsen cognitive dysfunction.

Xiangyuan Huang, Saima Hilal
Marital History and Cognition in a Chinese Longevity Cohort
Abstract: Background: Marital factor has been associated with dementia and Alzheimer’s disease, but there is limited evidence on the impact of holistic marital history over time. Objective: This study aimed to examine association of marital history with cognition. Methods: The study included 24,596 dementia-free participants from the Chinese Longitudinal Healthy Longevity Study (CLHLS). Holistic marital history was collected at baseline, categorizing participants into five groups: widow-single, widow-remarried, divorce-single, divorce-remarried and married based on the first two marriages. Dementia was collected at follow-up through self-report or from a delegate if the participant was deceased. For 15,355 participants, the Chinese Mini-Mental Status Examination (CMMSE) was administered at both baseline and follow-ups. Cognitive impairment was defined as a follow-up CMMSE score below 18, and rate of cognitive change was calculated as the change in CMMSE score between consecutive visits divided by the duration. Results: Compared with married older adults, widow-single group had significantly higher risk of dementia (HR 1.28, 95%CI 1.05, 1.54), cognitive impairment (HR 1.31, 95%CI 1.17, 1.47) and significantly faster decline of MMSE score (β -0.09, 95%CI -0.17, -0.01). Meanwhile, widow-remarried group had significantly lower risk of dementia, cognitive impairment and slower MMSE score decline, although the differences were only significant among female but not male. Conclusions: In this prospective cohort, married older adults and those widowed but with a second marriage had significantly better cognition than widowed individuals who did not remarry.

Tatyana Sakharova, Siqi Mao, Mikhail Osadchuk
Updated Models of Alzheimer’s Disease with Deep Neural Networks
Abstract: Background: In recent years, researchers have focused on developing precise models for the progression of Alzheimer’s disease (AD) using deep neural networks. Forecasting the progression of AD through the analysis of time series data represents a promising approach. Objective: The primary objective of this research is to formulate an effective methodology for forecasting the progression of AD through the integration of multi-task learning techniques and the analysis of pertinent medical data. Methods: This study primarily utilized volumetric measurements obtained through magnetic resonance imaging (MRI), trajectories of cognitive assessments, and clinical status indicators. The research encompassed 150 patients diagnosed with AD who underwent examination between 2020 and 2022 in Beijing, China. A multi-task learning approach was employed to train forecasting models using MRI data, trajectories of cognitive assessments, and clinical status. Correlation analysis was conducted at various time points. Results: At the baseline, a robust correlation was observed among the forecasting tasks: 0.75 for volumetric MRI measurements, 0.62 for trajectories of cognitive assessment, and 0.48 for clinical status. The implementation of a multi-task learning framework enhanced performance by 12.7% for imputing missing values and 14.8% for prediction accuracy. Conclusions: The findings of our study, indicate that multi-task learning can effectively predict the progression of AD. However, it is important to note that the study's generalizability may be limited due to the restricted dataset and the specific population under examination. These conclusions represent a significant stride toward more precise diagnosis and treatment of this neurological disorder.

Christine W. Musyimi, Levi A. Muyela, David M. Ndetei, Sara Evans-Lacko, Nicolas Farina
Acceptability and Feasibility of a Community Dementia Stigma Reduction Program in Kenya
Abstract: Background: Dementia stigma has adverse effects on people with dementia and their carers. These effects can lead to poor quality of life among other negative impacts. Objective: The aim of this study is to develop and pilot a novel dementia stigma reduction intervention in rural Kenya, leveraging existing Community Health Workers (CHWs) for its delivery. Methods: The pre-post pilot study was conducted, utilizing a parallel mixed-methods design. Ten CHWs were trained to deliver a contextually developed dementia anti-stigma intervention. These CHWs delivered four workshops to 59 members of the general public in Makueni County, each workshop lasted between 1.5 to 2 hours. Focus group discussions and pre/post surveys were used as measures. Results: The intervention was well received amongst the participants, particularly in terms of its format and accessibility. We observed the largest effects in reducing negative beliefs related to treatment (η2=0.34), living well with dementia (η2=0.98), and care (η2=0.56) for the general public post intervention. Improvements to attitudes were also observed in the CHWs, but the effect sizes were typically smaller. Conclusions: The intervention was accessible and feasible in rural Kenya, while also showing preliminary benefits to stigma related outcomes. The findings indicate that culturally sensitive interventions can be delivered in a pragmatic and context specific manner, thus filling an important knowledge gap in addressing stigma in low-resource settings. Future research is needed to ascertain the intervention’s long-term benefits and whether it tackles important behavioral outcomes and beliefs deeply ingrained within communities.

Stephanie Tan, Erin Kelty, Amy Page, Christopher Etherton-Beer, Frank Sanfilippo, Osvaldo P. Almeida
Cross-Sectional and Longitudinal Associations Between Treatment for Herpes Virus Infection and the Dispensing of Antidementia Medicines: An Analysis of the Australian Pharmaceutical Benefits Scheme Database
Abstract: Background: Evidence from previous observational studies suggest that infection by herpes simplex virus (HSV) and varicella zoster virus (VZV) increase the risk of dementia. Objective: To investigate if older adults exposed to HSV treatment have lower risk of dementia than the rest of the population. Methods: We used the 10% Australian Pharmaceutical Benefits Scheme (PBS) database from 2013 to 2022 to ascertain the cross-sectional, time-series and longitudinal association between exposure to HSV treatment and the dispensing of antidementia medicines. Participants were men and women aged 60 years or older. We used Anatomical Therapeutic Chemical (ATC) codes to identify medicines dispensed for the treatment of HSV and dementia. Results: During the year 2022 6,868 (1.2%) of 559,561 of participants aged 60 years or over were dispensed antidementia agent. The odds ratio (OR) of being dispensed an antidementia agent among individuals dispensed treatment for HSV was 0.73 (99%CI=0.56-0.95). Multilevel logistic regression for the 2013-2022 period for those dispensed HSV treatment was 0.87 (99%CI=0.75-1.00). Split-time span series from 2013 was associated with hazard ratio of 0.98 (99%CI=0.89-1.07) for individuals dispensed relative to those not dispensed HSV treatment. All analyses were adjusted for age, sex, and the dispensing of medicines for the treatment of diabetes, hyperlipidemia, hypertension, and ischemic heart disease. Conclusions: The dispensing of antiviral medicines for the treatment of HSV and VZV is consistently, but not conclusively, associated with decreased dispensing of antidementia medicines. This suggests that treatment of HSV and VZV infections may contribute to reduce the risk of dementia.

Guido Maria Giuffrè, Davide Quaranta, Salvatore Citro, Tommaso Giuseppe Morganti, Noemi Martellacci, Maria Gabriella Vita, Paolo Maria Rossini, Paolo Calabresi, Camillo Marra
Associations Between Free and Cued Selective Reminding Test and Cerebrospinal Fluid Biomarkers in Amnestic Mild Cognitive Impairment
Abstract: Background: The Free and Cued Selective Reminding Test (FCSRT), assessing verbal episodic memory with controlled learning and semantic cueing, has been recommended for detecting the genuine encoding and storage deficits characterizing AD-related memory disorders. Objective: The present study aims at investigating the ability of FCSRT in predicting cerebrospinal fluid (CSF) evidence of amyloid-β positivity in subjects with amnestic mild cognitive impairment (aMCI) and exploring its associations with amyloidopathy, tauopathy and neurodegeneration biomarkers. Methods: 120 aMCI subjects underwent comprehensive neurological and neuropsychological examinations, including the FCSRT assessment, and CSF collection; CSF Aβ42/40 ratio, p-tau181, and total-tau quantification were conducted by an automated CLEIA method on Lumipulse G1200. Based on the Aβ42/40 ratio value, subjects were classified as either A+ or A-. Results: All FCSRT subitem scores were significantly lower in A+ group and significantly predicted the amyloid-β status, with Immediate Total Recall (ITR) being the best predictor. No significant correlations were found between FCSRT and CSF biomarkers in the A- aMCI group, while in the A+ aMCI group, all FCSRT subitem scores were negatively correlated with CSF p-tau181 and total-tau, but not with the Aβ42/40 ratio. Conclusions: FCSRT confirms its validity as a tool for the diagnosis of AD, being able to predict the presence of amyloid-β deposition with high specificity. The associations between FCSRT subitem scores and CSF p-tau-181 and total-tau levels in aMCI due to AD could further encourage the clinical use of this simple and cost-effective test in the evaluation of individuals with aMCI.

Pietro Gareri, Antonino Maria Cotroneo, Roberta Montella, Matteo Gaglianone, Salvatore Putignano
Citicoline: A Cholinergic Precursor with a Pivotal Role in Dementia and Alzheimer’s Disease
Abstract: Background: Citicoline is a naturally occurring compound with pleiotropic effects on neuronal function and cognitive processes. Objective: Based on previous studies, which shed light on the positive effects of citicoline 1 g when combined with acetylcholinesterase inhibitors (AChEIs) and/or memantine, we further investigated the benefits of citicoline in combination therapy in Alzheimer's disease and mixed dementia. Methods: We integrated the datasets of CITIMEM and CITIDEMAGE, increasing the overall sample size to enhance statistical power. We analyzed data from these two investigator-initiated studies involving 295 patients. The primary outcome was the assessment over time of the effects of combined treatment versus memantine given alone or AChEI plus memantine on cognitive functions assessed by Mini-Mental State Examination (MMSE). The secondary outcomes were the influence of combined treatment on daily life functions, mood, and behavioral symptoms assessed by activities of daily life (ADL) and instrumental ADL, Geriatric Depression Scale, and Neuropsychiatric Inventory Scale. One-hundred-forty-three patients were treated with memantine and/or AChEI (control group), and 152 patients were treated with memantine and/or AChEI plus citicoline 1g/day orally (Citicoline group). Results: A significant difference in MMSE score was found in the average between the two groups of treatment at 6 and 12 months. Conclusions: This study confirmed the effectiveness of combined citicoline treatment in patients with mixed dementia and Alzheimer's disease, with a significant effect on the increase of MMSE score over time. The treated group also showed a significant reduction in the Geriatric Depression Scale and a significant increase in the instrumental ADL scale.

Book Review
Alzheimer’s Disease: Are We There Yet? A review of Alzheimer’s Disease Research: What Has Guided Research So Far and Why It Is High Time for a Paradigm Shift by Christian Behl, 2023, Springer, Cham, Switzerland, 677 pp. Reviewed by George Perry and Rudolph Castellani