Volume 94, Number 2, IN PRESS

Francesca R. Farina, Laura Booi, Jo-An Occhipinti, Vinciane Quoidbach, Frédéric Destrebecq, Graciela Muniz-Terrera, Harris A. Eyre
Young Adult Brain Capital: A New Opportunity for Dementia Prevention
Abstract: The potential for future prevention of Alzheimer’s disease and related dementias (ADRD) through healthy lifestyle change is spurring a positive brain health movement. However, most ADRD research continues to focus on mid- and later life. We lack evidence regarding risk exposure and protective factors in young adulthood, i.e., 18-39 years. Brain capital is an emerging framework that represents the combination of education, knowledge, skills, and optimal brain health that people accumulate over their lives. Building on this framework, we present a new model that focuses on optimizing brain health in young adulthood; namely, young adult brain capital. Increasing focus on younger populations is critical for developing citizens who are emotionally intelligent, resilient and can anticipate and cope with rapid changes in the world. By understanding the values that are key drivers and motivators for young adults, we can empower the next generation to become active agents in optimizing their brain health and reducing their risk for future ADRD.

Systematic Review
Angel Gabriel Garrido-Dzib, Geovanni Chávez-Loría, Valeria Magallón-Zertuche, Azalia Avila-Nava, Berenice Palacios-González, Ana Ligia Gutiérrez-Solis
Micro- and Macronutrient Intake and Food Group Frequency Consumed by Subjects with Cognitive Impairment and Dementia in Latin America: A Systematic Review
Abstract: Background: Nutrition has relevant role in the pathogenesis of dementia. However, in Latin American Countries (LAC), it is unknown which type of diet the subjects with dementia and cognitive dysfunction have. Objective: The main purpose of this study was to determine micro- and macronutrients and food frequency intake among the LAC population with mild cognitive impairment (MCI) and dementia. Methods: A systematic review using PubMed, Cochrane, Lilacs, and Scielo databases. Energy intake as well as micro- and macronutrients intake were analyzed using a random-effect model and presented in a forest plot. Results: Nine articles were included, an estimated energy intake of 1598.47 kcal (95% CI 1351.07–1845.88) was obtained. A daily consumption of 73.64 g/day (95% CI 64.07–83.2) of protein; 262.17 g/day (95% CI 214.51–309.93) of carbohydrates, and 57.91 g/day (95% CI 49.16–66.66) of fats were reported. A micronutrients daily intake consumption of 201.35 µg/day of vitamin B9 (95% CI 125.32–277.38); 5.61 µg/day of vitamin B12 (95% CI 2.53–8.70), and 139.67 mg/day of vitamin C (95% CI 59.33–220.02). Mineral intake of 637.32 mg/day of calcium (95% CI 288.54-986.11) and 9 mg/day of iron (95% CI 2.28–15.71) was obtained. A low intake of fruits and vegetables was found. Conclusion: Individuals with MCI and dementia from LAC have a nutritional deficiency characterized by a lower intake of fruits and vegetables, a high consumption of carbohydrates and protein, adequate fats intake and vitamins B12, vitamin C, and iron consumption, but a low intake of vitamin B9 and calcium.

Systematic Review
Lina Sun*, Kaisy Xinhong Ye*, Hoi Lin Kathleen Wong, Lingyan Wang, Su Lin Lim, Yin Xia Chao, Can Zhang, Kai Zhen Yap, Lei Feng *These authors contributed equally to this work.
The Effects of Medium Chain Triglyceride for Alzheimer’s Disease Related Cognitive Impairment: A Systematic Review and Meta-Analysis
Abstract: Background: The current lack of effective drug therapies for Alzheimer's disease (AD) has prompted researchers to seek alternative nutritional therapies, such as medium chain triglycerides (MCTs). However, results are inconclusive. Objective: This systematic review and meta-analysis aims to summarize current evidence on the effect of MCT on cognitive function in patients with mild cognitive impairment (MCI) or AD. Methods: A systematic search was conducted up until December 16, 2022, to identify human interventions reporting the effects of MCT on cognitive functioning of MCI or AD patients. 995 non-duplicated publications were identified, of which nine (n=10 studies) met the inclusion criteria. Results: Meta-analysis showed cognitive improvements in general (SMD = 0.64; 95% CI [0.05, 1.24]), but not in memory, language, and attention domains after oral MCT administration, compared to placebo. The effect of MCT was greater among APOE ε4 (–) subjects than APOE ε4 (+) subjects (SMD = 1.87; 95% CI [0.35, 3.40]). Conclusion: This review provides some evidence that treatment with MCT could improve general cognitive function in APOE ε4 (–) cognitive impaired patients. Better characterized clinical studies are warranted before making a definitive conclusion on the use of MCT for MCI and AD management.

Jonathan D'Arcy Rudge
The Lipid Invasion Model: Growing Evidence for This New Explanation of Alzheimer’s Disease
Abstract: The Lipid Invasion Model (LIM) is a new hypothesis for Alzheimer’s disease (AD) which argues that AD is a result of external lipid invasion to the brain, following damage to the blood-brain barrier (BBB). The LIM provides a comprehensive explanation of the observed neuropathologies associated with the disease, including the lipid irregularities first described by Alois Alzheimer himself, and accounts for the wide range of risk factors now identified with AD, all of which are also associated with damage to the BBB. This article summarizes the main arguments of the LIM, and new evidence and arguments in support of it. The LIM incorporates and extends the amyloid hypothesis, the current main explanation of the disease, but argues that the greatest cause of late-onset AD is not amyloid-β (Aβ) but bad cholesterol and free fatty acids, let into the brain by a damaged BBB. It suggests that the focus on Aβ is the reason why we have made so little progress in treating the disease in the last 30 years. As well as offering new perspectives for further research into the diagnosis, prevention, and treatment of AD, based on protecting and repairing the BBB, the LIM provides potential new insights into other neurodegenerative diseases such as Parkinson's disease and amyotrophic lateral sclerosis/motor neuron disease.

Jemma Hazan, Kathy Liu, Nick Fox, Robert Howard
Advancing Diagnostic Certainty in Alzheimer’s Disease: A Synthesis of the Diagnostic Process
Abstract: Changes in diagnostic certainty can be evaluated by assessing the impact of a diagnostic test in driving decision making. Diagnostic tests can be appraised using validated measures of accuracy, i.e., sensitivity, specificity, and positive or negative predictive values against a known reference standard. However, other less well formalized factors affect diagnostic certainty. These inputs are under-researched and more difficult to quantify. Clinicians assess the significance of available data in the context of their expertise, pre-diagnostic confidence, and background knowledge of populations and disease. Inherent qualities of the diagnostic test and an individual clinician’s interpretation of the meaning of test results will also affect the subsequent level of diagnostic certainty. These factors are only infrequently considered alongside the diagnostic accuracy of a test. In this paper, we present a model of the different processes which can affect diagnostic certainty in Alzheimer’s disease (AD). This model builds upon existing understanding and provides further insights into the complexity of diagnostic certainty in AD and how we might improve this.

Short Communication
Smita Patel*, Jun Wei*, Zhuqing Shi, Andrew S. Rifkin, S. Lilly Zheng, Elizabeth Gelfman, David Duggan, Brian T. Helfand, Peter J. Hulick, Jianfeng Xu *These authors contributed equally to this work.
Refining Risk for Alzheimer’s Disease Among Heterozygous APOE ε4 Carriers
Abstract: In a large population-based cohort, we show not all heterozygous APOE ε4 carriers are at increased risk for Alzheimer’s disease (AD); a significantly higher AD proportion was only found for ε3/ε4, not ε2/ε4. Among ε3/ε4 carriers (24% in the cohort), the AD proportion differed considerably by polygenic risk score (PRS). In particular, the AD proportion was lower than the entire cohort for subjects in the bottom 20-percentile PRS and was higher than that of homozygous ε4 carriers for subjects at the top 5th-percentile PRS. Family history was no longer a significant predictor of AD risk after adjusting APOE and PRS.

Jesús Avila, George Perry (Handling Editor: Paula Moreira)
Memory, Sleep, and Tau Function
Abstract: Memory consolidation related to the hippocampal-cortex connection takes place during sleep. This connection may involve at least two steps—one in the NREM phase of sleep (transmission) and the other in the REM phase (consolidation). In this brief report, we comment on the role of tau protein in these two phases of sleep. The absence of tau decreases δ waves in NREM, whereas the overexpression of modified (phosphorylated and/or mutated) tau alters θ waves in REM.

Kasper P. Kepp, Stefano L. Sensi, Kasper B. Johnsen, Jorge R. Barrio, Poul F. Høilund-Carlsen, Rachael L. Neve, Abass Alavi, Karl Herrup, George Perry, Nikolaos K. Robakis, Bryce Vissel, Alberto J. Espay (Handling Editor: Paula Moreira)
The Anti-Amyloid Monoclonal Antibody Lecanemab: 16 Cautionary Notes
Abstract: After the CLARITY-AD clinical trial results of lecanemab were interpreted as positive, and supporting the amyloid hypothesis, the drug received accelerated Food and Drug Administration approval. However, we argue that benefits of lecanemab treatment are uncertain and may yield net harm for some patients, and that the data do not support the amyloid hypothesis. We note potential biases from inclusion, unblinding, dropouts, and other issues. Given substantial adverse effects and subgroup heterogeneity, we conclude that lecanemab’s efficacy is not clinically meaningful, consistent with numerous analyses suggesting that amyloid-β and its derivatives are not the main causative agents of Alzheimer’s disease dementia.

Mary Elizabeth Curtis, Tiffany Smith, Miroslav Nenov, Benjamin E. Blass, Domenico Praticò
Retromer Stabilization Improves Cognitive Function and Synaptic Plasticity in a Mouse Model of Down Syndrome
Abstract: Background: Retromer complex proteins are decreased in postmortem brain tissues from Down syndrome subjects and inversely correlate with the Alzheimer’s disease-like neuropathology. However, whether targeting in vivo the retromer system affects cognitive deficits and synaptic function in Down syndrome remains unknown. Objective: The aim of the current study was to examine the effects of pharmacological retromer stabilization on cognitive and synaptic functions in a mouse model of Down syndrome. Methods: Ts65dn mice were administered the pharmacological chaperone, TPT-172, or vehicle from 4 to 9 months of age and then assessed for changes in cognitive function. To assess the effects of TPT-172 on synaptic plasticity, hippocampal slices from Ts65dn mice were incubated in TPT-172 and used for field potential recordings. Results: Chronic TPT-172 treatment improved performance in cognitive function tests, its incubation with hippocampal slices ameliorated synaptic function response. Conclusion: Pharmacological stabilization of the retromer complex improves synaptic plasticity and memory in a mouse model of Down syndrome. These results support the therapeutic potential of pharmacological retromer stabilization for individual with Down syndrome.

Xiaoyu Zhang, Yan Liu, Ming Huang, Sumedha Gunewardena, Mohammad Haeri, Russell H. Swerdlow, Ning Wang (Handling Associate Editor: Hemachandra Reddy)
Landscape of Double-Stranded DNA Breaks in Postmortem Brains from Alzheimer’s Disease and Non-Demented Individuals
Abstract: Background: Alzheimer’s disease (AD) brains accumulate DNA double-strand breaks (DSBs), which could contribute to neurodegeneration and dysfunction. The genomic distribution of AD brain DSBs is unclear. Objective: To map genome-wide DSB distributions in AD and age-matched control brains. Methods: We obtained autopsy brain tissue from 3 AD and 3 age-matched control individuals. The donors were men between the ages of 78 to 91. Nuclei extracted from frontal cortex tissue were subjected to Cleavage Under Targets & Release Using Nuclease (CUT&RUN) assay with an antibody against γH2AX, a marker of DSB formation. γH2AX-enriched chromatins were purified and analyzed via high-throughput genomic sequencing. Results: The AD brains contained 18 times more DSBs than the control brains and the pattern of AD DSBs differed from the control brain pattern. In conjunction with published genome, epigenome, and transcriptome analyses, our data revealed aberrant DSB formation correlates with AD-associated single-nucleotide polymorphisms, increased chromatin accessibility, and upregulated gene expression. Conclusion: To our knowledge, this study is the first to characterize the AD brain DSB landscape. Our data suggest in AD, an accumulation of DSBs at ectopic genomic loci could contribute to an aberrant upregulation of gene expression.

Guang-Yu Xu*, Yu-Hao Liu*, Xiao-Qin Zeng, Dong-Wan Chen, Gui-Hua Zeng, Dong-Yu Fan, Yu-Hui Liu, Yan-Jiang Wang (Handling Associate Editor: Peng Lei) *These authors contributed equally to this work.
The Diagnostic Potential of Circulating Autoantibodies to Amyloid-β in Alzheimer’s Disease
Abstract: Background: The profile of naturally occurring antibodies to amyloid-β (NAbs-Aβ) are altered in patients with Alzheimer’s disease (AD). However, the diagnostic potential of NAbs-Aβ is not clear yet. Objective: This study aims to investigate the diagnostic capacities of NAbs-Aβ for AD. Methods: A total of 40 AD patients and 40 cognitively normal (CN) controls were enrolled in this study. Levels of NAbs-Aβs were detected by ELISA. The correlations of NAbs-Aβ levels with cognitive function and AD-associated biomarkers were examined by Spearman correlation analysis. Diagnostic abilities of NAbs-Aβ were evaluated by the receiver operating characteristic (ROC) curve analyses. The integrative diagnostic models were established by logistic regression analyses. Results: We found that NAbs-Aβ7-18 had the highest diagnostic capability (AUC=0.72) among all separate NAbs-Aβ targeting different epitopes. The combined model (NAbs-Aβ7-18, NAbs-Aβ19-30, and NAbs-Aβ25-36) had a noticeable improvement (AUC=0.84) in diagnostic capacity compared with each single NAbs-Aβ. Conclusion: NAbs-Aβs are promising in the diagnosis of AD. Further investigations are needed to confirm the translational potential of this diagnostic strategy.

Oscar Hou In Chou*, Jiandong Zhou*, Lifang Li , Jeffrey Shi Kai Chan, Danish Iltaf Satti, Vanessa Hou Cheng Chou, Wing Tak Wong, Sharen Lee, Bernard Man Yung Cheung, Gary Tse, Carlin Chang, Tong Liu (Handling Associate Editor: Yi Tang) *These authors contributed equally to this work.
The Association Between Neutrophil-Lymphocyte Ratio and Variability with New-Onset Dementia: A Population-Based Cohort Study
Abstract: Background: Previous studies identified that neutrophil-to-lymphocyte ratio (NLR) may be a predictor of dementia. However, the associations between NLR and dementia at the population level were less explored. Objective: This retrospective population-based cohort study was designed to identify the associations between NLR and dementia among patients visiting for family medicine consultation in Hong Kong. Methods: The patients were recruited from January 1, 2000, to December 31, 2003, and followed up until December 31, 2019. The demographics, prior comorbidities, medications, and laboratory results were collected. The primary outcomes were Alzheimer’s disease and related dementia and non-Alzheimer’s dementia. Cox regression and restricted cubic spline were applied to identify associations between NLR and dementia. Results: A cohort of 9,760 patients (male: 41.08%; baseline age median: 70.2; median follow-up duration: 4756.5 days) with complete NLR were included. Multivariable Cox regression identified that patients with NLR >5.44 had higher risks of developing Alzheimer's disease and related dementia (hazard ratio [HR]: 1.50, 95% Confidence interval [CI]: 1.17-1.93) but not non-Alzheimer’s dementia (HR: 1.33; 95% CI: 0.60-2.95). The restricted cubic splines demonstrated that higher NLR was associated with Alzheimer's disease and related dementia. The relationship between the NLR variability and dementia was also explored; of all the NLR variability measures, only the coefficient of variation was predictive of non-Alzheimer’s dementia (HR: 4.93; 95% CI: 1.03-23.61). Conclusion: In this population-based cohort, the baseline NLR predicts the risks of developing dementia. Utilizing the baseline NLR during family medicine consultation may help predict the risks of dementia.

Anja Mäurer, Gudrun Himmel, Catharina Lange, Franziska Mathies, Ivayla Apostolova, Oliver Peters, Ralph Buchert
Individualized Summary Assessment of Detailed Neuropsychological Testing for the Etiological Diagnosis of Newly Detected Cognitive Impairment in Hospitalized Geriatric Patients
Abstract: Background: Neuropsychological testing (NPT) of geriatric inpatients can be affected by the acute illness and/or the hospitalization. Objective: To test individualized interpretation of detailed NPT for the differentiation between primary ‘neurodegenerative’ etiologies (predominantly Alzheimer’s disease) and ‘other’ etiologies (including cerebrovascular disease) of newly detected cognitive impairment in geriatric inpatients without and with delirium in remission. Methods: 96 geriatric inpatients (81.9±5.6 years, 64.6% females) with clinically uncertain cognitive impairment were included. 31.3% had delirium in remission that was not considered the primary cause of the cognitive impairment. Categorization of the most likely etiology as ‘neurodegenerative’ or ‘other’ was established retrospectively by a study neuropsychologist based on individualized summary assessment of detailed NPT compiled in a standardized vignette. The etiological diagnosis based on FDG-PET served as gold standard (54.2% ‘neurodegenerative’, 45.8% ‘other’). Results: Individualized summary assessment by the study neuropsychologist was correct in 80 patients (83.3%, 8 false positive, 8 false negative). The impact of delirium in remission was not significant (p=0.237). Individualized summary assessment by an independent neuropsychologist resulted in more false positive cases (n=22) at the same rate of false negative cases (n=8). Automatic categorization with a decision tree model based on the most discriminative NPT scores was correct in 68 patients (70.8%, 14 false positive, 14 false negative). Conclusion: Individualized summary assessment of detailed NPT in the context of relevant clinical information might be useful for the etiological diagnosis of newly detected cognitive impairment in hospitalized geriatric patients, also in patients with delirium in remission, but requires task-specific expertise.

Christina S. Dintica, Amaia Calderón-Larrañaga, Davide Liborio Vetrano, Weili Xu
Association Between Sensory Impairment and Dementia: The Roles of Social Network and Leisure Activity
Abstract: Background: Evidence suggests that sensory impairment is linked to dementia; however, the role of social network and leisure activity in this relationship is unclear. Objective: Examine the association of hearing and visual impairment with dementia, and whether a rich social network and leisure activity moderates this association. Methods: Dementia-free older adults from the Swedish National Study on Aging and Care in Kungsholmen (n = 2,579) were followed up for up for a median of 10 years (interquartile range= 6). Visual impairment was assessed with a reading acuity test, and hearing impairment was ascertained via self-report and medical records. Dementia was diagnosed following international criteria. Data on social network and leisure activity was collected via self-report. Hazard ratios (HRs) of dementia risk were derived from Cox regression models. Results: Dual impairment, but not single impairment in hearing and vision was associated with a higher risk of dementia (HR: 1.62, 95% CI: 1.16 to 2.27). Compared to participants with no sensory impairment and a moderate-to-rich social network, those with dual impairment and low social network or leisure activity had higher dementia risk (HR: 2.08, 95% CI: 1.43 to 3.22; HR: 2.08, 95% CI: 1.43 to 3.22, respectively), whereas participants with dual impairment with a moderate-to-rich social network or leisure activity did not have significantly higher dementia risk (HR; 1.42, 95% CI: 0.87 to 2.33; HR; 1.42, 95% CI: 0.87 to 2.33, respectively). Conclusion: A richer social network and participation in stimulating activities may mitigate the higher dementia risk in older adults with dual impairment in vision and hearing.

Marco Toccaceli Blasi, Martina Valletta, Alessandro Trebbastoni, Fabrizia D'Antonio, Giuseppina Talarico, Alessandra Campanelli, Micaela Sepe Monti, Emanuela Salati, Marina Gasparini, Simona Buscarnera, Martina Salzillo, Marco Canevelli, Giuseppe Bruno (Handling Associate Editor: Carlo Abbate)
Sundowning in Patients with Dementia: Identification, Prevalence, and Clinical Correlates
Abstract: Background: The term sundowning is used to describe the emergence or worsening of neuropsychiatric symptoms in late afternoon or early evening in people with dementia. Objective: Our aim was to evaluate sundowning’s prevalence and clinical manifestations among patients attending a tertiary memory clinic and to investigate its clinical and neuropsychological correlates. Methods: Patients with dementia attending our memory clinic were enrolled in the study. Sundowning was identified through a specifically designed questionnaire. Sociodemographic and clinical features of sundowners and non-sundowners were compared, and a logistic regression was performed to identify the variables associated with the phenomenon. A subgroup of patients underwent a complete neuropsychological assessment. Results: Among 184 recruited patients, 39 (21.2%) exhibited sundowning, mostly expressed as agitation (56.4%), irritability (53.8%), and anxiety (46.2%). Sundowners were significantly older, had a later dementia onset, exhibited more severe cognitive and functional impairment, more frequent nocturnal awakenings, and hearing loss relative to non-sundowners. They were also more likely to use anticholinergic medications and antipsychotics, and less likely to use memantine. In a multi-adjusted model, the factors significantly associated with sundowning were the Clinical Dementia Rating score (OR 3.88, 95% CI 1.39–10.90) and the use of memantine (OR 0.20; 95% CI 0.05–0.74). Participants with and without sundowning obtained similar results in single domain neuropsychological tests. Conclusion: Sundowning is commonly experienced by patients with dementia and appears as a multiply determined condition. Its presence should always be evaluated in clinical practice and a multidimensional approach should be adopted to identify its predictors.

Chiara Milano, Domeniko Hoxhaj, Marta Del Chicca, Alessia Pascazio, Davide Paoli, Luca Tommasini, Andrea Vergallo, Chiara Pizzanelli, Gloria Tognoni, Angelo Nuti, Roberto Ceravolo, Gabriele Siciliano, Harald Hampel, Filippo Baldacci; Neurodegeneration Precision Medicine Initiative (NPMI)
Alzheimer’s Disease and Neurosyphilis: Meaningful Commonalities and Differences of Clinical Phenotype and Pathophysiological Biomarkers
Abstract: Background: Neurosyphilis-associated cognitive and behavioral impairment—historically coined as “general paralysis of the insane”—share clinical and neuroradiological features with the neurodegenerative disease spectrum, in particular Alzheimer’s disease (AD). Anatomopathological similarities have been extensively documented, i.e., neuronal loss, fibrillary alterations, and local amyloid-β deposition. Consequently, accurate classification and timely differential diagnosis may be challenging. Objective: To describe clinical, bio-humoral, brain MRI, FDG-PET, and amyloid-PET features in cases of neurosyphilis with an AD-like phenotypical presentation, as well as clinical outcome in terms of response to antibiotic therapy. Methods: We selected the studies comparing patients with AD and with neurosyphilis associated cognitive impairment, to investigate candidate biomarkers classifying the two neurological diseases. Results: The neuropsychological phenotype of general paralysis, characterized by episodic memory impairment and executive disfunction, substantially mimics clinical AD features. Neuroimaging often shows diffuse or medial temporal cortical atrophy, thus contributing to a high rate of misdiagnosis. Cerebrospinal fluid (CSF)-based analysis may provide supportive diagnostic value, since increased proteins or cells are often found in neurosyphilis, while published data on pathophysiological AD candidate biomarkers are controversial. Finally, psychometric testing using cross-domain cognitive tests, may highlight a wider range of compromised functions in neurosyphilis, involving language, attention, executive function, and spatial ability, which are atypical for AD. Conclusion: Neurosyphilis should be considered a potential etiological differential diagnosis of cognitive impairment whenever imaging, neuropsychological or CSF features are atypical for AD, in order to promptly start antibiotic therapy and delay or halt cognitive decline and disease progression.

Bingyu Li*, Kening Shi*, Chao Ren, Min Kong, Maowen Ba, Alzheimer’s Disease Neuroimaging Initiative (Handling Associate Editor: Liyong Wu) *These authors contributed equally to this work.
Detection of Tau-PET Positivity in Clinically Diagnosed Mild Cognitive Impairment with Multidimensional Features
Abstract: Background: The way to evaluate brain tau pathology in vivo is tau positron emission tomography (tau-PET) or cerebrospinal fluid (CSF) analysis. In the clinically diagnosed mild cognitive impairment (MCI), a significant proportion of tau-PET are negative. Interest in less expensive and convenient ways to detect tau pathology in Alzheimer's disease has increased due to the high cost of tau-PET and the invasiveness of lumbar puncture, which typically slows down the cost and enrollment of clinical trials. Objective: We aimed to investigate one simple and effective method in predicting tau-PET status in MCI individuals. Methods: The sample included 154 individuals which were dichotomized into tau-PET (+) and tau-PET (-) using a cut-off of >1.33. We used stepwise regression to select the unitary or combination of variables that best predicted tau-PET. The receiver operating characteristic curve was used to assess the accuracy of single and multiple clinical markers. Results: The combined performance of three variables [Alzheimer’s Disease Assessment Scale-Cognitive Subscale 13 (ADAS-Cog13), Mini-Mental State Examination (MMSE), ADNI-Memory summary score (ADNI-MEM)] in neurocognitive measures demonstrated good predictive accuracy of tau-PET status [accuracy=85.7%, area under the curve (AUC)=0.879]. The combination of clinical markers model (APOE ε4, neurocognitive measures and structural MRI imaging of middle temporal) had the best discriminative power (AUC=0.946). Conclusion: As a noninvasive test, the combination of APOE ε4, neurocognitive measures and structural MRI imaging of middle temporal accurately predicts tau-PET status. The finding may provide a non-invasive, cost-effective tool for clinical application in predicting tau pathology among MCI individuals.

Rizwan Qaisar, Asima Karim, M. Shahid Iqbal, Shaea A. Alkahtani, Firdos Ahmad, Hossam Kamli
ACE Inhibitors Improve Skeletal Muscle by Preserving Neuromuscular Junctions in Patients with Alzheimer’s Disease
Abstract: Background: Hypertension and skeletal muscle decline are common findings in patients with Alzheimer’s disease (AD). Angiotensin-converting enzyme (ACE) inhibitors preserve skeletal muscle and physical capacity; however, the driving mechanisms are poorly understood. Objective: We investigated the effects of ACE inhibitors on the neuromuscular junction (NMJ) with relevance to skeletal muscle and physical capacity in AD patients and age-matched controls. Methods: We evaluated controls (n=59) and three groups of AD patients, including normotensive (n=51) and patients with hypertension taking ACE inhibitors (n=53) or other anti-hypertensive medications (n=49) at baseline and one year later. We measure plasma c-terminal agrin fragment-22 (CAF22) as a marker of NMJ degradation, handgrip strength (HGS), and Short Physical Performance Battery (SPPB) as markers of physical capacity. Results: At baseline AD patients demonstrated lower HGS and SPPB scores and higher CAF22 levels than controls, irrespective of the hypertension status (all p<0.05). The use of ACE inhibitors was associated with higher HGS and relative maintenance of SPPB scores, gait speed, and plasma CAF22 levels. Conversely, other anti-hypertensive medications were associated with an unaltered HGS, reduced SPPB scores and elevated plasma CAF22 levels (both p<0.05). We also found dynamic associations of CAF22 with HGS, gait speed, and SPPB in AD patients taking ACE inhibitors (all p<0.05). These changes were associated with reduced oxidative stress in AD patients taking ACE inhibitors (p<0.05). Conclusion: Altogether, ACE inhibitors are associated with higher HGS, preserved physical capacity, and the prevention of NMJ degradation in hypertensive AD patients.

Jing Zhu*, Xin Ji*, Ruirui Shi, Tianqi He, Su-ying Chen, Ruochen Cong, Bosheng He, Su Liu, Hui Xu, Jin-hua Gu (Handling Associate Editor: Chunling Dai) *These authors contributed equally to this work.
Hyperglycemia Aggravates the Cerebral Ischemia Injury via Protein O-GlcNAcylation
Abstract: Background: At least one-third of Alzheimer's disease (AD) patients have cerebrovascular abnormalities, micro- and macro-infarctions, and ischemic white matter alterations. Stroke prognosis impacts AD development due to vascular disease. Hyperglycemia can readily produce vascular lesions and atherosclerosis, increasing the risk of cerebral ischemia. Our previous studies have proved that protein O-GlcNAcylation-a dynamic and reversible post-translational modification, protects against ischemic stroke. However, the role of O-GlcNAcylation in hyperglycemia aggravating cerebral ischemia injury remained unclear. Objective: In the present study, we investigated the role and mechanism of protein O-GlcNAcylation in hyperglycemia exacerbating cerebral ischemia injury. Methods: High glucose-cultured brain microvascular endothelial (bEnd3) cells were injured by oxygen-glucose deprivation. Cell viability was used as the assay result. Stroke outcomes and hemorrhagic transformation incidence were assessed in mice after middle cerebral artery occlusion under high glucose and streptozotocin-induced hyperglycemic conditions. Western blot estimated that O-GlcNAcylation influenced apoptosis levels in vitro and in vivo. Results: In in vitro analyses showed that Thiamet-G induces upregulation of protein O-GlcNAcylation, which attenuates oxygen-glucose deprivation/R-induce injury in bEnd3 cells cultured under normal glucose conditions, while aggravated it under high glucose conditions. In in vivo analyses, Thiamet-G exacerbated cerebral ischemic injury and induced hemorrhagic transformation, accompanied by increased apoptosis. While blocking protein O-GlcNAcylation with 6-diazo-5-oxo-L-norleucine alleviated cerebral injury of ischemic stroke in different hyperglycemic mice. Conclusion: Overall, our study indicates a critical role for O-GlcNAcylation in that hyperglycemia aggravates cerebral ischemia injury. O-GlcNAcylation may be a potential therapeutic drug for ischemic stroke associated with AD.

Florian Melchior, Birgit Teichmann
Measuring Dementia Knowledge in German: Validation and Comparison of the Dementia Knowledge Assessment Scale, the Knowledge in Dementia Scale, and the Dementia Knowledge Assessment Tool 2
Abstract: Background: Assessing dementia knowledge is critical for developing and improving effective interventions. There are many different tools to assess dementia knowledge, but only one has been validated in German so far. Objective: To validate two tools for assessing dementia knowledge—the Dementia Knowledge Assessment Scale (DKAS-D) and the Knowledge in Dementia Scale (KIDE-D) for the German general population—and compare their psychometric properties with the Dementia Knowledge Assessment Tool 2 (DKAT2-D). Methods: A convenience sample of 272 participants completed online surveys. Analyses included internal consistency, structural validity, construct validity through the known-groups method, retest-reliability with a subgroup of n = 88, and floor and ceiling effects. This study used the STROBE checklist. Results: Internal consistency was acceptable for DKAT2-D (α = 0.780), very good for DKAS-D (α = 0.873), and poor for KIDE-D (α = 0.506). Construct validity was confirmed for all questionnaires. Retest-reliability was good for DKAT2-D (0.886; 0.825-0.926) and KIDE-D (0.813; 0.714-0.878), while it was great for DKAS-D (0.928; 0.891-0.953). Trends toward ceiling effects were observed for DKAT2-D and KIDE-D, but not for DKAS-D. The principal component analysis did not reveal a coherent structure for DKAT2-D or KIDE-D, while the confirmatory factor analysis proposed the removal of 5 items for DKAS-D resulting in the shortened DKAS20-D, which had nearly identical properties. Conclusion: Both DKAS-D and its shortened version, DKAS20-D, are reliable instruments for evaluating programs intended for the general population, as they were found to be convincing in all aspects.

Yu Nakamura, Takumi Omori, Rei Kim, Kenichi Nishiyama, Takashi Kikuchi, Ichiro Ishikawa, Hiroshi Aoki
Efficacy and Safety of a Transdermal Donepezil Patch in Patients with Mild to Moderate Alzheimer’s Disease: Open-Label, Extension Study
Abstract: Background: In Japan, only oral formulation of donepezil hydrochloride is approved for the treatment of Alzheimer's disease. Objective: To evaluate safety and efficacy of a donepezil patch 27.5 mg application for 52 weeks in patients with mild-to-moderate Alzheimer’s disease; and to evaluate safety on switching from donepezil hydrochloride tablets. Methods: This 28-week, open-label study (jRCT2080224517) is an extension of a 24-week double-blind (donepezil patch 27.5 mg versus donepezil hydrochloride tablet 5 mg) noninferiority study. The patch group (continuation group) continued administration of the patch and the tablet group (switch group) switched to the patch in this study. Results: A total of 301 patients participated (156 patients continued using patches; 145 patients switched). Both groups showed similar course on the Alzheimer’s Disease Assessment Scale-cognitive component-Japanese version (ADAS-Jcog) and ABC dementia scales. At weeks 36 and 52, changes in ADAS-Jcog from week 24 [mean (standard deviation)] were 1.4 (4.8) and 2.1 (4.9) in the continuation group, and 1.0 (4.2), and 1.6 (5.4) in the switch group. The incidence of adverse events at application site in the continuation group over 52 weeks was 56.6% (98/173). Erythema, pruritus, and contact dermatitis at application site were observed in more than 10 patients each. There was no additional adverse event of clinical concern, and no increase in their incidence from the double-blind study. During the four weeks following switching, no patient discontinued or suspended administration due to adverse events. Conclusion: Application of the patch for 52 weeks was well tolerated and feasible, including switching from tablets.

Lauren Edwards, Kelsey R. Thomas, Alexandra J. Weigand, Emily C. Edmonds, Alexandra L. Clark, Kayla S. Walker, Einat K. Brenner, Daniel A. Nation, Pauline Maillard, Mark W. Bondi, Katherine J. Bangen for the Alzheimer’s Disease Neuroimaging Initiative
White Matter Hyperintensity Volume and Amyloid-PET Synergistically Impact Memory Independent of Tau-PET in Older Adults Without Dementia
Abstract: Background: Alzheimer’s disease (AD) and cerebrovascular disease are common, co-existing pathologies in older adults. Whether the effects of cerebrovascular disease and AD biomarkers on cognition are additive or synergistic remains unclear. Objective: To examine whether white matter hyperintensity (WMH) volume moderates the independent association between each AD biomarker and cognition. Methods: In 586 older adults without dementia, linear regressions tested the interaction between amyloid-β (Aβ) positron emission tomography (PET) and WMH volume on cognition, independent of tau-PET. We also tested the interaction between tau-PET and WMH volume on cognition, independent of Aβ-PET. Results: Adjusting for tau-PET, the quadratic effect of WMH interacted with Aβ-PET to impact memory. There was no interaction between either the linear or quadratic effect of WMH and Aβ-PET on executive function. There was no interaction between WMH volume and tau-PET on either cognitive measure. Conclusion: Results suggest that cerebrovascular lesions act synergistically with Aβ to affect memory, independent of tau, highlighting the importance of incorporating vascular pathology into biomarker assessment of AD.

Neha Atulkumar Singh, Jonathan Graff-Radford, Mary M. Machulda, Nha Trang Thu Pham, Christopher G. Schwarz, Robert I. Reid, Val J. Lowe, Ronald C. Petersen, Clifford R. Jack, Jr, Keith A. Josephs, Jennifer L. Whitwell
Diffusivity Changes in Posterior Cortical Atrophy and Logopenic Progressive Aphasia: A Longitudinal Diffusion Tensor Imaging Study
Abstract: Background: Posterior cortical atrophy (PCA) and logopenic progressive aphasia (LPA) are associated with characteristic patterns of structural network degeneration. Little is known about longitudinal patterns of white matter tract degeneration in these phenotypes. Objective: To assess longitudinal patterns of white matter degeneration and identify phenotype specific cross-sectional and longitudinal diffusion tensor imaging (DTI) biomarkers in PCA and LPA. Methods: Twenty-five PCA, 22 LPA and 25 cognitively unimpaired (CU) individuals were recruited and underwent structural MRI that included a DTI sequence with a follow-up one year later. Cross-sectional and longitudinal mixed effects models were fit to assess the effects of diagnosis on baseline and annualized change in regional DTI metrics. Discriminatory power was investigated using the area under the receiver operating characteristic curves (AUROC). Results: PCA and LPA showed overlapping white matter degeneration profiles predominantly in the left occipital and temporal lobes, the posterior thalamic radiation and sagittal stratum at baseline, as well as the parietal lobe longitudinally. PCA showed degeneration in the occipital and parietal white matter, cross-sectionally and longitudinally, compared to CU, while LPA showed greater degeneration in the temporal and inferior parietal white matter and the inferior fronto-occipital fasciculus cross-sectionally, and in parietal white matter longitudinally compared to CU. Cross-sectionally, integrity of the inferior occipital white matter was best able to differentiate PCA from LPA, with an AUROC of 0.82. Conclusion: These findings contribute to our understanding of white matter degeneration and support usage of DTI as a useful additional diagnostic biomarker for PCA and LPA.

Aleksi Vanninen, Heikki Lukkarinen, Tarja Kokkola, Anne M. Koivisto, Merja Kokki, Tadeusz Musialowicz, Mikko Hiltunen, Henrik Zetterberg, Ville Leinonen, Sanna-Kaisa Herukka, Tuomas Rauramaa
Cerebrospinal Fluid Diagnostics of Alzheimer’s Disease in Patients with Idiopathic Normal Pressure Hydrocephalus
Abstract: Background: Alzheimer’s disease (AD) is the most common cause of dementia worldwide and a frequent comorbidity in idiopathic normal pressure hydrocephalus (iNPH). The presence of AD pathology is associated with worse outcomes after a shunt procedure in iNPH. Preoperative diagnosis of AD is challenging in patients with iNPH, which involves reduced concentrations of the cerebrospinal fluid (CSF) AD biomarkers. Objective: Our aim was to estimate the effect size of iNPH as a factor in CSF levels of AD biomarkers and to test if correction could be used to improve diagnostic value. Methods: Our cohort included 222 iNPH patients with data in the Kuopio NPH registry and brain biopsy and CSF samples available. We divided the patients into groups according to AD pathology per brain biopsy. For control cohorts, we had CSF samples from cognitively healthy individuals (n=33) and patients with diagnosed AD and no iNPH (n=39). Results: Levels of all investigated biomarkers differed significantly between groups, with the exception of t-Tau levels between healthy individuals and iNPH patients with AD pathology. Applying a correction factor for each biomarker (0.842*Aβ1-42, 0.779*t-Tau, and 0.610*P-Tau181) for the effect of iNPH yielded a sensitivity of 2.4% and specificity of 100%. The ratio of P-Tau181 to Aβ1-42 was moderately effective in aiding recognition of AD pathology in iNPH patients (sensitivity 0.79, specificity 0.76, area under the curve 0.824). Conclusion: Correcting for iNPH as a factor failed to improve diagnostic effectiveness, but the P-Tau181/Aβ1-42 ratio showed some utility in the diagnosis of AD in iNPH patients.

Dongjie Hu, Xiangjun Dong, Qunxian Wang, Mingjing Liu, Shuyue Luo, Zijun Meng, Zijuan Feng, Weihui Zhou, Weihong Song (Handling Associate Editor: Ling-Qiang Zhu)
PCP4 Promotes Alzheimer’s Disease Pathogenesis by Affecting Amyloid-β Protein Precursor Processing
Abstract: Background: Down syndrome (DS) is caused by an extra copy of all or part of chromosome 21. The patients with DS develop typical Alzheimer's disease (AD) neuropathology, indicating the role of genes on human chromosome 21 (HSA21) in the pathogenesis of AD. Purkinje cell protein 4 (PCP4), also known as brain-specific protein 19, is a critical gene located on HSA21. However, the role of PCP4 in DS and AD pathogenesis is not clear. Objective: To explore the role of PCP4 in amyloid-β protein precursor (AβPP) processing in AD. Methods: In this study, we investigated the role of PCP4 in AD progression in vitro and in vivo. In vitro experiments, we overexpressed PCP4 in human Swedish mutant AβPP stable expression or neural cell lines. In vitro experiments, APP23/PS45 double transgenic mice were selected and treated with AAV-PCP4. Multiple topics were detected by western blot, RT-PCR, immunohistochemical and behavioral test. Results: We found that PCP4 expression was altered in AD. PCP4 was overexpressed in APP23/PS45 transgenic mice and PCP4 affected the processing of AβPP. The production of amyloid-β protein (Aβ) was also promoted by PCP4. The upregulation of endogenous AβPP expression and the downregulation of ADAM10 were due to the transcriptional regulation of PCP4. In addition, PCP4 increased Aβ deposition and neural plaque formation in the brain, and exuberated learning and memory impairment in transgenic AD model mice. Conclusion: Our finding reveals that PCP4 contributes to the pathogenesis of AD by affecting AβPP processing and suggests PCP4 as a novel therapeutic target for AD by targeting Aβ pathology.

Bodil Weidung, Maria Josefsson, Peter Lyttkens, Jan Olsson, Fredrik Elgh, Lars Lind, Lena Kilander, Hugo Lövheim
Longitudinal Effects of Herpesviruses on Multiple Cognitive Outcomes in Healthy Elderly Adults
Abstract: Background: Herpesviruses have been proposed to be involved in Alzheimer’s disease development as potentially modifiable pathology triggers. Objective: To investigate associations of serum antibodies for herpes simplex virus (HSV)-1 and cytomegalovirus (CMV) and anti-herpesvirus treatment with cognitive outcomes in relation to interactions with APOE ε4. Methods: The study included 849 participants in the population-based Prospective Investigation of the Vasculature in Uppsala Seniors study. Cognitive performance at the ages of 75 and 80 years was assessed using the Mini-Mental State Examination (MMSE), trail-making test (TMT) A and B, and 7-minute screening test (7MS). Results: Anti–HSV-1 IgG positivity was associated cross-sectionally with worse performance on the MMSE, TMT-A, TMT-B, 7MS, enhanced free recall, and verbal fluency tests (p = 0.016, p = 0.016, p < 0.001, p = 0.001, p = 0.033, and p < 0.001, respectively), but not orientation or clock drawing. Cognitive scores did not decline over time and longitudinal changes did not differ according to HSV-1 positivity. Anti–CMV IgG positivity was not associated cross-sectionally with cognition, but TMT-B scores declined more in anti–CMV IgG carriers. Anti–HSV-1 IgG interacted with APOEε4 in association with worse TMT-A and better enhanced cued recall. Anti–HSV IgM interacted with APOEε4 and anti-herpesvirus treatment in association with worse TMT-A and clock drawing, respectively. Conclusion: These findings indicate that HSV-1 is linked to poorer cognition in cognitively healthy elderly adults, including impairments in executive function, memory, and expressive language. Cognitive performance did not decline over time, nor was longitudinal decline associated with HSV-1.

Jie Wang, Mengjie Wang, Shuhua Ren, Lin Huang, Kun He, Junpeng Li, Fengchun Hua, Yihui Guan, Qihao Guo, Qi Huang, Fang Xie
The Effect of Gender and APOE ε4 Status on Brain Amyloid-β Deposition in Different Age Groups of Mild Cognitively Impaired Individuals: A PET-CT Study
Abstract: Background: Gender, APOE ε4 status and age have different effects on brain amyloid deposition in patients with mild cognitively impaired (MCI). Objective: To investigate the effect of gender × APOE ε4 status interaction on Aβ deposition in the brains of individuals with MCI in different age groups by PET scanning. Methods: 204 individuals with MCI were classified into younger or older groups based on whether they were under or over 65 years of age. APOE genotyping, structural MRI, amyloid PET scans, and neuropsychological tests were performed. The effect of gender × APOE ε4 status interaction on Aβ deposition was assessed in different age groups. Results: APOE ε4 carriers had higher amyloid deposition than noncarriers in the whole group. Females with MCI had more amyloid deposition in the medial temporal lobe than males in the whole cohort and younger group. Older individuals with MCI had higher amyloid deposition than younger individuals. In stratified analysis by age, female APOE ε4 carriers had significantly increased amyloid deposition compared to their male counterparts only in the medial temporal lobe in the younger group. Amyloid deposition was increased in female APOE ε4 carriers compared to noncarriers in the younger group, whereas higher amyloid deposition was observed in male APOE ε4 carriers in the older group. Conclusion: Women in the younger group with MCI who were APOE ε4 carriers had more amyloid deposition in the brain, while men in the older group with MCI who were APOE ε4 carriers had higher amyloid deposition.

Eleanor Curran, Victoria J. Palmer, Kathryn A. Ellis, Terence W.H. Chong, Thomas Rego, Kay L. Cox, Kaarin J. Anstey, Alissa Westphal, Rebecca Moorhead, Jenny Southam, Rhoda Lai, Emily You, Nicola T. Lautenschlager
Physical Activity for Cognitive Health: A Model for Intervention Design for People Experiencing Cognitive Concerns and Symptoms of Depression or Anxiety
Abstract: Background: People experiencing cognitive concerns and symptoms of depression or anxiety are at risk for Alzheimer’s disease and dementia. We know physical activity can benefit cognition but understanding how to best support engagement is an ongoing challenge. Evidence-based conceptual models of factors underpinning physical activity engagement in target populations can inform intervention tailoring to address this challenge. Objective: This study (part of a pragmatic physical activity implementation trial) aimed to develop a specified model of physical activity engagement in people experiencing depressive or anxiety symptoms and cognitive concerns, to enable optimized dementia risk reduction intervention tailoring. Methods: We employed a qualitative design, triangulating data from three sources: semi-structured individual interviews with people experiencing cognitive concerns and mild to moderate depressive or anxiety symptoms; review of published evidence; and the Capability, Opportunity and Motivation system of behavior, an existing behavioral science model. Findings were integrated to develop a contextualized model of mechanisms of action for optimizing engagement. Results: Twenty-one participants were interviewed, and 24 relevant papers included. Convergent and complementary themes extended understanding of intervention needs. Findings highlighted emotional regulation, capacities to enact intentions despite barriers, and confidence in existing skills as areas of population-specific need that have not previously been emphasized. The final model provides specificity, directionality, and linked approaches for intervention tailoring. Conclusion: This study demonstrated that people experiencing cognitive concerns and symptoms of depression or anxiety require different interventions to improve physical activity engagement. The novel model can enable more precise intervention tailoring, and, ultimately, benefits for a key at-risk population.

Terence W. H. Chong, Thomas Rego, Rhoda Lai, Alissa Westphal, Constance Dimity Pond, Eleanor Curran, Scherazad Kootar, Ruth Peters, Kaarin J. Anstey, Nicola T. Lautenschlager
Preferences and Perspectives of Australian General Practitioners’ Towards a New “Four-in-One” Risk Assessment Tool for Preventative Health: The LEAD! GP Project
Abstract: Background: Dementia risk reduction is a public health priority and general practitioners (GPs) play a pivotal role in preventative healthcare. Therefore, risk assessment tools should be designed with GPs’ preferences and perspectives in mind. Objective: The LEAD! GP project aimed to investigate Australian GPs’ preferences and perspectives relating to design, use and implementation of a new risk assessment tool that simultaneously calculates risk for four outcomes—dementia, diabetes mellitus, myocardial infarct, and stroke. Methods: A mixed methods study using semi-structured interviews of a diverse group of 30 Australian GPs was conducted. Interview transcripts were analyzed thematically. Demographics and questions that elicited categorical answers were analyzed descriptively. Results: Overall, GPs felt that preventative healthcare was important with some finding it rewarding, and others finding it difficult. GPs currently use many risk assessment tools. GPs’ perception of the usefulness and negatives/barriers of tools related to clinical practice applicability, patient engagement, and practical aspects. The largest barrier was lack of time. GPs responded positively to the concept of a four-in-one tool and preferred it to be relatively short, supported by practice nurses and some patient involvement, linked to education resources, available in different formats, and integrated into practice software. Conclusion: GPs recognize the importance of preventative healthcare and the potential benefit of a new tool that simultaneously predicts risk for those four outcomes. Findings provide important guidance to inform the final development and piloting of this tool with potential to improve efficiency and practical integration of preventative healthcare for dementia risk reduction.

Wan-rong Jiang*, Wei Wu*, Li-jie Yang, Wanzhexi Yang, Qing Tian, Zhao-hui Yao (Handling Associate Editor: Ling-Qiang Zhu) *These authors contributed equally to this work.
Alteration of Cognitive Function in Aging and Alzheimer’s Disease Mice Is Related to Dysfunction of the Neuroimmune System
Abstract: Background: Both Alzheimer’s disease (AD) and aging have aging-related cognitive dysfunction with a high incidence. These neurological diseases cause serious cognitive problems in patients’ daily life. But the cognitive dysfunction mechanism in-depth of aging is far less known than that of AD. Objective: To reveal the different mechanisms of AD and aging-related cognitive dysfunction, we compared the mechanisms of aging and AD through analysis of differentially expressed genes. Methods: Mice were divided into four groups (3-month C57BL, 16-month C57BL, 3-month 3xTg AD mice, and 16-month 3xTg AD mice) according to genotype and age. The Morris water maze was employed to investigate the spatial cognition of mice. Differential expressions of genes of AD and aging were analyzed through RNA sequencing and GO, KEGG, Reactome analysis, and the dynamic change trend analysis. Microglia was stained with immunofluorescence and its numbers were counted for analysis. Results: The cognitive function of elderly mice were worse through testing with the Morris water maze. The cognitive function of 16-month 3xTg AD mice were worse than 16-month C57BL mice. The alteration tendencies of DE genes were uncovered, and microglia numbers increased during aging and AD progression through immunofluorescence. Conclusion: These results suggest that immune-related pathways might play a critical role in aging and AD-related cognitive dysfunction. Our research will help to provide some new potential targets for treating cognitive dysfunction in aging and AD.

Clinical Trial Protocol
Ciara Treacy, Jacob M. Levenstein, Annelise Jefferies, Alexandra P. Metse, Mia A. Schaumberg, Anthony Villani, Ana P. Boucas, Daniel F. Hermens, Jim Lagopoulos, Sophie C. Andrews (Handling Associate Editor: Christina Polidori)
The LEISURE Study: A Longitudinal Randomized Controlled Trial Protocol for a Multi-Modal Lifestyle Intervention Study to Reduce Dementia Risk in Healthy Older Adults
Abstract: Dementia is understood to arise from a mixed etiology, enveloping chronic inflammatory and vascular impacts on the brain, driven by a constellation of modifiable risk factors which are largely mediated by lifestyle-related behaviors. These risk factors manifest over a prolonged preclinical period and account for up to 40% of the population attributable risk for dementia, representing viable targets for early interventions aimed at abating disease onset and progression. Here we outline the protocol for a 12-week randomized control trial (RCT) of a multimodal Lifestyle Intervention Study for Dementia Risk Reduction (LEISURE), with longitudinal follow-up at 6-months and 24-months post-intervention. This trial integrates exercise, diet, sleep, and mindfulness to simultaneously target multiple different etiopathogenetic mechanisms and their interplay in a healthy older adult population (aged 50-85 years), and assesses dementia risk reduction as the primary endpoint. The LEISURE study is located in the Sunshine Coast region of Australia, which has one of the nation’s highest proportions of adults aged over 50 years (36.4%), and corresponding dementia prevalence. This trial is novel in its inclusion of mindfulness and sleep as multidomain lifestyle targets, and in its comprehensive suite of secondary outcomes (based on psychological, physical health, sleep activity, and cognitive data) as well as exploratory neuroimaging (magnetic resonance imaging and electroencephalography) and molecular biology measures. These measures will provide greater insights into the brain-behavioral underpinnings of dementia prevention, as well as the predictors and impacts of the proposed lifestyle intervention. The LEISURE study was prospectively registered (ACTRN12620000054910) on 19 January 2020.