Volume 92, Number 3, IN PRESS

Ethics Review
Shana D. Stites, Norma B. Coe (Handling Editor: Allyson Rosen)
Let’s Not Repeat History’s Mistakes: Two Cautions to Scientists on the Use of Race in Alzheimer’s Disease and Alzheimer’s Disease Related Dementias Research
Abstract: Alzheimer’s disease and Alzheimer’s disease related dementias (AD/ADRD) research has advanced gene and biomarker technologies to aid identification of individuals at risk for dementia. This innovation is a lynchpin in development of disease-modifying therapies. The emerging science could transform outcomes for patients and families. However, current limitations in the racial representation and inclusion of racial diversity in research limits the relevance of these technologies: AD/ADRD research cohorts used to define biomarker cutoffs are mostly White, despite clinical and epidemiologic research that shows Black populations are among those experiencing the greatest burdens of AD/ADRD. White cohorts alone are insufficient to characterize heterogeneity in disease and in life experiences that can alter AD/ADRD’s courses. The National Institute on Aging (NIA) has called for increased racial diversity in AD/ADRD research. While scientists are working to implement NIA’s plan to build more diverse research cohorts, they are also seeking out opportunities to consider race in AD/ADRD research. Recently, scientists have posed two ways of including race in AD/ADRD research: ancestry-based verification of race and race-based adjustment of biomarker test results. Both warrant careful examination for how they are impacting AD/ADRD science with respect to specific study objectives and the broader mission of the field. If these research methods are not grounded in pursuit of equity and justice, biases they introduce into AD/ADRD science could perpetuate, or even worsen, disparities in AD/ADRD research and care.

Systematic Review
Munira Sultana, Neil Alexander, Frederico Pierucini-Faria, Susan W. Hunter, Nellie Kamkar, Mark R. Speechley, Surim Son, Joe Verghese, Manuel Montero-Odasso, the Task Force on Global Guidelines for Falls in Older Adults
Involvement of Informal Caregivers in Preventing Falls in Older Adults with Cognitive Impairment: A Rapid Review
Abstract: Background: The prevalence of falls and related injuries is double in older adults with cognitive impairment compared with cognitively healthy older adults. A growing body of literature shows that falls prevention interventions in the cognitively impaired are difficult to implement and that the feasibility and adherence to interventions depend on a number of factors including informal caregiver involvement. However, no systematic review exists on the topic. Objective: Our objective is to determine whether involvement of informal caregivers can reduce falls in older adults with cognitive impairment. Methods: Rapid review following Cochrane collaboration guidelines. Results: Seven randomized controlled trials were identified involving 2,202 participants. We identified the following areas where informal caregiving may have an important role in fall prevention in older adults with cognitive impairment: 1) enhancing adherence to the exercise program; 2) identifying and recording falls incidents and circumstances; 3) identifying and modifying possible environmental falls risk factors inside patient’s home; and 4) playing an active role in modifying lifestyle in terms of diet/nutrition, limiting antipsychotics, and avoiding movements risking falls. However, informal caregiver involvement was identified as an incidental finding in these studies and the level of evidence ranged from low to moderate. Conclusion: Informal caregiver involvement in planning and delivering interventions to reduce falls has been found to increase the adherence of individuals with cognitive impairment in falls prevention programs. Future research should address whether involvement of informal caregivers may improve efficacy of prevention programs by reducing the number of falls as a primary outcome.

Russell H. Swerdlow
The Alzheimer’s Disease Mitochondrial Cascade Hypothesis: A Current Overview
Abstract: Viable Alzheimer’s disease (AD) hypotheses must account for its age-dependence; commonality; association with amyloid precursor protein, tau, and apolipoprotein E biology; connection with vascular, inflammation, and insulin signaling changes; and systemic features. Mitochondria and parameters influenced by mitochondria could link these diverse characteristics. Mitochondrial biology can initiate changes in pathways tied to AD and mediate the dysfunction that produces the clinical phenotype. For these reasons, conceptualizing a mitochondrial cascade hypothesis is a straightforward process and data accumulating over decades argue the validity of its principles. Alternative AD hypotheses may yet account for its mitochondria-related phenomena, but absent this happening a primary mitochondrial cascade hypothesis will continue to evolve and attract interest.

Barbara Kania, Alexis Sotelo, Darren Ty, Jonathan J. Wisco
The Prevention of Inflammation and the Maintenance of Iron and Hepcidin Homeostasis in the Gut, Liver, and Brain Pathologies
Abstract: The human gut microbiome consists of a variety of microorganisms that inhabit the intestinal tract. This flora has recently been shown to play an important role in human disease. The crosstalk between the gut and brain axis has been investigated through hepcidin, derived from both hepatocytes and dendritic cells. Hepcidin could potentially play an anti-inflammatory role in the process of gut dysbiosis through a means of either a localized approach of nutritional immunity, or a systemic approach. Like hepcidin, mBDNF and IL-6 are part of the gut-brain axis: gut microbiota affects their levels of expression, and this relationship is thought to play a role in cognitive function and decline, which could ultimately lead to a number of neurodegenerative diseases such as Alzheimer’s disease. This review will focus on the interplay between gut dysbiosis and the crosstalk between the gut, liver, and brain and how this is mediated by hepcidin through different mechanisms including the vagus nerve and several different biomolecules. This overview will also focus on the gut microbiota-induced dysbiotic state on a systemic level, and how gut dysbiosis can contribute to beginnings and the progression of Alzheimer's disease and neuroinflammation.

Short Communication
Zhe Wang, Lin Tan, Yu Zong, Ya-Hui Ma, Zhi-Bo Wang, for the Alzheimer’s Disease Neuroimaging Initiative, Hui-Fu Wang, Lan Tan
sTREM2 and GFAP Mediated the Association of IGF-1 Signaling Biomarkers with Alzheimer’s Disease Pathology
Abstract: Defects in insulin-like growth factor 1 (IGF-1) signaling is a key contributor to Alzheimer’s disease (AD). However, the mechanism of how IGF-1 signaling relates to AD remained unclear. Here, we investigated the association of IGF-1 signaling associated biomarkers with AD pathology, sTREM2, and GFAP. Finally, insulin-like growth factor binding protein 2 (IGFBP-2) was associated with AD pathology, and the association was partly medicated by sTREM2 (Aβ42, β=0.794, p=0.016; T-tau, β=0.291, p<0.001; P-tau181, β=0.031, p<0.001) and GFAP (T-tau, β=0.427, p<0.001; P-tau181, β=0.044, p<0.001). It suggested that sTREM2 and GFAP mediated the relationship between IGF-1 signaling and AD pathology.

Craig S. Atwood, George Perry
Playing Russian Roulette with Alzheimer’s Disease Patients: Do the Cognitive Benefits of Lecanemab Outweigh the Risk of Edema, Stroke, and Encephalitis?
Abstract: The questionable approval of aducanumab and the recent approval of lecanemab (Leqembi; Eisai and Biogen) by the FDA has raised the issue of safety (stroke, meningitis, and encephalitis) over efficacy (slowing of cognitive decline). This communication recounts the important physiological functions of amyloid-β as a barrier protein with unique sealant and anti-pathogenic activities important for maintaining vascular integrity coupled with innate immune functions that prevent encephalitis and meningitis. The approval of a drug that obviates both of these purposive functions increases the risk of hemorrhage, edema and downstream pathogenic outcomes and should be clearly outlined to patients.

Bum Soo Kim*, Sungmin Jun*, Heeyoung Kim, Alzheimer’s Disease Neuroimaging Initiative (Handling Associate Editor: Sang Won Seo) *These authors contributed equally to this work.
Cognitive Trajectories and Associated Biomarkers in Patients with Mild Cognitive Impairment
Abstract: Background: To diagnose mild cognitive impairment (MCI) patients at risk of progression to dementia is clinically important but challenging. Objective: We classified MCI patients based on cognitive trajectories and compared biomarkers among groups. Methods: This study analyzed amnestic MCI patients with at least three Clinical Dementia Rating (CDR) scores available over a minimum of 36 months from the Alzheimer’s Disease Neuroimaging Initiative database. Patients were classified based on their progression using trajectory modeling with the CDR-sum of box scores. We compared clinical and neuroimaging biomarkers across groups. Results: Of 569 eligible MCI patients (age 72.7±7.4 years, women n=223), three trajectory groups were identified: stable (58.2%), slow decliners (24.6%), and fast decliners (17.2%). In the fifth year after diagnosis, the CDR-sum of box scores increased by 1.2, 5.4, and 11.8 points for the stable, slow, and fast decliners, respectively. Biomarkers associated with cognitive decline were amyloid-β 42, total tau, and phosphorylated tau protein in cerebrospinal fluid, hippocampal volume, cortical metabolism, and amount of cortical and subcortical amyloid deposits. Cortical metabolism and the amount of amyloid deposits were associated with the rate of cognitive decline. Conclusion: Data-driven trajectory analysis provides new insights into the various cognitive trajectories of MCI. Baseline brain metabolism, and the amount of cortical and subcortical amyloid burden can provide additional information on the rate of cognitive decline.

Marco Calabria, Francesco Ciongoli, Nicholas Grunden, Celia Ordás, Carmen García-Sánchez
Background Music and Memory in Mild Cognitive Impairment: The Role of Interindividual Differences
Abstract: Background: Recent research has shown that background music may improve memory consolidation and retrieval. Nevertheless, in the clinical conditions preceding dementia such as mild cognitive impairment (MCI), there is no current evidence speaking to what effect background music during memory tasks has on impaired cognition. Objective: Across three experiments, we investigated if background music is able to improve memory performance, the most impacted cognitive domain in amnestic MCI. Methods: We tested the effect of background music by using a face recognition memory task in patients with amnestic MCI. In Experiment 1, we tested the effect of background music on memory when it was played solely during an encoding phase. In Experiment 2, we explored effects of background music when played during both encoding and recognition phases. In Experiment 3, we explored the role of musically induced arousal on memory. Results: The main finding from these three experiments was that background music played during a memory task did not improve or worsen participant performance. However, when exposed to high-arousal music, memory performance was predicted by individual mood regulation. For low-arousal music conditions, there was a negative relationship between rating scores for music pleasantness and performance on the memory task. Conclusion: Our results suggest that the benefits of background music on memory in individuals with MCI are modulated by interindividual preferences towards music.

Knut Engedal, Jūratė Šaltytė Benth, Linda Gjøra, Håvard Kjesbu Skjellegrind, Marit Nåvik, Geir Selbæk (Handling Associate Editor: Anne Fink)
Normative Scores on the Norwegian Version of the Mini-Mental State Examination
Abstract: Background: The Mini-Mental State Examination (MMSE), a simple test for measuring global cognitive function, is frequently used to evaluate cognition in older adults. To decide whether a score on the test indicates a significant deviation from the mean score, normative scores should be defined. Moreover, because the test may vary depending on its translation and cultural differences, normative scores should be established for national versions of the MMSE. Objective: We aimed to examine normative scores for the third Norwegian version of the MMSE. Methods: We used data from two sources: the Norwegian Registry of Persons Assessed for Cognitive Symptoms (NorCog) and the Trøndelag Health Study (HUNT). After persons with dementia, mild cognitive impairment, and disorders that may cause cognitive impairment were excluded, the sample contained 1,050 cognitively healthy persons, 860 from NorCog, and 190 from HUNT, whose data we subjected to regression analyses. Results: The normative MMSE score varied from 25 to 29, depending on years of education and age. More years of education and younger age were associated with higher MMSE scores, and years of education was the strongest predictor. Conclusion: Mean normative MMSE scores depend on test takers’ years of education and age, with level of education being the strongest predictor.

Silvia Cascini, Marco Canevelli, Nera Agabiti, Laura Angelici, Marina Davoli, Ilaria Bacigalupo, Ilaria Cova, Nicola Vanacore, Simone Pomati, Leonardo Pantoni, Anna Acampora, Anna Maria Bargagli, ImmiDem Study Group (Handling Associate Editor: Claudio Abbate)
Case Identification and Characterization of Migrants with Dementia in the Lazio Region Using Health Administrative Data
Abstract: Background: A crucial step for planning effective public health policies for migrants with dementia is the collection of data on the local dimensions of the phenomenon and patients’ characteristics. Objective: This study aimed to identify and characterize migrants with dementia in the Lazio region using health administrative databases. Methods: Residents with dementia aged 50 years or older, living in the Lazio region as of December 31, 2018, were identified using a validated algorithm based on hospital discharge(s), claims for antidementia drugs, and co-payment exemption for dementia. Migrants were defined as people born abroad and grouped in migrants from High Migratory Pressure Countries (HMPCs) and Highly Developed Countries (HDCs). Overall and age-specific prevalence rates were estimated in native- and foreign-born patients. Results: Dementia was ascertained in 38,460 residents. Among them, 37,280 (96.9%) were born in Italy, 337 (0.9%) were migrants from HDCs, and 843 (2.2%) from HMPCs. Dementia prevalence was higher among natives (1.15%, 95%CI 1.14-1.16) relative to migrants from HDCs (0.60%, 95%CI 0.54-0.67) and HMPCs (0.29%, 95%CI 0.27-0.31). The prevalence of comorbidities did not differ between groups. Migrants with dementia had a lower likelihood of receiving antidementia treatments compared with natives (51.6% in migrants from HDCs, 49.3% in migrants from HMPCs, and 53.5% among Italians). Conclusion: Routinely collected data in healthcare administrative databases can support the identification of migrants with dementia. Migrants exhibited a lower age-standardized prevalence of registered dementia and lower access to dedicated treatments than Italians. These findings are suggestive of underdiagnosis and undertreatment of dementia in migrants.

Qiong-Yao Li, Xue-Mei Li, He-Ying Hu, Ya-Hui Ma, Ya-Nan Ou, An-Yi Wang, Lan Tan, Jin-Tai Yu (Handling Associate Editor: Jiu Chen)
Associations of Lung Function Decline with Risks of Cognitive Impairment and Dementia: A Meta-Analysis and Systematic Review
Abstract: Background: There are controversies surrounding the effects of lung function decline on cognitive impairment and dementia. Objective: We conducted a meta-analysis and systematic review to explore the associations of lung function decline with the risks of cognitive impairment and dementia. Methods: The PubMed, EMBASE, and the Cochrane Library were searched to identify prospective studies published from database inception through January 10, 2023. We pooled relative risk (RR) and 95% confidence intervals (CI) using random-effects models. The Egger test, funnel plots, meta-regression, sensitivity, and subgroup analyses were conducted to detect publication bias and investigate the source of heterogeneity. Results: Thirty-three articles with a total of 8,816,992 participants were subjected to meta-analysis. Poorer pulmonary function was associated with an increased risk of dementia (FEV: RR=1.25 [95%CI, 1.17-1.33]; FVC: RR=1.40 [95%CI, 1.16-1.69]; PEF: RR=1.84 [95%CI, 1.37-2.46]). The results of the subgroup analyses were similar to the primary results. Individuals with lung diseases had a higher combined risk of dementia and cognitive impairment (RR=1.39 [95%CI, 1.20-1.61]). Lung disease conferred an elevated risk of cognitive impairment (RR=1.37 [95%CI, 1.14-1.65]). The relationship between lung disease and an increased risk of dementia was only shown in total study participants (RR=1.32 [95%CI, 1.11-1.57]), but not in the participants with Alzheimer’s disease (RR=1.39 [95%CI, 1.00-1.93]) or vascular dementia (RR=2.11 [95%CI, 0.57-7.83]). Conclusion: Lung function decline was significantly associated with higher risks of cognitive impairment and dementia. These findings might provide implications for the prevention of cognitive disorders and the promotion of brain health.

Che-Sheng Chu, Di-Yuan Wang, Chih-Kuang Liang, Ming-Yueh Chou, Ying-Hsin Hsu, Yu-Chun Wang, Mei-Chen Liao, Wei-Ta Chu*, Yu-Te Lin* *These authors contributed equally to this work.
Automated Video Analysis of Audio-Visual Approaches to Predict and Detect Mild Cognitive Impairment and Dementia in Older Adults
Abstract: Background: Early identification of different stages of cognitive impairment is important to provide available intervention and timely care for the elderly. Objective: This study aimed to examine the ability of the artificial intelligence (AI) technology to distinguish participants with mild cognitive impairment (MCI) from those with mild to moderate dementia based on automated video analysis. Methods: A total of 95 participants were recruited (MCI, 41; mild to moderate dementia, 54). The videos were captured during the Short Portable Mental Status Questionnaire process; the visual and aural features were extracted using these videos. Deep learning models were subsequently constructed for the binary differentiation of MCI and mild to moderate dementia. Correlation analysis of the predicted Mini-Mental State Examination, Cognitive Abilities Screening Instrument scores, and ground truth was also performed. Results: Deep learning models combining both the visual and aural features discriminated MCI from mild to moderate dementia with an area under the curve (AUC) of 77.0% and accuracy of 76.0%. The AUC and accuracy increased to 93.0% and 88.0%, respectively, when depression and anxiety were excluded. Significant moderate correlations were observed between the predicted cognitive function and ground truth, and the correlation was strong excluding depression and anxiety. Interestingly, female, but not male, exhibited a correlation. Conclusion: The study showed that video-based deep learning models can differentiate participants with MCI from those with mild to moderate dementia and can predict cognitive function. This approach may offer a cost-effective and easily applicable method for early detection of cognitive impairment.

Dror Shir, Michelle M. Mielke, Ekaterina I. Hofrenning, Timothy G. Lesnick, David S. Knopman, Ronald C. Petersen, Clifford R. Jack Jr, Alicia Algeciras-Schimnich , Prashanthi Vemuri, Jonathan Graff-Radford
Associations of Neurodegeneration Biomarkers in Cerebrospinal Fluid with Markers of Alzheimer’s Disease and Vascular Pathology
Abstract: Background: The National Institute on Aging-Alzheimer’s Association Research Framework proposes defining Alzheimer’s disease by grouping imaging and fluid biomarkers by their respective pathologic processes. The AT(N) structure proposes several neurodegenerative fluid biomarkers (N) including total tau (t-tau), neurogranin (Ng), and neurofilament light chain (NfL). However, pathologic drivers influencing each biomarker remain unclear. Objective: To determine whether cerebrospinal fluid (CSF)-neurodegenerative biomarkers (N) map differentially to Alzheimer’s disease pathology measured by Aβ42 (an indicator of amyloidosis, [A]), p-tau (an indicator of tau deposition, [T]), and MRI vascular pathology indicators (measured by white-matter integrity, infarcts, and microbleeds [V]). Methods: Participants were from Mayo Clinic Study of Aging (MCSA) with CSF measures of NfL, Ng, t-tau, Aβ42, and p-tau and available MRI brain imaging. Linear models assessed associations between CSF neurodegeneration (N) markers, amyloid markers (A), tau (T), and vascular pathology (V). Results: Participants (n=408) had a mean age of 69.2±10.7; male, 217 (53.2%); cognitively unimpaired, 359 (88%). All three neurodegeneration biomarkers correlated with age (p < 0.001 for NfL and t-tau, p=0.018 for Ng). Men had higher CSF-NfL levels; women had higher Ng (p < 0.001). NfL and t-tau levels correlated with infarcts (p=0.009, p=0.034 respectively); no biomarkers correlated with white-matter integrity. N biomarkers correlated with p-tau levels (T, p < 0.001). Higher Aβ42 levels associated with higher N-biomarker levels but only among cognitively unimpaired (A, p < 0.001). Conclusion: The influence of vascular pathology in the general population on CSF (N) biomarkers is modest, with greater influence of infarcts than white-matter disruption. Neurodegeneration markers more closely correlated with tau than amyloid markers.

Shu-Wen Hao*, Tao-Ran Li*, Chao Han*, Ying Han, Yan-Ning Cai *These authors contributed equally to this work.
Associations Between Levels of Peripheral NCAPH2 Promoter Methylation and Different Stages of Alzheimer’s Disease: A Cross-Sectional Study
Abstract: Background: Several studies have examined NCAPH2 methylation in amnestic mild cognitive impairment (aMCI) and Alzheimer’s disease (AD), but little is known of NCAPH2 methylation in subjective cognitive decline (SCD). Objective: To examine whether methylation of peripheral NCAPH2 are differentially changed at various phases of AD, and whether it could serve as a diagnostic biomarker for SCD. Methods: A total of 40 AD patients, 52 aMCI patients, 148 SCD patients, and 193 cognitively normal controls (NCs) were recruited in the current case-control study. Besides, 54 cognitively normal individuals have received amyloid positron emission tomography (amyloid PET) scans. Using bisulfite pyrosequencing method, we measured blood DNA methylation in the NCAPH2 gene promoter. Results: The main outcomes were: 1) For SCD, there was no significant difference between SCD and NC regarding NCAPH2 methylation; 2) For aMCI, NCAPH2 methylation at CpG2 were significantly lower in aMCI compared with NC and SCD in the entire population and male subgroup; 3) For AD, NCAPH2 methylation at CpG1 were significantly lower in AD compared with NC among females; 4) A relationship with apolipoprotein E (APOE) ε4 status was shown. Receiver operating characteristic (ROC) analysis by combining NCAPH2 methylation, age, education, and APOE ε4 status could distinguish between patients with aMCI (area under the curve (AUC): 0.742) and AD (AUC: 0.873) from NCs. Conclusion: NCAPH2 methylation levels were altered at the aMCI and AD stage and may be convenient and cost-effective biomarkers of AD and aMCI.

Natalia Acosta-Baena, Carlos M. Lopera-Gómez, Mario C. Jaramillo-Elorza, Lina Velilla-Jiménez, Carlos Andrés Villegas-Lanau, Diego Sepúlveda-Falla, Mauricio Arcos-Burgos, Francisco Lopera
Early Depressive Symptoms Predict Faster Dementia Progression in Autosomal-Dominant Alzheimer's Disease
Abstract: Background: Depression is associated with Alzheimer's disease (AD). Objective: To evaluate the association between depressive symptoms and age of onset of cognitive decline in autosomal dominant AD, and to determine possible factors associated to early depressive symptoms in this population. Methods: We conducted a retrospective study to identify depressive symptoms among 190 presenilin 1 (PSEN1) E280A mutation carriers, subjected to comprehensive clinical evaluations in up to a 20-year longitudinal follow-up. We controlled for the following potential confounders: APOE, sex, hypothyroidism, education, marital status, residence, tobacco, alcohol, and drug abuse. Results: PSEN1 E280A carriers with depressive symptoms before mild cognitive impairment (MCI) develop dementia faster than E280A carriers without depressive symptoms (Hazard Ratio, HR = 1.95; 95% CI, 1.15 - 3.31). Not having a stable partner accelerated the onset of MCI (HR=1.60; 95 % CI, 1.03-2.47) and dementia (HR=1.68; 95 % CI, 1.09-2.60). E280A carriers with controlled hypothyroidism had later age of onset of depressive symptoms (HR=0.48; 95 % CI, 0.25-0.92), dementia (HR=0.43; 95 % CI, 0.21-0.84), and death (HR=0.35; 95 % CI, 0.13-0.95). APOE ε2 significantly affected AD progression in all stages. APOE polymorphisms were not associate to depressive symptoms. Women had a higher frequency and developed earlier depressive symptoms than men throughout the illness (HR=1.63; 95 % CI, 1.14-2.32). Conclusion: Depressive symptoms accelerated progress and faster cognitive decline of autosomal dominant AD. Not having a stable partner and factors associated with early depressive symptoms (e.g., in females and individuals with untreated hypothyroidism), could impact prognosis, burden, and costs.

Ersin Ersoezlue*, Robert Perneczky*, Maia Tato, Julia Utecht, Carolin Kurz, Jan Häckert, Selim Guersel, Lena Burow, Gabriele Koller, Sophia Stoecklein, Daniel Keeser, Boris Papazov, Marie Totzke, Tommaso Ballarini, Frederic Brosseron, Katharina Buerger, Peter Dechent, Laura Dobisch, Michael Ewers, Klaus Fliessbach, Wenzel Glanz, John Dylan Haynes, Michael T Heneka, Daniel Janowitz, Ingo Kilimann, Luca Kleineidam, Christoph Laske, Franziska Maier, Matthias H. Munk, Oliver Peters, Josef Priller, Alfredo Ramirez, Sandra Roeske, Nina Roy, Klaus Scheffler, Anja Schneider, Björn H. Schott, Annika Spottke, Eike J. Spruth, Stefan Teipel, Chantal Unterfeld, Michael Wagner, Xiao Wang, Jens Wiltfang, Steffen Wolfsgruber, Renat Yakupov, Emrah Duezel, Frank Jessen, Boris-Stephan Rauchmann for the DELCODE study group *These two authors contributed equally to this work.
A Residual Marker of Cognitive Reserve Is Associated with Resting-State Intrinsic Functional Connectivity Along the Alzheimer’s Disease Continuum
Abstract: Background: Cognitive reserve (CR) explains inter-individual differences in the impact of the neurodegenerative burden on cognitive functioning. A residual model was proposed to estimate CR more accurately than previous measures. However, associations between residual CR markers (CRM) and functional connectivity (FC) remain unexplored. Objective: To explore the associations between the CRM and intrinsic network connectivity (INC) in resting-state networks along the neuropathological-continuum of Alzheimer’s disease (ADN). Methods: Three hundred eighteen participants from the DELCODE cohort were stratified using cerebrospinal fluid biomarkers according to the A(myloid-β)/T(au)/N(eurodegeneration) classification. CRM was calculated utilizing residuals obtained from a multilinear regression model predicting cognition from markers of disease burden. Using an independent component analysis in resting-state fMRI data, we measured INC of resting-state networks, i.e., default mode network (DMN), frontoparietal network (FPN), salience network (SAL), and dorsal attention network. The associations of INC with a composite memory score and CRM and the associations of CRM with the seed-to-voxel functional connectivity of memory-related were tested in general linear models. Results: CRM was positively associated with INC in the DMN in the entire cohort. The A+T+N+ group revealed an anti-correlation between the SAL and the DMN. Furthermore, CRM was positively associated with anti-correlation between memory-related regions in FPN and DMN in ADN and A+T/N+. Conclusion: Our results provide evidence that INC is associated with CRM in ADN defined as participants with amyloid pathology with or without cognitive symptoms, suggesting that the neural correlates of CR are mirrored in network FC in resting-state.

Anna Marcisz, for the Alzheimer's Disease Neuroimaging Initiative, Joanna Polanska
Can T1-Weighted Magnetic Resonance Imaging Significantly Improve Mini-Mental State Examination-Based Distinguishing Between Mild Cognitive Impairment and Early-Stage Alzheimer’s Disease?
Abstract: Background: Detecting early-stage Alzheimer's disease (AD) is still problematic in clinical practice. This work aimed to find T1-weighted MRI-based markers for AD and mild cognitive impairment (MCI) to improve the screening process. Objective: Our assumption was to build a screening model that would be accessible and easy to use for physicians in their daily clinical routine. Methods: The multinomial logistic regression was used to detect status: AD, MCI, and normal control (NC) combined with the Bayesian information criterion for model selection. Several T1-weighted MRI-based radiomic features were considered explanatory variables in the prediction model. Results: The best radiomic predictor was the relative brain volume. The proposed method confirmed its quality by achieving a balanced accuracy of 95.18%, AUC of 93.25%, NPV of 97.93%, and PPV of 90.48% for classifying AD versus NC for the European DTI Study on Dementia (EDSD). The comparison of the two models: with the MMSE score only as an independent variable and corrected for the relative brain value and age, shows that the addition of the T1-weighted MRI-based biomarker improves the quality of MCI detection (AUC: 67.04% versus 71.08%) while maintaining quality for AD (AUC: 93.35% versus 93.25%). Additionally, among MCI patients predicted as AD inconsistently with the original diagnosis, 60% from ADNI and 76.47% from EDSD were re-diagnosed as AD within a 48-month follow-up. It shows that our model can detect AD patients a few years earlier than a standard medical diagnosis. Conclusion: The created method is non-invasive, inexpensive, clinically accessible, and efficiently supports AD/MCI screening.

Heidi J. Welberry, Tiffany Chau, Megan Heffernan, Juan Carlo San Jose, Louisa R. Jorm, Maria Fiaratone Singh, Perminder S. Sachdev, Kaarin J. Anstey, Nicola T. Lautenschlager, Michael Valenzuela, John McNeil, Henry Brodaty (Handling Associate Editor: Andrea Fairley)
Factors Associated with Participation in a Multidomain Web-Based Dementia Prevention Trial: Evidence from Maintain Your Brain (MYB)
Abstract: Background: The Maintain Your Brain (MYB) trial aims to prevent cognitive decline and dementia through multidomain, web-based risk-reduction. To facilitate translation, it is important to understand drivers of participation. Objective: To describe characteristics associated with participation in MYB. Methods: This was an observational ancillary study of MYB, a randomized controlled trial nested within the 45 and Up Study in New South Wales, Australia. We linked 45 and Up Study survey and MYB participation data. The study cohort comprised 45 and Up Study participants, aged 55-77 years at 1 January 2018, who were invited to participate in MYB. 45 and Up Study participant characteristics and subsequent MYB consent and participation were examined. Results: Of 98,836 invited, 13,882 (14%) consented to participate and 6,190 participated (6%). Adjusting for age and sex, a wide range of factors were related to participation. Higher educational attainment had the strongest relationship with increased MYB participation (university versus school non-completion; AdjOR=5.15; 95%CI:4.70-5.64) and lower self-rated quality of life with reduced participation (Poor versus Excellent: AdjOR=0.19; 95%CI:0.11-0.32). A family history of Alzheimer’s disease was related to increased participation but most other dementia risk factors such as diabetes, obesity, stroke, high blood pressure, and current smoking were associated with reduced participation. Conclusion: Higher socio-economic status, particularly educational attainment, is strongly associated with engagement in online dementia prevention research. Increasing population awareness of dementia risk factors, and better understanding the participation barriers in at-risk groups, is necessary to ensure online interventions are optimally designed to promote maximum participation.

Imtiaz Masfique Dowllah, Juan Lopez-Alvarenga, Gladys E. Maestre, Ulku Karabulut, Michael Lehker, Murat Karabulut
Relationship Between Cognitive Performance, Physical Activity, and Socio-Demographic/Individual Characteristics Among Aging Americans
Abstract: Background: Physical activity (PA) has emerged as a promising approach to delay Alzheimer’s disease and related dementias, but the optimal intensity of PA to improve cognitive health remains unknown. Objective: To evaluate the association between duration and intensity of PA and cognitive domains (executive function, processing speed, and memory) in aging Americans. Methods: Linear regressions in hierarchical blocks for variable adjustment and the size of effect (η2) were analyzed by using the data of 2,377 adults (age=69.3±6.7 years) from the NHANES 2011-2014. Results: Participants with 3-6 h/week of vigorous- and >1 h/week of moderate-intensity PA scored significantly higher in executive function and processing speed domains of cognition compared to inactive peers (η2=0.005 & 0.007 respectively, p<0.05). After adjustment, the beneficial effects of 1-3 h/week of vigorous-intensity PA became trivial for delayed recall memory domain test scores (β=0.33; 95%CI: -0.01,0.67; η2=0.002; p=0.56). There was no linear dose-response relationship between the cognitive test scores and weekly moderate-intensity of PA. Interestingly, higher handgrip strength and higher late-life body mass index were associated with a higher performance across all cognitive domains. Conclusion: Our study supports habitual PA with superior cognition health in some but not all domains among older adults. Furthermore, increased muscle strength and higher late-life adiposity may also impact cognition.

Pingjian Ding, Maria P. Gorenflo, Xiaofeng Zhu, Rong Xu
Aspirin Use and Risk of Alzheimer’s Disease: A 2-Sample Mendelian Randomization Study
Abstract: Background: Observational studies have shown inconsistent findings of the relationships between aspirin use and the risk of Alzheimer’s disease (AD). Objective: Since residual confounding and reverse causality were challenging issues inherent in observational studies, we conducted a 2-sample Mendelian randomization analysis (MR) to investigate whether aspirin use was causally associated with the risk of AD. Methods: We conducted 2-sample MR analyses utilizing summary genetic association statistics to estimate the potential causal relationship between aspirin use and AD. Single-nucleotide variants associated with aspirin use in a genome-wide association study (GWAS) of UK Biobank were considered as genetic proxies for aspirin use. The GWAS summary-level data of AD were derived from a meta-analysis of GWAS data from the International Genomics of Alzheimer’s Project (IGAP) stage I. Results: Univariable MR analysis based on these two large GWAS data sources showed that genetically proxied aspirin use was associated with a decreased risk of AD (Odds Ratio (OR): 0.87; 95% CI: 0.77-0.99). In multivariate MR analyses, the causal estimates remained significant after adjusting for chronic pain, inflammation, heart failure (OR=0.88, 95% CI=0.78-0.98), or stroke (OR=0.87, 95% CI=0.77-0.99), but was attenuated when adjusting for coronary heart disease, blood pressure, and blood lipids. Conclusion: Findings from this MR analysis suggest a genetic protective effect of aspirin use on AD, possibly influenced by coronary heart disease, blood pressure, and lipid levels.

Wenwen Yin*, Ke Wan*, Wenhao Zhu, Xia Zhou, Yating Tang, Wenhui Zheng, Jing Cao, Yu Song, Han Zhao, Xiaoqun Zhu, Zhongwu Sun *These authors contributed equally to this work.
Bilateral Hippocampal Volume Mediated the Relationship Between Plasma BACE1 Concentration and Memory Function in the Early Stage of Alzheimer’s Disease: A Cross-Sectional Study
Abstract: Background: β-site amyloid precursor protein cleaving enzyme 1 (BACE1) is a key enzyme in the formation of amyloid-β (Aβ) protein. Increasing evidence suggests that BACE1 concentration is a potential biomarker for Alzheimer’s disease (AD). Objective: To evaluate the correlations between plasma BACE1 concentration, cognition, and hippocampal volume at different stages of the AD continuum. Methods: Plasma BACE1 concentrations were measured in 32 patients with probable dementia due to AD (ADD), 48 patients with mild cognitive impairment (MCI) due to AD, and 40 cognitively unimpaired (CU) individuals. Memory function was evaluated using the auditory verbal learning test (AVLT), and voxel-based morphometry was used to analyze bilateral hippocampal volumes. Correlation and mediation analyses were performed to investigate the associations between plasma BACE1 concentration, cognition, and hippocampal atrophy. Results: The MCI and ADD groups exhibited elevated BACE1 concentrations compared with the CU group after adjusting for age, sex, and apolipoprotein E (APOE) genotype. Increased BACE1 concentration was found in AD continuum patients who were APOE ε4 carriers (p < 0.05). BACE1 concentration was negatively associated with the scores of the subitems of the AVLT and hippocampal volume (p < 0.05, false discovery rate correction) in the MCI group. Moreover, bilateral hippocampal volume mediated the relationship between BACE1 concentration and recognition in the MCI group. Conclusion: BACE1 expression increased in the AD continuum, and bilateral hippocampal volume mediated the effect of BACE1 concentration on memory function in patients with MCI. Research has indicated that the plasma BACE1 concentration might be a biomarker at the early stage of AD.

Amanda E. Selwood, Vibeke S. Catts, Katya Numbers, Teresa Lee, Anbupalam Thalamuthu, Margaret J. Wright, Perminder Sachdev
The Heritability of Subjective Cognitive Complaints in Older Australian Twins
Abstract: Background: Subjective cognitive complaints (SCCs) may be a precursor to mild cognitive impairment (MCI) and dementia. Objective: This study aimed to examine the heritability of SCCs, correlations between SCC and memory ability, and the influence of personality and mood on these relationships. Methods: Participants were 306 twin pairs. The heritability of SCCs and the genetic correlations between SCCs and memory performance, personality, and mood scores were determined using structural equation modelling. Results: SCCs were low to moderately heritable. Memory performance, personality and mood were genetically, environmentally, and phenotypically correlated with SCCs in bivariate analysis. However, in multivariate analysis, only mood and memory performance had significant correlations with SCCs. Mood appeared to be related to SCCs by an environmental correlation, whereas memory performance was related to SCCs by a genetic correlation. The link between personality and SCCs was mediated by mood. SCCs had a significant amount of both genetic and environmental variances not explained by memory performance, personality, or mood. Conclusion: Our results suggest that SCCs are influenced both by a person’s mood and their memory performance, and that these determinants are not mutually exclusive. While SCCs had genetic overlap with memory performance and environmental association with mood, much of the genetic and environmental components that comprised SCCs were specific to SCCs, though these specific factors are yet to be determined.

Chelsea N. Johnson, Colin S. McCoin, Paul J. Kueck, Amelia G. Hawley, Casey S. John, John P. Thyfault, Russell H. Swerdlow, Paige C. Geiger, Jill K. Morris
Relationship of Muscle Apolipoprotein E Expression with Markers of Cellular Stress, Metabolism, and Blood Biomarkers in Cognitively Healthy and Impaired Older Adults
Abstract: Background: Individuals with mild cognitive impairment (MCI) have reduced lipid-stimulated mitochondrial respiration in skeletal muscle. A major risk factor for Alzheimer's disease (AD), the apolipoprotein E4 (APOE4) allele, is implicated in lipid metabolism and is associated with metabolic and oxidative stress that can result from dysfunctional mitochondria. Heat shock protein 72 (Hsp72) is protective against these stressors and is elevated in the AD brain. Objective: Our goal was to characterize skeletal muscle ApoE and Hsp72 protein expression in APOE4 carriers in relationship to cognitive status, muscle mitochondrial respiration and AD biomarkers. Methods: We analyzed previously collected skeletal muscle tissue from 24 APOE4 carriers (60y+) who were cognitively healthy (CH, n=9) or MCI (n=15). We measured ApoE and Hsp72 protein levels in muscle and phosphorylated tau181 (pTau181) levels in plasma, and leveraged previously collected data on APOE genotype, mitochondrial respiration during lipid oxidation, and VO2 max. Results: Muscle ApoE (p = 0.013) and plasma pTau181 levels (p < 0.001) were higher in MCI APOE4 carriers. Muscle ApoE positively correlated with plasma pTau181 in all APOE4 carriers (R2 = 0.338, p = 0.003). Hsp72 expression negatively correlated with ADP (R2 = 0.775, p = <0.001) and succinate-stimulated respiration (R2 = 0.405, p = 0.003) in skeletal muscle of MCI APOE4 carriers. Plasma pTau181 negatively tracked with VO2 max in all APOE4 carriers (R2 = 0.389, p = 0.003). Analyses were controlled for age. Conclusion: This work supports a relationship between cellular stress in skeletal muscle and cognitive status in APOE4 carriers.

Jamie M. Walker, Mitzi M. Gonzales, William Goette, Kurt Farrell, Charles L. White9, John F. Crary, Timothy E. Richardson
Cognitive and Neuropsychological Profiles in Alzheimer’s Disease and Primary Age-Related Tauopathy and the Influence of Comorbid Neuropathologies
Abstract: Background: Alzheimer’s disease neuropathologic change (ADNC) is defined by the progression of both hyperphosphorylated-tau (p-tau) and amyloid-β (Aβ) and is the most common underlying cause of dementia worldwide. Primary age-related tauopathy (PART), an Aβ-negative tauopathy largely confined to the medial temporal lobe, is increasingly being recognized as an entity separate from ADNC with diverging clinical, genetic, neuroanatomic, and radiologic profiles. Objective: The specific clinical correlates of PART are largely unknown; we aimed to identify cognitive and neuropsychological differences between PART, ADNC, and subjects with no tauopathy (NT). Methods: We compared 2,884 subjects with autopsy-confirmed intermediate-high stage ADNC to 208 subjects with definite PART (Braak stage I-IV, Thal phase 0, CERAD NP score “absent”) and 178 NT subjects from the National Alzheimer’s Coordinating Center dataset. Results: PART subjects were older than either ADNC or NT patients. The ADNC cohort had more frequent neuropathological comorbidities as well as APOE ε4 alleles than the PART or NT cohort, and less frequent APOE ε2 alleles than either group. Clinically, ADNC patients performed significantly worse than NT or PART subjects across cognitive measures, but PART subjects had selective deficits in measures of processing speed, executive function, and visuospatial function, although additional cognitive measures were further impaired in the presence of neuropathologic comorbidities. In isolated cases of PART with Braak stage III-IV, there are additional deficits in measures of language. Conclusion: Overall, these findings demonstrate underlying cognitive features specifically associated with PART, and reinforce the concept that PART is a distinct entity from ADNC.

Stephen M. Rao, Rachel Galioto, Megan Sokolowski, Madelyn Pierce, Lisa Penn, Anna Sturtevant, Blazenka Skugor, Brent Anstead, James B. Leverenz, David Schindler, David Blum, Jay L. Alberts, Lori Posk (Handling Associate Editor: Mark Bondi)
Cleveland Clinic Cognitive Battery (C3B): Normative, Reliability, and Validation Studies of a Self-Administered Computerized Tool for Screening Cognitive Dysfunction in Primary Care
Abstract: Background: The self-administered iPad-based Cleveland Clinic Cognitive Battery (C3B) was designed specifically for the efficient screening of cognitive functioning of older adults in a primary care setting. Objective: 1) Generate regression-based norms from healthy participants to enable demographic corrections to facilitate clinical interpretation; 2) estimate test-retest reliability and practice effects; 3) examine ability to discriminate mild cognitive impairment (MCI) from healthy aging; 4) determine validity of screening in a distracting clinical environment; and 5) determine completion rates and patient satisfaction in a primary care setting. Methods: Study 1 (S1) recruited a stratified sample of 428 healthy adults, ages 18-89, to generate regression-based equations. S2 assessed 2-week test-retest reliability and practice effects in 30 healthy elders. S3 recruited 30 MCI patients and 30 demographically-matched healthy controls. In S4, 30 healthy elders self-administered the C3B in a distracting environment and in a quiet private room in counterbalanced order. In a demonstration project, 470 consecutive primary care patients were administered the C3B as part of routine clinical care (S5). Results: C3B performance was primarily influenced by age, education, and race (S1), had acceptably high test-retest reliability and minimal practice effects (S2), discriminated MCI from healthy controls (S3), was not negatively impacted by a distracting clinical environment (S4), had high completion rates (>92%) and positive ratings from primary care patients (S5). Conclusion: The C3B is a computerized cognitive screening tool that is reliable, validated, self-administered, and is conducive to integration into a busy primary care clinical workflow for detecting MCI, early Alzheimer’s disease, and other related dementias.

Jaime Perales-Puchalt, Kelsey Strube, Ryan Townley, Michelle Niedens, Hector Arreaza, Jana Zaudke, Jeffrey M. Burns
Primary Care Provider Preferences on Dementia Training: A Qualitative Study
Abstract: Background: Dementia has no cure, but interventions can stabilize the progression of cognitive, functional, and behavioral symptoms. Primary care providers (PCPs) are vital for the early detection, and long-term management of these diseases, given their gatekeeping role in the healthcare system. However, PCPs rarely implement evidence-based dementia care due to time limitations and knowledge about diagnosis and treatment. Training PCPs may help address these barriers. Objective: We explored the preferences of PCPs for dementia care training programs. Methods: We conducted qualitative interviews with 23 PCPs recruited nationally via snowball sampling. We conducted remote interviews and organized the transcripts for qualitative review to identify codes and themes, using thematic analysis methods. Results: PCP preferences varied regarding many aspects of ADRD training. Preferences varied regarding how to best increase PCP participation in training, and what content and materials were needed to help them and the families they serve. We also found differences regarding the duration and timing of training, and the modality of training sessions (remote versus in-person). Conclusion: The recommendations arising from these interviews have the potential to inform the development and refinement of dementia training programs to optimize their implementation and success.

Cassandra A. DeMarshall, Jeffrey Viviano, Sheina Emrani, Umashanger Thayasivam, George A. Godsey, Abhirup Sarkar, Benjamin Belinka, David J. Libon, Robert G. Nagele, and on behalf of the Parkinson’s Study Group and the Alzheimer’s Disease Neuroimaging Initiative (Handling Associate Editor: Mark Bondi)
Early Detection of Alzheimer’s Disease-Related Pathology Using a Multi-Disease Diagnostic Platform Employing Autoantibodies as Blood-Based Biomarkers
Abstract: Background: Evidence for the universal presence of IgG autoantibodies in blood and their potential utility for the diagnosis of Alzheimer’s disease (AD) and other neurodegenerative diseases has been extensively demonstrated by our laboratory. The fact that AD-related neuropathological changes in the brain can begin more than a decade before tell-tale symptoms emerge has made it difficult to develop diagnostic tests useful for detecting the earliest stages of AD pathogenesis. Objective: To determine the utility of a panel of autoantibodies for detecting the presence of AD-related pathology along the early AD continuum, including at pre-symptomatic [an average of 4 years before the transition to mild cognitive impairment (MCI)/AD)], prodromal AD (MCI), and mild-moderate AD stages. Methods: A total of 328 serum samples from multiple cohorts, including ADNI subjects with confirmed pre-symptomatic, prodromal, and mild-moderate AD, were screened using Luminex xMAP® technology to predict the probability of the presence of AD-related pathology. A panel of eight autoantibodies with age as a covariate was evaluated using randomForest and receiver operating characteristic (ROC) curves. Results: Autoantibody biomarkers alone predicted the probability of the presence of AD-related pathology with 81.0% accuracy and an area under the curve (AUC) of 0.84 (95% CI=0.78-0.91). Inclusion of age as a parameter to the model improved the AUC (0.96; 95% CI=0.93-0.99) and overall accuracy (93.0%). Conclusion: Blood-based autoantibodies can be used as an accurate, non-invasive, inexpensive, and widely accessible diagnostic screener for detecting AD-related pathology at pre-symptomatic and prodromal AD stages that could aid clinicians in diagnosing AD.

Hadeel Y. Tarawneh, Dona M.P. Jayakody, Shipra Verma, Vincent Doré, Ying Xia, Wilhelmina H.A.M. Mulders, Ralph N. Martins, Hamid R. Sohrabi
Auditory Event-Related Potentials in Older Adults with Subjective Memory Complaints
Abstract: Background: Auditory event-related potentials (AERPs) have been suggested as possible biomarkers for the early diagnosis of Alzheimer’s disease (AD). However, no study has investigated AERP measures in individuals with subjective memory complaints (SMCs), who have been suggested to be at a pre-clinical stage of AD. Objective: This study investigated whether AERPs in older adults with SMC can be used to objectively identify those at high risk of developing AD. Methods: AERPs were measured in older adults. Presence of SMC was determined using the Memory Assessment Clinics Questionnaire (MAC-Q). Hearing thresholds using pure-tone audiometry, neuropsychological data, levels of amyloid-β burden and Apolipoprotein E (APOE) ɛ4 genotype were also obtained A classic two-tone discrimination (oddball) paradigm was used to elicit AERPs (i.e., P50, N100, P200, N200, and P300). Results: Sixty-two individuals (14 male, mean age 71.9 ± 5.2 years) participated in this study, of which, 43 (11 male, mean age 72.4 ± 5.5 years) were SMC and 19 (3 male, mean age 70.8 ± 4.3 years) were non-SMC (controls). P50 latency was weakly but significantly correlated with MAC-Q scores. In addition, P50 latencies were significantly longer in Aβ+ individuals compared to Aβ- individuals. Conclusion: Results suggest that P50 latencies may be a useful tool to identify individuals at higher risk (i.e., participants with high Aβ burden) of developing measurable cognitive decline. Further longitudinal and cross-sectional studies in a larger cohort on SMC individuals are warranted to determine if AERP measures could be of significance for the detection of pre-clinical AD.