Volume 96, Number 1, IN PRESS

Systematic Review
Carina Fernandes, Gemma Montalvo, Michael Caligiuri, Michael Pertsinakis, Joana Guimarães
Handwriting Changes in Alzheimer’s Disease: A Systematic Review
Abstract: Background: Handwriting is a complex process involving fine motor skills, kinesthetic components, and several cognitive domains, often impaired by Alzheimer’s disease (AD). Objective: Provide a systematic review of handwriting changes in AD, highlighting the effects on motor, visuospatial and linguistic features, and to identify new research topics. Methods: A search was conducted on PubMed, Scopus, and Web of Science to identify studies on AD and handwriting. The review followed PRISMA norms and analyzed 91 articles after screening and final selection. Results: Handwriting is impaired at all levels of the motor-cognitive hierarchy in AD, particularly in text, with higher preservation of signatures. Visuospatial and linguistic features were more affected. Established findings for motor features included higher variability in AD signatures, higher in-air/on-surface time ratio and longer duration in text, longer start time/reaction time, and lower fluency. There were conflicting findings for pressure and velocity in motor features, as well as size, legibility, and pen lifts in general features. For linguistic features, findings were contradictory for error patterns, as well as the association between agraphia and severity of cognitive deficits. Conclusions: Further re-evaluation studies are needed to clarify the divergent results on motor, general, and linguistic features. There is also a lack of research on the influence of AD on signatures and the effect of AD variants on handwriting. Such research would have an impact on clinical management (e.g., for early detection and patient follow-up using handwriting tasks), or forensic examination aimed at signatory identification.

Michael Lardelli
An Alternative View of Familial Alzheimer’s Disease Genetics
Abstract: Probabilistic and parsimony-based arguments regarding available genetics data are used to propose that Hardy and Higgin’s amyloid cascade hypothesis is valid but is commonly interpreted too narrowly to support, incorrectly, the primacy of the amyloid-β peptide (Aβ) in driving Alzheimer’s disease pathogenesis. Instead, increased activity of the βCTF (C99) fragment of AβPP is the critical pathogenic determinant altered by mutations in the APP gene. This model is consistent with the regulation of APP mRNA translation via its 5’ iron responsive element. Similar arguments support that the pathological effects of familial Alzheimer’s disease mutations in the genes PSEN1 and PSEN2 are not exerted directly via changes in AβPP cleavage to produce different ratios of Aβ length. Rather, these mutations likely act through effects on presenilin holoprotein conformation and function, and possibly the formation and stability of multimers of presenilin holoprotein and/or of the γ-secretase complex. All fAD mutations in APP, PSEN1, and PSEN2 likely find unity of pathological mechanism in their actions on endolysosomal acidification and mitochondrial function, with detrimental effects on iron homeostasis and promotion of “pseudo-hypoxia” being of central importance. Aβ production is enhanced and distorted by oxidative stress and accumulates due to decreased lysosomal function. It may act as a disease-associated molecular pattern enhancing oxidative stress-driven neuroinflammation during the cognitive phase of the disease.

Jack T. Rogers, Catherine M. Cahill
Iron Responsiveness to Lysosomal Disruption: A Novel Pathway to Alzheimer’s Disease
Abstract: Familial Alzheimer’s disease (fAD) mutations in the amyloid-β protein precursor (AβPP) enhance brain AβPP C-Terminal Fragment (CTF) levels to inhibit lysosomal v-ATPase. Consequent disrupted acidification of the endolysosomal pathway may trigger brain iron deficiencies and mitochondrial dysfunction. The iron responsive element (IRE) in the 5’Untranslated-region of AβPP mRNA should be factored into this cycle where reduced bioavailable Fe-II would decrease IRE-dependent AβPP translation and levels APP-CTFβ in a cycle to adaptively restore iron homeostasis while increases of transferrin-receptors is evident. In healthy younger individuals, Fe-dependent translational modulation of AβPP is part of the neuroprotective function of sAβPPα with its role in iron transport.

Mayra Pacheco Pachado, Ana I. Casas, Mahmoud H. Elbatreek, Cristian Nogales, Emre Guney, Alberto J. Espay, Harald H.H.W. Schmidt
Re-Addressing Dementia by Network Medicine and Mechanism-Based Molecular Endotypes
Abstract: Alzheimer’s disease (AD) and other forms of dementia are together a leading cause of disability and death in the aging global population, imposing a high personal, societal, and economic burden. They are also among the most prominent examples of failed drug developments. Indeed, after more than 40 AD trials of anti-amyloid interventions, reduction of amyloid-β (Aβ) has never translated into clinically relevant benefits, and in several cases yielded harm. The fundamental problem is the century-old, brain-centric phenotype-based definitions of diseases that ignore causal mechanisms and comorbidities. In this hypothesis article, we discuss how such current outdated nosology of dementia is a key roadblock to precision medicine and articulate how Network Medicine enables the substitution of clinicopathologic phenotypes with molecular endotypes and propose a new framework to achieve precision and curative medicine for patients with neurodegenerative disorders.

Short Communication
Yan Zhang*, Yanli Xue*, Longcai Wang, Zhifa Han, Tao Wang, Haihua Zhang, Guiyou Liu, Xingjun Xiao *These authors contributed equally to this work.
rs56405341 Variant Associates with Expression of C4orf33 and C4orf33 Was Downregulated in Alzheimer’s Disease and Progressive Supranuclear Palsy
Abstract: The first primary age-related tauopathy (PART) genome-wide association study confirmed significant associations of Alzheimer’s disease (AD) and progressive supranuclear palsy (PSP) genetic variants with PART, and highlighted a novel genetic variant rs56405341. Here, we perform a comprehensive analysis of rs56405341. We found that rs56405341 was significantly associated with C4orf33 mRNA expression, but not JADE1 mRNA expression in multiple brain tissues. C4orf33 was mainly expressed in cerebellar hemisphere and cerebellum, and JADE1 was mainly expressed in thyroid, and coronary artery. Meanwhile, we found significantly downregulated C4orf33 expression both AD and PSP compared with normal controls, respectively.

Short Communication
Clémence Cavaillès, Kristine Yaffe, Terri Blackwell, Daniel Buysse, Katie Stone, Yue Leng
Multidimensional Sleep Health and Long-Term Cognitive Decline in Community-Dwelling Older Men
Abstract: Specific sleep characteristics have been associated with cognitive decline, Alzheimer’s disease, and related dementias; however, studies examining the association between multidimensional sleep (a more comprehensive integration of sleep parameters) and cognitive decline are lacking. Among 2,811 older men without dementia, those with none, 1-2, and 3-5 “poor” self-reported sleep health dimensions had an adjusted 10-year change score of global cognition (3MS) of 2.9, 4.0 and 3.5 points (p-trend=0.05), and in executive function (Trails B) completion time of 36.7, 42.7, and 46.7 seconds (p-trend<0.01), respectively. In conclusion, a multidimensional measure of sleep health was associated with greater cognitive decline.

I-Shiang Tzeng
Examination of Matching Methods, Sparse Effects, and Limitations in a Nationwide Database Study on Alzheimer’s Disease
Abstract: Akada et al. conducted a nationwide database study on patients with Alzheimer’s disease, examining risk factors and outcomes over 3 years. A significant association emerged between decreased daily activities and hip fractures. However, the odds ratio was 1.95 (with p = 0.020) may be inaccurate in men, considering the wide 95% confidence interval (1.12–3.51). Possible influencing factors include an inappropriate outcome variable, sparse-data bias, collinear covariates, and comorbidities. Moreover, exact propensity-score matching would be more efficient than nested matching. Limitations include potential recall bias in measuring daily activities and limited applicability of cause-effect relationships in a national database study.

Sara Merlo*, Lara Costa*, Santina Chiechio, Carla Letizia Busceti, Lucia Ciranna, Rosa Santangelo, Maria Angela Sortino, Francesco Fornai, Ferdinando Nicoletti, Agata Copani *These authors contributed equally to this work.
Increased Heat Pain Tolerance but Hyperalgesia to Tonic Inflammatory Pain in the CRND8 Mouse Model of Alzheimer’s Disease
Abstract: Background: The effects of Alzheimer's disease (AD) pathology on the experience of pain are poorly understood. Objective: To understand the pathophysiological mechanisms underlying pain sensory transmission in the transgenic mouse model of AD, CRND8. Methods: We explored AD-related pathology in the spinal cord and dorsal root ganglia of 18-week-old female CRND8 mice. We assessed nociceptive responses to both acute heat stimuli and persistent inflammatory pain in CRND8 mice and non-transgenic (non-Tg) littermates. In addition, we searched for differences in biochemical correlates of inflammatory pain between CRND8 and non-Tg mice. Finally, we investigated the excitability of dorsal horn nociceptive neurons in spinal cord slices from CRND8 and non-Tg mice. Results: We demonstrated the presence of intracellular AD-like pathology in the spinal cord and in the dorsal root ganglia nociceptive sensory neurons of CRND8 mice. We found that CRND8 mice had a reduced susceptibility to acute noxious heat stimuli and an increased sensitivity to tonic inflammatory pain. Tonic inflammatory pain correlated with a lack of induction of pro-opiomelanocortin in the spinal cord of CRND8 mice as compared to non-Tg mice. Electrophysiological recording in acute spinal cord slice preparations indicated an increased probability of glutamate release at the membrane of dorsal horn nociceptive neurons in CRND8 mice. Conclusions: This study suggests that an increased thermal tolerance and a facilitation of nociception by peripheral inflammation can coexist in AD.

Li-Yang Liu, Yi Xing, Zi-Heng Zhang, Qing-Ge Zhang, Ming Dong, Haibo Wang, Longjun Cai, Xiaoyi Wang, Yi Tang
Validation of a Computerized Cognitive Training Tool to Assess Cognitive Impairment and Enable Differentiation Between Mild Cognitive Impairment and Dementia
Abstract: Background: Age-related cognitive decline is a chronic, progressive process that requires active clinical management as cognitive status changes. Computerized cognitive training (CCT) provides cognitive exercises targeting specific cognitive domains delivered by computer or tablet. Meanwhile, CCT can be used to regularly monitor the cognitive status of patients, but it is not clear whether CCT can reliably assess cognitive ability or be used to diagnose different stages of cognitive impairment. Objective: To investigate whether CCT can accurately monitor the cognitive status of patients with cognitive impairment as well as distinguish patients with dementia from patients with mild cognitive impairment (MCI). Method: We included 116 patients (42 dementia and 74 MCI) in final analysis. Cognitive ability was assessed by averaging the patient performance on the CCT to determine the Cognitive Index. The validity of the Cognitive Index was evaluated by its correlation with neuropsychological tests, and internal consistency was measured to assess the reliability. Additionally, we determined the diagnostic ability of the Cognitive Index to detect dementia using receiver operating characteristic (ROC) analysis. Results: The Cognitive Index was highly correlated with the Montreal Cognitive Assessment (r=0.812) and the Mini-Mental State Examination (r=0.694), indicating good convergent validity, and the Cronbach’s alpha coefficient was 0.936, indicating excellent internal consistency. The area under the ROC curve, sensitivity, and specificity of the Cognitive Index to diagnose dementia were 0.943, 83.3%, and 91.9%, respectively. Conclusions: CCT can be used to assess cognitive status and detect dementia in patients with cognitive impairment.

Matthew P. Pase, Adlin Pinheiro, Ella Rowsthorn, Serkalem Demissie, Saoresho Hurmez, Hugo Aparicio, Frances Rodriguez-Lara, Mitzi M. Gonzales, Alexa Beiser, Charles DeCarli, Sudha Seshadri, Jose Rafael Romero
MRI Visible Perivascular Spaces and the Risk of Incident Mild Cognitive Impairment in a Community Sample
Abstract: Background: Magnetic resonance imaging (MRI) visible perivascular spaces (PVS) are associated with the risk of incident dementia but their association with the early stages of cognitive impairment remains equivocal. Objective: We examined the association between MRI visible PVS and the risk of incident mild cognitive impairment (MCI) in the community-based Framingham Heart Study (FHS). Methods: FHS participants aged at least 50 years free of stroke, cognitive impairment, and dementia at the time of MRI were included. PVS were rated according to severity in the basal ganglia and centrum semiovale (CSO) using established criteria. Cox regression analyses were used to relate PVS to incident MCI adjusted for demographic and cardiovascular variables. Results: The mean age of the sample (1,314 participants) at MRI was 68 years (SD, 9; 54% women). There were 263 cases of incident MCI over a median 7.4 years follow-up (max, 19.8 years). MCI risk increased with higher PVS severity in the CSO. Relative to persons with the lowest severity rating, persons with the highest severity rating in the CSO had a higher risk of incident MCI (hazard ratio [HR] = 2.55; 95% confidence interval [CI], 1.48-4.37; p = 0.0007). In secondary analysis, this association seemed stronger in women. Risk of incident MCI was nominally higher for participants with the highest severity grade of PVS in the basal ganglia, though not statistically significant relative to the lowest grade (HR = 2.19; 95% CI, 0.78-6.14; p = 0.14). Conclusions: PVS burden in the CSO may be a risk marker for early cognitive impairment.

Anne-Marie C. Leiby*, Kiana A. Scambray*, Hannah L. Nguyen, Farheen Basith, Shahrzad Fakhraee, Zarui A. Melikyan, Syed A. Bukhari, Thomas J. Montine, María M. Corrada, Claudia H. Kawas, S. Ahmad Sajjadi (Handling Associate Editor: Jennifer Whitwell) *These authors contributed equally to this work.
Characterizing Limbic-Predominant Age-Related TDP-43 Encephalopathy Without Alzheimer’s Disease and Lewy Body Dementia in the Oldest Old: A Case Series
Abstract: Background: Limbic-predominant age-related TDP-43 encephalopathy neuropathologic change (LATE-NC) is a clinicopathological construct proposed to facilitate studying TDP-43 pathology in older individuals. Objective: Our aim was to describe clinical and cognitive characteristics of LATE-NC without Alzheimer’s disease neuropathologic change (ADNC) and Lewy body (LB) and to compare this with ADNC and primary age related tauopathy (PART). Methods: In 364 autopsies of the oldest-old of The 90+ Study, we identified those with LATE-NC without ADNC and LB. Control groups were participants with ADNC and PART. Results: Of 31% of participants who had LATE-NC , only 5 (1.4%) had LATE-NC without ADNC and LB, all of whom had tau. These participants had a gradual and progressive cognitive decline. Four (80%) had dementia at death, a rate that was higher than ADNC (50%) and PART (21.7%). Mean duration of cognitive impairment was twice as long in LATE-NC without ADNC and LB (6.2 years) compared to ADNC (2.9 years) and PART (3 years). LATE-NC without ADNC and LB group had a higher prevalence of syncope, depression, and extrapyramidal signs than the ADNC and PART groups. Conclusions: Despite the high prevalence of LATE-NC, LATE-NC without ADNC and LB was rare in this large oldest-old cohort, highlighting the very high prevalence of multiple pathologic changes in the oldest old. Slowly progressive cognitive decline, ubiquitous memory impairment, history of syncope and depression, and extrapyramidal signs were prominent features among our LATE-NC without ADNC and LB group.

Jiao Wang*, Chun Wang*, Xuan Li, Jie Guo, Abigail Dove, Zhuang Cui, Weili Xu *These authors contributed equally to this manuscript.
Association of Anemia with Cognitive Function and Dementia Among Older Adults: The Role of Inflammation
Abstract: Background: The association of anemia with cognitive function and dementia remains unclear. Objective: We aimed to investigate the association of anemia with cognitive function and dementia risk and to explore the role of inflammation in these associations. Methods: Within the UK Biobank, 207,203 dementia-free participants aged 60+ were followed for up to 16 years. Hemoglobin (HGB) and C-creative protein (CRP) were measured from blood samples taken at baseline. Anemia was defined as HGB < 13 g/dL for males and < 12 g/dL for females. Inflammation was categorized as low or high according to the median CRP level (1.50 mg/L). A subset of 18,211 participants underwent cognitive assessments (including global and domain-specific cognitive). Data were analyzed using linear mixed-effects model, Cox regression, and Laplace regression. Results: Anemia was associated with faster declines in global cognition (β=-0.08, 95% confidence interval [CI]: -0.14, -0.01) and processing speed (β=-0.10, 95% CI: -0.19, -0.01). During the follow-up of 9.76 years (interquartile range 7.55 to 11.39), 6,272 developed dementia. The hazard ratio of dementia was 1.57 (95% CI: 1.38, 1.78) for people with anemia, and anemia accelerated dementia onset by 1.53 (95% CI: 1.08, 1.97) years. The risk of dementia tended to be higher in people with both anemia and high CRP (1.89, 95% CI: 1.60, 2.22). There was a statistically significant interaction between anemia and CRP on dementia risk (p-interaction=0.032). Conclusions: Anemia is associated with cognitive decline (specifically for processing speed) and increased risk of dementia, especially in people with high inflammation.

Shihao Chen, Wenting Huang, Tao He, Mulan Zhang, Xing Jin, Lelin Jiang, Huiqin Xu, Keyang Chen
Exploring the Causality Between Plasma Brain-Derived Neurotrophic Factor and Neurological Diseases: A Mendelian Randomization Study
Abstract: Background: Brain-derived neurotrophic factor (BDNF) is a protein synthesized in the brain and widely expressed in the nervous system. Previous studies have demonstrated a controversial role of BDNF in neurological diseases. Objective: In this study, we aimed to assess the association between BDNF levels and the risk of neurological diseases by Mendelian randomization analysis. Methods: From a genome-wide association analysis of plasma proteins comprising 3,301 European participants, we isolated 25 genetic variations as instrumental variables for BDNF levels. Summary statistics data on six common neurological diseases as outcome variables. Two-sample Mendelian randomization (MR) analysis was used to assess whether plasma BDNF is causally related to neurological diseases. We also performed sensitivity analysis to ensure the robustness of the results and reverse MR to exclude potential reverse causality. Results: We confirmed the significant causal relationship between BDNF levels and the risk of Alzheimer’s disease (AD) (OR, 0.91; 95% CI, 0.83, 0.99; p=0.033). Other methods have also shown similar results. We infer that BDNF also reduces the risk of epilepsy (OR, 0.94; 95% CI, 0.90, 0.99; p=0.0103). In reverse MR analysis, we also found that AD can affect the level of BDNF. Conclusions: Our study suggests higher plasma BDNF was associated with the reduced risk of AD. Moreover, higher plasma BDNF is a protective factor on AD and focal epilepsy. The results provide credence to the idea that BDNF may play a significant role in the development of focal epilepsy and AD.

Marina G. Cavuoto, Stephen R. Robinson, Fergal J. O’Donoghue, Maree Barnes, Mark E. Howard, Julie Tolson, Bronwyn Stevens, Rachel Schembri, Ivana Rosenzweig, Christopher C. Rowe, Melinda L. Jackson
Associations Between Amyloid Burden, Hypoxemia, Sleep Architecture, and Cognition in Obstructive Sleep Apnea
Abstract: Background: Obstructive sleep apnea (OSA) is associated with an increased risk of amyloid-β (Aβ) burden, the hallmark of Alzheimer’s disease, and cognitive decline. Objective: To determine the differential impacts of hypoxemia and slow-wave sleep disruption on brain amyloid burden, and to explore the effects of hypoxemia, slow-wave sleep disruption, and amyloid burden on cognition in individuals with and without OSA. Methods: Thirty-four individuals with confirmed OSA (mean±SD age 57.5±4.1 years; 19 males) and 12 healthy controls (58.5±4.2 years; 6 males) underwent a clinical polysomnogram, a NAV4694 positron emission tomography (PET) scan for Aβ burden, assessment of APOE ԑ4 status and cognitive assessments. Linear hierarchical regressions were conducted to determine the contributions of demographic and sleep variables on amyloid burden and cognition. Results: Aβ burden was associated with nocturnal hypoxemia, and impaired verbal episodic memory, autobiographical memory and set shifting. Hypoxemia was correlated with impaired autobiographical memory, and only set shifting performance remained significantly associated with Aβ burden when controlling for sleep variables. Conclusions: Nocturnal hypoxemia was related to brain Aβ burden in this sample of OSA participants. Aβ burden and hypoxemia had differential impacts on cognition. This study reveals aspects of sleep disturbance in OSA that are most strongly associated with brain Aβ burden and poor cognition, which are markers of early Alzheimer’s disease. These findings add weight to the possibility that hypoxemia may be causally related to the development of dementia; however, whether they may be a therapeutic target for dementia prevention in OSA is yet to be determined.

Magnus Lindh-Rengifo, Stina B. Jonasson, Susann Ullén, Sebastian Palmqvist, Danielle van Westen, Erik Stomrud, Niklas Mattsson-Carlgren, Maria H. Nilsson*, Oskar Hansson* *These authors contributed equally to this work.
Effects of Brain Pathologies on Spatiotemporal Gait Parameters in Patients with Mild Cognitive Impairment
Abstract: Background: Impaired gait can precede dementia. The associations between gait parameters and brain pathologies are therefore of interest. Objective: To explore how different brain pathologies (i.e., vascular and Alzheimer’s) are associated with specific gait parameters from various gait components in persons with mild cognitive impairment (MCI), who have an increased risk of developing dementia. Methods: This cross-sectional study included 96 patients with MCI (mean 72, ±7.5 years; 52% women). Gait was evaluated by using an electronic walkway, GAITRite®. Four gait parameters (step velocity variability; step length; step time; stance time asymmetry) were used as dependent variables in multivariable linear regression analyses. Independent variables included Alzheimer’s disease pathologies (amyloid-β and tau) by using PET imaging and white matter hyperintensities (WMH) by using MRI. Covariates included age, sex, comorbidities (and intracranial volume in analyses that included WMH). Results: Increased tau-PET (Braak I-IV region of interest [ROI]) was associated with step velocity variability (standardized regression coefficient, β=0.383, p<0.001) and step length (β=0.336, p<0.001), which remained significant when using different Braak ROIs (I-II, III-IV, V-VI). The associations remained significant when adjusting for WMH (p<0.001). When also controlling for gait speed, tau was no longer significantly (p=0.168) associated with an increased step length. No significant associations between gait and Aβ-PET load or WMH were identified. Conclusions: The results indicate that one should pay specific attention to assess step velocity variability when targeting single task gait in patients with MCI. Future studies should address additional gait variability measures and dual tasking in larger cohorts.

Hongtao Liang*, Xiang Yin*, Tian Chen*, Yan Zhang, Qin Zhang, Jie Lin, Huan Yin, Jinghua Tang, Yingyi He, Ping Xia, Yongping Zhu, Haihua Li, Yongbiao Mo, Yongyong Li, Ying Wang, Xiao Yang, Zicheng Hu (Handling Associate Editor: Jian-Hong Wang) *These authors contributed equally to this work.
Excessive Sedentary Time Is Associated with Cognitive Decline in Older Patients with Minor Ischemic Stroke
Background: Cognitive impairment is commonly seen after acute ischemic stroke (AIS). Sedentary behaviors increase the risk of dementia among community dwelling population. Objective: This study aims to investigate the association of sedentary behaviors with poststroke cognitive impairment among older adults of minor AIS. Methods: This cohort study recruited 594 older subjects with minor AIS from three hospitals in China during February 1, 2016, and December 31, 2018. Participants were followed up for two years and the sedentary time per day was self-reported at the endpoint of follow-up. Cognitive functions were assessed by Mini-Mental State Examination (MMSE). Participants were categorized into the high and low sedentary time group according to the median sedentary time of the participants. Results: At two years of follow-up, the long sedentary time group had significantly lower MMSE scores than the short sedentary time group [median, (95%CI): 21 (18 to 25) versus 22 (18 to 25), p=0.368]. The long sedentary time group had a higher speed of cognitive decline than the short sedentary time group. Excessive sedentary time was associated with a higher risk of longitudinal cognitive decline (OR: 2.267, 95%CI: 1.594 to 3.225), adjusting for age, sex, education, body mass index, APOE genotype, comorbidities, symptoms of depression, anxiety, and insomnia, baseline MMSE scores and National Institute of Health Stroke Scale scores, cognitive therapy, and TOAST ischemic stroke subtypes. Conclusions: This study identified a possible link between sedentary behaviors and longitudinal cognitive decline among older patients with minor AIS, suggesting that reducing sedentary time might be helpful for preventing poststroke dementia.

Cornelia Pieternella van Buuren, Jenny Theodora van der Steen, Maria Olthof-Nefkens, Christian Bakker, Raymond Theodorus Catherina Maria Koopmans, Marieke Perry, Johanna Gezina Kalf (Handling Associate Editor: Kimberly Campbell)
The Complexity of Nutritional Problems in Persons with Dementia: Expanding a Theoretical Model
Abstract: Background: Persons with dementia are at risk of developing nutritional problems. Theoretical models on nutritional problems have been developed, but have not been evaluated with healthcare professionals. Objective: This study aimed to explore the comprehensiveness and applicability of a theoretical model of nutritional problems in persons with dementia for daily nursing home practice. Methods: A qualitative design employing a combined deductive and inductive approach was used. Healthcare professionals were eligible to participate if they 1) had expert knowledge of and experience with nutritional problems related to dementia, and 2) worked in a nursing home affiliated with an academic network covering the east and south of the Netherlands. Three focus group interviews with 20 healthcare professionals from seven professions were held. We conducted thematic analysis and we compared themes with existing theoretical models from the literature. Results: We identified six themes, four of which corresponded with the existing models (observing and analysing nutritional problems; consequences of nutritional problems; functioning of the person with dementia; environmental factors). Interprofessional collaboration and ethical factors were identified as new themes. The analyses indicated interactions within each theme, between themes, and a bidirectional connection between themes. Conclusions: This study demonstrated the relevance of interprofessional collaboration and ethical considerations in nutritional problems related to dementia. It uncovered complex bidirectional relations within and between factors regarding nutritional problems. All aspects should be taken into account to minimize the consequences of nutritional problems for persons with dementia.

Dália Nogueira
Nutrition in People with Dementia: What We Know and What We Need to Know to Upskill Those Who Care
Abstract: Feeding and swallowing difficulties and their consequences on the nutritional status of people with dementia have been the subject of recurrent research, albeit strong evidence is still lacking. When a person no longer swallows safely, it is the caregivers who face difficulties of providing adequate care. Therefore, it is important to understand and analyze their perspectives on the topic. Despite the recent development of theoretical models to manage mealtimes and nutrition intake, the participation of health professionals and caregivers in these types of studies are still limited. The study of van Buuren et al., which this commentary refers to, aimed to identify key factors that contribute to the development of a conceptual model to step up nutritional care in dementia.

Dustin B. Hammers, Joshua H. Lin, Angelina J. Polsinelli, Paige E. Logan, Shannon L. Risacher, Adam J. Schwarz, Liana G. Apostolova for the Alzheimer’s Disease Neuroimaging Initiative
Criterion Validation of Tau PET Staging Schemes in Relation to Cognitive Outcomes
Abstract: Background: Utilization of NIA-AA Research Framework requires dichotomization of tau pathology. However, due to the novelty of tau-PET imaging, there is no consensus on methods to categorize scans into “positive” or “negative” (T+ or T-). In response, some tau topographical pathologic staging schemes have been developed. Objective: The aim of the current study is to establish criterion validity to support these recently-developed staging schemes. Methods: Tau-PET data from 465 participants from the Alzheimer’s Disease Neuroimaging Initiative (aged 55 to 90) were classified as T+ or T- using decision rules for the Temporal-Occipital Classification (TOC), Simplified TOC (STOC), and Lobar Classification (LC) tau pathologic schemes of Schwarz, and Chen staging scheme. Subsequent dichotomization was analyzed in comparison to memory and learning slope performances, and diagnostic accuracy using actuarial diagnostic methods. Results: Tau positivity was associated with worse cognitive performance across all staging schemes. Cognitive measures were nearly all categorized as having “fair” sensitivity at classifying tau status using TOC, STOC, and LC schemes. Results were comparable between Schwarz schemes, though ease of use and better data fit preferred the STOC and LC schemes. While some evidence was supportive for Chen’s scheme, validity lagged behind others—likely due to elevated false positive rates. Conclusions: Tau-PET staging schemes appear to be valuable for Alzheimer’s disease diagnosis, tracking, and screening for clinical trials. Their validation provides support as options for tau pathologic dichotomization, as necessary for use of NIA-AA Research Framework. Future research should consider other staging schemes and validation with other outcome benchmarks.

Gwenn S. Smith, Hiroto Kuwabara, Haijuan Yan, Najlla Nassery, Mark Yoon, Vidya Kamath, Michael Kraut, Neda F. Gould, Alena Savonenko, Jennifer M. Coughlin, Martin Lodge, Martin G. Pomper, Ayon Nandi, Daniel Holt, Robert F. Dannals, Jeannie M. Leoutsakos (Handling Associate Editor: Jordi A. Matias-Guiu)
Serotonin Degeneration and Amyloid-β Deposition in Mild Cognitive Impairment: Relationship to Cognitive Deficits
Abstract: Background: Neuropathological and neuroimaging studies have demonstrated degeneration of the serotonin system in Alzheimer’s disease (AD). Neuroimaging studies have extended these observations to the preclinical stages of AD, mild cognitive impairment (MCI). Serotonin degeneration has been observed also in transgenic amyloid mouse models, prior to widespread cortical distribution of amyloid-β (Aβ). Objective: The present study evaluated the regional distribution of the serotonin transporter (5-HTT) and of Aβ in individuals with MCI and healthy older controls, as well as the contribution of 5-HTT and Aβ to cognitive deficits. Methods: Forty-nine MCI participants and 45 healthy older controls underwent positron emission tomography (PET) imaging of 5-HTT and Aβ, structural magnetic resonance imaging and neuropsychological assessments. Results: Lower cortical, striatal, and limbic 5-HTT and higher cortical Aβ was observed in MCIs relative to healthy controls. Lower 5-HTT, mainly in limbic regions, was correlated with greater deficits in auditory-verbal and visual-spatial memory and semantic, not phonemic fluency. Higher cortical Aβ was associated with greater deficits in auditory-verbal and visual-spatial memory and in semantic, not phonemic fluency. When modeling the association between cognition, gray matter volumes and Aβ, inclusion of 5-HTT in limbic and in select cortical regions significantly improved model fit for auditory-verbal and visual-spatial memory and semantic, but not phonemic fluency. Conclusions: These results support the role of serotonin degeneration in the memory and semantic fluency deficits observed in MCI.

Fares Qeadan, Ashlie McCunn, Benjamin Tingey, Ron Price Jr, Kathleen L Bobay, Kevin English, Erin F. Madden
Exploring the Association Between Opioid Use Disorder and Alzheimer’s Disease and Dementia Among a National Sample of the U.S. Population
Abstract: Background: Past research suggests associations between heavy alcohol use and later life dementia. However, little is known about whether opioid use disorder (OUD) and dementia share this association, especially among age groups younger than 65 years old. Objective: Examine the association between OUD and Alzheimer’s disease (AD) and dementia. Methods: Electronic health records between 2000 and 2021 for patients age 12 or older were identified in the Cerner Real-World database™. Patients with a prior diagnosis of dementia were excluded. Patients were followed for 1-10 years (grouped by one, three, five, and ten-year follow-up periods) in a matched retrospective cohort study. Cox proportional hazards regressions were used to estimate adjusted hazard ratios (aHRs) of incident AD/dementia stratified by age and follow-up group. Results: A sample of 627,810 individuals with OUD were compared to 646,340 without OUD. Individuals with OUD exhibited 88% higher risk for developing AD/dementia compared to those without OUD (aHR=1.88, 95% CI 1.74, 2.03) within 1 year follow-up and 211% (aHR=3.11, 95% CI 2.63, 3.69) within 10 years follow-up. When stratifying by age, younger patients (age 12-44) had a greater disparity in odds of AD/dementia between OUD and non-OUD groups compared with patients older than 65 years. Conclusions: Additional research is needed to understand why an association exists between OUD and AD/dementia, especially among younger populations. The results suggest that cognitive functioning screening programs for younger people diagnosed with OUD may be useful for targeting early identification and intervention for AD/dementia in particularly high risk and marginalized populations.

Ayoub Boulares, Claudine Fabre, Ala Cherni, Hela Jdidi, Sabri Gaied Chortane, Carlo Trompetto, Luca Puce, Nicola Luigi Bragazzi
Effects of a Physical Activity Program that Incorporates Exercises Targeting Balance, Strength, and Proprioception on Cognitive Functions and Physical Performance in Old Adults with Mild Cognitive Impairment
Abstract: Background: Aging often leads to cognitive function decline, sensory structure deterioration, and musculoskeletal system weakening. This impacts postural control during static and dynamic activities like walking, increasing the fall risk among the elderly. Older adults with mild cognitive impairment (MCI) face an elevated fall risk and cognitive decline, magnifying the public health concern. Objective: This study aimed to explore solutions by investigating the effects of a multi-component physical activity program on cognitive and motor functions in MCI patients. Methods: Twenty-three participants were enrolled in the study and assigned into two groups: an intervention group (n=13; age=85.7±5.5 years) and a control group (n=9; age=85±6.7 years). The study spanned two months, with participants engaging in three 60-minute weekly physical exercise sessions. The intervention focused on improving proprioception, muscle strength, and balance. Results: Results demonstrated significant enhancements in physical performance, fall risk reduction, and balance (p<0.05). Various tests, including the timed up and go test, Unipedal Stance test, Tinetti test, Short Physical Performance Battery, and 6-minute walking test, indicated these improvements. Cognitive function was evaluated with the Mini-Mental State Examination, revealing non-significant progress (p>0.05). Predictive models for outcomes were developed using linear regression analysis during the follow-up stage. Conclusions: This study underscores the effectiveness of a multi-component physical activity program encompassing balance, proprioception, and muscle-strengthening exercises as a non- pharmaceutical approach in improving balance skills and playing a key role in mitigating the risk of falls among old adults with MCI.

Janine Utz, Pauline Olm, Johannes Jablonowski, Eva-Maria Siegmann, Philipp Spitzer, Piotr Lewczuk, Johannes Kornhuber, Juan Manuel Maler, Timo Jan Oberstein (Handling Associate Editor: Henrik Zetterberg)
Reconceptualization of the Erlangen Score for the Assessment of Dementia Risk: The ERlangen Score
Abstract: Background: The established Erlangen Score (ES) for the interpretation of cerebrospinal fluid (CSF) biomarkers in the diagnostics of Alzheimer’s disease (AD) uses markers of amyloidopathy and tauopathy, equally weighted to form an easy-interpretable ordinal scale. However, these biomarkers are not equally predictive for AD. Objective: The higher weighting of the Aβ42/Aβ40 ratio, as a reconceptualized ERlangen Score (ERS), was tested for advantages in diagnostic performance. Methods: Non-demented subjects (N=154) with a mean follow up of 5 years were assigned to a group ranging from 0 to 4 in ES or ERS. Psychometric trajectories and dementia risk were assessed. Results: The distribution of subjects between ES and ERS among the groups differed considerably, as grouping allocated 32 subjects to ES group 2, but only 2 to ERS group 2. The discriminative accuracy between the ES (AUC 73.2%, 95% CI [64.2, 82.2]) and ERS (AUC 72.0%, 95% CI [63.1, 81.0]) for dementia risk showed no significant difference. Without consideration of the Aβ42/Aβ40 ratio in ES grouping, the optimal cut-off of the ES shifted to ≥2. Conclusions: The ERS showed advantages over the ES in test interpretation with comparable overall test performance, as fewer cases were allocated to the intermediate risk group. The established cut-off of ≥2 can be maintained for the ERS, whereas it must be adjusted for the ES when determining the Aβ42/Aβ40 ratio.

Huitong Ding, Amiya Mandapati, Alexander P. Hamel, Cody Karjadi, Ting F.A. Ang, Weiming Xia, Rhoda Au, Honghuang Lin
Multimodal Machine Learning for 10-Year Dementia Risk Prediction: The Framingham Heart Study
Abstract: Background: Early prediction of dementia risk is crucial for effective interventions. Given the known etiologic heterogeneity, machine learning methods leveraging multimodal data, such as clinical manifestations, neuroimaging biomarkers, and well-documented risk factors, could predict dementia more accurately than single modal data. Objective: This study aims to develop machine learning models that capitalize on neuropsychological (NP) tests, magnetic resonance imaging (MRI) measures, and clinical risk factors for 10-year dementia prediction. Methods: This study included participants from the Framingham Heart Study, and various data modalities such as NP tests, MRI measures, and demographic variables were collected. CatBoost was used with Optuna hyperparameter optimization to create prediction models for 10-year dementia risk using different combinations of data modalities. The contribution of each modality and feature for the prediction task was also quantified using Shapley values. Results: This study included 1,031 participants with normal cognitive status at baseline (age 75 ± 5 years, 55.3% women), of whom 205 were diagnosed with dementia during the 10-year follow-up. The model built on three modalities demonstrated the best dementia prediction performance (AUC 0.90 ± 0.01) compared to single modality models (AUC range: 0.82-0.84). MRI measures contributed most to dementia prediction (mean absolute Shapley value: 3.19), suggesting the necessity of multimodal inputs. Conclusions: This study shows that a multimodal machine learning framework had a superior performance for 10-year dementia risk prediction. The model can be used to increase vigilance for cognitive deterioration and select high-risk individuals for early intervention and risk management.

Yifei Sun, Abhay Moghekar, Anja Soldan, Corinne Pettigrew, Barry Greenberg, Marilyn Albert, Mei-Cheng Wang, the BIOCARD Research Team
Cerebrospinal Fluid Alzheimer’s Disease Biomarker Patterns of Change Prior to the Onset of Mild Cognitive Impairment
Abstract: Background: Cerebrospinal fluid (CSF) biomarkers of Alzheimer’s disease (AD) are altered many years before the onset of clinical symptoms of mild cognitive impairment (MCI). Incorporating clinical symptom onset time into biomarker modeling may enhance our understanding of changes preceding MCI. Objective: Using a new analytical approach, we examined patterns of biomarker change prior to MCI symptom onset among individuals who progressed from normal cognition to MCI, stratified based on the age of symptom onset. We also analyzed biomarker patterns of change among participants who remained cognitively normal, and examined potential modifiers of biomarker trajectories, including demographics and apolipoprotein E (APOE) status. Methods: Analyses included 93 participants who progressed from normal cognition to MCI and 186 participants who remained cognitively normal, over an average follow-up period of 16.2 years. CSF biomarkers, including Aβ42, Aβ40, total tau (t-tau), and phosphorylated tau181 (p-tau181), were measured using the fully automated Lumipulse assays. Results: Among participants who progressed to MCI, Aβ42/Aβ40 decreased, and t-tau and p-tau181 increased. For participants who did not progress to MCI, CSF biomarkers showed relatively stable patterns. In both progressors and non-progressors, APOE4 carriers showed lower Aβ42/Aβ40 levels (compared to non-carriers) at each point of the mean curves. Among non-progressors, APOE4 carriers had higher levels of p-tau181, p-tau181/(Aβ42/Aβ40), and t-tau/(Aβ42/Aβ40). Additionally, among those who did not progress, female sex was associated with higher levels of t-tau, p-tau181, t-tau/(Aβ42/Aβ40), and p-tau181/(Aβ42/Aβ40). Conclusions: These findings suggest that this analytic approach may provide additional insights into biomarker changes during early phases of AD.</p.

Katherine Kero, Colt M. Halter, Allison C. Moll, Sophie M. Hanna, John L. Woodard, Bruno Giordani, Ana M. Daugherty, Voyko Kavcic
Metacognition in Community-Dwelling Older Black and African American Adults During the COVID-19 Pandemic
Abstract: Background: Cognitive assessment of older adults typically includes symptom reports and objective evaluations. However, there is often poor agreement between these measures. Cultural norms, stress, and anxiety may also influence cognitive self-appraisal and performance. Little research describes how other factors affect the self-report/objective test discrepancies noted in the literature. Objective: This study investigated whether the disparity between subjective cognitive concerns and objective cognitive performance is related to measures of anxiety and stress in older Black and African American adults. Methods: Telephone screenings were administered to 206 older adults (ages 64–94) during the first year of the pandemic. Demographic data, objective memory (Telephone Interview for Cognitive Status [TICS-m]), an adaptation of the subjective memory measure, the Cognitive Change Questionnaire, emphasizing executive functioning in everyday life [CCQ-e]), Generalized Anxiety Disorder-7 (GAD-7), and Perceived Stress Scale-4 (PSS4) were measured. Metacognition Discrepancy Index (MDI) was calculated from the standardized residual after regressing TICS-m on CCQ-e scores to quantify the discrepancy between cognitive self-appraisal and objective cognitive functioning. Results: Neither GAD-7 nor PSS-4 moderated the relationship between TICS-m and CCQ-e, and TICS-m scores weakly predicted subjective CCQ-e scores (F(1, 197)=4.37, p=0.038, R2=0.022). The MDI correlated with stress and anxiety (rs=0.294, 0.396, ps<0.001). Conclusions: Discrepancies exist between objectively measured and self-evaluated cognition. Elevations in stress and anxiety are associated with greater overestimation of cognitive difficulties relative to objective performance. Pandemic-related stressors may have worsened anxiety and diminished self-appraisal of cognitive abilities for some individuals, while others may remain reluctant to acknowledge impairments. Social and emotional factors are meaningful considerations in assessing cognitive difficulties.

Tiffany E. Chow, Christina R. Veziris, Nidhi Mundada, Alexis I. Martinez-Arroyo, Joel H. Kramer, Bruce L. Miller, Howard J. Rosen, Maria Luisa Gorno-Tempini, Katherine P. Rankin, William W. Seeley, Gil D. Rabinovici, Renaud La Joie, Virginia E. Sturm (Handling Associate Editor: Juan Zhou)
Medial Temporal Lobe Tau Aggregation Relates to Divergent Cognitive and Emotional Empathy Abilities in Alzheimer’s Disease
Abstract: Background: In Alzheimer’s disease (AD), the gradual accumulation of amyloid-β (Aβ) and tau proteins may underlie alterations in empathy. Objective: To assess whether tau aggregation in the medial temporal lobes relates to differences in cognitive empathy (the ability to take others’ perspectives) and emotional empathy (the ability to experience others’ feelings) in AD. Methods: Older adults (n = 105) completed molecular Aβ positron emission tomography (PET) scans. Sixty-eight of the participants (35 women) were Aβ positive and symptomatic with diagnoses of mild cognitive impairment, dementia of the Alzheimer’s type, logopenic variant primary progressive aphasia, or posterior cortical atrophy. The remaining 37 (22 women) were asymptomatic Aβ negative healthy older controls. Using the Interpersonal Reactivity Index, we compared current levels of informant-rated cognitive empathy (perspective-taking subscale) and emotional empathy (empathic concern subscale) in the Aβ positive and negative participants. The Aβ positive participants also underwent molecular tau-PET scans, which were used to investigate whether regional tau burden in the bilateral medial temporal lobes related to empathy. Results: Aβ positive participants had lower perspective-taking and higher empathic concern than Aβ negative healthy controls. Medial temporal tau aggregation in the Aβ positive participants had divergent associations with cognitive and emotional empathy. Whereas greater tau burden in the amygdala predicted lower perspective-taking, greater tau burden in the entorhinal cortex predicted greater empathic concern. Tau burden in the parahippocampal cortex did not predict either form of empathy. Conclusions: Across AD clinical syndromes, medial temporal lobe tau aggregation is associated with lower perspective-taking yet higher empathic concern.

Jennifer E. Bramen, Prabha Siddarth, Emily S. Popa, Gavin T. Kress, Molly K. Rapozo, John F. Hodes, Aarthi S. Ganapathi, Colby B. Slyapich, Ryan M. Glatt, Kyron Pierce, Verna R. Porter, Claudia Wong, Mihae Kim, Richelin V. Dye, Stella Panos, Tess Bookheimer, Tori Togashi, Spencer Loong, Cyrus A. Raji, Susan Y. Bookheimer, Jared C. Roach, David A. Merrill
Impact of Eating a Carbohydrate-Restricted Diet on Cortical Atrophy in a Cross-Section of Amyloid Positive Patients with Alzheimer’s Disease: A Small Sample Study
Abstract: Background: A carbohydrate-restricted diet aimed at lowering insulin levels has the potential to slow Alzheimer’s disease (AD). Restricting carbohydrate consumption reduces insulin resistance, which could improve glucose uptake and neural health. A hallmark feature of AD is widespread cortical thinning; however, no study has demonstrated that lower net carbohydrate (nCHO) intake is linked to attenuated cortical atrophy in patients with AD and confirmed amyloidosis. Objective: We tested the hypothesis that individuals with AD and confirmed amyloid burden eating a carbohydrate-restricted diet have thicker cortex than those eating a moderate-to-high carbohydrate diet. Methods: A total of 31 patients (mean age 71.4±7.0 years) with AD and confirmed amyloid burden were divided into two groups based on a 130 g/day nCHO cutoff. Cortical thickness was estimated from T1-weighted MRI using FreeSurfer. Cortical surface analyses were corrected for multiple comparisons using cluster-wise probability. We assessed group differences using a two-tailed two-independent sample t-test. Linear regression analyses using nCHO as a continuous variable, accounting for confounders, were also conducted. Results: The lower nCHO group had significantly thicker cortex within somatomotor and visual networks. Linear regression analysis revealed that lower nCHO intake levels had a significant association with cortical thickness within the frontoparietal, cingulo-opercular, and visual networks. Conclusions: Restricting carbohydrates may be associated with reduced atrophy in patients with AD. Lowering nCHO to under 130 g/day would allow patients to follow the well-validated MIND diet while benefiting from lower insulin levels.

Wonjae Sung*, Hyuk Sung Kwon*, Yeonjae Park, Seung Hyun Kim, Sojeong Park, Dae Ryong Kang, Hojin Choi *These authors contributed equally to this work.
Gout and the Prevalence of Dementia: A Nationwide Population-Based Study
Abstract: Background: Hyperuricemia in patients with gout is associated with a low risk of neurodegenerative diseases, including dementia. However, the prevalence of dementia in patients with gout has not yet been reported. Objective: To analyze the prevalence of dementia among patients diagnosed with gout by utilizing the Health Insurance and Review Assessment database, a nationwide registry of the South Korean population. Methods: Data from the Health Insurance and Review Assessment database of patients diagnosed with gout between 2011 and 2018 were extracted. The annual prevalence of dementia according to age and sex was analyzed. We investigated whether there was an association between comorbidities and gout medication in patients with both gout and dementia and in patients with only gout. Results: Between 2011 and 2018, the age-adjusted prevalence of dementia per 100,000 persons ranged from 54.0 (95% confidence interval: 47.7–60.2) to 69.9 (95% confidence interval: 65.3–74.5). Compared to previous studies, the prevalence of dementia was lower in patients with gout than in the general population. Patients with both gout and dementia were more likely to be women, have a wide range of comorbidities, and be prescribed gout-related drugs, including allopurinol, febuxostat, nonsteroidal anti-inflammatory drugs, and steroids than patients with gout without dementia. Conclusions: This study demonstrated a relatively low prevalence of dementia in patients with gout. Gout, characterized by hyperuricemia, might be associated with a reduced risk of dementia.

Lindsay Y. Datlow, Jay King, Mark Leventhal, Taylor C. Wallace
Association of Pork Intake with Cognitive Performance in Older Adults Enrolled in the National Health and Nutrition Examination Survey (NHANES), 2011–2014 Data Cycles
Abstract: Background: Pork provides higher levels of several nutrients important for cognitive maintenance in older adults. A pilot clinical study suggests the addition of moderate amounts of pork to a Mediterranean-style diet improves cognition in older adults. There is an absence of observational research that isolates effects of pork from other red meats. Objective: To examine the relationship of pork intake on cognitive performance in older adults. Methods: Cross-sectional data from the U.S. National Health and Nutrition Examination Survey (NHANES) 2011–2014 cycles were used in these analyses. Pork intake was assessed using data from two non-consecutive 24-h dietary recalls. Cognitive function was assessed by the Consortium to Establish a Registry for Alzheimer’s Disease (CERAD) Word Learning, CERAD Delayed Recall, Animal Fluency, and Digital Substitution tests. Statistical analyses were adjusted for sample weighting and survey design variables to account for the complex design. Student t-tests (continuous variables) and Pearson chi-squared tests (categorical variables) were employed to compare participant characteristics between the low and normal cognitive performance groups. Logistic regression was used to determine the relationship of pork intake (low, medium, and high) with prevalence of low cognitive performance, with the non-consumer group as the referent category. Results: Pork intake was not beneficially or detrimentally associated performance on the any of the cognitive tests in both the crude and multivariate models (p>0.05). Conclusions: Prospective cohort investigations and larger/longer-term clinical trials are needed to fully elucidate effects of pork intake on cognition in older adults.

Carolyn W. Zhu, Yian Gu, Stephanie Cosentino, Anton J. Kociolek, Michelle Hernandez, Yaakov Stern
Racial/Ethnic Disparities in Misidentification of Dementia in Medicare Claims: Results from the Washington Heights-Inwood Columbia Aging Project
Abstract: Background: Misidentification of dementia in Medicare claims is quite common. Objective: We examined potential race/ethnic disparities in misidentification of dementia in Medicare claims in a diverse cohort of older adults who underwent careful clinical assessment. Methods: Participants were enrolled the Washington Heights-Inwood Columbia Aging Project (WHICAP), a multiethnic, population-based, prospective study of cognitive aging in which dementia status was assessed using a rigorous clinical protocol. ICD-9-CM and ICD-10-CM diagnosis codes in all available Medicare claims (1999-2019) were compared to clinical dementia diagnosis and categorized into three mutually exclusive groups: 1) congruent-, 2) over-, and 3) under- identification during the study period. Multinomial logistic regression model was used to examine the relationship between race (White, African American/Black, other) and ethnicity (Hispanic/Latinx, non-Hispanic/Latinx) and congruency of dementia identification after controlling for clinical (cognition, function, comorbidities) and demographic characteristics (age, sex, education), and inpatient and outpatient utilization. Results: Across all person-years, 88.4% had congruent identification of dementia compared to clinical diagnosis, in 4.1% of the times participants were over-identified with dementia, and 7.5% of the times the participants were under-identified. Rates of misidentification was higher in minority participants than in White, non-Hispanic participants. Multivariable estimation results showed that the probability of over-identification with dementia was 2.2% higher for African American/Black than White (p=0.05) and 2.7% higher for Hispanic participants than non-Hispanics (p=0.03) participants. Differences in under-identification by race/ethnicity were not statistically significant. Conclusions: African American/Black and Hispanic participants were more likely over-identified with dementia in Medicare claims.

Naoki Saji, Yuichi Ishihara, Kenta Murotani, Akira Uchiyama, Akinori Takeda, Takashi Sakurai, Kenji Matsushita
Cross-Sectional Analysis of Periodontal Disease and Cognitive Impairment Conducted in a Memory Clinic: The Pearl Study
Abstract: Background: Periodontal disease (PeD) is a risk factor of Alzheimer’s disease and is associated with cognitive decline in older adults. However, the relationships between subitems of neuropsychological tests and PeD have not been fully clarified. Objective: To evaluate associations between PeD and subitems of neuropsychological tests. Methods: We performed a cross-sectional analysis of data of 183 participants (women: 50%, mean age: 79 years) from a clinical study. We enrolled patients who visited our memory clinic and assessed demographics, dementia-related risk factors, neuropsychological tests, brain magnetic resonance images, and a dental screening check. We evaluated the relationships between cognitive function and PeD using multivariable logistic regression analyses. Results: Participants with dementia were less likely to make periodical visits to the dentist, had fewer teeth, had less frequent tooth brushing habits, and were more likely to have PeD. Impaired cognitive function was significantly associated with an increasing degree of PeD. In multivariable logistic regression analyses, impaired visuospatial function and attention were associated with twice the risk of moderate or severe PeD compared with individuals with preserved visuospatial function and attention (odds ratio: 2.11, 95% confidence interval: 1.04–4.29, p = 0.037). Impaired word recall and recognition and following commands were associated with increased risk of PeD (odds ratio: 2.80, 95% confidence interval: 1.41–5.32, p = 0.003). Conclusions: Cognitive decline, such as impaired visuospatial function, attention, word recall and recognition, and inability to follow commands were independently and strongly associated with PeD. These items can be assessed easily on a daily basis.

Kanika Mehta, Mohammadreza Mohebbi, Julie A. Pasco, Lana J. Williams, Ken Walder, Boon Lung Ng, Veer Bala Gupta
Impact of Mood Disorder History and Bone Health on Cognitive Function Among Men Without Dementia
Abstract: Background: Poor cognitive function, a major disabling condition of older age, is often considered a prodromal feature of dementia. High mortality and the lack of a cure for dementia have necessitated a focus on the identification of potentially modifiable risk factors. Mental and physical health conditions such as mood disorders and bone loss have been previously linked with poor cognition individually although their combined effect remains largely unknown. Objective: Considering the multifactorial nature of dementia pathology, we investigated whether mood disorders, bone health and their interaction are associated with cognitive function in a population-based sample of men. Methods: Four hundred and forty-two male participants were drawn from the Geelong Osteoporosis Study. Cognitive function was assessed using the CogState Brief Battery, which measured cognitive performance across four domains and was used to compute overall cognitive function. Mood disorders and hip bone mineral density (BMD) were determined using a semi-structured clinical interview and dual energy x-ray absorptiometry, respectively. Results: Hip BMD (Bcoeff = 0.56, 95% CI: [0.07, 1.05], p = 0.025) but not mood disorder (Bcoeff = -0.50, 95% CI: [-0.20, 0.10], p = 0.529) was associated with overall cognitive function after accounting for potential confounders. Interaction effects were observed between the two exposures (Bcoeff = -1.37, 95% CI: [-2.49, -0.26], p = 0.016) suggesting that individuals without a mood disorder displayed better cognitive performance with increasing BMD, whereas those with a lifetime history of mood disorder displayed poorer cognitive function with increasing BMD. Conclusions: These findings highlight the importance of exploring interactions among potentially modifiable health conditions associated with cognitive function.

Jean Ikanga, Sabrina Hickle, Megan Schwinne, Emmanuel Epenge, Guy Gikelekele, Immaculee Kavugho, Nathan Tsengele, Mampunza Samuel, Liping Zhao, Deqiang Qiu, Anthony Stringer, Amit M. Saindane, Alvaro Alonso, Daniel L. Drane
Association Between Hippocampal Volume and African Neuropsychology Memory Tests in Adult Individuals with Probable Alzheimer’s Disease in Democratic Republic of Congo
Abstract: Background: Western studies indicate potential associations between hippocampal volume and memory in the trajectory of Alzheimer’s disease (AD). However, limited availability of neuroimaging technology and neuropsychological tests appropriate for sub-Saharan African (SSA) countries makes it difficult to establish neuroanatomical associations of hippocampus and memory in this locale. Objective: This study examined hippocampal volumes and memory in healthy control (HC) and probable AD groups in the Democratic Republic of Congo (DRC). Methods: Forty-six subjects with probable AD and 29 HC subjects were screened using the Community Instrument for Dementia and the Alzheimer Questionnaire. Participants underwent neuroimaging in Kinshasa, DRC, and memory was evaluated using the African Neuropsychology Battery (ANB). Multiple linear regression was used to determine associations between hippocampal volumes and memory. Results: Patients with probable AD performed significantly worse than HCs on ANB memory measures, and exhibited greater cerebral atrophy, which was significantly pronounced in the medial temporal lobe region (hippocampus, entorhinal cortex). Both AD and HC subjects exhibited high rates of white matter hyperintensities compared to international base rate prevalence, which was significantly worse for probable AD. Both also exhibited elevated rates of microhemorrhages. Regression analysis demonstrated a significant association between hippocampal volume and ANB memory tests. Hippocampal atrophy discriminated probable AD from the HC group. Conclusions: This study establishes the feasibility of conducting neuroimaging research in the SSA, demonstrates many known neuroimaging findings in probable AD patients hold up using culturally appropriate memory tasks, and suggest cardiovascular problems are a greater issue in SSA than in Western countries.

Clinical Trial Protocol
Andrew Pipingas*, Karen J. Murphy*, Courtney R. Davis, Catherine Itsiopoulos, Michael Kingsley, Andrew Scholey, Helen Macpherson, Leonie Segal, Jeff Breckon, Anne-Marie Minihanej, Denny Meyer, Edward Ogden, Kathryn A. Dyer, Emily Eversteyn, Roy J. Hardman, Kaylass Poorun, Keri Justice, Maher Hana, Jonathan D. Buckley, David White, Kade Davison, Jessie S. Clark, Ella L. Bracci, Greg Kennedy on behalf of MedWalk collaborative team (Handling Associate Editor: M. Cristina Polidori) *These authors contributed equally to this work.
A Mediterranean Diet and Walking Intervention to Reduce Cognitive Decline and Dementia Risk in Independently Living Older Australians: The MedWalk Randomized Controlled Trial Experimental Protocol, Including COVID-19 Related Modifications and Baseline Characteristics
Abstract: Background: Several clinical trials have examined diet and physical activity lifestyle changes as mitigation strategies for risk factors linked to cognitive decline and dementias such as Alzheimer's disease. However, the ability to modify these behaviors longer term, to impact cognitive health has remained elusive. Objective: The MedWalk trial’s primary aim is to investigate whether long-term adherence to a Mediterranean-style diet and regular walking, delivered through motivational interviewing and cognitive-behavioral therapy (MI-CBT), can reduce age-associated cognitive decline and other dementia risk factors in older, independently living individuals without cognitive impairment. Methods: MedWalk, a one-year cluster-randomized controlled trial across two Australian states, recruited 60–90-year-old people from independent living retirement villages and the wider community. Participants were assigned to either the MedWalk intervention or a Control group (maintaining their usual diet and physical activity). The primary outcome is 12-month change in visual memory and learning assessed from errors on the Paired Associates Learning Task of the Cambridge Neuropsychological Test Automated Battery. Secondary outcomes include cognition, mood, cardiovascular function, biomarkers related to nutrient status and cognitive decline, MI-CBT effectiveness, Mediterranean diet adherence, physical activity, quality of life, cost-effectiveness, and health economic evaluation. Progress and Discussion: Although COVID-19 impacts over two years necessitated a reduced timeline and sample size, MedWalk retains sufficient power to address its aims and hypotheses. Baseline testing has been completed with 157 participants, who will be followed over 12 months. If successful, MedWalk will inform interventions that could substantially reduce dementia incidence and ameliorate cognitive decline in the community.