Volume 85, Number 2, IN PRESS

Review
Staley A. Brod
Anti-Inflammatory Agents: An Approach to Prevent Cognitive Decline in Alzheimer’s Disease
Abstract: Systemic inflammation is an organism’s response to an assault by the non-self. However, that inflammation may predispose humans to illnesses targeted to organs, including Alzheimer’s disease (AD). Lesions in AD have pro-inflammatory cytokines and activated microglial/monocyte/macrophage cells. Up to this point, clinical trials using anti-amyloid monoclonal antibodies have not shown success. Maybe it is time to look elsewhere by combating inflammation. Neuroinflammation with CNS cellular activation and excessive expression of immune cytokines is suspected as the “principal culprit” in the higher risk for sporadic AD. Microglia, the resident immune cell of the CNS, perivascular myeloid cells, and activated macrophages produce IL-1, IL-6 at higher levels in patients with AD. Anti-inflammatory measures that target cellular/cytokine-mediated damage provide a rational therapeutic strategy. We propose a clinical trial using oral type 1 IFNs to act as such an agent; one that decreases IL-1 and IL-6 secretion by activating lamina propria lymphocytes in the gut associated lymphoid tissue with subsequent migration to the brain undergoing inflammatory responses. A clinical trial would be double-blind, parallel 1-year clinical trial randomized 1:1 oral active type 1 IFN versus best medical therapy to determine whether ingested type I IFN would decrease the rate of cognitive decline in mild cognitive impairment or mild AD. Using cognitive psychometrics, imaging, and fluid biomarkers (MxA for effective type I IFN activity beyond the gut), we can determine if oral type I IFN can prevent cognitive decline in AD.

Review
Lai Wang, Hongyang Chen, Jing Tang, Zhengwei Guo, Yanming Wang
Peptidylarginine Deiminase and Alzheimer’s Disease
Abstract: Peptidylarginine deiminases (PADs) are indispensable enzymes for post-translational modification of proteins, which can convert Arg residues on the surface of proteins to citrulline residues. The PAD family has five isozymes, PAD1, 2, 3, 4, and 6, which have been found in multiple tissues and organs. PAD2 and PAD4 were detected in cerebral cortex and hippocampus from human and rodent brain. In the central nervous system, abnormal expression and activation of PADs are involved in the pathological changes and pathogenesis of Alzheimer’s disease (AD). This article reviews the classification, distribution, and function of PADs, with an emphasis on the relationship between the abnormal activation of PADs and AD pathogenesis, diagnosis, and the therapeutic potential of PADs as drug targets for AD.

Review
Jessica Lynn*, Mingi Park*, Christiana Ogunwale, George K. Acquaah-Mensah *These authors contributed equally to this work.
A Tale of Two Diseases: Exploring Mechanisms Linking Diabetes Mellitus with Alzheimer’s Disease
Abstract: Dementias, including the type associated with Alzheimer’s disease (AD), are on the rise worldwide. Similarly, type 2 diabetes mellitus (T2DM) is one of the most prevalent chronic diseases globally. Although mechanisms and treatments are well-established for T2DM, there remains much to be discovered. Recent research efforts have further investigated factors involved in the etiology of AD. Previously perceived to be unrelated diseases, commonalities between T2DM and AD have more recently been observed. As a result, AD has been labeled as “type 3 diabetes”. In this review, we detail the shared processes that contribute to these two diseases. Insulin resistance, the main component of the pathogenesis of T2DM, is also present in AD, causing impaired brain glucose metabolism, neurodegeneration, and cognitive impairment. Dysregulation of insulin receptors and components of the insulin signaling pathway, including protein kinase B, glycogen synthase kinase 3β, and mammalian target of rapamycin are reported in both diseases. T2DM and AD also show evidence of inflammation, oxidative stress, mitochondrial dysfunction, advanced glycation end products, and amyloid deposition. The impact that changes in neurovascular structure and genetics have on the development of these conditions is also being examined. With the discovery of factors contributing to AD, innovative treatment approaches are being explored. Investigators are evaluating the efficacy of various T2DM medications for possible use in AD, including but not limited to glucagon-like peptide-1 receptor agonists, and peroxisome proliferator-activated receptor-gamma agonists. Furthermore, there are 136 active trials involving 121 therapeutic agents targeting novel AD biomarkers. With these efforts, we are one step closer to alleviating the ravaging impact of AD on our communities.

Review
Alessio Crestini, Francesca Santilli, Stefano Martellucci, Elena Carbone, Maurizio Sorice, Paola Piscopo, Vincenzo Mattei
Prions and Neurodegenerative Diseases: A Focus on Alzheimer’s Disease
Abstract: Specific protein misfolding and aggregation are mechanisms underlying various neurodegenerative diseases such as prion disease and Alzheimer's disease (AD). The misfolded proteins are involved in prions, amyloid-β (Aβ), tau, and α-synuclein disorders; they share common structural, biological, and biochemical characteristics, as well as similar mechanisms of aggregation and self-propagation. Pathological features of AD include the appearance of plaques consisting of deposition of protein Aβ and neurofibrillary tangles formed by the hyperphosphorylated tau protein. Although it is not clear how protein aggregation leads to AD, we are learning that the cellular prion protein (PrPC) plays an important role in the pathogenesis of AD. Herein, we first examined the pathogenesis of prion and AD with a focus on the contribution of PrPC to the development of AD. We analyzed the mechanisms that lead to the formation of a high affinity bond between Aβ oligomers (AβOs) and PrPC. Also, we studied the role of PrPC as an AβO receptor that initiates an AβO-induced signal cascade involving mGluR5, Fyn, Pyk2, and eEF2K linking Aβ and tau pathologies, resulting in the death of neurons in the central nervous system. Finally, we have described how the PrPC-AβOs interaction can be used as a new potential therapeutic target for the treatment of PrPC-dependent AD.

Short Communication
Szymon Zdanowski, Alieke Tieks, Bertus F. Jeronimus, Marij Zuidersma
Intra-Individual Variability in Cognitive Performance Can Befuddle the Study of Cognitive Impairments and Decline
Abstract: Using group-aggregated results and snapshot assessments of cognitive performance may prove problematic if the assessed construct shows substantial and rapid variation over time. To illustrate the significance of this issue, we analyzed cognitive performance data of ten older adults undergoing daily computerized cognitive assessments (CogState Brief Battery) for 36–93 days. In all cases, the day-to-day intra-individual variability was substantial when compared with group-level, between-person variability. This indicates that the results of studies using single snapshot assessments of cognitive functioning should be interpreted with caution. Additionally, group-aggregated measures of cognitive performance may not directly extrapolate to an individual.

Commentary
Andrew J. Larner, Anthony G. Marson
Epileptic Seizures in Alzheimer’s Disease: What Are the Implications of SANAD II?
Abstract: Epileptic seizures are increasingly recognized as part of the clinical phenotype of patients with Alzheimer’s disease (AD). However, the evidence based on which to make treatment decisions for such patients is slim, there being no clear recommendation based on systematic review of the few existing studies of anti-seizure drugs in AD patients. Here the authors examine the potential implications for the treatment of seizures in AD of the results of the recently published SANAD II pragmatic study, which examined the effectiveness of levetiracetam, zonisamide, or lamotrigine in newly diagnosed focal epilepsy, and of valproate and levetiracetam in generalized and unclassifiable epilepsy.

Editorial
Jamie Talan
Reactive Astrocytes and Alzheimer’s Disease

Rifat B. Alam, Chelsea R. Singleton, Susan Aguiñaga, Wojtek Chodzko-Zajko, Nilufer A. Jahan, Adeyosola Oke, Andiara Schwingel (Handling Associate Editor: Mayra Estrella)
Is Acculturation Associated with the Cognitive Performance of Older Hispanics?
Abstract: Background: Hispanics in the United Statues are disproportionately affected by Alzheimer’s disease and related dementias. Little is known about the impact of acculturation on cognitive performance. Objective: This study examined the association between acculturation and cognitive performance among older Hispanics. Methods: We analyzed cross-sectional data of 616 Hispanic participants in the National Health and Nutrition Examination Survey (NHANES) 2011-2014 [average age= 67.15 years, % Female= 51.46, % less than high-school graduate= 52.60]. Cognitive performance was measured by two neuropsychological tests: Animal Fluency Test (AFT) and Digit Symbol Substitution Test (DSST). We used two single-item proxy measures to quantify acculturation: nativity status (non-US-born residing <15 years in the US (low acculturation), non-US-born residing ≥15 years in the US, and US-born (high acculturation)); and language acculturation (only/mostly Spanish (low acculturation), Spanish and English, only/mostly English (high acculturation)). We used adjusted linear regression to evaluate associations between acculturation and cognitive performance. Results: Results indicated poorer cognitive performance among the low-acculturated groups for both nativity and linguistic measures. Participants who were non-US-born living ≥15 years (p= 0.02) and speaking only/mostly Spanish or Spanish and English (p=0.01 and 0.006 respectively) had significantly lower AFT scores compared to US-born and only/mostly English-speaking groups. Participants who were non-US-born living <15 years (p<0.0001) or non-US-born living ≥15 years (p<0.0001) and speaking only/mostly Spanish (p=0.0008) scored lower on the DSST than the US-born and only/mostly English-speaking participants. Conclusion: In summary, low acculturation is associated with poorer cognitive performance among older Hispanics. Acculturation might be an important attribute to help understand cognitive decline and dementias among Hispanics.

Shraddha Sapkota, G. Peggy McFall, Mario Masellis, Roger A. Dixon*, Sandra E. Black* *These authors contributed equally to this work as co-senior authors.
Differential Cognitive Decline in Alzheimer’s Disease Is Predicted by Changes in Ventricular Size but Moderated by Apolipoprotein E and Pulse Pressure
Abstract: Background: Differential cognitive trajectories in Alzheimer’s disease (AD) may be predicted by biomarkers from multiple domains. Objective: In a longitudinal sample of AD and AD-related dementias patients (n = 312), we tested whether 1) change in brain morphometry (ventricular enlargement) predicts differential cognitive trajectories, 2) further risk is contributed by genetic (Apolipoprotein E [APOE] ɛ4+) and vascular (pulse pressure [PP]) factors separately, and 3) the genetic + vascular risk moderates this pattern. Methods: We applied a dynamic computational approach (parallel process models) to test both concurrent and change-related associations between predictor (ventricular size) and cognition (executive function [EF]/attention). We then tested these associations as stratified by APOE (ɛ4-/ɛ4+), PP (low/high), and APOE + PP (low/intermediate/high) risk. Results: First, concurrently, higher ventricular size predicted lower EF/attention performance and, longitudinally, increasing ventricular size predicted steeper EF/attention decline. Second, concurrently, higher ventricular size predicted lower EF/attention performance selectively in APOE ɛ4+ carriers, and longitudinally, increasing ventricular size predicted steeper EF/attention decline selectively in the low PP group. Third, ventricular size and EF/attention associations were absent in the high APOE + PP risk group both concurrently and longitudinally. Conclusion: As AD progresses, a threshold effect may be present in which ventricular enlargement in the context of exacerbated APOE + PP risk does not produce further cognitive decline.

Lin Li*, Gui-rong Cheng*, Dan Liu*, Fei-fei Hu, Xu-guang Gan, Bo Zhang, Lina An, Cong Chen, Ming-jun Zou, Lang Xu, Yang-ming Ou, Yu-shan Chen, Jin-quan Li, Zhen Wei, Qiong Wu, Xing-xing Chen, Man-qing Guo, Qing-ming Wu, Ru Wang, Yan Zeng (Handling Associate Editor: Ling-Qiang Zhu) *These authors contributed equally to this work.
The Hubei Memory & Aging Cohort Study: Study Design, Baseline Characteristics, and Prevalence of Cognitive Impairments
Abstract: Background: Despite the improved access to health services in China, inadequate diagnosis and management of dementia are common issues, especially in rural regions. Objective: The Hubei Memory & Aging Cohort Study was designed as a prospective study in Central China to determine the prevalence, incidence, and risk factors for dementia and mild cognitive impairment (MCI) among urban and rural older adults. Methods: From 2018–2020, participants aged ≥65 years were screened, and data regarding their life behaviors, families, socio-economic status, physical and mental health, social and psychological factors, and cognition were collected. Diagnoses of MCI and dementia were made via consensus diagnosis using the Diagnostic and Statistical Manual of Mental Disorders fourth edition criteria. Results: Of 8,221 individuals who completed their baseline clinical evaluation, 4,449 (54.1%) were women and 3,164 (38.4%) were from remote rural areas (average age: 71.96 years; mean education period: 7.58 years). At baseline, 25.98% (95% confidence interval [CI]: 24.99–26.96) and 7.24% (95% CI: 6.68–7.80) of the participants were diagnosed with MCI and dementia, respectively. Prevalence showed a strong relationship with age. The substantial disparities between rural and urban regions in MCI and dementia prevalence and multiple dementia-related risk factors were revealed. Especially for dementia, the prevalence rate in rural areas was 2.65 times higher than that in urban regions. Conclusion: Our results suggested that public health interventions are urgently needed to achieve equitable diagnosis and management for people living with dementia in the communities across urban and rural areas.

Lei Chen, Qianqian Shen, Shunliang Xu, Hongzhuan Yu, Shengjie Pei, Yangting, Zhang, Xin He, QiuZhen Wang, Duo Li
5-Hydroxymethylcytosine Signatures in Circulating Cell-Free DNA as Diagnostic Biomarkers for Late-Onset Alzheimer’s Disease
Abstract: Background: 5-Hydroxymethylcytosine (5hmC) is an epigenetic DNA modification that is highly abundant in central nervous system. It has been reported that DNA 5hmC dysregulation play a critical role in Alzheimer’s disease (AD) pathology. Changes in 5hmC signatures can be detected in circulating cell-free DNA (cfDNA), which has shown potential as a non-invasive liquid biopsy material. Objective: However, the genome-wide profiling of 5hmC in cfDNA and its potential for the diagnosis of AD has not been reported to date. Methods: We carried out a case-control study and used a genome-wide chemical capture followed by high-throughput sequencing to detect the genome-wide profiles of 5hmC in human cfDNA and identified differentially hydroxymethylated regions (DhMRs) in late-onset AD patients and the control. Results: We discovered significant differences of 5hmC enrichment in gene bodies which were linked to multiple AD pathogenesis-associated signaling pathways in AD patients compared with cognitively normal controls, indicating they can be well distinguished from normal controls by DhMRs in cfDNA. Specially, we identified 7 distinct genes (RABEP1, CPNE4, DNAJC15, REEP3, ROR1, CAMK1D, and RBFOX1) with predicting diagnostic potential based on their significant correlations with MMSE and MoCA scores of subjects. Conclusion: The present results suggest that 5hmC markers derived from plasma cfDNA can served as an effective, minimally invasive biomarkers for clinical auxiliary diagnosis of late-onset AD.

Valérie Turcotte, Olivier Potvin, Mahsa Dadar, Carol Hudon, Simon Duchesne, for the Alzheimer's Disease Neuroimaging Initiative (Handling Associate Editor: Insa Feinkohl)
Birth Cohorts and Cognitive Reserve Influence Cognitive Performances in Older Adults
Abstract: Background: Evidence suggests birth cohort differences in cognitive performance of older adults. Proxies of cognitive reserve (CR), such as educational attainment and occupational complexity, could also partly account for these differences as they are influenced by the sociocultural environment of the birth cohorts. Objective: To predict cognitive performance using birth cohorts and CR and examine the moderating influence of CR on cognitive performance and structural brain health association. Methods: Using ADNI data (n=1628), four birth cohorts were defined (1915-1928; 1929-1938; 1939-1945; 1946-1964). CR proxies were education, occupational complexity, and verbal IQ. We predicted baseline cognitive performances (verbal episodic memory; language and semantic memory; attention capacities; executive functions) using multiple linear regressions with CR, birth cohorts, age, structural brain health (total brain volume; total white matter hyperintensities volume) and vascular risk factors burden as predictors. Sex and CR interactions were also explored. Results: Recent birth cohorts, higher CR, and healthier brain structures predicted better performance in verbal episodic memory, language and semantic memory, and attention capacities, with large effect sizes. Better performance in executive functions was predicted by a higher CR and a larger total brain volume, with a small effect size. With equal score of CR, women outperformed men in verbal episodic memory and language and semantic memory in all cohorts. Higher level of CR predicted better performance in verbal episodic memory, only when total brain volume was lower. Conclusion: Cohort differences in cognitive performance favor more recent birth cohorts and suggests that this association may be partly explained by proxies of CR.

Feifei Ge*, Lin Dong*, Donglin Zhu, Xingjian Lin, Jingping Shi, Ming Xiao *These authors contributed equally to this work.
Comparison of Serum Triiodothyronine with Biomarkers for Alzheimer’s Disease Continuum in Euthyroid Subjects
Abstract: Background: Accumulating studies have implicated thyroid dysfunction in the pathogenesis of Alzheimer's disease (AD). Objective: This study aimed to explore the association between thyroid hormone (TH) levels and cerebrospinal fluid (CSF) biomarkers for AD continuum among euthyroid subjects. Methods: In all, 93 clinically euthyroid subjects with a cognitive decline were included in this prospective cross-sectional study and were divided into groups with abnormal AD biomarkers (belonging to the “Alzheimer’s continuum”; A+ patients) and those with “normal AD biomarkers” or “non-AD pathological changes” (A− patients), according to the ATN research framework classification for AD. A partial correlation analysis of serum thyroid-stimulating hormone (TSH) or TH levels with CSF biomarkers was conducted. The predictor for A+ patients was analyzed via binary logistic regressions. Finally, the diagnostic significance of individual biochemical predictors for A+ patients was estimated via receiver operating characteristic curve analysis. Results: Serum total triiodothyronine (TT3) and free triiodothyronine (FT3) levels were found to affect the levels of CSF amyloid-β (Aβ)42 and the ratios of Aβ42/40. Further, FT3 was found to be a significant predictor for A+ via binary logistic regression modeling. Moreover, FT3 showed a high diagnostic value for A+ in euthyroid subjects. Conclusion: Even in a clinical euthyroid state, low serum FT3 and TT3 levels appear to be differentially associated with AD-specific CSF changes. These data indicate that serum FT3 is a strong candidate for differential diagnosis between AD continuum and non-AD dementia, which benefits the early diagnosis and effective management of preclinical and clinical AD patients.

Sarah Haoudy, Thérèse Jonveaux, Salomé Puisieux, Jonathan Epstein, Lucie Hopes, Louis Maillard, Olivier Aron, Louise Tyvaert (Handling Associate Editor: Mario Tombini)
Epilepsy in Early Onset Alzheimer’s Disease
Abstract: Background: Epilepsy seems to be an important comorbidity in patients with early onset Alzheimer’s disease (EOAD). Currently, seizures are still underestimated in this population. However, seizures may interact with AD evolution with possible acceleration of cognitive decline and early institutionalization. Objective: To better define the epileptic disorders observed in patients with EOAD. Methods: All patients diagnosed as EOAD in our hospital between 2013 and 2019 and with positive CSF biomarkers for AD were selected. The usual follow-up was extended with a 3-h EEG and a consultation with an epilepsy expert. Information on epilepsy and AD were collected and analyzed. Results: Among the 25 included patients, 10 (40%) were classified as epileptic. Considering the seizure types, patients presented tonic-clonic seizures (n=3), typical temporal seizures (n=3), myoclonus (n=3), focal extra-temporal seizures (n=1), and other seizure types (n=2). AD-E patients had a significant lower MMSE (15.3 ± 8.4 AD-E versus 22.1 ± 5.1 AD-NE, p=0.036) and a lower autonomy (IADL 4.1 ± 2.7 AD-E versus 6.4 ± 1.9 AD-NE, p=0.046) at AD diagnosis with comparable ages between AD-E and AD-NE. Epileptic patients seemed to present a faster cognitive decline compared to AD patients without seizures ([ΔMMSE per year 1.7 ± 1.3 AD-E versus 0.9 ± 1.4 AD-NE; p=0.09). All patients with severe cognitive impairment (MMSE ± 10) had an epileptic comorbidity. Conclusion: Epilepsy is a frequent comorbidity in EOAD patients, with a percentage of 40% in our study. This comorbidity may be associated with a severe form of EOAD. The role of epilepsy in the acceleration of cognitive decline and the positive impact of antiepileptic drugs on cognition need further research.

Kathryn N. Devlin, Laura Brennan, Laura Saad, Tania Giovannetti, Roy H. Hamilton, David A. Wolk, Sharon X. Xie, Dawn Mechanic-Hamilton (Handling Associate Editor: Ozioma Okonkwo)
Diagnosing Mild Cognitive Impairment Among Racially Diverse Older Adults: Comparison of Consensus, Actuarial, and Statistical Methods
Abstract: Background: Actuarial and statistical methods have been proposed as alternatives to conventional methods of diagnosing mild cognitive impairment (MCI), with the aim of enhancing diagnostic and prognostic validity, but have not been compared in racially diverse samples. Objective: We compared the agreement of consensus, actuarial, and statistical MCI diagnostic methods, and their relationship to race and prognostic indicators among diverse older adults. Methods: Participants (N = 354; M age = 71; 68% White, 29% Black) were diagnosed with MCI or normal cognition (NC) according to clinical consensus, actuarial neuropsychological criteria (Jak/Bondi), and latent class analysis (LCA). We examined associations with race/ethnicity, longitudinal cognitive and functional change, and incident dementia. Results: MCI rates by consensus, actuarial criteria, and LCA were 44%, 53%, and 41%, respectively. LCA identified three MCI subtypes (memory; memory/language; memory/executive) and two NC classes (low normal; high normal). Diagnostic agreement was substantial, but agreement of the actuarial method with consensus and LCA was weaker than the agreement between consensus and LCA. Among cases classified as MCI by actuarial criteria only, Black participants were over-represented, and outcomes were generally similar to those of NC participants. Consensus diagnoses best predicted longitudinal outcomes overall, whereas actuarial diagnoses best predicted longitudinal functional change among Black participants. Conclusion: Consensus diagnoses optimize specificity in predicting dementia, but among Black older adults, actuarial diagnoses may be more sensitive to early signs of decline. Results highlight the need for cross-cultural validity in MCI diagnosis and should be explored in community- and population-based samples.

Masoud Neshan, Seyed Kazem Malakouti, Leila Kamalzadeh, Mina Makvand, Arezoo Campbell, Ghasem Ahangari
Alterations in T-Cell Transcription Factors and Cytokine Gene Expression in Late-Onset Alzheimer’s Disease
Abstract: Background: Late-onset Alzheimer's disease (LOAD) is associated with many environmental and genetic factors. The effect of systemic inflammation on the pathogenesis of neurodegenerative diseases such as AD has been strongly suggested. T helper cells (Th) are one of the important components of the immune system and can easily infiltrate the brain in pathological conditions. The development of each Th-subset depends on the production of unique cytokines and their main regulator. Objective: This study aimed to compare the mRNA levels of Th-related genes derived from peripheral blood mononuclear cells of LOAD patients with control. Also, the identification of the most important Th1/Th2 genes and downstream pathways that may be involved in the pathogenesis of AD was followed by computational approaches. Methods: This study invloved 30 patients with LOAD and 30 non-demented controls. The relative expression of T-cell cytokines (IFN-γ, TNF-α, IL-4, and IL-5) and transcription factors (T-bet and GATA-3) were assessed using real-time PCR. Additionally, protein-protein interaction (PPI) was investigated by gene network construction. Results: A significant decrease at T-bet, IFN-γ, TNF-α, and GATA-3 mRNA levels was detected in the LOAD group, compared to the controls. However, there was no significant difference in IL-4 or IL-5 mRNA levels. Network analysis revealed a list of the highly connected protein (hubs) related to mitogen-activated protein kinase (MAPK) signaling and Th17 cell differentiation pathways. Conclusion: The findings point to a molecular dysregulation in Th-related genes, which can promising in the early diagnosis or targeted interventions of AD. Furthermore, the PPI analysis showed that upstream off-target stimulation may involve MAPK cascade activation and Th17 axis induction.

Norio Sugawara, Norio Yasui-Furukori, Kazushi Maruo, Kazutaka Shimoda, Tomiki Sumiyoshi
Psychological Distress in Caregivers for People with Dementia: A Population-Based Analysis of a National Cross-Sectional Study
Abstract: Background: Taking care of patients with dementia is often stressful and exhausting. The burden placed on caregivers (CGs) for care recipients with dementia (CRDs) has been reported to cause psychological distress. Objective: The aim of this study was to evaluate the psychological distress experienced by CGs for CRDs and identify the sociodemographic factors affecting that distress. Methods: We utilized the 2013 Comprehensive Survey of the Living Conditions for CRDs and CGs. Linked data from 643 pairs of CRDs and CGs were extracted. Serious psychological distress experienced by CGs was measured by Kessler’s Psychological Distress scale (K6) with a cutoff point of 13. Factors predictive of psychological distress were evaluated using multivariable logistic regression analysis with the forward selection method. Results: Overall, the mean age of the CGs was 63.5 ± 11.6 years, and 5.3% (34/643) experienced serious psychological distress. Male sex of CRDs, knowing how to access consulting services, spending almost all day for nursing care, and having subjective symptoms within a few days of completing the survey were associated with having serious psychological distress, while older age, participating in shopping as part of the nursing activities, and having their own house were related to freedom from serious psychological distress. Conclusion: Clinicians should be aware of the risk factors for psychological distress in CGs and consider providing support to reduce the distress imposed by modifiable factors. Further studies are warranted to examine whether such efforts would improve the mental health of CGs for CRDs.

Éimear M. Foley, Yorghos Tripodis, Eukyung Yhang, Inga K. Koerte, Brett M. Martin, Joseph Palmisano, Nikos Makris, Vivian Schultz, Chris Lepage, Marc Muehlmann, Paweł P. Wróbel, Jeffrey P. Guenette, Robert C. Cantu, Alexander P. Lin, Michael Coleman, Jesse Mez, Sylvain Bouix, Martha E. Shenton, Robert A. Stern, Michael L. Alosco
Quantifying and Examining Reserve in Symptomatic Former National Football League Players
Abstract: Background: Repetitive head impacts (RHI) from contact sports have been associated with cognitive and neuropsychiatric disorders. However, not all individuals exposed to RHI develop such disorders. This may be explained by the reserve hypothesis. It remains unclear if the reserve hypothesis accounts for the heterogenous symptom presentation in RHI-exposed individuals. Moreover, optimal measurement of reserve in this population is unclear and likely unique from non-athlete populations. Objective: We examined the association between metrics of reserve and cognitive and neuropsychiatric functioning in 89 symptomatic former National Football League players. Methods: Individual-level proxies (e.g., education) defined reserve. We additionally quantified reserve as remaining residual variance in 1) episodic memory and 2) executive functioning performance, after accounting for demographics and brain pathology. Associations between reserve metrics and cognitive and neuropsychiatric functioning were examined. Results: Higher reading ability was associated with better attention/information processing (β=0.25; 95%CI, -0.13-0.64), episodic memory (β=0.27; 95%CI, 0.16-0.38), semantic fluency (β=0.24; 95%CI, 0.01-0.47; β=0.38; 95%CI, -0.14-0.90), and behavioral regulation (β=-0.26; 95%CI, -0.78-0.27) performance. There were no effects for other individual-level proxies. Residual episodic memory variance was associated with better attention/information processing (β=0.45; 95%CI, -0.34-1.24), executive functioning (β=0.36; 95%CI, -3.14-3.86), and semantic fluency (β=0.38; 95%CI, -0.08-0.84) performance. Residual executive functioning variance was associated with better attention/information processing (β=0.44; 95%CI, 0.39-0.49) and episodic memory (β=0.37; 95%CI, 0.36-0.39) performance. Conclusion: Traditional reserve proxies (e.g., years of education, occupational attainment) have limitations and may be unsuitable for use in elite athlete samples. Alternative approaches of reserve quantification may prove more suitable for this population.

Natalia Altomari*, Francesco Bruno*, Valentina Laganà, Nicoletta Smirne, Rosanna Colao, Sabrina Curcio, Raffaele Di Lorenzo, Francesca Frangipane, Raffaele Maletta, Gianfranco Puccio, Amalia Cecilia Bruni *These authors contributed equally to this work.
A Comparison of Behavioral and Psychological Symptoms of Dementia (BPSD) and BPSD Sub-Syndromes in Early-Onset and Late-Onset Alzheimer’s Disease
Abstract: Background: Behavioral and psychological symptoms of dementia (BPSD) have a large impact on the quality of life of patients with Alzheimer’s disease (AD). Few studies have compared BPSD between early-onset (EOAD) and late-onset (LOAD) patients, finding conflicting results. Objective: The aims of this study were to: 1) characterize the presence, overall prevalence, and time of occurrence of BPSD in EOAD versus LOAD; 2) estimate the prevalence over time and severity of each BPSD in EOAD versus LOAD in three stages: pre-T0 (before the onset of the disease), T0 (from onset to 5 years), and T1 (from 5 years onwards); 3) track the manifestation of BPSD sub-syndromes (i.e., hyperactivity, psychosis, affective, and apathy) in EOAD versus LOAD at T0 and T1. Methods: The sample includes 1,538 LOAD and 387 EOAD diagnosed from 1996 to 2018. Comprehensive assessment batteries, including the Neuropsychiatric Inventory (NPI), were administered at the first medical assessment and at different follow-up period. Results: The overall prevalence for the most of BPSD was significantly higher in EOAD compared to LOAD whereas most BPSD appeared significantly later in EOAD patients. Between the two groups, from pre-T0 to T1 we recorded a different pattern of BPSD prevalence over time as well as for BPSD sub-syndromes at T0 and T1. Results on severity of BPSD did not show significant differences. Conclusion: EOAD and LOAD represent two different forms of a single entity not only from a neuropathological, cognitive, and functional level but also from a psychiatric point of view.

Jendé L. Zijlmans, Sander Lamballais, Meike W. Vernooij, M. Arfan Ikram, Annemarie I. Luik
Sociodemographic, Lifestyle, Physical, and Psychosocial Determinants of Cognitive Reserve
Abstract: Background: Cognitive reserve aims to explain individual differences in the susceptibility to the functional impact of dementia in the presence of equal amount of neuropathological damage. It is thought to be shaped by a combination of innate individual differences and lifetime exposures. Which determinants are associated with cognitive reserve remains unknown. Objective: The objective of this study was to investigate the associations of sociodemographic, lifestyle, physical, and psychosocial determinants with cognitive reserve, and potential sex differences. Methods: This cross-sectional study included 4,309 participants from the Rotterdam Study (mean age 63.9±10.7) between 2006-2016. Participants completed five cognitive tests and a brain MRI-scan. Cognitive reserve was defined as a latent variable that captures variance common across five cognitive tests, while adjusting for demographic and MRI-inferred neuropathological factors. The associations of potential determinants and cognitive reserve, adjusted for relevant confounders, were assessed with structural equation models. Results: Current smoking (adjusted mean difference: -0.31, 95% confidence interval -0.42; -0.19), diabetes mellitus (-0.25, -0.40; -0.10) and depressive symptoms (-0.07/SD, -0.12; -0.03) were associated with a lower cognitive reserve whereas alcohol use (0.07/SD, 0.03; 0.12) was associated with higher cognitive reserve. Only smoking was associated with cognitive reserve in both men and women. Employment, alcohol use, diabetes, history of cancer, COPD, and depressive symptoms were only associated with cognitive reserve in women. Conclusion: Our study found that current smoking, diabetes mellitus, and depressive symptoms were associated with a lower cognitive reserve, whereas more alcohol use was associated with a higher cognitive reserve, but with clear differences between men and women.

Kristel Metsla*, Sigrid Kirss*, Katrina Laks, Gertrud Sildnik, Mari Palgi, Teele Palumaa, Vello Tõugu, Peep Palumaa (Handling Associate Editor: Colin Masters) *These authors contributed equally to this work.
α-Lipoic Acid Has the Potential to Normalize Copper Metabolism, Which Is Dysregulated in Alzheimer’s Disease
Abstract: Background: Alzheimer’s disease (AD) is an age-dependent progressive neurodegenerative disorder and the most common cause of dementia. The treatment and prevention of AD present immense yet unmet needs. One of the hallmarks of AD is the formation of extracellular amyloid plaques in the brain, composed of amyloid-β (Aβ) peptides. Besides major amyloid-targeting approach there is the necessity to focus also on alternative therapeutic strategies. One factor contributing to the development of AD is dysregulated copper metabolism, reflected in the intracellular copper deficit and excess of extracellular copper. Objective: In the current study, we follow the widely accepted hypothesis that the normalization of copper metabolism leads to the prevention or slowing of the disease and search for new copper-regulating ligands. Methods: We used cell culture, ICP MS, and Drosophila melanogaster models of AD. Results: We demonstrate that the natural intracellular copper chelator, α-lipoic acid (LA) translocates copper from extracellular to intracellular space in an SH-SY5Y-based neuronal cell model and is thus suitable to alleviate the intracellular copper deficit characteristic of AD neurons. Furthermore, we show that supplementation with LA protects the Drosophila melanogaster models of AD from developing AD phenotype by improving locomotor activity of fruit fly with overexpression of human Aβ with Iowa mutation in the fly brain. In addition, LA slightly weakens copper-induced smooth eye phenotype when amyloid-β protein precursor (AβPP) and beta-site AβPP cleaving enzyme 1 (BACE1) are overexpressed in eye photoreceptor cells. Conclusion: Collectively, these results provide evidence that LA has the potential to normalize copper metabolism in AD.

Fang Wang, Jia Xu, Shu-jun Xu, Jie-jie Guo, Feiming Wang, Qin-wen Wang (Handling Associate Editor: Ling-Qiang Zhu)
Analysis and Identification Genetic Effect of SARS-CoV-2 Infections to Alzheimer’s Disease Patients by Integrated Bioinformatics
Abstract: Background: COVID-19 pandemic is a global crisis which results in millions of deaths and causes long-term neurological sequelae, such as Alzheimer’s disease (AD). Objective: We aimed to explore the interaction between COVID-19 and AD by integrating bioinformatics to find the biomarkers which lead to AD occurrence and development with COVID-19 and provide early intervention. Methods: The differential expressed genes (DEGs) were found by GSE147507 and GSE132903, respectively. The common genes between COVID-19 and AD were identified. Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG), and protein–protein interactions (PPI) network analysis were carried out. Hub genes were found by cytoscape. A multivariate logistic regression model was constructed. NetworkAnalyst was used for the analysis of TF-gene interactions, TF-miRNA coregulatory network, and Protein-chemical Interactions. Results: Forty common DEGs for AD and COVID-19 were found. GO and KEGG analysis indicated that the DEGs were enriched in the calcium signal pathway and other pathways. A PPI network was constructed, and 5 hub genes were identified (ITPR1, ITPR3, ITPKB, RAPGEF3, MFGE8). Four hub genes (ITPR1, ITPR3, ITPKB, RAPGEF3) which were considered as important factors in the development of AD that were affected by COVID-19 were shown by nomogram. Utilizing NetworkAnalyst, the interaction network of 4 hub genes and TF, miRNA, common AD risk genes, and known compounds is displayed, respectively. Conclusion: COVID-19 patients are at high risk of developing AD. Vaccination is required. Four hub genes can be considered as biomarkers for prediction and treatment of AD development caused by COVID-19. Compounds with neuroprotective effects can be used as adjuvant therapy for COVID-19 patients.

Ben Chen, Melanie Espin, Robert Haussmann, Claudia Matthes, Markus Donix, Thomas Hummel, Antje Haehner
The Effect of Olfactory Training on Olfaction, Cognition, and Brain Function in Patients with Mild Cognitive Impairment
Abstract: Background: The olfactory system is affected very early in Alzheimer’s disease and olfactory loss can already be observed in patients with mild cognitive impairment (MCI), an early stage of AD. Objective: The aim of this randomized, prospective, controlled, blinded study was to evaluate whether olfactory training (OT) may have an effect on olfactory function, cognitive impairment, and brain activation in MCI patients after a 4-month period of frequent short-term exposure to various odors. Methods: A total of 38 MCI outpatients were randomly assigned to OT or a control training condition, which were performed twice a day for 4 months. Olfactory testing, comprehensive neuropsychological assessment, and magnetic resonance imaging were performed before and after training. Results: The results suggested that OT exhibited no significant effect on olfaction and cognitive function. However, OT exhibited a positive effect on frontal lobe activation (left middle frontal gyrus and orbital-frontal cortex) but exhibited no effect on grey matter volume. Moreover, the change of olfactory scores was positively associated with the change of frontal activation. Conclusion: OT was found to have a limited effect on olfaction and cognition in patients with MCI compared to a non-OT condition but increased their functional response to odors in frontal area.

Annesha Sil, Arina Erfani, Nicola Lamb, Rachel Copland, Gernot Riedel, Bettina Platt (Handling Associate Editor: Oliver Wirths)
Sex Differences in Behavior and Molecular Pathology in the 5XFAD Model
Abstract: Background: The prevalence of Alzheimer’s disease (AD) is greater in women compared to men, but the reasons for this remain unknown. This sex difference has been widely neglected in experimental studies using transgenic mouse models of AD. Objective: Here, we studied behavior and molecular pathology of 5-month-old 5XFAD mice, which express mutated human amyloid precursor protein and presenilin-1 on a C57BL/6J background, versus their wild-type littermate controls, to compared both sex- and genotype-dependent differences. Methods: A novel behavioral paradigm was utilized (OF-NO-SI), comprising activity measures (Open Field, OF) arena, followed by Novel Object exploration (NO) and Social Interaction (SI) of a sex-matched conspecific. Each segment consisted of two repeated trials to assess between-trial habituation. Subsequently, brain pathology (amyloid load, stress response and inflammation markers, synaptic integrity, trophic support) was assessed using qPCR and western blotting. Results: Female 5XFAD mice had higher levels of human APP and amyloid-β and heightened inflammation versus males. These markers correlated with hyperactivity observed in both sexes, yet only female 5XFAD mice presented with deficits in object and social exploration. Male animals had higher expression of stress markers and neurotrophic factors irrespective of genotype, this correlated with cognitive performance. Conclusion: The impact of sex on AD-relevant phenotypes is in line with human data and emphasizes the necessity of appropriate study design and reporting. Differential molecular profiles observed in male versus female mice offer insights into possible protective mechanisms, and hence treatment strategies.

Haobin Zhou*, Zongyuan Zhu*, Changsong Liu, Yujia Bai, Qiong Zhan, Xingfu Huang, Qingchun Zeng, Hao Ren, Dingli Xu *These authors contributed equally to this work.
Effect of Hypertension Duration and Blood Pressure Control During Early Adulthood on Cognitive Function in Middle Age
Abstract: Background: Elevated blood pressure (BP) is a risk factor for cognitive impairment. Objective: We aim to explore the association between the duration of hypertension in early adulthood, with cognitive function in midlife. Furthermore, we investigate whether this asssociation is altered among participants with controlled BP. Methods: This prospective study included 2,718 adults aged 18-30 years without hypertension at baseline who participated in the Coronary Artery Risk Development in Young Adults (CARDIA) Study. Duration of hypertension was calculated based on repeat measurements of BP performed at 2, 5, 7, 10, 15, 20, and 25 years after baseline. Cognitive function was assessed at Year-25 using the Rey Auditory Verbal Learning Test (RAVLT), Digit Symbol Substitution Test (DSST), and Stroop test. Results: After multivariable adjustment, a longer hypertension duration was associated with worse verbal memory (RAVLT, p trend=0.002) but not with processing speed (DSST, p trend=0.112) and executive function (Stroop test, p trend=0.975). Among subgroups of participants with controlled (BP <140/90 mmHg) and uncontrolled (SBP ≥140 mmHg or DBP ≥90 mmHg) BP at the time of cognitive assessment (i.e., Year-25 BP), longer duration of hypertension was associated with worse verbal memory. Similar results were observed in subgroups with controlled and uncontrolled average BP prior to cognitive assessment. Conclusion: Longer duration of hypertension during early adulthood is associated with worse verbal memory in midlife regardless of current or long-term BP control status. The potential risk of hypertension associated cognitive decline should not be overlooked in individuals with a long duration of hypertension, even if BP levels are controlled.

Xianwen Shang, Edward Hill, Zhuoting Zhu, Jiahao Liu, Zongyuan Ge, Wei Wang, Mingguang He
Macronutrient Intake and Risk of Dementia in Community-Dwelling Older Adults: A Nine-Year Follow-Up Cohort Study
Abstract: Background: Little is known about the association between macronutrient intake and incident dementia. Objective: To identify an optimal range of macronutrient intake associated with reduced risk of dementia. Methods: Our analysis included 93,389 adults aged 60-75 years from the UK Biobank. Diet was assessed using a web-based 24-h recall questionnaire between 2009-2012. Dementia was ascertained using hospital inpatient, death records, and self-reported data up to January 2021. We calculated a macronutrient score based on associations between an individual’s macronutrient intake and incident dementia. Results: During a median follow-up of 8.7 years, 1,171 incident dementia cases were documented. We found U-shape relationships for carbohydrate, fat, and protein intake with incident dementia. Compared to individuals with optimal carbohydrate intake, those with high intake (HR (95% CI): 1.48(1.15-1.91)) but not low intake (1.19(0.89-1.57)) had a higher risk of dementia. In the multivariable analysis, a low-fat intake (HR (95% CI): 1.42(1.11-1.82)) was associated with a higher risk of all-cause dementia. After adjustment for covariates, a high (HR (95% CI): 1.41(1.09-1.83)) but not low protein intake (1.22(0.94-1.57)) was associated with an increased risk of dementia. Individuals in quintiles 3-5 of optimal macronutrient score had a lower risk of dementia compared with those in quintile 1 (HR (95% CI): 0.76(0.64-0.91) for quintile 3, 0.71(0.60-0.85) for quintile 4, 0.74(0.61-0.91) for quintile 5). The association between macronutrient score and incident dementia was significant across subgroups of age, gender, education, and smoking. Conclusion: Moderate intakes of carbohydrate, fat, and protein were associated with the lowest risk of incident dementia.

Nicole L. Spartano, Jayandra J. Himali, Ludovic Trinquart, Qiong Yang, Galit Weinstein, Claudia L. Satizabal, Kimberly A. Dukes, Alexa S. Beiser, Joanne M. Murabito, Ramachandran S. Vasan, Sudha Seshadri
Accelerometer-Measured, Habitual Physical Activity and Circulating Brain-Derived Neurotrophic Factor: A Cross-Sectional Study
Abstract: Background: One of the mechanisms suggested to link physical activity (PA) to favorable brain health is through stimulation of neural growth factors such as brain-derived neurotrophic factor (BDNF). Acute bouts of PA stimulate circulating BDNF levels. Objective: In this investigation, we assessed whether habitual, accelerometer-measured PA levels were related to circulating BDNF levels in a middle-aged cohort. Methods: In the Framingham Heart Study Third Generation cohort, 1,769 participants provided reliable accelerometry data and were not missing BDNF measurement and platelet counts. In a cross-sectional analysis, using multivariable regression, we related PA measures to serum BDNF levels, adjusting for age, sex, smoking status, platelet count, depression status, and accelerometer wear time. Results: Our study participants (mean age 47±9 years, 50.8% women) spent an average of 22.3 mins/day moderate-to-vigorous (MV)PA. Most PA variables (steps, MVPA, light activity, and sedentary time) were not related to BDNF levels (p>0.05). We observed a non-linear trend, where 15-50 mins/week vigorous activity was associated with lower BDNF compared to those with 0 min vigorous activity (β=-0.049 ± 0.024, p=0.05), but with no significant associations at lower or higher vigorous activity levels. In smokers, MVPA was also associated with lower BDNF levels (β=-0.216 ± 0.079, p=0.01). Conclusion: Our study reveals that circulating BDNF is not chronically elevated in individuals with higher levels of habitual PA in middle-aged adults from the community and may even be chronically suppressed with higher PA in subgroups, including current smokers. These results do not contradict previous studies demonstrating that circulating BDNF rises acutely after PA.

Sarah Gauci, Lauren M. Young, David J. White, Jeffery M. Reddan, Annie-Claude Lassemillante, Denny Meyer, Andrew Pipingas, Andrew Scholey
Diet May Moderate the Relationship Between Arterial Stiffness and Cognitive Performance in Older Adults
Abstract: Background: Cognitive decline is influenced by various factors including diet, cardiovascular disease, and glucose control. However, the combined effect of these risk factors on cognitive performance is yet to be fully understood. Objective: The current study aimed to explore the inter-relationship between these risk factors and cognitive performance in older adults at risk of future cognitive decline. Methods: The sample comprised 163 (Age: M=65.23 years, SD=6.50) participants. Food Frequency Questionnaire data was used to score diet quality and adherence to the Western Style Diet (WSD) and Prudent Style Diet (PSD). Glucose control was gauged by serum levels of glycated hemoglobin (HbA1c) and arterial stiffness was measured using carotid to femoral pulse wave velocity. Cognitive performance was assessed using two subtests of the Swinburne University Computerized Cognitive Assessment Battery (SUCCAB) and Rey’s Verbal Learning Test (RVLT). Results: Diet quality, adherence to the WSD or PSD, and glucose control were not significantly related to cognitive outcomes. However, a significant negative association was found between arterial stiffness and the spatial working memory subtest of SUCCAB (β= -0.21, p < 0.05). Arterial stiffness also significantly interacted with the PSD to impact total recall (F change (1,134) = 5.37, p < 0.05) and the composite score of RVLT (F change (1,134) = 4.03, p < 0.05). Conclusion: In this sample of older adults at risk of cognitive decline, diet alone was not found to predict cognitive performance; however, it was found to moderate the relationship between arterial stiffness and cognition.

Xi-Xi Liu, Peng-Fei Wu, Ying-Zi Liu, Ya-Ling Jiang, Mei-Dan Wan, Xue-Wen Xiao, Qi-Jie Yang, Bin Jiao, Xin-Xin Liao, Jun-Ling Wang, Shao-Hui Liu, Xuewei Zhang, Lu Shen (Handling Associate Editor: Gui-you Liu)
Association Between Serum Vitamins and the Risk of Alzheimer’s Disease in Chinese Population
Abstract: Background: Alzheimer’s disease (AD) is a chronic and fatal neurodegenerative disease; accumulating evidence suggests that vitamin deficiency is associated with the risk of AD. However, studies attempting to elucidate the relationship between vitamins and AD varied widely. Objective: This study aimed to investigate the relationship between serum vitamin levels and AD in a cohort of the Chinese population. Methods: A total of 368 AD patients and 574 healthy controls were recruited in this study; serum vitamin A, B1, B6, B9, B12, C, D, and E were measured in all participants. Results: Compared with the controls, vitamin B2, B9, B12, D, and E were significantly reduced in AD patients. Lower levels of vitamin B2, B9, B12, D, and E were associated with the risk of AD. After adjusting for age and gender, low levels of vitamin B2, B9, and B12 were still related to the risk of AD. In addition, a negative correlation was determined between vitamin E concentration and Activity of Daily Living Scale score while no significant association was found between serum vitamins and age at onset, disease duration, Mini-Mental State Examination, and Neuropsychiatric Inventory Questionnaire score. Conclusion: We conclude that lower vitamin B2, B9, B12, D, and E might be associated with the risk of AD, especially vitamin B2, B9, and B12. And lower vitamin E might be related to severe ability impairment of daily activities.

Boshra Khajehpiri, Hamid Abrishami Moghaddam, Mohamad Forouzanfar, Reza Lashgari, Jaime Ramos-Cejudo, Ricardo S. Osorio, Babak A. Ardekani; for the Alzheimer’s Disease Neuroimaging Initiative (Handling Associate Editor: Ali Ezzati)
Survival Analysis in Cognitively Normal Subjects and in Patients with Mild Cognitive Impairment Using a Proportional Hazards Model with Extreme Gradient Boosting Regression
Abstract: Background: Evaluating the risk of Alzheimer’s disease (AD) in cognitively normal (CN) and patients with mild cognitive impairment (MCI) is extremely important. While MCI-to-AD progression risk has been studied extensively, few studies estimate CN-to-MCI conversion risk. The Cox proportional hazards (PH), a widely used survival analysis model, assumes a linear predictor-risk relationship. Generalizing the PH model to more complex predictor-risk relationships may increase risk estimation accuracy. Objective: The aim of this study was to develop a PH model using an Xgboost regressor, based on demographic, genetic, neuropsychiatric, and neuroimaging predictors to estimate risk of AD in patients with MCI, and the risk of MCI in CN subjects. Methods: We replaced the Cox PH linear model with an Xgboost regressor to capture complex interactions between predictors, and non-linear predictor-risk associations. We endeavored to limit model inputs to noninvasive and more widely available predictors in order to facilitate future applicability in a wider setting. Results: In MCI-to-AD (n=882), the Xgboost model achieved a concordance index (C-index) of 84.5%. When the model was used for MCI risk prediction in CN (n=100) individuals, the C-index was 73.3%. In both applications, the C-index was statistically significantly higher in the Xgboost in comparison to the Cox PH model. Conclusion: Using non-linear regressors such as Xgboost improves AD dementia risk assessment in CN and MCI. It is possible to achieve reasonable risk stratification using predictors that are relatively low-cost in terms of time, invasiveness, and availability. Future strategies for improving AD dementia risk estimation are discussed.

Takeshi Kuroda, Motoyasu Honma, Yukiko Mori, Akinori Futamura, Azusa Sugimoto, Hideyo Kasai, Satoshi Yano, Sotaro Hieda, Kensaku Kasuga, Takeshi Ikeuchi, Kenjiro Ono (Handling Associate Editor: Kengo Uemura)
White Matter Lesions May Aid in Differentiating Idiopathic Normal Pressure Hydrocephalus and Alzheimer’s Disease
Abstract: Background: Idiopathic normal pressure hydrocephalus (iNPH) is often misdiagnosed as Alzheimer’s disease (AD) due to overlapping pathophysiology and similar imaging characteristics, including ventricular enlargement and increased white matter lesions (WMLs). Objective: To compare the extent and distribution of WMLs directly between iNPH and AD and examine the association with underlying pathophysiology. Methods: Twelve patients with iNPH (mean age: 78.08 years; 5 females), 20 with AD (mean age: 75.40 years; 13 females), and 10 normal cognition (NC) participants (mean age: 76.60 years; 7 females) were recruited. The extent and distribution of WMLs and the lateral ventricular volume (LV-V) were evaluated on MRI using voxel-based morphometry analysis. Concentrations of cerebrospinal fluid biomarkers, such as amyloid-β protein (Aβ)42, Aβ40, Aβ38, and tau species, were also measured. Risk factors for small vessel disease (SVD) were assessed by blood examination and medical records. Results: The periventricular WML volume (PWML-V) and deep WML volume (DWML-V) were significantly larger in iNPH than in AD and NC. The DWML-V was dominant in iNPH, while the PWML-V was dominant in AD and NC. GM-V was significantly smaller in AD than in iNPH and NC. The LV-V positively correlated with WML-V in all participants. There was a significant negative correlation between LV-V and Aβ38 in iNPH. Furthermore, there was no significant difference in SVD risk factors between the groups. Conclusion: The differences in the extent and distribution of WMLs between iNPH and AD, especially predominance of DWML-V over PWML-V in iNPH, may reflect decreased fluid and Aβ clearance.

Jian Bao*, Zheng Liang*, Xiaokang Gong, Jing Yu, Yifan Xiao, Wei Liu, Xiaochuan Wang, Jian-Zhi Wang, Xiji Shu (Handling Associate Editor: Jinhua Gu) *These authors contributed equally to this work.
High Fat Diet Mediates Amyloid-β Cleaving Enzyme 1 Phosphorylation and SUMOylation, Enhancing Cognitive Impairment in APP/PS1 Mice
Abstract: Background: Alzheimer’s disease (AD) is the most common form of dementia in older adults and extracellular accumulation of amyloid-β (Aβ) is one of the two characterized pathologies of AD. Obesity is significantly associated with AD developing factors. Several studies have reported that high fat diet (HFD) influenced Aβ accumulation and cognitive performance during AD pathology. However, the underlying neurobiological mechanisms have not yet been elucidated. Objective: The objective of this study was to explore the underlying neurobiological mechanisms of HFD influenced Aβ accumulation and cognitive performance during AD pathology. Methods: 2.5-month-old male APP/PS1 mice were randomly separated into two groups: 1) the normal diet (ND) group, fed a standard diet (10 kcal% fat); and 2) the HFD group, fed a high fat diet (40 kcal% fat, D12492; Research Diets). After 4 months of HFD or ND feeding, mice in the two groups were subjected for further ethological, morphological, and biochemical analyses. Results: A long-term HFD diet significantly increased perirenal fat and impaired dendritic integrity and aggravated neurodegeneration, and augmented learning and memory deficits in APP/PS1 mice. Furthermore, the HFD increased beta amyloid cleaving enzyme 1 (BACE1) dephosphorylation and SUMOylation, resulting in enhanced enzyme activity and stability, which exacerbated the deposition of amyloid plaques. Conclusion: Our study demonstrates that long-term HFD consumption aggravates amyloid-β accumulation and cognitive impairments, and that modifiable lifestyle factors, such as obesity, can induce BACE1 post-modifications which may contribute to AD pathogenesis.

Xiao-Xue Zhang, Ya-Hui Ma, He-Ying Hu, Ling-Zhi Ma, Lan Tan, Jin-Tai Yu
Late-Life Obesity Associated with Tau Pathology in Cognitively Normal Individuals: The CABLE Study
Abstract: Background: Existed evidence suggests that midlife obesity increases the risk of Alzheimer’s disease (AD), while there is an inverse association between AD and obesity in late life. However, the underlying metabolic changes of AD pathological proteins attributed to obesity in two life stages were not clear. Objective: To investigate the associations of obesity types and obesity indices with AD biomarkers in cerebrospinal fluid (CSF) in different life stages. Methods: We recruited 1,051 cognitively normal individuals (61.94 ± 10.29 years, 59.66% male) from the Chinese Alzheimer’s Biomarker and LifestylE (CABLE) study with CSF detections for amyloid-β 42 (Aβ42), total-tau (T-tau), and phosphorylated tau (P-tau). We utilized body mass index, waist circumference, waist-to-height ratio, and metabolic risk factors to determine human obesity types. Multiple linear models and interaction analyses were run to assess the impacts of obesity on AD biomarkers. Results: The metabolically unhealthy obesity or healthy obesity might exert a reduced tau pathology burden (p < 0.05). Individuals with overweight, general obesity, and central obesity presented lower levels of tau-related proteins in CSF than normal controls (p < 0.05). Specially, for late-life individuals, higher levels of obesity indices were associated with a lower load of tau pathology as measured by CSF T-tau and T-tau/Aβ42 (p < 0.05). No similar significant associations were observed in midlife. Conclusion: Collectively, late-life general and central obesity seems to be associated with the reduced load of tau pathology, which further consolidates the favorable influence of obesity in specific life courses for AD prevention.

Alireza G. Senejani, Jasmin Maghsoudlou, Dina El-Zohiry, Gauri Gaur, Keith Wawrzeniak, Cristina Caravaglia, Vishwa A. Khatri, Alan MacDonald, Eva Sapi
Borrelia burgdorferi Co-Localizing with Amyloid Markers in Alzheimer’s Disease Brain Tissues
Abstract: Background: Infections by bacterial or viral agents have been hypothesized to influence the etiology of neurodegenerative diseases. Objective: This study examined the potential presence of Borrelia burgdorferi spirochete, the causative agent of Lyme disease, in brain autopsy tissue of patients diagnosed with either Alzheimer’s (AD) or Parkinson’s diseases. Methods: Brain tissue sections from patients with age-matched controls were evaluated for antigen and DNA presence of B. burgdorferi using various methods. Positive Borrelia structures were evaluated for co-localization with biofilm and AD markers such as amyloid and phospho-tau (p-Tau) using immunohistochemical methods. Results: The results showed the presence of B. burgdorferi antigen and DNA in patients with AD pathology and among those, one of them was previously diagnosed with Lyme disease. Interestingly, a significant number of Borrelia-positive aggregates with a known biofilm marker, alginate, were found along with the spirochetal structures. Our immunohistochemical data also showed that Borrelia-positive aggregates co-localized with amyloid and anti-phospho-tau markers. To further prove the potential relationship of B. burgdorferi and amyloids, we infected two mammalian cell lines with B. burgdorferi which resulted in a significant increase in the expression of amyloid-β and p-Tau proteins in both cells lines post-infection. Conclusion: These results indicate that B. burgdorferi can be found in AD brain tissues, not just in spirochete but a known antibiotics resistant biofilm form, and its co-localized amyloid markers. In summary, this study provides evidence for a likely association between B. burgdorferi infections and biofilm formation, AD pathology, and chronic neurodegenerative diseases.

Satya V.V.N. Kothapalli, Tammie L. Benzinger, Andrew J. Aschenbrenner, Richard J. Perrin, Charles F. Hildebolt, Manu S. Goyal, Anne M. Fagan, Marcus E. Raichle, John C. Morris, Dmitriy A. Yablonskiy (Handling Associate Editor: Caroline Dallaire-Théroux)
Quantitative Gradient Echo MRI Identifies Dark Matter as a New Imaging Biomarker of Neurodegeneration that Precedes Tissue Atrophy in Early Alzheimer’s Disease
Abstract: Background: Currently, brain tissue atrophy serves as an in vivo MRI biomarker of neurodegeneration in Alzheimer’s disease (AD). However, postmortem histopathological studies show that neuronal loss in AD exceeds volumetric loss of tissue and that loss of memory in AD begins when neurons and synapses are lost. Therefore, in vivo detection of neuronal loss prior to detectable atrophy in MRI is essential for early AD diagnosis. Objective: To apply a recently developed quantitative Gradient Recalled Echo (qGRE) MRI technique for in vivo evaluation of neuronal loss in human hippocampus. Methods: Seventy participants were recruited from the Knight Alzheimer Disease Research Center, representing three groups: Healthy controls [Clinical Dementia Rating® (CDR®)=0, amyloid β (Aβ)-negative), n=34]; Preclinical AD (CDR=0, Aβ-positive, n=19); and mild AD (CDR=0.5 or 1, Aβ-positive, n=17). Results: In hippocampal tissue, qGRE identified two types of regions: one, practically devoid of neurons, we designate as “Dark Matter”, and the other, with relatively preserved neurons, “Viable Tissue”. Data showed a greater loss of neurons than defined by atrophy in the mild AD group compared with the healthy control group; neuronal loss ranged between 31% and 43%, while volume loss ranged only between 10% and 19%. The concept of Dark Matter was confirmed with histopathological study of one participant who underwent in vivo qGRE 14 months prior to expiration. Conclusion: In vivo qGRE method identifies neuronal loss that is associated with impaired AD-related cognition but is not recognized by MRI measurements of tissue atrophy, therefore providing new biomarkers for early AD detection.

Linda Clare, Anthony Martyr, Laura D. Gamble, Claire Pentecost, Rachel Collins, Eleanor Dawson, Anna Hunt, Sophie Parker, Louise Allan, Alistair Burns, Alexandra Hillman, Rachael Litherland, Catherine Quinn, Fiona E. Matthews, Christina Victor (Handling Associate Editor: Andrea Tales)
Impact of COVID-19 on ‘Living Well’ with Mild-to-Moderate Dementia in the Community: Findings from the IDEAL Cohort
Abstract: Background: Negative impacts of the COVID-19 pandemic on people with dementia have been widely-documented, but most studies have relied on carer reports and few have compared responses to information collected before the pandemic. Objective: We aimed to explore the impact of the pandemic on community-dwelling individuals with mild-to-moderate dementia and compare responses with pre-pandemic data. Methods: During the second wave of the pandemic, we conducted structured telephone interviews with 173 people with dementia and 242 carers acting as informants, all of whom had previously participated in the IDEAL cohort. Where possible, we benchmarked responses against pre-pandemic data. Results: Significant perceived negative impacts were identified in cognitive and functional skills and ability to engage in self-care and manage everyday activities, along with increased levels of loneliness and discontinuity in sense of self and a decline in perceived capability to ‘live well’. Compared to pre-pandemic data, there were lower levels of pain, depression, and anxiety, higher levels of optimism, and better satisfaction with family support. There was little impact on physical health, mood, social connections and relationships, or perceptions of neighborhood characteristics. Conclusion: Efforts to mitigate negative impacts of pandemic-related restrictions and restore quality of life could focus on reablement to address the effects on participation in everyday activities, creating opportunities for social contact to reduce loneliness, and personalized planning to reconnect people with their pre-COVID selves. Such efforts may build on the resilience demonstrated by people with dementia and carers in coping with the pandemic.