Volume 92, Number 2, 2023

Pages 391-393

Mohammad Rafi Khezri, Morteza Ghasemnejad-Berenji, Donya Moloodsouri
The PI3K/AKT Signaling Pathway and Caspase-3 in Alzheimer’s Disease: Which One Is the Beginner?
Abstract: One of the main players in apoptosis during Alzheimer’s disease progression are different members of caspase family of proteases. The most well-known member of this family is caspase-3, in which alterations of its levels have been detected in samples from Alzheimer’s disease patients. There are numerous intracellular factors involved in regulation of cellular apoptosis through regulation of caspase-3 activity, the most important of which is the PI3K/AKT signaling pathway. This commentary tries to highlight the probable relations between PI3K/AKT signaling pathway and caspase-3 in Alzheimer’s disease.

Pages 395-409
Daniel J. Panyard, Yuetiva K. Deming, Burcu F. Darst, Carol A. Van Hulle, Henrik Zetterberg, Kaj Blennow, Gwendlyn Kollmorgen, Ivonne Suridjan, Cynthia M. Carlsson, Sterling C. Johnson, Sanjay Asthana, Corinne D. Engelman, Qiongshi Lu
Liver-Specific Polygenic Risk Score Is Associated with Alzheimer’s Disease Diagnosis
Abstract: Background: Our understanding of the pathophysiology underlying Alzheimer’s disease (AD) has benefited from genomic analyses, including those that leverage polygenic risk score (PRS) models of disease. The use of functional annotation has been able to improve the power of genomic models. Objective: We sought to leverage genomic functional annotations to build tissue-specific AD PRS models and study their relationship with AD and its biomarkers. Methods: We built 13 tissue-specific AD PRS and studied the scores’ relationships with AD diagnosis, cerebrospinal fluid (CSF) amyloid, CSF tau, and other CSF biomarkers in two longitudinal cohort studies of AD. Results: The AD PRS model that was most predictive of AD diagnosis (even without APOE) was the liver AD PRS: n = 1,115; odds ratio = 2.15 (1.67-2.78), p = 3.62 x 10-9. The liver AD PRS was also statistically significantly associated with cerebrospinal fluid biomarker evidence of amyloid-β (Aβ42:Aβ40 ratio, p = 3.53 x 10-6) and the phosphorylated tau:amyloid-β ratio (p = 1.45 x 10-5). Conclusion: These findings provide further evidence of the role of the liver-functional genome in AD and the benefits of incorporating functional annotation into genomic research.

Pages 411-424
Raghav Tandon, Allan I. Levey, James J. Lah, Nicholas T. Seyfried, Cassie S. Mitchell
Machine Learning Selection of Most Predictive Brain Proteins Suggests Role of Sugar Metabolism in Alzheimer’s Disease
Abstract: Background: The complex and not yet fully understood etiology of Alzheimer’s disease (AD) shows important proteopathic signs which are unlikely to be linked to a single protein. However, protein subsets from deep proteomic datasets can be useful in stratifying patient risk, identifying stage dependent disease markers, and suggesting possible disease mechanisms. Objective: The objective was to identify protein subsets that best classify subjects into control, asymptomatic Alzheimer’s disease (AsymAD), and AD. Methods: Data comprised 6 cohorts; 620 subjects; 3,334 proteins. Brain tissue-derived predictive protein subsets for classifying AD, AsymAD, or control were identified and validated with label-free quantification and machine learning. Results: A 29-protein subset accurately classified AD (AUC = 0.94). However, an 88-protein subset best predicted AsymAD (AUC = 0.92) or Control (AUC= 0.92) from AD (AUC = 0.98). AD versus Control: APP, DHX15, NRXN1, PBXIP1, RABEP1, STOM, and VGF. AD versus AsymAD: ALDH1A1, BDH2, C4A, FABP7, GABBR2, GNAI3, PBXIP1, and PKAR1B. AsymAD versus Control: APP, C4A, DMXL1, EXOC2, PITPNB, REBEP1, and VGF. Additional predictors: DNAJA3, PTBP2, SLC30A9, VAT1L, CROCC, PNP, SNCB, PRKAR1B, ENPP6, HAPLN2, PSMD4, and CMAS. Conclusion: Biomarkers were dynamically separable across disease stages. Predictive proteins were significantly enriched to sugar metabolism.

Pages 425-443
Hind A. Beydoun*, May A. Beydoun*, Ana I. Maldonado, Marie T. Fanelli-Kuczmarski, Jordan Weiss, Michele K. Evans, Alan B. Zonderman *These authors contributed equally to this work.
Allostatic Load and Cognitive Function Among Urban Adults in the Healthy Aging in Neighborhoods of Diversity across the Life Span Study
Abstract: Background: Cross-sectional studies have linked cognition to allostatic load (AL) which reflects multisystem dysregulation from life course exposure to stressors. Objective: To examine baseline and changes in AL and their relationships with 11 cognitive function test scores, while exploring health disparities according to sex and race. Methods: Longitudinal [Visit 1 (2004-2009) and Visit 2 (2009-2013)] data were analyzed from 2,223 Healthy Aging in Neighborhoods of Diversity across the Life Span participants. We calculated AL total score using cardiovascular, metabolic, and inflammatory risk indicators, and applied group-based trajectory modeling to define AL change. Results: Overall and stratum-specific relationships were evaluated using mixed-effects linear regression models that controlled for socio-demographic, lifestyle, and health characteristics. Baseline AL was significantly associated with higher log-transformed Part A Trail Making Test score [Loge (TRAILS A)] (β=0.020, p=0.004) and increasing AL was associated with higher Benton Visual Retention Test score [BVRT] (β=0.35, p=0.002) at baseline, in models that controlled for age, sex, race, poverty status, education, literacy, smoking, drug use, the 2010 healthy eating index and body mass index. Baseline AL and AL change were not related to change in cognitive function between visits. There were no statistically significant interaction effects by sex or race in fully-adjusted models. Conclusion: At baseline, AL was associated with worse attention or executive functioning. Increasing AL was associated with worse non-verbal memory or visuo-constructional abilities at baseline. AL was not related to change in cognitive function over time, and relationships did not vary by sex or race.

Pages 445-455
Nicole Shu Ning Teoh, Bibek Gyanwali, Mitchell K.P. Lai, Yuek Ling Chai, Joyce R. Chong, Eddie Jun Yi Chong, Christopher Chen, Chuen Seng Tan, Saima Hilal (Handling Associate Editor: Masafumi Ihara)
Association of Interleukin-6 and Interleukin-8 with Cognitive Decline in an Asian Memory Clinic Population
Abstract: Background: Neuroinflammation has been postulated to play an important role in cognitive impairment, cognitive decline, and dementia. Inflammatory biomarkers such as interleukin-6 (IL-6) and IL-8 are found to be associated with the neuro-inflammatory process and worse cognitive function. However, it is unknown whether these interleukins are associated with long-term cognitive function. Objective: To investigate the association of baseline IL-6 and IL-8 with cognitive function at baseline as well as its association with cognitive decline over five-year follow-up. Methods: 387 patients were recruited from an ongoing memory clinic-based study who underwent comprehensive physical, medical, neuropsychological and blood assessments together with brain MRI. IL-6 and IL-8 were measured using LUMINEX assays. The National Institute of Neurological Disorders and Stroke-Canadian Stroke Network neuropsychological battery was used to assess cognitive decline across multiple domains. Results: Among the 387 (mean age=72.9 years and 53.7% males) participants, 322 had at least two follow-up assessments and were included in the longitudinal analysis. Negative linear trend associations were found between tertiles of IL-8 with baseline global cognition (p-trend<0.001), attention (p-trend=0.005), executive function (p-trend<0.001), and visuospatial function (p-trend=0.002) domains. No association was found between baseline IL-8 and cognitive decline. IL-6 was not associated with both baseline and follow-up cognition. Conclusion: IL-8 was associated with worse cognition especially in attention, executive function, and visuospatial function, suggesting the role of neuroinflammation in cognitive impairment. Hence, blood inflammatory biomarkers may be useful indicators in identifying patients at risk of cognitive impairment and warrant consideration for inclusion in treatment trials.

Pages 457-466
Carolyn W. Zhu, Yian Gu, Anton J. Kociolek, Kayri K. Fernandez, Stephanie Cosentino, Yaakov Stern
Costs During the Last Five Years of Life for Patients with Clinical and Pathological Confirmed Diagnosis of Lewy Body Dementia and Alzheimer’s Disease
Abstract: Background: Little is known regarding healthcare expenditures for patients with dementia with Lewy bodies (DLB) during the end of life. Objective: This study estimated Medicare expenditures during the last 5 years of life in a decedent sample of patients who were clinically diagnosed with Alzheimer’s disease (AD) or DLB and had autopsy confirmed diagnosis. Methods: The study included 58 participants clinically diagnosed with mild dementia at study entry (AD: n=44, DLB: n=14) and also had autopsy-confirmed diagnoses of pure AD (n=32), mixed AD+Lewy body (LB) (n=5), or pure LB (n=11). Total Medicare expenditures were compared by clinical and pathology confirmed diagnosis, adjusting for sex, age at death, and patient's cognition, function, comorbidities, and psychiatric and extrapyramidal symptoms. Results: When pathology diagnoses were not considered, predicted annualized total Medicare expenditures during the last 5 years of life were similar between clinically diagnosed AD ($7,465±1,098) and DLB ($7,783±1,803). When clinical diagnoses were not considered, predicted expenditures were substantially higher in patients with pathology confirmed mixed AD+LB ($12,005±2,455) than either pure AD ($6,173±941) or pure LB ($4,629±1,968) cases. Considering clinical and pathology diagnosis together, expenditures for patients with clinical DLB and pathology mixed AD+LB ($23,592±3,679) dwarfed other groups. Conclusion: Medicare expenditures during the last 5 years of life were substantially higher in patients with mixed AD+LB pathology compared to those with pure-AD and pure-DLB pathologies, particularly in those clinically diagnosed with DLB. Results highlight the importance of having both clinical and pathology diagnoses in examining healthcare costs.

Pages 467-475
Emma van den Berg*, Johanna Nilsson*, Iris Kersten, Gunnar Brinkmalm, Anna M. de Kort, Catharina J.M. Klijn, Floris H.B.M. Schreuder, Lieke Jäkel, Johan Gobom, Erik Portelius, Henrik Zetterberg, Ann Brinkmalm, Kaj Blennow, H. Bea Kuiperij, Marcel M. Verbeek *These authors contributed equally to this work.
Cerebrospinal Fluid Panel of Synaptic Proteins in Cerebral Amyloid Angiopathy and Alzheimer’s Disease
Abstract: Background: Alzheimer’s disease (AD) and cerebral amyloid angiopathy (CAA) share pathogenic pathways related to amyloid-β deposition. Whereas AD is known to affect synaptic function, such an association for CAA remains yet unknown. Objective: We therefore aimed to investigate synaptic dysfunction in CAA. Methods: Multiple reaction monitoring mass spectrometry was used to quantify cerebrospinal fluid (CSF) concentrations of 15 synaptic proteins in CAA and AD patients, and age- and sex-matched cognitively unimpaired controls. Results: We included 25 patients with CAA, 49 patients with AD, and 25 controls. Only neuronal pentraxin-2 levels were decreased in the CSF of CAA patients compared with controls (p = 0.04). CSF concentrations of 12 other synaptic proteins were all increased in AD compared with CAA or controls (all p ≤ 0.01) and were unchanged between CAA and controls. Synaptic protein concentrations in the subgroup of CAA patients positive for AD biomarkers (CAA/ATN+; n=6) were similar to AD patients, while levels in CAA/ATN- (n=19) were comparable with those in controls. A regression model including all synaptic proteins differentiated CAA from AD at high accuracy levels (area under the curve 0.987). Conclusion: In contrast to AD, synaptic CSF biomarkers were found to be largely unchanged in CAA. Moreover, concomitant AD pathology in CAA is associated with abnormal synaptic protein levels. Impaired synaptic function in AD was confirmed in this independent cohort. Our findings support an apparent differential involvement of synaptic dysfunction in CAA and AD and may reflect distinct pathological mechanisms.

Pages 477-485
Jun-Rong Ren, Zhen Wang, Yuan Cheng, Chen-Yang He, Jie-Ming Jian, Dong-Yu Fan, Ying-Ying Shen, Dong-Wan Chen, Hui-Yun Li, Xu Yi, Gui-Hua Zeng, Cheng-Rong Tan, An-Yu Shi, Li-Yong Chen, Qing-Xiang Mao, Yan-Jiang Wang, Jun Wang (Handling Associate Editor: Jin-Tai Yu)
Associations Between Plasma Klotho with Renal Function and Cerebrospinal Fluid Amyloid-β Levels in Alzheimer’s Disease: The Chongqing Ageing & Dementia Study
Abstract: Background: The kidney-brain crosstalk has been involved in Alzheimer's disease (AD) with the mechanism remaining unclear. The anti-aging factor Klotho was reported to attenuate both kidney injury and AD pathologies. Objective: To investigate whether plasma Klotho participated in kidney-brain crosstalk in AD. Methods: We enrolled 33 PiB-PET-positive AD patients and 33 amyloid-β (Aβ)-negative age- and sex-matched cognitively normal (CN) controls from the Chongqing Ageing & Dementia Study (CADS). The levels of plasma Klotho, Aβ, and tau in the cerebrospinal fluid (CSF) were measured by enzyme-linked immunosorbent assay. Results: We found higher plasma Klotho and lower estimated glomerular filtration rate (eGFR) levels in AD patients compared with CN. The eGFR was positively associated with Aβ42, Aβ40 levels in CSF and negatively associated with CSF T-tau levels. Plasma Klotho levels were both negatively correlated with CSF Aβ42 and eGFR. Mediation analysis showed that plasma Klotho mediated 24.96% of the association between eGFR and CSF Aβ42. Conclusion: Renal function impacts brain Aβ metabolism via the kidney-brain crosstalk, in which the plasma Klotho may be involved as a mediator. Targeting Klotho to regulate the kidney-brain crosstalk provides potential therapeutic approaches for AD.

Pages 487-498
Rei Ono*, Takashi Sakurai*, Taiki Sugimoto, Kazuaki Uchida, Takeshi Nakagawa, Taiji Noguchi, Ayane Komatsu, Hidenori Arai, Tami Saito *These authors contributed equally to this work.
Mortality Risks and Causes of Death by Dementia Types in a Japanese Cohort with Dementia: NCGG-STORIES
Abstract: Background: Prognosis-related information regarding dementia needs to be updated, as changes in medical and long-term care environments for patients with dementia in recent decades may be improving the prognosis of the disease. Objective: We aimed to investigate the mortality, cause of death, and prognostic factors by types of dementia in a Japanese clinic-based cohort. Methods: The National Center for Geriatrics and Gerontology-Life Stories of People with Dementia consists of clinical records and prognostic data of patients who visited the Memory Clinic in Japan. Patients who attended the clinic between July 2010 and September 2018, or their close relatives, were asked about death information via a postal survey. A cohort of 3,229 patients (mean age, 76.9; female, 1,953) was classified into six groups: normal cognition (NC), mild cognitive impairment (MCI), Alzheimer’s disease (AD), vascular dementia, dementia with Lewy bodies (DLB), and frontotemporal lobar degeneration. A Cox proportional hazards model was employed to compare the mortality of each type of dementia, MCI, and NC. Results: Patients with all types of dementia and MCI had higher mortality rates than those with NC (hazard risks: 2.61–5.20). The most common cause of death was pneumonia, followed by cancer. In the MCI, AD, and DLB groups, older age, male sex, and low cognitive function were common prognostic factors but not presence of apolipoprotein E ε4 allele. Conclusion: Our findings suggest important differences in the mortality risk and cause of death among patients with dementia, which will be useful in advanced care planning and policymaking.

Pages 499-511
Hiroyuki Kikuchi, Miki Takahashi, Hiroaki Komatsu, Paul H. Axelsen
Post-Translational Chemical Modifications of Amyloid-β Peptides by 4-Hydroxy-2-Nonenal
Abstract: Background: The extraction and quantification of amyloid-β (Aβ) peptides in brain tissue commonly uses formic acid (FA) to disaggregate Aβ fibrils. However, it is not clear whether FA can disaggregate post-translationally modified Aβ peptides, or whether it induces artifact by covalent modification during disaggregation. Of particular interest are Aβ peptides that have been covalently modified by 4-hydroxy-2-nonenal (HNE), an oxidative lipid degradation product produced in the vicinity of amyloid plaques that dramatically accelerates the aggregation of Aβ peptides. Objective: Test the ability of FA to disaggregate Aβ peptides modified by HNE and to induce covalent artifacts. Methods: Quantitative liquid-chromatography-tandem-mass spectrometry of monomeric Aβ peptides and identify covalently modified forms. Results: FA disaggregated ordinary Aβ fibrils but also induced the time-dependent formylation of at least 2 residue side chains in Aβ peptides, as well as oxidation of its methionine side chain. FA was unable to disaggregate Aβ peptides that had been covalently modified by HNE. Conclusion: The inability of FA to disaggregate Aβ peptides modified by HNE prevents FA-based approaches from quantifying a pool of HNE-modified Aβ peptides in brain tissue that may have pathological significance.

Pages 513-527
Jane Stocks, Ashley Heywood, Karteek Popuri, Mirza Faisal Beg, Howie Rosen, Lei Wang, for the Alzheimer’s Disease Neuroimaging Initiative (Handling Associate Editor: Sofia Toniolo)
Longitudinal Spatial Relationships Between Atrophy and Hypometabolism Across the Alzheimer’s Disease Continuum
Abstract: Background: The A/T/N framework allows for the assessment of pathology-specific markers of MRI-derived structural atrophy and hypometabolism on 18FDG-PET. However, how these measures relate to each other locally and distantly across pathology-defined A/T/N groups is currently unclear. Objective: To determine the regions of association between atrophy and hypometabolism in A/T/N groups both within and across time points. Methods: We examined multivariate multimodal neuroimaging relationships between MRI and 18FDG-PET among suspected non-Alzheimer’s disease pathology (SNAP) (A-T/N+; n=14), Amyloid Only (A+T-N-; n=24) and Probable AD (A+T+N+; n = 77) groups. Sparse canonical correlation analyses were employed to model spatially disjointed regions of association between MRI and 18FDG-PET data. These relationships were assessed at three combinations of time points – cross-sectionally, between baseline visits and between month 12 (M-12) follow-up visits, as well as longitudinally between baseline and M-12 follow-up. Results: In the SNAP group, spatially overlapping relationships between atrophy and hypometabolism were apparent in the bilateral temporal lobes when both modalities were assessed at the M-12 timepoint. Amyloid-Only subjects showed spatially discordant distributed atrophy-hypometabolism relationships at all time points assessed. In Probable AD subjects, local correlations were evident in the bilateral temporal lobes when both modalities were assessed at baseline and at M-12. Across groups, hypometabolism at baseline correlated with non-local, or distant, atrophy at M-12. Conclusion: These results support the view that local concordance of atrophy and hypometabolism is the result of a tau-mediated process driving neurodegeneration.

Pages 529-546
Marina Makri, Alexandra Christakidou, Magda Tsolaki
A Novel Method of Teaching English to People with Mild Cognitive Impairment Using Songs: A Randomized Controlled Trial Protocol
Abstract: Background: People with mild cognitive impairment (MCI) need to prevent the further decline of their cognitive functions, and one way to do so is by learning a foreign language. Objective: This study describes the development of a protocol for a novel, non-pharmacological intervention for people with MCI that seeks to prevent or reduce cognitive decline by teaching English through songs. Methods: The development of this protocol follows a mixed-methodology approach, consisting of three stages: 1) development of the protocol of the intervention, 2) a randomized controlled trial study with two arms over six months that includes an intervention group and a control group, and 3) the evaluation of the protocol by trainers. In the second stage, we recruited a total of 128 people with MCI from the five participating countries of this study (Greece, Spain, Croatia, Slovenia, and Italy). This educational program will assess three main outcomes after 6 months of the English Lessons with the Use of Songs for People with Mild Cognitive Impairment (E.L.So.M.C.I.) workshops. Results: Our primary outcome will hopefully be an improvement in general cognition in the intervention group compared to the control group from baseline to 6 months follow-up. Secondary outcomes include a decrease in participants' anxiety and depression and an improvement in their quality of life. Development of English language skills is the third outcome. Conclusion: This is the first study to develop a protocol and implement and assess this intervention in a randomized controlled trial. We expect this intervention to help people with MCI in cognitive, psychological, and social aspects.

Pages 547-564
Ulla Petti, Simon Baker, Anna Korhonen, Jessica Robin
The Generalizability of Longitudinal Changes in Speech Before Alzheimer’s Disease Diagnosis
Abstract: Background: Language impairment in Alzheimer’s disease (AD) has been widely studied but due to limited data availability, relatively few studies have focused on the longitudinal change in language in the individuals who later develop AD. Significant differences in speech have previously been found by comparing the press conference transcripts of President Bush and President Reagan, who was later diagnosed with AD. Objective: In the current study, we explored whether the patterns previously established in the single AD-healthy control (HC) participant pair apply to a larger group of individuals who later receive AD diagnosis. Methods: We replicated previous methods on two larger corpora of longitudinal spontaneous speech samples of public figures, consisting of 10 and 9 AD-HC participant pairs. As we failed to find generalizable patterns of language change using previous methodology, we proposed alternative methods for data analysis, investigating the benefits of using different language features and their change with age, and compiling the single features into aggregate scores. Results: The single features that showed the strongest results were moving average type:token ratio (MATTR) and pronoun-related features. The aggregate scores performed better than the single features, with lexical diversity capturing a similar change in two-thirds of the participants. Conclusion: Capturing universal patterns of language change prior to AD can be challenging, but the decline in lexical diversity and changes in MATTR and pronoun-related features act as promising measures that reflect the cognitive changes in many participants.

Pages 565-572
Seunghoon Lee, Hyunsuk Jeong, Im-Seok Koh, Jeewon Suh, HyunSung Cho, YongBok Kim, EunJung Cho, Jhin Goo Chang, Minha Hong, Su Young Lee
Association of Knowledge About Dementia with Two Dimensional Attitudes Among a Community Population in South Korea
Abstract: Background: Providing correct information about dementia and people living with dementia and improving the attitude toward the disease have important implications in overcoming prejudice and negative perceptions and strengthening the social support system. However, studies are limited about which aspects of dementia knowledge affect attitudes toward it and the influence of such knowledge on particular aspects of such attitudes. Objective: This study examined which part of dementia knowledge affects attitudes toward dementia and, furthermore, the influence of such knowledge on two aspects of attitudes in the general population. Methods: A population-based cross-sectional survey of 1,200 participants aged 20 years or older was adopted. A landline and wireless telephone survey was conducted from October 12 to October 22, 2021. The survey data included self-report questions about dementia knowledge, dementia attitudes, demographics, and family information. Multiple linear regression analysis was performed. Results: Dementia knowledge was positively associated with global dementia attitudes. In terms of the relationship between the two dimensions of dementia attitudes and knowledge, the latter displayed a significant positive association with accepting attitudes (β=0.121, p<0.001) but not with affective attitudes (β=0.064, p=0.084). Among dementia knowledge, dementia symptom/diagnosis and policy categories were positively associated with accepting attitudes (β=0.198, p=0.006; β=0.357, p<0.001). Conclusion: Our study suggests that people with more dementia knowledge have more accepting attitudes toward dementia. It may be effective to continue education on dementia to improve the public accepting attitudes. However, to improve negative emotional attitudes toward dementia, various approaches beyond education may be needed.

Pages 573-580
Yi Jayne Tan*, Isabel Siow*, Seyed Ehsan Saffari, Simon K.S. Ting, Zeng Li, Nagaendran Kandiah, Louis C.S. Tan, Eng King Tan, Adeline S.L. Ng *These authors contributed equally to this work.
Plasma Soluble ST2 Levels Are Higher in Neurodegenerative Disorders and Associated with Poorer Cognition
Abstract: Background: Suppressor of tumorgenicity 2 (ST2) is highly expressed in brain tissue and is a receptor for interleukin 33 (IL-33). ST2 exists in two forms, a transmembrane receptor (ST2L) and a soluble decoy receptor (sST2). IL-33 binds to ST2L, triggering downstream signaling pathways involved in amyloid plaque clearance. Conversely, sST2 binds competitively to IL-33, attenuating its neuroprotective effects. High sST2 levels have been reported in mild cognitive impairment (MCI) and Alzheimer’s disease (AD), suggesting that the IL-33/ST2 signaling pathway may be implicated in neurodegenerative diseases. Objective: To investigate plasma sST2 levels in controls and patients with MCI, AD, frontotemporal dementia (FTD), and Parkinson’s disease (PD). Methods: Plasma sST2 levels were measured using ELISA in 397 subjects (91 HC, 46 MCI, 38 AD, 28 FTD, and 194 PD). Cerebrospinal fluid (CSF) levels of sST2 were measured in 22 subjects. Relationship between sST2 and clinical outcomes were analyzed. Results: Plasma sST2 levels were increased across all disease groups compared to controls, with highest levels seen in FTD followed by AD and PD. Dementia patients with higher sST2 had lower cross-sectional cognitive scores in Frontal Assessment Battery and Digit Span Backward. At baseline, PD-MCI patients had higher sST2, associated with worse attention. In the longitudinal PD cohort, higher sST2 significantly associated with decline in global cognition and visuospatial domains. Plasma sST2 levels correlated with CSF sST2 levels. Conclusion: Plasma sST2 is raised across neurodegenerative diseases and is associated with poorer cognition. Higher baseline sST2 is a potential biomarker of disease severity in neurodegeneration.

Pages 581-590
Yong-Li Zhao*, Ya-Nan Ou*, Ya-Hui Ma, Lan Tan, Jin-Tai Yu (Handling Associate Editor: Ling-Qiang Zhu) *These authors contributed equally to this work.
Characteristics of Subjective Cognitive Decline Associated with Alzheimer's Disease Amyloid Pathology: Findings from The CABLE Study
Abstract: Background: Subjective cognitive decline (SCD) is considered as a preclinical hallmark of Alzheimer’s disease (AD). However, the characteristics of SCD associated with amyloid pathology remain unclear. Objective: We aimed to explore the associations between SCD characteristics with amyloid pathology. Methods: Using logistic regression analyses, we analyzed the associations between cerebrospinal fluid (CSF) amyloid pathology with AD risk factors, SCD-specific characteristics (onset of SCD within the last five years, age at onset ≥60 years, feelings of worse performance, informant confirmation of complaints, worries, other domains of cognition complaints), as well as subthreshold depressive and anxiety symptoms among individuals with SCD. Results: A total of 535 SCD individuals with available CSF Aβ42 information from the Chinese Alzheimer’s Biomarker and LifestylE (CABLE) study (mean age of 63.5 years, range 40 to 88 years; 47.10% female) were enrolled. The characteristics of informant confirmation of complaints (OR, 95% CI = 2.00, 1.19-3.36), subthreshold depressive symptoms (OR, 95% CI = 2.31, 1.05-5.09), and subthreshold anxiety symptoms (OR, 95% CI = 2.22, 1.09-4.51) were found to be significantly associated with pathological amyloid in multivariate analyses when adjusting for age, sex, education, and APOE ε4. Besides, age and females were observed risks for amyloid pathology in subscale analyses. Nonetheless, we did not find any associations of other SCD-specific characteristics with amyloid pathology in this study. Conclusion: Our study suggested that informant confirmed complaints and subthreshold psychiatric symptoms might be critical for discriminating AD-related SCD from non-AD related SCD.

Pages 591-604
Alexander P. Gabrielli, Ian Weidling, Amol Ranjan, Xiaowan Wang, Lesya Novikova, Subir Roy Chowdhury, Blaise Menta, Alexandra Berkowicz, Heather M. Wilkins, Kenneth R. Peterson, Russell H. Swerdlow
Mitochondria Profoundly Influence Apolipoprotein E Biology
Abstract: Background: Mitochondria can trigger Alzheimer’s disease (AD)-associated molecular phenomena, but how mitochondria impact apolipoprotein E (APOE; apoE) is not well known. Objective: Consider whether and how mitochondrial biology influences APOE and apoE biology. Methods: We measured APOE expression in human SH-SY5Y neuronal cells with different forms of mitochondrial dysfunction including total, chronic mitochondrial DNA (mtDNA) depletion (ρ0 cells); acute, partial mtDNA depletion; and toxin-induced mitochondrial dysfunction. We further assessed intracellular and secreted apoE protein levels in the ρ0 cells and interrogated the impact of transcription factors and stress signaling pathways known to influence APOE expression. Results: SH-SY5Y ρ0 cells exhibited a 65-fold increase in APOE mRNA, an 8-fold increase in secreted apoE protein, and increased intracellular apoE protein. Other models of primary mitochondrial dysfunction including partial mtDNA-depletion, toxin-induced respiratory chain inhibition, and chemical-induced manipulations of the mitochondrial membrane potential similarly increased SH-SY5Y cell APOE mRNA. We explored potential mediators and found in the ρ0 cells knock-down of the C/EBPα and NFE2L2 (Nrf2) transcription factors reduced APOE mRNA. The activity of two mitogen-activated protein kinases, JNK and ERK, also strongly influenced ρ0 cell APOE mRNA levels. Conclusion: Primary mitochondrial dysfunction either directly or indirectly activates APOE expression in a neuronal cell model by altering transcription factors and stress signaling pathways. These studies demonstrate mitochondrial biology can influence the biology of the APOE gene and apoE protein, which are implicated in AD.

Pages 605-614
Måns Gyllenhammar, Anna Rennie, Daniel Ferreira Padilla, John Wallert, Anders Rydström, Lars-Olof Wahlund, Maria Eriksdotter, Eric Westman, Urban Ekman
The Association Between Temporal Atrophy and Episodic Memory Is Moderated by Education in a Multi-Center Memory Clinic Sample
Abstract: Background: Cognitive reserve (CR) is hypothesized to partially explain the discrepancy between Alzheimer’s disease related brain pathology and cognitive performance. Educational attainment is often used as a proxy for CR. Objective: To examine the association of years of education and the relationship between atrophy in the medial temporal lobe and episodic memory, in a cross-sectional ecological multi-center memory clinic cohort. Methods: Included patients (n=702) had undergone memory clinic examination and were diagnosed with subjective cognitive impairment (n=99), mild cognitive impairment (n=471), or dementia (n=132). Total years of education were used as a moderating variable and neuropathology was operationalized as visual ratings of medial temporal lobe atrophy (MTA) on magnetic resonance imaging and computer tomography images. Weighted least squares regression and multiple regression were used to analyze moderation and the effect of education separately by diagnostic group. A composite score of two episodic memory tests constituted the dependent variable. Results: After controlling for age and gender the interaction term between MTA and years of education was significant indicating moderation. In particular, the regression model showed that at low levels of MTA, high education individuals had better episodic memory performance. However, at higher MTA levels, high education individuals had the lowest episodic memory performance. Education had a significant positive effect on episodic memory in SCI and MCI, but not dementia. Conclusion: These results extend the findings of education moderating the effect of MTA on cognition to a naturalistic memory clinic setting. Implications of the findings for theories on CR are discussed.

Pages 615-628
Pratishtha Chatterjee*, Vincent Doré*, Steve Pedrini, Natasha Krishnadas, Rohith Thota, Pierrick Bourgeat, Milos D. Ikonomovic, Stephanie R. Rainey-Smith, Samantha C. Burnham, Christopher Fowler, Kevin Taddei, Rachel Mulligan, David Ames, Colin L. Masters, Jürgen Fripp, Christopher C. Rowe, Ralph N. Martins, Victor L. Villemagne for the AIBL Research Group *These authors contributed equally to this work.
Plasma Glial Fibrillary Acidic Protein Is Associated with 18F-SMBT-1 PET: Two Putative Astrocyte Reactivity Biomarkers for Alzheimer’s Disease
Abstract: Background: Astrocyte reactivity is an early event along the Alzheimer’s disease (AD) continuum. Plasma glial fibrillary acidic protein (GFAP), posited to reflect astrocyte reactivity, is elevated across the AD continuum from preclinical to dementia stages. Monoamine oxidase-B (MAO-B) is also elevated in reactive astrocytes observed using 18F-SMBT-1 PET in AD. Objective: The objective of this study was to evaluate the association between the abovementioned astrocyte reactivity biomarkers. Methods: Plasma GFAP and Aβ were measured using the Simoa® platform in participants who underwent brain 18F-SMBT-1 and Aβ-PET imaging, comprising 54 healthy control (13 Aβ-PET+ and 41 Aβ-PET-), 11 mild cognitively impaired (3 Aβ-PET+ and 8 Aβ-PET-) and 6 probable AD (5 Aβ-PET+ and 1 Aβ-PET-) individuals. Linear regressions were used to assess associations of interest. Results: Plasma GFAP was associated with 18F-SMBT-1 signal in brain regions prone to early Aβ deposition in AD, such as the supramarginal gyrus (SG), posterior cingulate (PC), lateral temporal (LT) and lateral occipital cortex (LO). After adjusting for age, sex, APOE ε4 genotype, and soluble Aβ (plasma Aβ42/40 ratio), plasma GFAP was associated with 18F-SMBT-1 signal in the SG, PC, LT, LO, and superior parietal cortex (SP). On adjusting for age, sex, APOE ε4 genotype and insoluble Aβ (Aβ-PET), plasma GFAP was associated with 18F-SMBT-1 signal in the SG. Conclusion: There is an association between plasma GFAP and regional 18F-SMBT-1 PET, and this association appears to be dependent on brain Aβ load.

Pages 629-638
Roaa Zayed Atef, Bernhard Michalowsky, Anika Raedke, Moritz Platen, Wiebke Mohr, Franka Mühlichen, Jochen René Thyrian, Wolfgang Hoffmann
Impact of Hearing Aids on Progression of Cognitive Decline, Depression, and Quality of Life Among People with Cognitive Impairment and Dementia
Abstract: Background: Hearing loss is common in people with dementia (PwD) and a modifiable risk factor for cognitive decline. Recent studies revealed that hearing loss could cause social isolation and depression, which is associated with health-related quality of life (HRQoL). However, there is a lack of knowledge about the impact of the utilization of hearing aids on these outcomes. Objective: To assess whether hearing aids use might be positively associated with the progression of cognitive function, depression, and HRQoL among PwD. Methods: We analyzed two-year follow-up data from 258 PwD (≥70 years, living at home). Cognitive decline was measured with Mini-Mental Status Examination (MMSE), depression using Geriatric Depression Scale (GDS), and HRQoL with Quality of Life in Alzheimer's Disease Scale (QoL-AD). The impact of hearing aid utilization on the progression of outcomes was assessed using multivariate regression models. Results: 123 patients had hearing loss (47.7%), from which n=54 (43.9%) used hearing aids. Patients with hearing loss were older and had a lower HRQoL than those without hearing loss. Use of hearing aids in patients with hearing loss was associated with a lower increase in depressive symptoms (b= -0.74, CI95 -1.48 – -0.01, p=0.047) over time as compared to those not using hearing aids. There was no effect on PwD's cognition, and the association with higher HRQoL was significant after one, but not consistently over two years. Conclusion: Early detection and intervention of presbycusis using hearing aids might improve mental health and HRQoL in dementia.

Pages 639-652
Donald R. Royall, Raymond F. Palmer (Handling Associate Editor: James Galvin)
Multiple Adipokines Predict Dementia Severity as Measured by δ: Replication Across Biofluids and Cohorts
Abstract: Background: We have explored dementia’s blood-based protein biomarkers in the Texas Alzheimer’s Research and Care Consortium (TARCC) study. Among them are adipokines, i.e., proteins secreted by adipose tissue some of which have been associated with cognitive impairment. Objective: To associate adipokines with dementia severity and replicate their association across cohorts and biofluids (serum /plasma). Methods: We used eight rationally chosen blood-based protein biomarkers as indicators of a latent variable, i.e., “Adipokines”. We then associated that construct with dementia severity as measured by the latent dementia-specific phenotype “δ” in structural equation models (SEM). Significant factor loadings and Adipokines’ association with δ were replicated across biofluids in the Alzheimer’s Disease Neuroimaging Initiative (ADNI). Results: Eight adipokine proteins loaded significantly on the Adipokines construct. Adipokines measured in plasma (ADNI) or serum (TARCC) explained 24 and 70% of δ’s variance, respectively. An Adipokine composite score, derived from the latent variables, rose significantly across clinical diagnoses and achieved high areas under the receiver operating characteristic curve (ROC/AUC) for discrimination of Alzheimer’s disease from normal controls (NC) or cases of mild cognitive impairment (MCI) and between NC and MCI. Conclusion: These results again suggest that SEM can be used to create latent biomarker classifiers that replicate across samples and biofluids, and that a substantial fraction of dementia’s variance is attributable to peripheral blood-based protein levels via the patterns codified in those latent constructs.

Pages 653-665
Mikkel Pejstrup Agger, Else Rubæk Danielsen, Marcus Schultz Carstensen, N. Mai Nguyen, Maibritt Horning, Mark Alexander Henney, Christopher Boe Ravn Jensen, Anders Ohlhues Baandrup, Troels Wesenberg Kjær, Kristoffer Hougaard Madsen, Kamilla Miskowiak, Paul Michael Petersen, Peter Høgh
Safety, Feasibility, and Potential Clinical Efficacy of 40 Hz Invisible Spectral Flicker versus Placebo in Patients with Mild-to-Moderate Alzheimer’s Disease: A Randomized, Placebo-Controlled, Double-Blinded, Pilot Study
Abstract: Background: Recent studies suggested induction of 40 Hz neural activity as a potential treatment for Alzheimer’s disease (AD). However, prolonged exposure to flickering light raises adherence and safety concerns, encouraging investigation of tolerable light stimulation protocols. Objective: To investigate the safety, feasibility, and exploratory measures of efficacy Methods: This two-stage randomized placebo-controlled double-blinded clinical trial, recruited first cognitive healthy participants (n=3/2 active/placebo), and subsequently patients with mild-to-moderate AD (n=5/6, active/placebo). Participants were randomized 1:1 to receive either active intervention with 40 Hz Invisible Spectral Flicker (ISF) or placebo intervention with color and intensity matched non-flickering white light. Results: Few and mild adverse events were observed. Adherence was above 86.1% of intended treatment days, with participants remaining in front of the device for >51.3 min (60 max) and directed gaze >34.9 min. Secondary outcomes of cognition indicate a tendency towards improvement in the active group compared to placebo (mean: -2.6/1.5, SD: 6.58/6.53, active/placebo) at week 6. Changes in hippocampal and ventricular volume also showed no tendency of improvement in the active group at week 6 compared to placebo. At week 12, a potential delayed effect of the intervention was seen on the volume of the hippocampus in the active group compared to placebo (mean: 0.34/-2.03, SD: 3.26/1.18, active/placebo), and the ventricular volume active group (mean: -0.36/2.50, SD: 1.89/2.05, active/placebo), compared to placebo. Conclusion: Treatment with 40 Hz ISF offers no significant safety or adherence concerns. Potential impact on secondary outcomes must be tested in larger scale clinical trials.

Pages 667-678
Huimin Sun, Min Liu, Jue Liu
Association of Influenza Vaccination and Dementia Risk: A Meta-Analysis of Cohort Studies
Abstract: Background: Dementia is a critical global public health problem. Previous cohort studies have found that influenza vaccination can decrease the risk of dementia. Objective: This meta-analysis aimed to systematically examine the relationship between influenza vaccination and dementia risk. Methods: We searched PubMed, Embase, Web of Science, ScienceDirect, medRxiv, and bioRxiv for studies investigating dementia risk based on influenza vaccination status, up to September 14, 2022. Relative risks (RRs) and 95% confidence intervals (95% CIs) were pooled in the meta-analysis. Subgroup analyses and sensitivity analyses were conducted as well. Results: Of the 4,087 articles initially reviewed, 6 cohort studies were included in the final meta-analysis, and all eligible studies were at low risk of bias. There were 2,087,195 participants without dementia at baseline (mean age: 61.8-75.5 years, 57.05% males), and 149,804 (7.18%) cases of dementia occurred during 4.00-13.00 years of follow-up. Pooled analysis of adjusted RRs found that influenza vaccination could reduce dementia risk by 31% (RR = 0.69, 95% CI: 0.57-0.83). Subgroup analyses showed that in the study with a mean age of 75-80 years or 75%-100% males, the association was generally weakened compared with studies with a mean age of 60-75 years or 25%-50% males. The results were stable in the sensitivity analyses, and no publication bias was observed. Conclusion: Influenza vaccination in older adults was markedly associated with a decreased risk of dementia. More mechanistic studies and epidemiological studies are needed to clarify the association between influenza vaccination and decreased dementia risk.

Pages 679-689
John Andersson, Anna Sundström, Maria Nordin, David Segersson, Bertil Forsberg, Rolf Adolfsson, Anna Oudin
PM2.5 and Dementia in a Low Exposure Setting: The Influence of Odor Identification Ability and APOE
Abstract: Background: Growing evidence show that long term exposure to air pollution increases the risk of dementia. Objective: The aim of this study was to investigate associations between PM2.5 exposure and dementia in a low exposure area, and to investigate the role of olfaction and the APOE ε4 allele in these associations. Methods: Data were drawn from the Betula project, a longitudinal study on aging, memory, and dementia in Sweden. Odor identification ability was assessed using the Scandinavian Odor Identification Test (SOIT). Annual mean PM2.5 concentrations were obtained from a dispersion-model and matched at the participants’ residential address. Proportional hazard regression was used to calculate hazard ratios. Results: Of 1,846 participants, 348 developed dementia during the 21-year follow-up period. The average annual mean PM2.5 exposure at baseline was 6.77 µg/m3, which is 1.77 µg/m3 above the WHO definition of clean air. In a fully adjusted model (adjusted for age, sex, APOE, SOIT, cardiovascular diseases and risk factors, and education) each 1 µg/m3 difference in annual mean PM2.5-concentration was associated with a hazard ratio of 1.23 for dementia (95% CI: 1.01–1.50). Analyses stratified by APOE status (ε4 carriers versus non-carriers), and odor identification ability (high versus low), showed associations only for ε4 carriers, and for low performance on odor identification ability. Conclusion: PM2.5 was associated with an increased risk of dementia in this low pollution setting. The associations between PM2.5 and dementia seemed stronger in APOE carriers and those with below average odor identification ability.

Pages 691-700
Mingyu Tang*, Ning Su*, Dingding Zhang, Yi Dai, Ming Yao, Lixin Zhou, Liying Cui, Shuyang Zhang, Yicheng Zhu, Jun Ni (Handling Associate Editor: Liyong Wu) *These authors contributed equally to this work.
The Differential Effects of APOE ε4 on Cerebral Volumetric Structures in Different Lifespan in Community-Dwelling Populations
Abstract: Background: Apolipoprotein E (APOE) is closely related to Alzheimer’s disease and other age-related diseases. In recent years, several studies have shown an interaction of APOE by age on brain volume. However, validation in larger cohorts is required. Objective: We explored the age-related effect of APOE on brain volumes in a community-dwelling cohort. Methods: Inhabitants in Shunyi District in Beijing aged ≥35 years were invited to join this study from 2013 to 2016. The baseline assessments, APOE genotyping and brain magnetic resonance imaging were performed. Neuroimaging small vessel disease characteristics and brain volumes (global measures, cerebral lobes, hippocampus, brainstem, and subcortical nuclei) were acquired. The general linear model was used to analyze the interaction of APOE genotypes by age on brain volumes, and the age of 60 years was chosen as a cut-off value for stratification analysis. Results: A total of 1,105 subjects were enrolled in the final analysis with a mean age of 56.18 (9.30) years, and 37.7% were men. APOE ε3/ε3 carriers account for 71.8%, ε2 (+) 14.0%, and ε4 (+) 14.2%. Compared with APOE ε3/ε3, a significant protective effect for APOE ε4 (+) on brain parenchyma fraction (β = 0.450, p = 0.048) was observed in subjects aged ≤60 years; in participants aged >60 years, a negative effect for APOE ε4 (+) on hippocampus (β = 1.087, p = 0.021) was found. Conclusion: Our study reveals that APOE ε4 has differential effects on cerebral structures in different stages of lifespan, suggesting its complicated biological function and underlying antagonistic pleiotropy.

Pages 701-712
Frank D. Mann, Sean A.P. Clouston, Adolfo Cuevas, Monika A. Waszczuk, Pei-Fen Kuan, Melissa A. Carr, Anna R. Docherty, Andrea A. Shabalin, Sam E. Gandy, Benjamin J. Luft
Genetic Liability, Exposure Severity, and Post-Traumatic Stress Disorder Predict Cognitive Impairment in World Trade Center Responders
Abstract: Background: There is a high incidence of cognitive impairment among World Trade Center (WTC) responders, comorbid with post-traumatic stress disorder (PTSD). Yet, it remains unknown whether genetic liability for Alzheimer’s disease, PTSD, educational attainment, or for a combination of these phenotypes, is associated with cognitive impairment in this high-risk population. Similarly, whether the effects of genetic liability are comparable to PTSD and indicators of exposure severity remains unknown. Objective: In a study of 3,997 WTC responders, polygenic scores for Alzheimer’s disease, PTSD, and educational attainment were used to test whether genome-wide risk for one or more of these phenotypes is associated with cognitive impairment, controlling for population stratification, while simultaneously estimating the effects of demographic factors and indicators of 9/11 exposure severity, including symptoms of PTSD. Results: Polygenic scores for Alzheimer’s disease and educational attainment were significantly associated with an increase and decrease, respectively, in the hazard rate of mild cognitive impairment. The polygenic score for Alzheimer’s disease was marginally associated with an increase in the hazard rate of severe cognitive impairment, but only age, exposure severity, and symptoms of PTSD were statistically significant predictors. Conclusion: These results add to the emerging evidence that many WTC responders are suffering from mild cognitive impairments that resemble symptoms of Alzheimer’s disease, as genetic liability for Alzheimer’s disease predicted incidence of mild cognitive impairment. However, compared to polygenic scores, effect sizes were larger for PTSD and the type of work that responders completed during rescue and recovery efforts.

Pages 713-722
Zebin Wang, Shan Zeng, Yan Jing, Wenjuan Mao, Hongyan Li
Sarm1 Regulates Circadian Rhythm Disorder in Alzheimer’s Disease in Mice
Abstract: Background: Sarm1 (Sterile alpha and TIR motif-containing 1) is a key protein that regulates neurodegenerative pathologies. Alzheimer's disease (AD) is highly associated with neurodegenerative lesions and biorhythmic disturbances. Objective: This study aims to decipher the role of Sarm1 in AD-induced circadian rhythm disturbances and AD progression. Methods: Open field and water maze tests were used to assess the cognitive function of mice. Thioflavin-S staining was used to assess amyloid-β (Aβ) plaque deposition in the hippocampus and cortex. Rhythmic waveform of home cage activity and temperature was recorded to evaluate circadian rhythm. Expression of clock molecules including Bmal1 and Per2 in the hippocampus were analyzed using western blot and real-time PCR. Further, HT22 cells with Sam1 knockout were treated with Aβ31-35 treatment to initiate circadian rhythm disorder in the cellular level to assess the changes in Bmal1 and Per2. Results: Our data suggested that Sarm1 deficiency rescued cognitive disorder, decreased Aβ plaque deposition in the hippocampus and cortex, inhibited astrocyte activation, improved circadian rhythm, altered clock molecule expression in the cortex and hippocampus in APP/PS1 mice. Conclusion: Sarm1 attenuates circadian rhythm disturbances and reduces AD progression. These data support the potential use of Sarm1 as a therapeutic target to improve circadian rhythm to impede AD progression.