Volume 92, Number 1, 2023

Pages 1-12

Hans J. Moebius, Kevin J. Church
The Case for a Novel Therapeutic Approach to Dementia: Small Molecule Hepatocyte Growth Factor (HGF/MET) Positive Modulators
Abstract: An estimated 6.5 million Americans aged 65 years or older have Alzheimer’s disease (AD), which will grow to 13.8 million Americans by 2060. Despite the growing burden of dementia, no fundamental change in drug development for AD has been seen in >20 years. Currently approved drugs for AD produce only modest symptomatic improvements in cognition with small effect sizes. A growing mismatch exists between the urgent need to develop effective drugs for symptomatic AD and the largely failed search for disease modification. The failure rate of clinical trials in AD is high overall, and in particular for disease-modifying therapies. Research efforts in AD have focused predominantly on amyloid-β and tau pathologies, but limiting clinical research to these “classical hallmarks” of the disease does not address the most urgent patient, caregiver, or societal needs. Rather, clinical research should consider the complex pathophysiology of AD. Innovative approaches are needed that provide outside-the-box thinking, and re-imagine trial design, interventions, and outcomes as well as progress in proteomics and fluid biomarker analytics for both diagnostics and disease monitoring. A new approach offering a highly specific, yet multi-pronged intervention that exerts positive modulation on the HGF/MET neurotrophic system is currently being tested in mid-to-late-stage clinical trials in mild to moderate AD. Findings from such trials may provide data to support novel approaches for development of innovative drugs for treating AD at various disease stages and may offer benefits for those already symptomatic and disease alteration in AD and other neurodegenerative diseases.

Pages 13-27

Niyatee Samudra, Kamalini Ranasinghe, Heidi Kirsch, Katherine Rankin, Bruce Miller
Etiology and Clinical Significance of Network Hyperexcitability in Alzheimer’s Disease: Unanswered Questions and Next Steps
Abstract: Cortical network hyperexcitability related to synaptic dysfunction in Alzheimer’s disease (AD) is a potential target for therapeutic intervention. In recent years, there has been increased interest in the prevalence of silent seizures and interictal epileptiform discharges (IEDs, or seizure tendency), with both entities collectively termed “subclinical epileptiform activity” (SEA), on neurophysiologic studies in AD patients. SEA has been demonstrated to be common in AD, with prevalence estimates ranging between 22-54%. Converging lines of basic and clinical evidence imply that modifying a hyperexcitable state results in an improvement in cognition. In particular, though these results require further confirmation, post-hoc findings from a recent phase II clinical trial suggest a therapeutic effect with levetiracetam administration in patients with AD and IEDs. Here, we review key unanswered questions as well as potential clinical trial avenues. Specifically, we discuss postulated mechanisms and treatment of hyperexcitability in patients with AD, which are of interest in designing future disease-modifying therapies. Criteria to prompt screening and optimal screening methodology for hyperexcitability have yet to be defined, as does timing and personalization of therapeutic intervention.

Pages 29-57

Zhen Huang
A Function of Amyloid-β in Mediating Activity-Dependent Axon/Synapse Competition May Unify Its Roles in Brain Physiology and Pathology
Abstract: Amyloid-β protein precursor (AβPP) gives rise to amyloid-β (Aβ), a peptide at the center of Alzheimer’s disease (AD). AβPP, however, is also an ancient molecule dating back in evolution to some of the earliest forms of metazoans. This suggests a possible ancestral function that may have been obscured by those that evolve later. Based on literature from the functions of Aβ/AβPP in nervous system development, plasticity, and disease, to those of anti-microbial peptides (AMPs) in bacterial competition as well as mechanisms of cell competition uncovered first by Drosophila genetics, I propose that Aβ/AβPP may be part of an ancient mechanism employed in cell competition, which is subsequently co-opted during evolution for the regulation of activity-dependent neural circuit development and plasticity. This hypothesis is supported by foremost the high similarities of Aβ to AMPs, both of which possess unique, opposite (i.e., trophic versus toxic) activities as monomers and oligomers. A large body of data further suggests that the different Aβ oligomeric isoforms may serve as the protective and punishment signals long predicted to mediate activity-dependent axonal/synaptic competition in the developing nervous system and that the imbalance in their opposite regulation of innate immune and glial cells in the brain may ultimately underpin AD pathogenesis. This hypothesis can not only explain the diverse roles observed of Aβ and AβPP family molecules, but also provide a conceptual framework that can unify current hypotheses on AD. Furthermore, it may explain major clinical observations not accounted for and identify approaches for overcoming shortfalls in AD animal modeling.

Pages 59-70
Systematic Review

Getu Gamo Sagaro, Enea Traini, Francesco Amenta
Activity of Choline Alphoscerate on Adult-Onset Cognitive Dysfunctions: A Systematic Review and Meta-Analysis
Abstract: Background: Choline alphoscerate (alpha glyceryl phosphorylcholine, α-GPC) is a choline-containing phospholipid used as a medicine or nutraceutical to improve cognitive function impairment occurring in neurological conditions including adult-onset dementia disorders. Despite its 1985 marketing authorization, there are still discrepancies between countries regarding its approval as a prescription medicine and discussions about its effectiveness. Objective: This study aimed to evaluate the efficacy of the α-GPC compound for treating cognitive impairment in patients with adult-onset neurological disorders. Methods: Relevant studies were identified by searching PubMed, Web of Science, and Embase. Studies that evaluated the effects of α-GPC alone or in combination with other compounds on adult-onset cognitive impairment reporting cognition, function, and behavior were considered. We assessed the risk of bias of selected studies using the Cochrane risk of bias tool. Results: A total of 1,326 studies and 300 full-text articles were screened. We included seven randomized controlled trials (RCTs) and one prospective cohort study that met our eligibility criteria. We found significant effects of α-GPC in combination with donepezil on cognition [4 RCTs, mean difference (MD):1.72, 95% confidence interval (CI): 0.20 to 3.25], functional outcomes [3 RCTs, MD:0.79, 95% CI: 0.34 to 1.23], and behavioral outcomes [4 RCTs; MD: -7.61, 95% CI:-10.31 to -4.91]. We also observed that patients who received α-GPC had significantly better cognition than those who received either placebo or other medications [MD:3.50, 95% CI:0.36 to 6.63]. Conclusion: α-GPC alone or in combination with donepezil improved cognition, behavior, and functional outcomes among patients with neurological conditions associated with cerebrovascular injury.

Pages 71-79
Tamara Chithiramohan, Grace Threlfall, Hanin Abdelaziz, Amira Ellahi, Hari Subramaniam, Lucy Beishon, Elizabeta B. Mukaetova-Ladinska
Ethnic Variations in Patient Outcomes in a Memory Clinic Setting Between 2013 and 2021
Abstract: Background: The incidence of dementia in Black and Asian populations in the UK is set to rise. There is concern surrounding differences in services provided for different ethnic groups. Objective: This study aimed to examine ethnic variations in survival, services accessed, and medication use across White, Black, and Asian groups in routine memory clinic setting. Methods: We retrospectively examined referrals to a memory service between 2013 and 2021. A random sample of 104 White, 99 Asian, and 74 Black patients were analyzed for differences in support services, voluntary services, medication use, and survival rate. Results: There were statistically significant differences in survival of the Asian compared to the White group (Hazard ratio (HR=2.17,95% confidence interval (CI) 1.23-3.85, p=0.008)) following adjustment for age, gender, diagnosis, cognitive impairment, severity, access to support and voluntary services, and use of cholinesterase inhibitors, N-methyl-D-aspartate antagonists, and antipsychotics. The Asian group showed a statistically significantly reduction in access to support services compared to the White group (HR=0.05, 95% CI 0.01-0.37, p=0.003). In contrast, the survival rate was similar between the White and Black dementia patients. Conclusion: We found significantly reduced survival and reduced access to support services in Asian compared to White patients with dementia. Further research is needed to investigate the generalizability of our results, and determine the cause, and consequent remedies of these associations in ethnic minority groups.

Pages 81-93
Ke Wan*, Wenwen Yin*, Yating Tang, Wenhao Zhu, Zhiqiang Wang, Xia Zhou, Wei Zhang, Cun Zhang, Xianfeng Yu, Wenming Zhao, Chenchen Li, Xiaoqun Zhu, Zhongwu Sun *These authors contributed equally to this work.
Brain Gray Matter Volume Mediated the Correlation Between Plasma P-Tau and Cognitive Function of Early Alzheimer’s Disease in China: A Cross-Sectional Observational Study
Abstract: Background: The primary manifestations of Alzheimer’s disease (AD) include cognitive decline and brain gray matter volume (GMV) atrophy. Recent studies have found that plasma phosphorylated-tau (p-tau) concentrations perform better in diagnosing, differentiating, and monitoring the progression of AD. However, the correlation between plasma p-tau, GMV, and cognition remains unclear. Objective: To investigate whether GMV plays a mediating role in the association between plasma p-tau concentrations and cognition. Methods: In total, 99 participants (47 patients with AD and 52 cognitively unimpaired [CU] individuals) were included. All participants underwent neuropsychological assessments, laboratory examinations, and magnetic resonance imaging scans. Plasma p-tau217 and p-tau181 concentrations were measured using an enzyme-linked immunosorbent assay kit. Voxel-based morphometry was performed to assess participants’ brain GMV. Partial correlation and mediation analyses were conducted in AD group. Results: Plasma p-tau concentrations were significantly higher in the AD group than in the CU group. Patients with AD had significant brain GMV atrophy in the right hippocampus, bilateral middle temporal gyrus, and right inferior temporal gyrus. In the AD group, there were significant correlations between plasma p-tau217 concentrations, GMV, and Mini-Mental State Examination (MMSE) scores. Brain GMV of the right hippocampus mediated the association between plasma p-tau217 concentrations and MMSE scores. A significant correlation between plasma p-tau181 and MMSE scores was not identified. Conclusion: The findings indicate that p-tau217 is a promising biomarker for central processes affecting brain GMV and cognitive function. This may provide potential targets for future intervention and treatment of tau-targeting therapies in the early stages of AD.

Pages 95-107
Charisse N. Winston, Oliver Langford, Natalie Levin, Rema Raman, Kevin Yarasheski, Tim West, Sara Abdel-Latif, Michael Donohue, Akinori Nakamura, Kenji Toba, Colin L. Masters, James Doecke, Reisa A. Sperling, Paul S. Aisen, Robert A. Rissman (Handling Associate Editor: David Libon)
Evaluation of Blood-Based Plasma Biomarkers as Potential Markers of Amyloid Burden in Preclinical Alzheimer’s Disease
Abstract: Background: Participant eligibility for the A4 Study was determined by amyloid PET imaging. Given the disadvantages of amyloid PET imaging in accessibility and cost, blood-based biomarkers may serve as a sufficient biomarker and more cost-effective screening tool for patient enrollment into preclinical AD trials. Objective: To determine if a blood-based screening test can adequately identify amyloid burden in participants screened into a preclinical AD trial. Methods: In this cross-sectional study, 224 participants from the A4 Study received an amyloid PET scan (18Florbetapir) within 90 days of blood sample collection. Blood samples from all study participants were processed within 2 h after phlebotomy. Plasma amyloid measures were quantified by Shimazdu and C2N Diagnostics using mass spectrometry-based platforms. A corresponding subset of blood samples (n=100) was processed within 24 h after phlebotomy and analyzed by C2N. Results: Plasma Aβ42/Aβ40 demonstrated the highest association for Aβ accumulation in the brain with an AUC 0.76 (95% CI = 0.69, 0.82) at C2N and 0.80 (95% CI = 0.75, 0.86) at Shimadzu. Blood samples processed to plasma within 2 h after phlebotomy provided a better prediction of amyloid PET status than blood samples processed within 24 h (AUC 0.80 versus 0.64; p <0.001). Age, sex, and APOE ε4 carrier status did not the diagnostic performance of plasma Aβ42/Aβ40 to predict amyloid PET positivity in A4 Study participants. Conclusion: Plasma Aβ42/Aβ40 may serve as a potential biomarker for predicting elevated amyloid in the brain. Utilizing blood testing over PET imaging may improve screening efficiency into clinical trials.

Pages 109-128
Anthony N. Correro II, Kathryn Gauthreaux, Jaime Perales-Puchalt, Yen-Chi Chen, Kwun C.G. Chan, Walter A. Kukull, Jason D. Flatt (Handling Associate Editor: Katherine Gifford)
Cognitive Aging with Dementia, Mild Cognitive Impairment, or No Impairment: A Comparison of Same- and Mixed-Sex Couples
Abstract: Background: Lesbian and gay older adults have health disparities that are risk factors for Alzheimer’s disease, yet little is known about the neurocognitive aging of sexual minority groups. Objective: To explore cross-sectional and longitudinal dementia outcomes for adults in same-sex relationships (SSR) and those in mixed-sex relationships (MSR). Methods: This prospective observational study utilized data from the National Alzheimer’s Coordinating Center Uniform Data Set (NACC UDS) collected from contributing Alzheimer’s Disease Research Centers. Participants were adults aged 55+ years at baseline with at least two visits in NACC UDS (from September 2005 to March 2021) who had a spouse, partner, or companion as a co-participant. Outcome measures included CDR® Dementia Staging Instrument, NACC UDS neuropsychological testing, and the Functional Activities Questionnaire. Multivariable linear mixed-effects models accounted for center clustering and repeated measures by individual. Results: Both MSR and SSR groups experienced cognitive decline regardless of baseline diagnosis. In general, MSR and SSR groups did not differ statistically on cross-sectional or longitudinal estimates of functioning, dementia severity, or neuropsychological testing, with two primary exceptions. People in SSR with mild cognitive impairment showed less functional impairment at baseline (FAQ M = 2.61, SD = 3.18 vs. M = 3.97, SD = 4.53, respectively; p < 0.01). The SSR group with dementia had less steep decline in attention/working memory (β estimates = -0.10 versus -0.18; p < 0.01). Conclusion: Participants in SSR did not show cognitive health disparities consistent with a minority stress model. Additional research into protective factors is warranted.

Pages 129-139
Haitham Salem*, Robert Suchting*, Mitzi M. Gonzales, Sudha Seshadri, Antonio L. Teixeira *These authors contributed equally to this work.
Apathy as a Predictor of Conversion from Mild Cognitive Impairment to Alzheimer’s Disease: A Texas Alzheimer’s Research and Care Consortium (TARCC) Cohort-Based Analysis
Abstract: Background: Apathy is among the neuropsychiatric symptoms frequently observed in people with cognitive impairment. It has been postulated to be a potential predictor of conversion from mild cognitive impairment (MCI) to Alzheimer’s disease (AD). Objective: To detect conversion rates from MCI to AD, and to determine the effect of apathy on the progression to AD in patients with MCI enrolled in the Texas Alzheimer’s Research and Care Consortium (TARCC) cohort. Methods: Apathy was determined by a positive response to the respective item in the Neuropsychiatric Inventory – Questionnaire (NPI-Q) completed by family members or caregivers. The final dataset included 2,897 observations from 1,092 individuals with MCI at the baseline. Kaplan-Meier survival curves were estimated to provide indices of the probability of conversion to AD over time across all individuals as well as between those with and without apathy. Cox proportional hazards regression measured the hazard associated with apathy and several other predictors of interest. Results: Over a period of 8.21 years, 17.3% of individuals had conversion from MCI to AD (n = 190 of 1,092 total individuals) across observations. The median time-to-conversion across all participants was 6.41 years. Comparing individuals with apathy (n=158) versus without apathy (n=934), 36.1% and 14.2% had conversion to AD, respectively. The median time-to-conversion was 3.79 years for individuals with apathy and 6.83 years for individuals without apathy. Cox proportional hazards regression found significant effects of several predictors, including apathy, on time-to-conversion. Age and cognitive performance were found to moderate the relationship between apathy and time-to-conversion. Conclusions: Apathy is associated with progression from MCI to AD, suggesting that it might improve risk prediction and aid targeted intervention delivery.

Pages 141-151
Hannes Devos, Kathleen Gustafson, Ke Liao, Pedram Ahmadnezhad, Emily Kuhlmann, Bradley J. Estes, Laura E. Martin, Jonathan D. Mahnken, William M. Brooks, Jeffrey M. Burns
Effect of Cognitive Reserve on Physiological Measures of Cognitive Workload in Older Adults with Cognitive Impairments
Abstract: Background: Cognitive reserve may protect against cognitive decline. Objective: This cross-sectional study investigated the association between cognitive reserve and physiological measures of cognitive workload in older adults with cognitive impairment. Methods: 29 older adults with cognitive impairment (age: 75±6, 11 (38%) women, MoCA: 20±7) and 19 with normal cognition (age: 74±6; 11 (58%) women; MoCA: 28±2) completed a working memory test of increasing task demand (0-, 1-, 2-back). Cognitive workload was indexed using amplitude and latency of the P3 event-related potential (ERP) at electrode sites Fz, Cz, and Pz, and changes in pupillary size, converted to an index of cognitive activity (ICA). The Cognitive Reserve Index questionnaire (CRIq) evaluated Education, Work Activity, and Leisure Time as a proxy of cognitive reserve. Linear mixed models evaluated the main effects of cognitive status, CRIq, and the interaction effect of CRIq by cognitive status on ERP and ICA. Results: The interaction effect of CRIq total score by cognitive status on P3 ERP and ICA was not significant. However, higher CRIq total scores were associated with lower ICA (p = 0.03). The interaction effects of CRIq subscores showed that Work Activity affected P3 amplitude (p = 0.03) and ICA (p = 0.03) differently between older adults with and without cognitive impairments. Similarly, Education affected ICA (p = 0.02) differently between the two groups. No associations were observed between CRIq and P3 latency. Conclusion: Specific components of cognitive reserve affect cognitive workload and neural efficiency differently in older adults with and without cognitive impairments.

Pages 153-169
Sandra Baez, Catalina Trujillo-Llano, Leonardo Cruz de Souza, Patricia Lillo, Gonzalo Forno, Hernando Santamaría-García, Cecilia Okuma, Patricio Alegria, David Huepe, Agustín Ibáñez, Jean Decety, Andrea Slachevsky
Moral Emotions and Their Brain Structural Correlates Across Neurodegenerative Disorders
Abstract: Background: Although social cognition is compromised in patients with neurodegenerative disorders such as behavioral variant frontotemporal dementia (bvFTD) and Alzheimer’s disease (AD), research on moral emotions and their neural correlates in these populations is scarce. No previous study has explored the utility of moral emotions, compared to and in combination with classical general cognitive state tools, to discriminate bvFTD from AD patients. Objective: To examine self-conscious (guilt and embarrassment) and other-oriented (pity and indignation) moral emotions, their subjective experience, and their structural brain underpinnings in bvFTD (n =31) and AD (n =30) patients, compared to healthy controls (n = 37). We also explored the potential utility of moral emotions measures to discriminate bvFTD from AD. Methods: We used a modified version of the Moral Sentiment Task measuring the participants’ accuracy scores and their emotional subjective experiences. Results: bvFTD patients exhibited greater impairments in self-conscious and other-oriented moral emotions as compared with AD patients and healthy controls. Moral emotions combined with general cognitive state tools emerged as useful measures to discriminate bvFTD from AD patients. In bvFTD patients, lower moral emotions scores were associated with lower gray matter volumes in caudate nucleus and inferior and middle temporal gyri. In AD, these scores were associated with lower gray matter volumes in superior and middle frontal gyri, middle temporal gyrus, inferior parietal lobule and supramarginal gyrus. Conclusion: These findings contribute to a better understanding of moral emotion deficits across neurodegenerative disorders, highlighting the potential benefits of integrating this domain into the clinical assessment.

Pages 171-181
Fei He*, Huizi Luo*, Li Yin, Ann Roosaar, Tony Axéll, Hongwei Zhao, Weimin Ye *These authors contributed equally to this work.
Poor Oral Health as a Risk Factor for Dementia in a Swedish Population: A Cohort Study with 40 Years of Follow-Up
Abstract: Background: Whether poor oral health is associated with dementia risk remains unclear. Objective: We conducted a cohort study of 14,439 participants who were followed up for up to 40 years in Uppsala County, central Sweden, aiming to explore the association between poor oral health, namely the number of tooth loss, dental plaque status, and oral mucosal lesions, and the risk of dementia. Methods: We used Cox proportional hazards regression model to derive cause-specific hazard ratios (HR) and corresponding 95% confidence intervals (CI), while adjusting for baseline potential confounders as well as a time-varying covariate, Charlson’s Comorbidity Index score. Results: Dementia risk was substantially higher among those with a higher number of tooth loss; compared to the group with tooth loss 0-10, the HRs were 1.21 (95% CI: 1.02, 1.42), 1.17 (95% CI: 0.97, 1.40), and 1.30 (95% CI: 1.09, 1.54) respectively for groups with increasing number of tooth loss. There was some evidence of dose-risk association in this study, with a HR of 1.10 (1.04, 1.18) comparing adjacent groups (ptrend=0.001). In a stratified analysis by attained age, tooth loss was more pronouncedly associated with the risk of dementia onset before age 80 (those with 21-32 versus 0-10 lost teeth, HR=1.82, (95%CI: 1.32, 2.51); HR=1.22 (95%CI: 1.10, 1.35) comparing adjacent groups, ptrend<0.001). Conclusion: In summary, there are some indications that poor oral health, as indicated by more tooth loss, is positively associated with an increased risk of dementia, especially for dementia onset before age 80.

Pages 183-193
Leslie Grasset, Melinda C. Power, Fabrice Crivello, Christophe Tzourio, Geneviève Chêne, Carole Dufouil
How Traumatic Brain Injury History Relates to Brain Health MRI Markers and Dementia Risk: Findings from the 3C Dijon Cohort
Abstract: Background: The long-term effects of traumatic brain injury (TBI) with loss of consciousness (LOC) on magnetic resonance imaging (MRI) markers of brain health and on dementia risk are still debated. Objective: To investigate the associations of history of TBI with LOC with incident dementia and neuroimaging markers of brain structure and small vessel disease lesions. Methods: The analytical sample consisted in 4,144 participants aged 65 and older who were dementia-free at baseline from the Three City – Dijon study. History of TBI with LOC was self-reported at baseline. Clinical Dementia was assessed every two to three years, up to 12 years of follow-up. A subsample of 1,675 participants < 80 years old underwent a brain MRI at baseline. We investigated the associations between history of TBI with LOC and 1) incident all cause and Alzheimer’s disease (AD) dementia using illness-death models, and 2) neuroimaging markers at baseline. Results: At baseline, 8.3% of the participants reported a history of TBI with LOC. In fully-adjusted models, participants with a history of TBI with LOC had no statistically significant differences in dementia risk (HR=0.90, 95% CI=0.60 – 1.36) or AD risk (HR=1.03, 95% CI=0.69 – 1.52), compared to participants without TBI history. History of TBI with LOC was associated with lower white matter volume (β=-4.58, p=0.048), but not with other brain volumes, white matter hyperintensities volume, nor covert brain infarct. Conclusion: This study did not find evidence of an association between history of TBI with LOC and dementia or AD dementia risks over 12-year follow-up, brain atrophy, or markers of small vessel disease.

Pages 195-208
Xue Tao, Rong Zhang, Liguo Wang, Xiaoling Li, Weijun Gong
Luteolin and Exercise Combination Therapy Ameliorates Amyloid-β1-42 Oligomers-Induced Cognitive Impairment in Alzheimer’s Disease Mice by Mediating Neuroinflammation and Autophagy
Abstract: Background: Alzheimer's disease (AD) disturbs many patients and family. However, little progress has been made in finding effective treatments. Given AD is a multifactorial disease, luteolin and exercise combination therapy may be more effective than monotherapy. Objective: To explore the therapeutic effect and underlying mechanisms of luteolin and exercise combination therapy in AD treatment. Methods: This study utilized a validated mouse model of AD by bilateral injection of amyloid-β (Aβ)1-42 oligomers into the CA1 region of the hippocampus. By combining with animal behavioral test, thioflavin T detection, immunofluorescence and western blot test, the cognitive-enhancing effects of luteolin and exercise combination therapy and the underlying mechanisms were investigated. Results: Luteolin (100 mg/kg/d) combined with exercise could significantly improve the performance of AD model mice in novel object recognition test, and the improvement was greater than that of monotherapy. Further experiments showed that luteolin and exercise alone or in combination could reverse the increase of Aβ content, the activation of astrocytes and microglia, and the decrease of the level of autophagy in hippocampus and cortex in AD model induced by Aβ1-42 oligomers. While the combination therapy involved more intact hippocampal and cortical areas, with greater degree of changes. Conclusion: Luteolin and exercise combination therapy prevented Aβ1-42 oligomers-induced cognitive impairment, possibly by decreasing neuroinflammation and enhancing autophagy. The luteolin and exercise combination therapy may be a useful therapeutic option for preventing and/or delaying the progression of memory dysfunction of AD.

Pages 209-228
Lan Deng, Yuanjun Wang, Alzheimer’s Disease Neuroimaging Initiative
Fully Connected Multi-Kernel Convolutional Neural Network Based on Alzheimer’s Disease Diagnosis
Abstract: Background: There is a shortage of clinicians with sufficient expertise in the diagnosis of Alzheimer's disease (AD), and cerebrospinal fluid biometric collection and positron emission tomography diagnosis are invasive. Therefore, it is of potential significance to obtain high-precision automatic diagnosis results from diffusion tensor imaging (DTI) through deep learning, and simultaneously output feature probability maps to provide clinical auxiliary diagnosis. Objective: We proposed a factorization machine combined neural network (FMCNN) model combining a multi-function convolutional neural network (MCNN) with a fully convolutional network (FCN), while accurately diagnosing AD and mild cognitive impairment (MCI); corresponding fiber bundle visualization results are generated to describe their status. Methods: First, the DTI data is preprocessed to eliminate the influence of external factors. The fiber bundles of the corpus callosum (CC), cingulum (CG), uncinate fasciculus (UNC), and white matter (WM) were then tracked based on deterministic fiber tracking. Then the streamlines are input into CNN, MCNN, and FMCNN as one-dimensional features for classification, and the models are evaluated by performance evaluation indicators. Finally, the fiber risk probability map is output through FMCNN. Results: After comparing the model performance indicators of CNN, MCNN, and FMCNN, it was found that FMCNN showed the best performance in the indicators of accuracy, specificity, sensitivity, and area under the curve. By inputting the fiber bundles of the 10 regions of interest (UNC_L, UNC_R, UNC, CC, CG, CG+UNC, CG+CC, CC+UNC, CG+CC+UNC, and WM into CNN, MCNN, and FMCNN, respectively), WM shows the highest accuracy in CNN, MCNN, and FMCNN, which are 88.41%, 92.07%, and 96.95%, respectively. Conclusion: The FMCNN proposed here can accurately diagnose AD and MCI, and the generated fiber probability map can represent the risk status of AD and MCI.

Pages 229-239
Sanaz Sedaghat, Yuekai Ji, Timothy M. Hughes, Josef Coresh, Morgan E. Grams, Aaron R. Folsom, Kevin J. Sullivan, Anne M. Murray, Rebecca F. Gottesman, Thomas H. Mosley, Pamela L. Lutsey
The Association of Kidney Function with Plasma Amyloid-β Levels and Brain Amyloid Deposition
Abstract: Background: Reduced kidney function is related to brain atrophy and higher risk of dementia. It is not known whether kidney impairment is associated with higher levels of circulating amyloid-β and brain amyloid-β deposition, which could contribute to elevated risk of dementia. Objective: To investigate whether kidney impairment is associated with higher levels of circulating amyloid-β and brain amyloid-β deposition. Methods: This cross-sectional study was performed within the community–based Atherosclerosis Risk in Communities (ARIC) Study cohort. We used estimated glomerular filtration rate (eGFR) based on serum creatinine and cystatin C levels and urine albumin-to-creatinine ratio (ACR) to assess kidney function. Amyloid positivity was defined as a standardized uptake value ratios >1.2 measured with florbetapir positron emission tomography (PET) (n=340). Plasma amyloid-β1-40 and amyloid-β1-42 were measured using a fluorimetric bead-based immunoassay (n=2,569). Results: Independent of demographic and cardiovascular risk factors, a doubling of ACR was associated with 1.10 (95%CI: 1.01,1.20) higher odds of brain amyloid positivity, but not eGFR (odds ratio per 15 ml/min/1.73 m2 lower eGFR: 1.08; 95%CI: 0.95,1.23). A doubling of ACR was associated with a higher level of plasma amyloid-β1-40 (standardized difference: 0.12; 95%CI: 0.09,0.14) and higher plasma amyloid-β1-42 (0.08; 95%CI: 0.05,0.10). Lower eGFR was associated with higher plasma amyloid-β1-40 (0.36; 95%CI: 0.33,0.39) and higher amyloid-β1-42 (0.32; 95%CI: 0.29,0.35). Conclusion: Low clearance of amyloid-β and elevated brain amyloid positivity may link impaired kidney function with elevated risk of dementia. kidney function should be considered in interpreting amyloid biomarker results in clinical and research setting.

Pages 241-260
Jaclyn Lilek, Kaouther Ajroud, Alexander Z. Feldman, Sesha Krishnamachari, Shadi Ghourchian, Tamar Gefen, Callen L. Spencer, Allegra Kawles, Qinwen Mao, Jessica F. Tranovich, Clifford R. Jack Jr., M-Marsel Mesulam, R. Ross Reichard, Hui Zhang, Melissa E. Murray, David Knopman, Dennis W. Dickson, Ronald C. Petersen, Benjamin Smith, Karen H. Ashe, Michelle M. Mielke, Kathryn M. Nelson, Margaret E. Flanagan
Accumulation of pTau231 at the Postsynaptic Density in Early Alzheimer’s Disease
Abstract: Background: Phosphorylated cytoplasmic tau inclusions correlate with and precede cognitive deficits in Alzheimer's disease (AD). However, pathological tau accumulation and relationships to synaptic changes remain unclear. Objective: To address this, we examined postmortem brain from 50 individuals with the full spectrum of AD (clinically and neuropathologically). Total tau, pTau231, and AMPA GluR1 were compared across two brain regions (entorhinal and middle frontal cortices), as well as clinically stratified groups (control, amnestic mild cognitive impairment, AD dementia), NIA-AA Alzheimer’s Disease Neuropathologic Change designations (Not, Low, Intermediate, High), and Braak tangle stages (1-6). Significant co-existing pathology was excluded to isolate changes attributed to pathologic AD. Methods: Synaptosomal fractionation and staining were performed to measure changes in total Tau, pTau231, and AMPA GluR1. Total Tau and pTau231 were quantified in synaptosomal fractions using Quanterix Simoa HD-X. Results: Increasing pTau231 in frontal postsynaptic fractions correlated positively with increasing clinical and neuropathological AD severity. Frontal cortex is representative of early AD, as it does not become involved by tau tangles until late in AD. Entorhinal total tau was significantly higher in the amnestic mild cognitive impairment group when compared to AD, but only after accounting for AD associated synaptic changes. Alterations in AMPA GluR1 observed in the entorhinal cortex, but not middle frontal cortex, suggest that pTau231 mislocalization and aggregation in postsynaptic structures may impair glutamatergic signaling by promoting AMPA receptor dephosphorylation and internalization. Conclusion: Results highlight the potential effectiveness of early pharmacological interventions targeting pTau231 accumulation at the postsynaptic density.

Pages 261-272
Yuanjing Li, Mingqi Wang, Lin Cong, Tingting Hou, Lin Song, Xiang Wang, Lin Shi, Serhiy Dekhtyar, Yongxiang Wang, Yifeng Du, Chengxuan Qiu
Lifelong Cognitive Reserve, Imaging Markers of Brain Aging, and Cognitive Function in Dementia-Free Rural Older Adults: A Population-Based Study
Abstract: Background: Cognitive reserve (CR) partly explains cognitive variability in the presence of pathological brain aging. Objective: We investigated the interplay of lifelong CR with age, sex, and brain aging markers in cognitive phenotypes among older adults with very limited education. Methods: This population-based cross-sectional study included 179 dementia-free participants (age≥65 years; 39.7% women; 67.0% had no or elementary education) examined in 2014-2016. We assessed lacunes and volumes of hippocampus, ventricles, grey matter, white matter (WM), and white matter hyperintensities. Lifelong CR score was generated from six lifespan intellectual factors (e.g., education and social support). We used Mini-Mental State Examination (MMSE) score to assess cognition and Petersen’s criteria to define mild cognitive impairment (MCI). Data were analyzed using general linear and logistic models. Results: The association of higher lifelong CR score (range: -4.0–5.0) with higher MMSE score was stronger in women (multivariable-adjusted β-coefficient and 95%CI: 1.75;0.99–2.51) than in men (0.68;0.33–1.03) (pinteraction=0.006). The association of higher CR with MCI (multivariable-adjusted odds ratio and 95%CI: 0.77;0.60–0.99) did not vary by age or sex. Among participants with low CR (<1.4[median]), greater hippocampal and WM volumes were related to higher MMSE scores with multivariable-adjusted β-coefficients being 1.77(0.41–3.13) and 0.44(0.15–0.74); the corresponding figures in those with high CR were 0.15(-0.76–1.07) and -0.17(-0.41–0.07) (pinteraction <0.01). There was no statistical interaction of CR with MRI markers on MCI. Conclusion: Greater lifelong CR capacity is associated with better late-life cognition among people with limited education, possibly by compensating for impact of neurodegeneration.

Pages 273-283
Chaoqun Wang, Ming Mao, Xiaolei Han, Tingting Hou, Xiaojie Wang, Qi Han, Yi Dong, Rui Liu, Lin Cong, Cuicui Liu, Yume Imahori, Davide L. Vetrano, Yongxiang Wang, Yifeng Du*, Chengxuan Qiu* *These authors shared senior authorship.
Associations of Cardiac Ventricular Repolarization with Serum Adhesion Molecules and Cognitive Function in Older Adults: The MIND-China Study
Abstract: Background: Emerging evidence has linked electrocardiographic parameters with serum adhesion molecules and cognition; however, their interrelationship has not been explored. Objective: We sought to investigate the associations of ventricular depolarization and repolarization intervals with serum adhesion molecules and cognitive function among rural-dwelling older adults. Methods: This population-based study engaged 4,886 dementia-free participants (age≥60 years, 56.2% women) in the baseline examination (March-September 2018) of MIND-China. Of these, serum intercellular and vascular adhesion molecules (ICAM-1 and VCAM-1) were measured in 1591 persons. We used a neuropsychological test battery to assess cognitive function. Resting heart rate, QT, JT intervals, and QRS duration were assessed with electrocardiogram. Data were analyzed using general linear models adjusting for multiple confounders. Results: Longer JT interval was significantly associated with lower z-scores of global cognition (multivariable-adjusted β=-0.035; 95% confidence interval=-0.055, -0.015), verbal fluency (-0.035; -0.063, -0.007), attention (-0.037; -0.065, -0.010), and executive function (-0.044; -0.072, -0.015), but not with memory function (-0.023; -0.054, 0.009). There were similar association patterns of QT interval with cognitive functions. In the serum biomarker subsample, longer JT and QT intervals remained significantly associated with poorer executive function and higher serum adhesion molecules. We detected statistical interactions of JT interval with adhesion molecules (pinteraction<0.05), such that longer JT interval was significantly associated with a lower executive function z-score only among individuals with higher serum ICAM-1 and VCAM-1. Conclusion: Longer ventricular depolarization and repolarization intervals are associated with worse cognitive function in older adults and vascular endothelial dysfunction may play a part in the associations.

Pages 285-294
Shenikqua Bouges, Barbara Fischer, Derek L. Norton, Mary F. Wyman, Nickolas Lambrou, Megan Zuelsdorff, Carol A. Van Hulle, Gilda E. Ennis, Taryn T. James, Adrienne L. Johnson, Nathaniel Chin, Cynthia M. Carlsson, Carey E. Gleason
Effect of Metabolic Syndrome Risk Factors on Processing Speed and Executive Function in Three Racialized Groups
Abstract: Background: Metabolic syndrome (MetS) has been associated with increased risk for Alzheimer’s disease and related dementias (ADRD). Understanding the association of MetS risk factors to processing speed and executive function in the pre-clinical stages of ADRD in under-represented groups would offer insight on potential mechanisms through which MetS associates with ADRD risk. Objective: Examine association of MetS features and processing speed and executive function across three racial groups. Methods: Cognitively unimpaired adults from the Wisconsin Alzheimer’s Disease Research Center and the Wisconsin Registry for Alzheimer’s Disease Prevention completed blood-draws and neuropsychological testing. Six cognitive outcomes were assessed in association to MetS risk factors: Trailmaking Tests A and B, Animal Fluency, Digit Symbol, and composite scores for Processing Speed and Executive Function. Linear mixed effect models were used to assess the relationship between MetS risk factor count and longitudinal cognitive performance across three racialized groups. Results: Participant sample sizes varied by outcome analyzed (N=714-1,088). African American and Native American groups exhibited higher rates of MetS than non-Hispanic Whites. MetS was associated with processing speed and executive function across all racialized groups. Three-way interaction by racialized group was limited to one cognitive outcome: Trailmaking Test A. Conclusion: Metabolic dysfunction incrementally affects cognitive trajectory, with generally similar associations across racial groups. Since racialized groups exhibit higher levels of both MetS and ADRD, MetS may represent a driving factor for increased ADRD risk experience by racialized group and an important and modifiable target through which to reduce risk of ADRD.

Pages 295-309
Shanquan Chen, Rudolf N. Cardinal, Stefan Gräf, John T. O'Brien, Benjamin R. Underwood
Risk Factors for Longer-Term Mortality in Discharged Patients with Dementia and SARS-CoV-2 Infection: A Matched Case-Control Study
Abstract: Background: Persisting symptoms and increased mortality after SARS­CoV­2 infection has been described in COVID-19 survivors. Objective: We examined longer-term mortality in patients with dementia and SARS-CoV-2 infection. Methods: A retrospective matched case-control study of 165 patients with dementia who survived an acute hospital admission with COVID-19 infection, and 1325 patients with dementia who survived a hospital admission but without SARS-CoV-2 infection. Potential risk factors investigated included socio-demographic factors, clinical features, and results of investigations. Data were fitted using a Cox proportional hazard model. Results: Compared to patients with dementia but without SARS-CoV-2 infection, people with dementia and SARS-CoV-2 infection had a 4.4-fold risk of death (adjusted hazard ratio [aHR]=4.44, 95% confidence interval [CI] 3.13–6.30) even beyond the acute phase of infection. This excess mortality could be seen up to 125 days after initial recovery but was not elevated beyond this time. Risk factors for COVID-19-associated mortality included prescription of antipsychotics (aHR=3.06, 95%CI 1.40–6.69) and benzodiazepines (aHR=3.00, 95%CI 1.28–7.03). Abnormalities on investigation associated with increased mortality included high white cell count (aHR=1.21, 95%CI 1.04–1.39), higher absolute neutrophil count (aHR=1.28, 95%CI 1.12–1.46), higher C-reactive protein (aHR=1.01, 95%CI 1.00–1.02), higher serum sodium (aHR=1.09, 95%CI 1.01–1.19), and higher ionized calcium (aHR=1.03, 95%CI 1.00–1.06). The post-acute COVID mortality could be modeled for the first 120 days after recovery with a balanced accuracy of 87.2%. Conclusion: We found an increased mortality in patients with dementia beyond the acute phase of illness. We identified several investigation results associated with increased mortality, and increased mortality in patients prescribed antipsychotics or benzodiazepines.

Pages 311-322
Chao Wu, Ya-Hui Ma, Hao Hu, Bing Zhao, Lan Tan, Alzheimer’s Disease Neuroimaging Initiative
Soluble TREM2, Alzheimer’s Disease Pathology, and Risk for Progression of Cerebral Small Vessel Disease: A Longitudinal Study
Abstract: Background: Until recently, studies on associations between neuroinflammation in vivo and cerebral small vessel disease (CSVD) are scarce. Cerebrospinal fluid (CSF) levels of soluble triggering receptor expressed on myeloid cells 2 (sTREM2), a candidate biomarker of microglial activation and neuroinflammation, were found elevated in Alzheimer’s disease (AD), but they have not been fully explored in CSVD. Objective: To determine whether CSF sTREM2 levels are associated with the increased risk of CSVD progression. Methods: A total of 426 individuals from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) database were included in this study. All participants underwent measurements of CSF sTREM2 and AD pathology (Aβ1-42, P-tau181P). The progression of CSVD burden and imaging markers, including cerebral microbleeds (CMBs), white matter hyperintensities and lacunes, were estimated based on neuroimaging changes. Logistic regression and moderation effect models were applied to explore associations of sTREM2 with CSVD progression and AD pathology. Results: Higher CSF sTREM2 levels at baseline were associated with increased CSVD burden (OR=1.28 [95% CI, 1.01-1.62]) and CMBs counts (OR=1.32 [95% CI, 1.03-1.68]). Similarly, increased change rates of CSF sTREM2 might predict elevated CMBs counts (OR=1.44 [95% CI, 1.05-1.98]). Participants with AD pathology (Aβ1-42 and P-tau181P) showed a stronger association between CSF sTREM2 and CSVD progression. Conclusion: This longitudinal study found a positive association between CSF sTREM2 and CSVD progression, suggesting that neuroinflammation might promote CSVD. Furthermore, neuroinflammation could be a shared pathogenesis of CSVD and AD at the early stage. Targeting neuroinflammation to intervene the progression of CSVD and AD warrants further investigation.

Pages 323-339
Princess Newton, Jonathan Tchounguen, Corinne Pettigrew, Chantelle Lim, Zixuan Lin, Hanzhang Lu, Abhay Moghekar, Marilyn Albert, Anja Soldan, and the BIOCARD Research Team
Regional White Matter Hyperintensities and Alzheimer’s Disease Biomarkers Among Older Adults with Normal Cognition and Mild Cognitive Impairment
Abstract: Background: Alzheimer’s disease (AD) frequently co-occurs with other brain pathologies. Recent studies suggest there may be a mechanistic link between AD and small vessel cerebrovascular disease (CVD), as opposed to simply the overlap of two disorders. Objective: We investigated the cross-sectional relationship between white matter hyperintensity (WMH) volumes (markers of CVD) and cerebrospinal fluid (CSF) biomarkers of AD. Methods: WMH volumes were assessed globally and regionally (i.e., frontal, parietal, temporal, occipital, and limbic). CSF AD biomarkers (i.e., Aβ40, Aβ42, Aβ42/Aβ40 ratio, phosphorylated tau-181 [p-tau181], and total tau [t-tau]) were measured among 152 non-demented individuals (134 cognitively unimpaired and 18 with mild cognitive impairment (MCI)). Results: Linear regression models showed that among all subjects, higher temporal WHM volumes were associated with AD biomarkers (higher levels of p-tau181, t-tau, and Aβ40), particularly among APOE ε4 carriers (independent of Aβ42 levels). Higher vascular risk scores were associated with greater parietal and frontal WMH volumes (independent of CSF AD biomarker levels). Among subjects with MCI only, parietal WMH volumes were associated with a lower level of Aβ42/Aβ40. In addition, there was an association between higher global WMH volumes and higher CSF t-tau levels among younger participants versus older ones (~<65 versus 65+ years), independent of Aβ42/Aβ40 and p-tau181. Conclusion: These findings suggest that although WMH are primarily related to systemic vascular risk and neurodegeneration (i.e., t-tau), AD-specific pathways may contribute to the formation of WMH in a regionally-specific manner, with neurofibrillary tangles (i.e., p-tau) playing a role in temporal WMHs and amyloid (i.e., Aβ42/Aβ40) in parietal WMHs.

Pages 341-348
Tiffini Voss, James Kost, Swati Pal Mercer, Christine Furtek, Christopher Randolph, Christopher Lines, Michael F. Egan, Jeffrey L. Cummings
Progression from Prodromal Alzheimer’s Disease to Mild Alzheimer’s Disease Dementia in the Verubecestat APECS Study: Adjudicating Diagnostic Transitions
Abstract: Background: Delay of progression from prodromal Alzheimer’s disease (AD) to dementia is an important outcome in AD trials. Centralized adjudication is intended to improve the consistency of dementia diagnosis but has not been scrutinized. Objective: To evaluate centralized adjudication for determining progression to dementia compared with Site Investigator opinion or change in Clinical Dementia Rating (CDR). Methods: We used data from the 2-year APECS trial of verubecestat versus placebo in 1,451 prodromal AD participants. Cases were triggered for central adjudication if: 1) the Site Investigator judged the participant had progressed to dementia, or 2) the participant’s CDR sum-of-boxes score increased ≥2 points from baseline. Post-hoc analyses were performed on pooled treatment-group data to compare methods of assessing progression. Results: 581/1,451 (40%) participants had changes triggering adjudication and most (83%) were confirmed as progression to dementia. Only 66% of those who met CDR criteria (regardless of whether they also met Site Investigator criteria) were adjudicated to have progressed to dementia and just 15% of those who met only CDR criteria were adjudicated to have progressed, representing 5% of progressors. In contrast, 99% of those who met Site Investigator criteria (regardless of whether they also met CDR criteria) were adjudicated to have progressed, and the same was true for those who met only Site Investigator criteria. Conclusion: A positive Site Investigator opinion is an excellent predictor for a positive adjudication decision regarding onset of dementia. Conversely, sole use of CDR sum-of-boxes change ≥2 is inadequate. The benefit of centralized adjudication appears doubtful.

Pages 349-359
Sini Toppala, Laura L. Ekblad, Matti Viitanen, Juha O. Rinne, Antti Jula
Impaired Early Insulin Response to Glucose Load Predicts Episodic Memory Decline: A 10-Year Population-Based Cohort Follow-Up of 45–74-Year-Old Men and Women
Abstract: Background: Diabetes increases the risk for cognitive decline, but the mechanisms behind this association remain unknown. Impaired early insulin secretion in elderly men and insulin resistance, both of which are pathophysiological features of type 2 diabetes, have previously been linked to Alzheimer’s disease. Objective: To examine if the early insulin response to oral glucose load predicts cognitive performance after 10 years in men and women aged 45-74 years. Methods: This study was based on a subpopulation of the Health 2000 Survey, a Finnish nationwide, population-based health examination study, and its follow-up, the Health 2011 Study. In total, 961 45–74-year-old individuals (mean age at baseline 55.6 years, 55.8% women) were examined. An oral glucose tolerance test was performed in 2001–2002, and early insulin response was defined as the ratio of the 30-min increment in insulin concentration to that of glucose concentration. Cognitive function was evaluated at baseline and follow-up with categorical verbal fluency, word-list learning, and word-list delayed recall. Statistical analyses were performed using multivariable linear models adjusted for age, sex, education, APOE ɛ4 genotype, vascular risk factors including diabetes, and depressive symptoms. Results: A lower early insulin response to glucose load predicted lower performance (β: 0.21, p=0.03) and greater decline (β: 0.19, p=0.03) in the word-list delayed recall test. Baseline early insulin response did not predict verbal fluency or word-list learning (all p-values ≥0.13). Conclusion: Our results suggest that decreased early insulin secretion predicts episodic memory decline in middle-aged to elderly men and women.

Pages 361-369
Madoka Yoshida*, Takeshi Uemura*, Mutsumi Mizoi, Masaaki Waragai, Akihiko Sakamoto, Yusuke Terui, Keiko Kashiwagi, Kazuei Igarashi *These authors equally contributed to this work.
Urinary Amino Acid-Conjugated Acrolein and Taurine as New Biomarkers for Detection of Dementia
Abstract: Background: Dementia, including Alzheimer’s disease (AD), is one of the serious diseases at advanced age, and its early detection is important for maintaining quality of life (QOL). Objective: In this study, we sought novel biomarkers for dementia in urine. Methods: Samples of urine were collected from 57 control subjects without dementia, 62 mild cognitive impairment (MCI) patients, and 42 AD patients. Mini-Mental State Examination (MMSE) was evaluated when subjects were examined by medical doctors. Urinary amino acid (lysine)-conjugated acrolein (AC-Acro) was measured using Nε-(3-formyl-3, 4-dehydropiperidine) lysine (FDP-Lys) ELISA kit, and taurine content was measured using a taurine assay kit. Values were normalized by creatinine content which was measured with the colorimetric assay kit. Results: We found that urinary amino acid (lysine)-conjugated acrolein (AC-Acro) and taurine negatively correlated with MMSE score and are significantly lower in dementia patients compared to the normal subjects. When AC-Acro and taurine were evaluated together with age using an artificial neural network model, median relative risk values for subjects with AD, subjects with mild cognitive impairment, and control subjects were 0.96, 0.53, and 0.06, respectively. Conclusion: Since urine is relatively easy to collect, our findings provide a novel biomarker for dementia without invasiveness.

Pages 371-390
Blake Highet, James A. Wiseman, Hannah Mein, Remai Parker, Brigid Ryan, Clinton P. Turner, Yu Jing, Malvindar K. Singh-Bains, Ping Liu, Mike Dragunow, Richard L.M. Faull, Helen C. Murray, Maurice A. Curtis
PSA-NCAM Regulatory Gene Expression Changes in the Alzheimer’s Disease Entorhinal Cortex Revealed with Multiplexed in situ Hybridization
Abstract: Background: Alzheimer’s disease (AD) is the most common form of dementia and is characterized by a substantial reduction of neuroplasticity. Our previous work demonstrated that neurons involved in memory function may lose plasticity because of decreased protein levels of polysialylated neural cell adhesion molecule (PSA-NCAM) in the entorhinal cortex (EC) of the human AD brain, but the cause of this decrease is unclear. Objective: To investigate genes involved in PSA-NCAM regulation which may underlie its decrease in the AD EC. Methods: We subjected neurologically normal and AD human EC sections to multiplexed fluorescent in situ hybridization and immunohistochemistry to investigate genes involved in PSA-NCAM regulation. Gene expression changes were sought to be validated in both human tissue and a mouse model of AD. Results: In the AD EC, a cell population expressing a high level of CALB2 mRNA and a cell population expressing a high level of PST mRNA were both decreased. CALB2 mRNA and protein were not decreased globally, indicating that the decrease in CALB2 was specific to a sub-population of cells. A significant decrease in PST mRNA expression was observed with single-plex in situ hybridization in middle temporal gyrus tissue microarray cores from AD patients, which negatively correlated with tau pathology, hinting at global loss in PST expression across the AD brain. No significant differences in PSA-NCAM or PST protein expression were observed in the MAPT P301S mouse brain at 9 months of age. Conclusion: We conclude that PSA-NCAM dysregulation may cause subsequent loss of structural plasticity in AD, and this may result from a loss of PST mRNA expression. Due PSTs involvement in structural plasticity, intervention for AD may be possible by targeting this disrupted plasticity pathway.