Volume 93, Number 4, IN PRESS

Yujiao Li, Jun Chang, Xi Chen, Jianwei Liu, Lan Zhao
Advances in the Study of APOE and Innate Immunity in Alzheimer’s Disease
Abstract: Alzheimer's disease (AD) is a progressive degenerative disease of the nervous system (CNS) with an insidious onset. Clinically, it is characterized by a full range of dementia manifestations including memory impairment, aphasia, loss of speech, loss of use, loss of recognition, impairment of visuospatial skills, and impairment of executive function, as well as changes in personality and behavior. The exact cause of AD has not yet been identified. Nevertheless, modern research indicates that genetic factors contribute to 70% of human’s risk of AD. Apolipoprotein (APOE) accounts for up to 90% of the genetic predisposition. APOE is a crucial gene that cannot be overstated. In addition, innate immunity plays a significant role in the etiology and treatment of AD. Understanding the different subtypes of APOE and their interconnections is of paramount importance. APOE and innate immunity, along with their relationship to AD, are primary research motivators for in-depth research and clinical trials. The exploration of novel technologies has led to an increasing trend in the study of AD at the cellular and molecular levels and continues to make more breakthroughs and progress. As of today, there is no effective treatment available for AD around the world. This paper aims to summarize and analyze the role of APOE and innate immunity, as well as development trends in recent years. It is anticipated that APOE and innate immunity will provide a breakthrough for humans to hinder AD progression in the near future.

Systematic Review
Paulien Moyaert, Soetkin Beun, Eric Achten, Patricia Clement
Effect of Acetylcholinesterase Inhibitors on Cerebral Perfusion and Cognition: A Systematic Review
Background: Perfusion imaging has the potential to identify neurodegenerative disorders in a preclinical stage. However, to correctly interpret perfusion-derived parameters, the impact of perfusion modifiers should be evaluated. Objective: In this systematic review, the impact of acute and chronic intake of four acetylcholinesterase inhibitors (AChEIs) on cerebral perfusion in adults was investigated: physostigmine, donepezil, galantamine, and rivastigmine. Results: Chronic AChEI treatment results in an increase of cerebral perfusion in treatment-responsive patients with Alzheimer’s disease, dementia with Lewy bodies, and Parkinson’s disease dementia in the frontal, parietal, temporal, and occipital lobes, as well as the cingulate gyrus. These effects appear to be temporary, dose-related, and consistent across populations and different AChEI types. On the contrary, further perfusion decline was reported in patients not receiving AChEIs or not responding to the treatment. Conclusion: AChEIs appear to be a potential perfusion modifier in neurodegenerative patients. More research focused on quantitative perfusion in both patients with and without a cholinergic deficit is needed to draw conclusions on whether AChEI intake should be considered when analyzing perfusion data.

Systematic Review
Yi Qu, Lin Zhuang, Huiying Zhang, Chang Liu, Xiaonan Wang
The Effects of Light Therapy for Depression in Dementia: A Systematic Review and Meta-Analysis
Abstract: Background: Depression is one of the most common symptoms in patients with dementia. Objective: This meta-analysis aimed to evaluate the effect of light therapy on depression associated with dementia by using a single scale. Methods: Published studies based on the terms including “Dementia”, “depression”, and “Phototherapy” were searched. Web of Science, PubMed, Embase, CiNii, CNKI, Wanfang Database, and China Biology Medicine disc were adopted to collect randomized controlled studies or cross-controlled studies using the Cornell Scale for Depression in Dementia (CSDD) until February 2022. GRADE and Review Manager Version 5.4.1 were employed to assess the risk of bias. A meta-analysis was conducted by R 4.0.2 software based on the changes in CSDD scores. Results: A total of 1,055 studies were retrieved from the databases, and six studies were included after screening. Some 406 people with dementia were included with an average age of over 80 years. Forest plot results showed that light intervention improved depression scores of dementia patients (MD = -2.59, 95% CI: -4.46 to -0.71), and light intensity less than 1,000 lux improved depression symptoms of dementia patients (MD = -2.76, 95% CI: -4.55 to -0.97). An intervention that lasted 8 to 12 weeks was the most effective (MD = -3.77, 95% CI: -6.93 to -0.60), and non-stable interventions such as ceiling LED lights exerted more positive effects (MD = -2.12, 95% CI: -3.38 to -0.85). Conclusion: The overall results of the meta-analysis suggested that light intervention can improve the depressive symptoms of older patients with dementia.

Carlo Abbate
The Adult Neurogenesis Theory of Alzheimer’s Disease
Abstract: Alzheimer’s disease starts in neural stem cells (NSCs) in the niches of adult neurogenesis. All primary factors responsible for pathological tau hyperphosphorylation are inherent to adult neurogenesis and migration. However, when amyloid pathology is present, it strongly amplifies tau pathogenesis. Indeed, the progressive accumulation of extracellular amyloid-β deposits in the brain triggers a state of chronic inflammation by microglia. Microglial activation has a significant pro-neurogenic effect that fosters the process of adult neurogenesis and supports neuronal migration. Unfortunately, this “reactive” pro-neurogenic activity ultimately perturbs homeostatic equilibrium in the niches of adult neurogenesis by amplifying tau pathogenesis in AD. This scenario involves NSCs in the subgranular zone of the hippocampal dentate gyrus in late-onset AD (LOAD) and NSCs in the ventricular-subventricular zone along the lateral ventricles in early-onset AD (EOAD), including familial AD (FAD). Neuroblasts carrying the initial seed of tau pathology travel throughout the brain via neuronal migration driven by complex signals and convey the disease from the niches of adult neurogenesis to near (LOAD) or distant (EOAD) brain regions. In these locations, or in close proximity, a focus of degeneration begins to develop. Then, tau pathology spreads from the initial foci to large neuronal networks along neural connections through neuron-to-neuron transmission.

Short Communication
Vladimir Volloch, Sophia Rits-Volloch
Effect of Lecanemab in Early Alzheimer’s Disease: Mechanistic Interpretation in the Amyloid Cascade Hypothesis 2.0 Perspective
Abstract: In clinical trials, lecanemab showed statistically significant yet marginal slowdown of Alzheimer’s disease (AD)-associated cognitive decline. This could be due to its sub-optimal design and/or deployment; alternatively, its limited efficiency could be intrinsic. Distinguishing between the two is of great importance considering the acute need of efficient AD therapy and tremendous resources being invested in its pursuit. The present study analyzes the mode of operation of lecanemab within the framework of recently proposed Amyloid Cascade Hypothesis 2.0 and concludes that the second is correct. It suggests that substantial improvement of the efficiency of lecanemab in symptomatic AD is unlikely and proposes the alternative therapeutic strategy.

Jan Krzysztof Blusztajn, Barbara E. Slack
Accelerated Breakdown of Phosphatidylcholine and Phosphatidylethanolamine Is a Predominant Brain Metabolic Defect in Alzheimer’s Disease
Abstract: Numerous studies have demonstrated defects in multiple metabolic pathways in Alzheimer’s disease (AD), detected in autopsy brains and in the cerebrospinal fluid in vivo. However, until the advent of techniques capable of measuring thousands of metabolites in a single sample, it has not been possible to rank the relative magnitude of these abnormalities. A recent study provides evidence that the abnormal turnover of the brain’s most abundant phospholipids: phosphatidylcholine and phosphatidylethanolamine, constitutes a major metabolic pathology in AD. We place this observation in a historical context and discuss the implications of a central role for phospholipid metabolism in AD pathogenesis.

Yujia Zhou, Jingyi Dong, Jingmei Song, Chaojie Lvy, Yuyan Zhang
Efficacy of Glucose Metabolism-Related Indexes on the Risk and Severity of Alzheimer's Disease: A Meta-Analysis
Abstract: Background: Considering the strong correlation made between Alzheimer's disease (AD) and the pathology of glucose metabolism disorder, we sought to analyze the effects of fasting blood glucose (FBG) level, fasting plasma insulin (FINS) level, and insulin resistance index (HOMA-IR) on the risk and severity of AD. Objective: Reveal the pathological relationship between AD and insulin resistance. Methods: We searched 5 databases from inception through April 4, 2022. Meta-regression was conducted to identify if there were significant differences between groups. Shapiro-Wilk test and the Q-Q diagram were applied to evaluate the normality of variables. A multiple logistic regression model was employed to explore the association between FBG, FINS, HOMA-IR, and Mini-Mental State Examination scale score (MMSE). Results: 47 qualified articles including 2,981 patients were enrolled in our study. FBG (p < 0.001), FINS (p < 0.001), and HOMA-IR (p < 0.001) were higher in AD patients than in controls. HOMA-IR was negatively correlated with MMSE (p = 0.001) and positively related to the sex ratio (male versus female) (p < 0.05). HOMA-IR obeyed lognormal distribution (p > 0.05), and the 95% bilateral boundary values were 0.73 and 10.67. FBG (p = 0.479) was positively correlated to MMSE, while FINS (p = 0.1657) was negatively correlated with MMSE. Conclusion: The increase in the levels of FBG, FINS, and HOMA-IR served as precise indicators of the risk of AD. HOMA-IR was found to be correlated to the increasing severity of AD, especially in male AD patients.

Maristella Yahagi-Estevam*, Daniela Souza Farias-Itao*, Renata Elaine Paraizo Leite, Roberta Diehl Rodriguez, Carlos Augusto Pasqualucci, Ricardo Nitrini, Wilson Jacob-Filho, Melinda C. Power, Claudia Kimie Suemoto *These authors contributed equally to this work.
The Potential Role of Selection Bias in the Association Between Coronary Atherosclerosis and Cognitive Impairment
Abstract: Background: Coronary atherosclerosis assessed in vivo was associated with cognitive impairment; however, conflicting findings have been reported in autopsy samples. Objective: Our aims were to assess the association between atherosclerotic stenosis in the coronary arteries and cognitive impairment and to investigate the possibility of selection bias in an autopsy study. Methods: Coronary arteries were collected, and the largest luminal stenosis was measured. Sociodemographic, clinical, and cognitive information were reported by a reliable next-of-kin. The association was tested using logistic and linear regressions adjusted for sociodemographic and clinical variables. We restricted the sample to individuals that were born in 1935 or earlier and stratified the analysis by cause of death to investigate the role of selection bias. Results: In 253 participants (mean age=78.0±8.5 years old, 48% male), stenosis was not associated with cognitive impairment (OR=0.85, 95%CI=0.69; 1.06, p=0.15). In individuals who were born before 1936 in the absence of cardiovascular disease as the cause of death, greater stenosis was associated with cognitive impairment (OR=4.02, 95%CI=1.39; 11.6, p=0.01). On the other hand, this association was not present among those born in 1935 or earlier who died of cardiovascular diseases (OR=0.83, 95%CI= 0.60; 1.16, p=0.28). Conclusion: We found that higher coronary stenosis was associated with cognitive impairment only in individuals born in 1935 or earlier and who had not died from cardiovascular diseases. Selection bias may be an important issue when investigating risk factors for chronic degenerative diseases in older individuals using autopsy samples.

Mingfeng Yang*, Ben Chen*, Huarong Zhou, Naikeng Mai, Min Zhang, Zhangying Wu, Qi Peng, Qiang Wang, Meiling Liu, Si Zhang, Gaohong Lin, Jingyi Lao, Yijie Zeng, Xiaomei Zhong, Yuping Ning *These authors contributed equally to this work.
Relationships Among Short Self-Reported Sleep Duration, Cognitive Impairment, and Insular Functional Connectivity in Late-Life Depression
Abstract: Background: Both late-life depression (LLD) and short sleep duration increase the risk of cognitive impairment. Increased insular resting-state functional connectivity (FC) has been reported in individuals with short sleep duration and dementia. Objective: This study aimed to investigate whether short sleep duration is associated with impaired cognition and higher insular FC in patients with LLD. Methods: This case–control study recruited 186 patients with LLD and 83 normal controls (NC), and comprehensive psychometric assessments, sleep duration reports and resting-state functional MRI scans (81 LLD patients and 54 NC) were conducted. Results: Patients with LLD and short sleep duration (LLD-SS patients) exhibited more severe depressive symptoms and worse cognitive function than those with normal sleep duration (LLD-NS patients) and NC. LLD-SS patients exhibited higher FC between the bilateral insula and inferior frontal gyrus (IFG) pars triangularis than LLD-NS patients and NC, while LLD-NS patients exhibited lower FC than NC. Increased insular FC was correlated with short sleep duration, severe depressive symptoms, and slower information processing speeds. Furthermore, an additive effect was found between sleep duration and LLD on global cognition and insular FC. Conclusion: LLD-SS patients exhibited impaired cognition and increased insular FC. Abnormal FC in LLD-SS patients may be a therapeutic target for neuromodulation to improve sleep and cognitive performance and thus decrease the risk of dementia.

Elena Rakuša, Anne Fink, Gültekin Tamgüney, Michael T. Heneka, Gabriele Doblhammer
Sporadic Use of Antibiotics in Older Adults and the Risk of Dementia: A Nested Case–Control Study Based on German Health Claims Data
Abstract: Background: Antibiotics for systemic use may increase the risk of neurodegeneration, yet antibiotic therapy may be able to halt or mitigate an episode of neurodegenerative decline. Objective: To investigate the association of sporadic use of antibiotics and subsequent dementia risk (including Alzheimer's disease). Methods: We used data from the largest public health insurance fund in Germany, the Allgemeine Ortskrankenkasse (AOK). Each of the 35,072 dementia cases aged 60 years and older with a new dementia diagnosis during the observation period from 2006 to 2018 was matched with two control-patients by age, sex, and time since 2006. We ran conditional logistic regression models for dementia risk in terms of odds ratios (OR) as a function of antibiotic use for the entire antibiotic group and for each antibiotic subgroup. We controlled for comorbidities, need for long-term care, hospitalizations, and nursing home placement. Results: Antibiotic use was positively associated with dementia (OR=1.18, 95% confidence interval (95%CI):1.14-1.22), which became negative after adjustment for comorbidities, at least one diagnosis of bacterial infection or disease, and covariates (OR=0.93, 95%CI:0.90–0.96). Subgroups of antibiotics were also negatively associated with dementia after controlling for covariates: tetracyclines (OR=0.94, 95%CI:0.90–0.98), beta-lactam antibacterials, penicillins (OR=0.93, 95%CI:0.90–0.97), other beta-lactam antibacterials (OR=0.92, 95%CI:0.88-0.95), macrolides, lincosamides, and streptogramins (OR=0.88, 95%CI:0.85–0.92), and quinolone antibacterials (OR=0.96, 95%CI:0.92–0.99). Conclusion: Our results suggest that there was a decreased likelihood of dementia for preceding antibiotic use. The benefits of antibiotics in reducing inflammation and thus the risk of dementia need to be carefully weighed against the increase in antibiotic resistance.

Fuxia Yang*, Lu Yang*, Xuhao Fang*, Yao Deng, Renling Mao, Aijuan Yan, Wenshi Wei *These authors contributed equally to this work.
Increased Cerebrospinal Fluid Levels of Soluble Triggering Receptor Expressed on Myeloid Cells 2 and Chitinase-3-Like Protein 1 in Idiopathic Normal-Pressure Hydrocephalus
Abstract: Background: Neurodegenerative disease pathology is associated with neuroinflammation, but evidence on idiopathic normal pressure hydrocephalus (iNPH) remains limited and cerebrospinal fluid (CSF) biomarker profiles need to be elucidated. Objective: To investigate whether iNPH pathological mechanisms are associated with greater CSF markers of core Alzheimer’s disease pathology (amyloid-β42 (Aβ42), phosphorylated tau (P-tau)), neurodegeneration (total tau (T-tau)), and neuroinflammation (soluble triggering receptor expressed on myeloid cells 2 (sTREM2), chitinase-3-like protein 1 (YKL-40)). Methods: The study analyzed lumbar CSF samples from 63 patients with iNPH and 20 age-matched orthopedic surgery patients who had no preoperative gait or cognitive impairment (control group). Aβ42, T-tau, P-tau, sTREM2, and YKL-40 in different subgroups were investigated. Results: CSF sTREM2 levels were significantly higher in the iNPH group than in the control group, but no significant between-group difference was noted in YKL-40. Moreover, YKL-40 levels were significantly higher in the tap test non-responders than in the tap test responders (p=0.021). At the 1-year follow-up after shunt surgery, the CSF P-tau levels were significantly lower (p=0.020) in those with gait improvement and the CSF sTREM2 levels were significantly lower (p=0.041) in those with cognitive improvement. In subgroup analysis, CSF sTREM2 levels were strongly correlated with CSF YKL-40 in the iNPH group (r=0.443, p<0.001), especially in the tap test non-responders (r=0.653, p=0.002). Conclusion: YKL-40 and sTREM2 are disease-specific markers of neuroinflammation, showing higher CSF levels in iNPH. In addition, sTREM2 is positively associated with YKL-40, indicating that interactions of glial cells play an important role in iNPH pathogenesis.

Shan Xu, Yifei Ren, Rui Liu, Yuanjing Li, Tingting Hou, Yongxiang Wang, Xiang Wang, Lidan Wang, Roberto Monastero, Yifeng Du, Lin Cong, Chengxuan Qiu
Prevalence and Progression of Subjective Cognitive Decline Among Rural Chinese Older Adults: A Population-Based Study
Abstract: Background: Few community-based studies have examined occurrence and progression of subjective cognitive decline (SCD). Objective: To investigate prevalence and progression of SCD among rural-dwelling Chinese elderly people. Methods: This cohort study included 2,488 cognitively unimpaired adults (age ≥65 years) who were examined at baseline (2014-2015) and followed in 2018. Demographic, epidemiological, clinical, and neuropsychological data were collected via in-person interviews and clinical examinations following a structured questionnaire. At baseline, SCD was assessed using the self-rated Ascertain Dementia 8-item Questionnaire. At follow-up, Alzheimer’s disease (AD) and vascular dementia (VaD) were clinically diagnosed following the international criteria. Data were analyzed using logistic regression models. Results: The prevalence of SCD was 40.07%. SCD at baseline was associated with the multivariable-adjusted odds ratio (OR) of 1.51 (95% confidence interval 1.10-2.07) for incident cognitive impairment, no dementia (CIND) and 3.11 (1.64-5.93) for incident AD. Among people with SCD at baseline, the multivariable-adjusted OR of incident CIND was 0.55(0.32-0.96) for hyperlipidemia; the multivariable-adjusted OR of incident AD was 1.21 (1.14-1.30) for older age, 0.32 (0.12-0.88) for high education, 2.60 (1.11-6.08) for carrying APOE ε4 allele, and 0.34 (0.13-0.86) for high social support, whereas the multivariable-adjusted OR of incident VaD was 6.30 (1.71-23.18) for obesity. Conclusion: SCD affects over 40% of rural-dwelling cognitively unimpaired older adults in China. SCD is associated with accelerated progression to CIND and AD. Older age, lack of school education, APOE ε4 allele, and low social support are associated with an increased risk of progression from SCD to AD, whereas obesity is related to accelerated progression to VaD.

Min Chu*, Deming Jiang*, Li Liu, Binbin Nie, Bo Cui, Yihao Wang, Pedro Rosa-Neto, Liyong Wu *These authors contributed equally to this work.
Altered Anterior Insular Metabolic Connectivity in Asymptomatic MAPT P301L Carriers
Abstract: Background: The insula is the predominant brain region impaired in behavior variant frontotemporal dementia (bvFTD). However, structural and functional changes in the sub-insula in the asymptomatic stage of bvFTD are unknown. Objective: To describe structural and functional changes in insula subregions in asymptomatic carriers of the P301L mutation of the microtubule-associated protein tau (MAPT) gene and patients with bvFTD. Methods: Six asymptomatic MAPT P301L mutation carriers and 12 MAPT negative control subjects of the same pedigree were enrolled, along with 30 patients with a clinical diagnosis of bvFTD and 30 matched controls. All subjects underwent hybrid positron emission tomography/magnetic resonance imaging. Atlas-based parcellation using a fine-grained Brainnetome Atlas was conducted to assess gray matter (GM) volume, metabolism, and metabolic connectivity in the sub-insula (region of interest). Results: There was no significant GM atrophy or hypometabolism in insula subregions in asymptomatic MAPT P301L carriers, although decreased metabolic connectivity between vIa-middle temporal gyrus, vIa-temporal poles, dIa-middle temporal gyrus and dIa-temporal poles; and increased connectivity between vIa-orbitofrontal, vIa-dorsal lateral superior frontal gyrus, and dIa-orbitofrontal and dIa-dorsal lateral superior frontal gyrus were observed. Patients with bvFTD had significant atrophy and hypometabolism in all insula subregions and decreased metabolic connectivity in the whole brain, including vIa/dIa-middle temporal and vIa/dIa-temporal poles. The standardized uptake value ratios of vIa and dIa were negatively associated with behavioral disinhibition scale scores. Conclusion: Metabolic connectivity is altered in vIa and dIa subregions of the sub-insula in MAPT P301L mutation carriers before the occurrence of atrophy, hypometabolism, and clinical symptoms.

Bhargav T. Nallapu, Kellen K. Petersen, Richard B. Lipton, Ellen Grober, Reisa A. Sperling, Ali Ezzati
Association of Alcohol Consumption with Cognition in Older Population: The A4 Study
Abstract: Background: Alcohol use disorders have been categorized as a ‘strongly modifiable’ risk factor for dementia. Objective: To investigate the cross-sectional association between alcohol consumption and cognition in older adults and if it is different across sexes or depends on amyloid-β (Aβ) accumulation in the brain. Methods: Cognitively unimpaired older adults (N=4387) with objective and subjective cognitive assessments and amyloid positron emission tomography (PET) imaging were classified into four categories based on their average daily alcohol use. Multivariable linear regression was then used to test the main effects and interactions with sex and Aβ levels. Results: Individuals who reported no alcohol consumption had lower scores on the Preclinical Alzheimer Cognitive Composite (PACC) compared to those consuming one or two drinks/day. In sex-stratified analysis, the association between alcohol consumption and cognition was more prominent in females. Female participants who consumed two drinks/day had better performance on PACC and Cognitive Function Index (CFI) than those who reported no alcohol consumption. In an Aβ-stratified sample, the association between alcohol consumption and cognition was present only in the Aβ- subgroup. The interaction between Aβ status and alcohol consumption on cognition was not significant. Conclusion: Low or moderate consumption of alcohol was associated with better objective cognitive performance and better subjective report of daily functioning in cognitively unimpaired individuals. The association was present only in Aβ- individuals, suggesting that the pathophysiologic mechanism underlying the effect of alcohol on cognition is independent of Aβ pathology. Further investigation is required with larger samples consuming three or more drinks/day.

Huamei Lin*, Tingting Pan*, Min Wang*, Jingjie Ge, Jiaying Lu, Zizhao Ju, Keliang Chen, Huiwei Zhang, Yihui Guan, Qianhua Zhao, Baoci Shan, Binbin Nie, Chuantao Zuo, Ping Wu *These authors contributed equally to this work
Metabolic Asymmetry Relates to Clinical Characteristics and Brain Network Abnormalities in Alzheimer’s Disease
Abstract: Background: Metabolic asymmetry has been observed in Alzheimer’s disease (AD), but different studies have inconsistent viewpoints. Objective: To analyze the asymmetry of cerebral glucose metabolism in AD and investigate its clinical significance and potential metabolic network abnormalities. Methods: Standardized uptake value ratios (SUVRs) were obtained from 18F-FDG positron emission tomography (PET) images of all participants, and the asymmetry indices (AIs) were calculated according to the SUVRs. AD group was divided into left/right-dominant or bilateral symmetric hypometabolism (AD-L/AD-R or AD-BI) when more than half of the AIs of the 20 regions of interest (ROIs) were < -2SD, > 2SD, or between ± 1SD. Differences in clinical features among the three AD groups were compared, and the abnormal network characteristics underlying metabolic asymmetry were explored. Results: In AD group, the proportions of AD-L, AD-R, and AD-BI were 28.4%, 17.9%, and 18.5%, respectively. AD-L/AD-R groups had younger age of onset and faster rate of cognitive decline than AD-BI group (p < 0.05). The absolute values of AIs in half of the 20 ROIs became higher at follow-up than at baseline (p < 0.05). Compared with those in AD-BI group, metabolic connection strength of network, global efficiency, cluster coefficient, degree centrality and local efficiency were lower, but shortest path length was longer in AD-L and AD-R groups (p < 0.05). Conclusion: Asymmetric and symmetric hypometabolism may represent different clinical subtypes of AD, which may provide a clue for future studies on the heterogeneity of AD and help to optimize the design of clinical trials.

Willem S. Eikelboom, Esther van den Berg, Michiel Coesmans, Jeannette A. Goudzwaard, Marc Koopmanschap, Najoua Lazaar, Rozemarijn L. van Bruchem-Visser, Jan J.M. Driesen, Tom den Heijer, Susanne Hoogers, Frank Jan de Jong, Francesco Mattace-Raso, Elsbeth C. Thomeer, Suzanne Vrenken, Lilian J.H.M. Vroegindeweij, Sytse U. Zuidema, Ellen H. Singleton, John C. van Swieten, Rik Ossenkoppele, Janne M. Papma (Handling Associate Editor: Fabricio Ferreira de Oliveira)
Effects of the DICE Method to Improve Timely Recognition and Treatment of Neuropsychiatric Symptoms in Early Alzheimer’s Disease at the Memory Clinic: The BEAT-IT Study
Abstract: Background: Neuropsychiatric symptoms (NPS) are highly prevalent in Alzheimer’s disease (AD) and are associated with negative outcomes. However, NPS are currently underrecognized at the memory clinic and non-pharmacological interventions are scarcely implemented. Objective: To evaluate the effectiveness of the Describe, Investigate, Create, Evaluate (DICE) method™ to improve the care for NPS in AD at the memory clinic. Methods: We enrolled sixty community-dwelling people with mild cognitive impairment or AD dementia and NPS across six Dutch memory clinics with their caregivers. The first wave underwent care as usual (n=36) and the second wave underwent the DICE method (n=24). Outcomes were quality of life (QoL), caregiver burden, NPS severity, NPS-related distress, competence managing NPS, and psychotropic drug use. Reliable change index was calculated to identify responders to the intervention. A cost-effectiveness analysis was performed and semi-structured interviews with a subsample of the intervention group (n=12). Results: The DICE method did not improve any outcomes over time compared to care as usual. Half of the participants of the intervention group (52%) were identified as responders and showed more NPS and NPS-related distress at baseline compared to non-responders. Interviews revealed substantial heterogeneity among participants regarding NPS-related distress, caregiver burden, and availability of social support. The intervention did not lead to significant gains in quality-adjusted life years and well-being years nor clear savings in health care and societal costs. Conclusion: The DICE method showed no benefits at group-level, but individuals with high levels of NPS and NPS-related distress may benefit from this intervention.

Merci N. Best, Yunu Lim, Nina N. Ferenc, Nayoung Kim, Lia Min, Dora Bigler Wang, Kamyar Sharifi, Anna E. Wasserman, Sloane A. McTavish, Karsten H. Siller, Marieke K. Jones, Paul M. Jenkins, James W. Mandell, George S. Bloom (Handling Associate Editor: Rakez Kayed)
Extracellular Tau Oligomers Damage the Axon Initial Segment
Abstract: Background: In Alzheimer’s disease (AD) brain, neuronal polarity and synaptic connectivity are compromised. A key structure for regulating polarity and functions of neurons is the axon initial segment (AIS), which segregates somatodendritic from axonal proteins and initiates action potentials. Toxic tau species, including extracellular oligomers (xcTauOs), spread tau pathology from neuron to neuron by a prion-like process, but few other cell biological effects of xcTauOs have been described. Objective: Test the hypothesis that AIS structure is sensitive to xcTauOs. Methods: Cultured wild type (WT) and tau knockout (KO) mouse cortical neurons were exposed to xcTauOs, and quantitative western blotting and immunofluorescence microscopy with anti-TRIM46 monitored effects on the AIS. The same methods were used to compare TRIM46 and two other resident AIS proteins in human hippocampal tissue obtained from AD and age-matched non-AD donors. Results: Without affecting total TRIM46 levels, xcTauOs reduce the concentration of TRIM46 within the AIS and cause AIS shortening in cultured WT, but not TKO neurons. Lentiviral-driven tau expression in tau KO neurons rescues AIS length sensitivity to xcTauOs. In human AD hippocampus, the overall protein levels of multiple resident AIS proteins are unchanged compared to non-AD brain, but TRIM46 concentration within the AIS and AIS length are reduced in neurons containing neurofibrillary tangles. Conclusion: xcTauOs cause partial AIS damage in cultured neurons by a mechanism dependent on intracellular tau, thereby raising the possibility that the observed AIS reduction in AD neurons in vivo is caused by xcTauOs working in concert with endogenous neuronal tau.

Yibing Yan*, Yue Wu*, Guixian Xiao, Lu Wang, Shanshan Zhou, Ling Wei, Yanghua Tian, Xingqi Wu, Panpan Hu, Kai Wang *These authors contributed equally to this work.
White Matter Changes as an Independent Predictor of Alzheimer’s Disease
Abstract: Background: Abnormalities in white matter (WM) may be a crucial physiologic feature of Alzheimer’s disease (AD). However, neuroimaging’s ability to visualize the underlying functional degradation of the WM region in AD is unclear. Objective: This study aimed to explore the differences in amplitude of low-frequency fluctuation (ALFF) and fractional ALFF (fALFF) in the WM region of patients with AD and healthy controls (HC) and to investigate further whether these values can provide supplementary information for diagnosing AD. Methods: Forty-eight patients with AD and 46 age-matched HC were enrolled and underwent resting-state functional magnetic resonance imaging and a neuropsychological battery assessment. We analyzed the differences in WM activity between the two groups and further explored the correlation between WM activity in the different regions and cognitive function in the AD group. Finally, a machine learning algorithm was adopted to construct a classifier in detecting the clinical classification ability of the values of ALFF/ALFF in the WM. Results: Compared with HCs, patients with AD had lower WM activity in the right anterior thalamic radiation, left frontal aslant tract, and left forceps minor, which are all positively related to global cognitive function, memory, and attention function (all p<0.05). Based on the combined WM ALFF and fALFF characteristics in the different regions, individuals not previously assessed were classified with moderate accuracy (75%), sensitivity (71%), specificity (79%), and area under the receiver operating characteristic curve (85%). Conclusion: Our results suggest that WM activity is reduced in AD and can be used for disease classification.

Qingyan Xiang, Stacy L. Andersen, Benjamin Sweigart, Sophia Gunn, Marianne Nygaard, Thomas T. Perls, Paola Sebastiani
Signatures of Neuropsychological Test Results in the Long Life Family Study: A Cluster Analysis
Abstract: Background: Discovering patterns of cognitive domains and characterizing how these patterns associate with other risk factors and biomarkers can improve our understanding of the determinants of cognitive aging. Objective: To discover patterns of cognitive domains using neuropsychological test results in Long Life Family Study (LLFS) and characterize how these patterns associate with aging markers. Methods: 5,086 LLFS participants were administered neuropsychological tests at enrollment. We performed a cluster analysis of six baseline neuropsychological test scores and tested the association between the identified clusters and various clinical variables, biomarkers, and polygenic risk scores using generalized estimating equations and the Chi-square test. We used Cox regression to correlate the clusters with the hazard of various medical events. We investigated whether the cluster information could enhance the prediction of cognitive decline using Bayesian beta regression. Results: We identified 12 clusters with different cognitive signatures that represent profiles of performance across multiple neuropsychological tests. These signatures significantly correlated with 26 variables including polygenic risk scores, physical and pulmonary functions, and blood biomarkers and were associated with the hazard of mortality (p<0.01), cardiovascular disease (p=0.03), dementia (p=0.01), and skin cancer (p=0.03). Conclusion: The identified cognitive signatures capture multiple domains simultaneously and provide a holistic vision of cognitive function, showing that different patterns of cognitive function can coexist in aging individuals. Such patterns can be used for clinical intervention and primary care.

Frank C.T. van der Heide*, Sara Mokhtar*, Anjani Khanna**, Mozhda Said**, Ronald M.A. Henry, Abraham A. Kroon, Pieter C. Dagnelie, Simone J.P.M. Eussen, Tos T.J.M. Berendschot, Jan S.A.G. Schouten, Miranda T. Schram, Carla J.H. van der Kallen, Marleen M.J. van Greevenbroek, Anke Wesselius, Hans H.C.M. Savelberg, Nicolaas C. Schaper, Carroll A.B. Webers, Coen D.A. Stehouwer *,**These authors contributed equally to this work.
Retinal Functional and Structural Neural Indices: Potential Biomarkers for the Monitoring of Cerebral Neurodegeneration: The Maastricht Study
Abstract: Background: If retinal indices of neurodegeneration are to be biomarkers for the monitoring of cerebral neurodegeneration, it is important to establish whether potentially modifiable risk factors for dementia are associated with retinal neurodegenerative changes. Objective: To study associations of dementia risk factors with retinal sensitivity, an index of retinal neural function, and retinal nerve fiber layer (RNFL) thickness, an index of retinal neural structure. Methods: We used cross-sectional data from The Maastricht Study (up to 5,666 participants, 50.5% men, mean age 59.7), and investigated associations with regression analyses (adjusted for potential confounders). Results: Most risk factors under study (i.e., hyperglycemia, unhealthy diet, lower cardiorespiratory fitness, smoking, alcohol consumption, and hypertension) were significantly associated with lower retinal sensitivity and lower RNFL thickness. Conclusion: Findings of this population-based study support the concept that retinal neural indices may be biomarkers for the monitoring of therapeutic strategies that aim to prevent early-stage cerebral neurodegeneration and, ultimately, dementia.

Marta Balietti*, Tiziana Casoli*, Belinda Giorgetti, Roberto Colangeli, Cristina Nicoletti, Moreno Solazzi, Arianna Pugliese, Fiorenzo Conti *These authors contributed equally to this work.
Generation and Characterization of the First Murine Model of Alzheimer’s Disease with Mutated AβPP Inserted in a BALB/c Background (C.B6/J-APPswe)
Abstract: Background: Numerous mouse models of Alzheimer’s disease (AD) are available, but all suffer from certain limitations, thus prompting further attempts. To date, no one model exists with amyloidopathy in a BALB/c strain. Objective: To generate and characterize the C.B6/J-APPswe mouse, a model of AD with a mutated human gene for the amyloid-β protein precursor (AβPP) inserted in a BALB/c background. Methods: We analyzed five groups at different ages (3, 6, 9, 12, and 16-18 months) of C.B6/J-APPswe and wild-type mice (50% males and 50% females) for the main hallmarks of AD by western blotting, amyloid-β (Aβ) ELISA, immunocytochemistry, electrophysiology, and behavioral tests. Results: The C.B6/J-APPswe mouse displays early AβPP and Aβ production, late amyloid plaques formation, high level of tau phosphorylation, synaptic deficits (reduced density and functional impairment due to a reduced post-synaptic responsiveness), neurodegeneration caused by apoptosis and necroptosis/necrosis, microgliosis, astrocytic abnormalities, and sex-related differences in explorative behavior, anxiety-like behavior, and spatial long-term and working memories. Social housing is feasible despite the intra-cage aggressiveness of male animals. Conclusion: C.B6/J-APPswe mice develop most of the distinctive features of AD and is a suitable model for the study of brain atrophy mechanisms and of the differences between males and females in the onset of cognitive/non-cognitive deficits.

Xiao Chen*, Wanlu Li*, Yuhui Huang, Jiaxi Yang, Yang Tao, Liyan Huang, Jiadong Shen, Yanan Ma, Zuyun Liu, Xin Xu, Xiaolin Xu, Geng Zong, Changzheng Yuan *These authors contributed equally to this work.
Association of Type 2 Diabetes Mellitus with Cognitive Function in Adults: A Prospective Cohort Study
Abstract: Background: Cognitive role of untreated type 2 diabetes mellitus (T2DM) has been less well substantiated. Objective: We sought to explore the prospective association of T2DM and untreated T2DM with cognitive function among middle-aged and older Chinese adults. Methods: Data of 7,230 participants without baseline brain damage, mental retardation, or memory-related diseases in China Health and Retirement Longitudinal Study (CHARLS) from 2011-2012 to 2015, were analyzed. Fasting plasma glucose and self-reported information on T2DM diagnosis and treatment were assessed. Participants were categorized into normoglycemia, impaired fasting glucose (IFG), and T2DM (including untreated and treated T2DM) groups. Episodic memory and executive function were assessed by modified Telephone Interview for Cognitive Status every two years. We used generalized estimating equation model to examine the association of baseline T2DM status with cognitive function in succeeding years. Results: Compared to those with normoglycemia, T2DM was associated with worse overall cognitive function after controlling for demographic variables, lifestyles, follow-up time, major clinical factors, and baseline cognitive function, although the associations were statistically non-significant (β=-0.19, 95% CI: -0.39, 0.00). However, a significant association was mainly observed for those with untreated T2DM (β=-0.26, 95% CI: -0.47, -0.04), especially in the domain of executive function (β=-0.19, 95% CI: -0.35, -0.03). In general, IFG and treated T2DM individuals had similar levels of cognitive function with normoglycemia participants. Conclusion: Our findings supported a detrimental role of untreated T2DM on cognitive function among middle-aged and older adults. Screening and early treatment for T2DM are warranted for maintaining better cognitive function in later life.

Arenn F. Carlos, Mary M. Machulda, Matthew H. Rutledge, Aivi T. Nguyen, R. Ross Reichard, Matthew C. Baker, Rosa Rademakers, Dennis W. Dickson, Ronald C. Petersen, Keith A. Josephs (Handling Associate Editor: S. Ahmad Sajjadi)
Comparison of Clinical, Genetic, and Pathologic Features of Limbic and Diffuse Transactive Response DNA-Binding Protein 43 Pathology in Alzheimer’s Disease Neuropathologic Spectrum
Abstract: Background: Increasing evidence suggests that TAR DNA-binding protein 43 (TDP-43) pathology in Alzheimer’s disease (AD), or AD-TDP, can be diffuse or limbic-predominant. Understanding whether diffuse AD-TDP has genetic, clinical, and pathological features that differ from limbic AD-TDP could have clinical and research implications. Objective: To better characterize the clinical and pathologic features of diffuse AD-TDP and differentiate it from limbic AD-TDP. Methods: 363 participants from the Mayo Clinic Study of Aging, Alzheimer’s Disease Research Center, and Neurodegenerative Research Group with autopsy confirmed AD and TDP-43 pathology were included. All underwent genetic, clinical, neuropsychologic, and neuropathologic evaluations. AD-TDP pathology distribution was assessed using the Josephs 6-stage scale. Stages 1-3 were classified as limbic, those 4-6 as diffuse. Multivariable logistic regression was used to identify clinicopathologic features that independently predicted diffuse pathology. Results: The cohort was 61% female and old at onset (median: 76 years [IQR:70-82]) and death (median: 88 years [IQR:82-92]). Fifty-four percent were limbic and 46% diffuse. Clinically, ~10-20% increases in odds of being diffuse associated with 5-year increments in age at onset (p=0.04), 1-year longer disease duration (p=0.02), and higher Neuropsychiatric Inventory scores p=0.03), while 15-s longer Trailmaking Test-B times (p=0.02) and higher Block Design Test scores (p=0.02) independently decreased the odds by ~10-15%. There was evidence for association of APOE ε4 allele with limbic AD-TDP and of TMEM106B rs3173615 C allele with diffuse AD-TDP. Pathologically, widespread amyloid-β plaques (Thal phases: 3-5) decreased the odds of diffuse TDP-43 pathology by 80-90%, while hippocampal sclerosis increased it sixfold (p<0.001). Conclusion: Diffuse AD-TDP shows clinicopathologic and genetic features different from limbic AD-TDP.

Marion Ortner, Korbinian Lanz, Oliver Goldhardt, Felix Müller-Sarnowski, Janine Diehl-Schmid, Hans Förstl, Dennis M. Hedderich, Igor Yakushev, Chad A. Logan, Jan-Philipp Weinberger, Maryline Simon, Timo Grimmer
Elecsys Cerebrospinal Fluid Immunoassays Accurately Detect Alzheimer’s Disease Regardless of Concomitant Small Vessel Disease
Abstract: Background: Differentiating dementia due to small vessel disease (SVD) from dementia due to Alzheimer’s disease (AD) with concomitant SVD is challenging in clinical practice. Accurate and early diagnosis of AD is critical to delivering stratified patient care. Objective: We characterized the results of Elecsys® cerebrospinal fluid (CSF) immunoassays (Roche Diagnostics International Ltd) in patients with early AD, diagnosed using core clinical criteria, with varying extent of SVD. Methods: Frozen CSF samples (n=84) were measured using Elecsys β-Amyloid(1−42) (Aβ42), Phospho-Tau (181P) (pTau181), and Total-Tau (tTau) CSF immunoassays, adapted for use on the cobas® e 411 analyzer (Roche Diagnostics International Ltd), and a robust prototype β-Amyloid(1−40) (Aβ40) CSF immunoassay. SVD was assessed by extent of white matter hyperintensities (WMH) using the lesion segmentation tool. Interrelations between WMH, biomarkers, fluorodeoxyglucose F18-positron emission tomography (FDG-PET), and other parameters (including age and Mini-Mental State examinations [MMSE]) were assessed using Spearman’s correlation, sensitivity/specificity, and logistic/linear regression analyses. Results: The extent of WMH showed significant correlation with Aβ42/Aβ40 ratio (Rho=-0.250; p=0.040), tTau (Rho=0.292; p=0.016), tTau/Aβ42 ratio (Rho=0.247; p=0.042), age (Rho=0.373; p=0.002), and MMSE (Rho=-0.410; p=0.001). Sensitivity/specificity point estimates for Elecsys CSF immunoassays versus FDG-PET positivity for underlying AD pathophysiology were mostly comparable or greater in patients with high versus low WMH. WMH were not a significant predictor and did not interact with CSF biomarker positivity but modified the association between pTau181 and tTau. Conclusion: Elecsys CSF immunoassays detect AD pathophysiology regardless of concomitant SVD and may help to identify patients with early dementia with underlying AD pathophysiology.

Jaegyeong Lee, Junhyoung Kim, Ayeong Park, Rak-kyeun Hong, Myungjin Ko, Mina Heo, Hoowon Kim, Ji Yeon Chung (Handling Associate Editor: Jianping Jia)
Efficacy of a Mobile-Based Multidomain Intervention to Improve Cognitive Function and Health-Related Outcomes Among Older Korean Adults with Subjective Cognitive Decline
Abstract: Background: Subjective cognitive decline (SCD) is a self-reported experience of declining cognitive function showing normal performance in cognitive assessments, which is a known risk factor for dementia. Recent studies highlight the importance of nonpharmacological multidomain interventions that can target multiple risk factors of dementia in older adults. Objective: This study investigated the efficacy of the Silvia program, a mobile-based multidomain intervention, to improve cognitive function and health-related outcomes of older adults with SCD. We compare its effects to a conventional paper-based multidomain program on various health indicators related to risk factors of dementia. Methods: This prospective randomized controlled trial involved 77 older adults with SCD recruited from the Dementia Prevention and Management Center in Gwangju, South Korea during May to October 2022. Participants were randomly assigned to either the mobile- or paper-based group. Interventions were administered for 12 weeks, where pre- and post-assessments were conducted. Results: The K-RBANS total score did not show significant differences between groups. The mobile group showed better improvement in K-PRMQ scores and PSS scores than the paper group. Differences within groups showed that mobile-based interventions significantly improved K-PRMQ, STAI-X-1, PSS, and EQ-5D-5L scores, while paper-based interventions significantly improved PSS, and EQ-5D-5L scores. Patient adherence rate was 76.6%. Conclusion: Overall, the Silvia program was effective for improving self-reported memory failures, stress, anxiety, and health-related quality of life in older adults with SCD. However, longer periods of administration for more than 12 weeks may be needed to achieve significant improvements in cognitive function by objective measures.

Chirag M. Vyas, Ruslan I. Sadreyev, Jennifer R. Gatchel, Jae H. Kang, Charles F. Reynolds, III, David Mischoulon, Grace Chang, Aditi Hazra, JoAnn E. Manson, Deborah Blacker, Immaculata De Vivo, Olivia I. Okereke
Pilot Study of Second-Generation DNA Methylation Epigenetic Markers in Relation to Cognitive and Neuropsychiatric Symptoms in Older Adults
Abstract: Background: Associations between epigenetic aging with cognitive aging and neuropsychiatric measures are not well-understood. Objective: 1) To assess cross-sectional correlations between second-generation DNA methylation (DNAm)-based clocks of healthspan and lifespan (i.e., GrimAge, PhenoAge, and DNAm-based estimator of telomere length [DNAmTL]) and cognitive and neuropsychiatric measures; 2) To examine longitudinal associations between change in DNAm markers and change in cognition over 2 years. Methods: Participants were members of VITAL-DEP (VITamin D and OmegA-3 TriaL- Depression Endpoint Prevention) study. From previously ascertained cognitive groups (i.e., cognitively normal and mild cognitive impairment), we randomly selected 45 participants, aged ≥60 years, who completed in-person neuropsychiatric assessments at baseline and 2 years. The primary outcome was global cognitive score (averaging z-scores of 9 tests). Neuropsychiatric Inventory severity scores were mapped from neuropsychiatric symptoms (NPS) from psychological scales and structured diagnostic interviews. DNAm was assayed using Illumina MethylationEPIC 850K BeadChip at baseline and 2 years. We calculated baseline partial Spearman correlations between DNAm markers and cognitive and NPS measures. We constructed multivariable linear regression models to examine longitudinal relations between DNAm markers and cognition. Results: At baseline, we observed a suggestive negative correlation between GrimAge clock markers and global cognition but no signal between DNAm markers and NPS measures. Over 2 years: each 1-year increase in DNAmGrimAge was significantly associated with faster declines in global cognition; each 100-base pair increase in DNAmTL was significantly associated with better global cognition. Conclusion: We found preliminary evidence of cross-sectional and longitudinal associations between DNAm markers and global cognition.