Volume 98, Number 2, IN PRESS

Review
Charles L. Greenblatt, Richard Lathe
Vaccines and Dementia: Part I. Non-Specific Immune Boosting with BCG: History, Ligands, and Receptors
Abstract: Vaccines such as Bacille Calmette–Guérin (BCG) can apparently defer dementia onset with an efficacy better than all drugs known to date, as initially reported by Gofrit et al. (PLoS One 14, e0224433), now confirmed by other studies. Understanding how and why is of immense importance because it could represent a sea-change in how we manage patients with mild cognitive impairment through to dementia. Given that infection and/or inflammation are likely contribute to the development of dementias such as Alzheimer's disease (Part II of this work), we provide a historical and molecular background to how vaccines, adjuvants, and their component molecules can elicit broad-spectrum protective effects against diverse agents. We review early studies in which poxvirus, herpes virus, and tuberculosis (TB) infections afford cross-protection against unrelated pathogens, a concept known as 'trained immunity'. We then focus on the attenuated TB vaccine, BCG, that was introduced to protect against the causative agent of TB, Mycobacterium tuberculosis. We trace the development of BCG in the 1920s through to the discovery, by Freund and McDermott in the 1940s, that extracts of mycobacteria can themselves exert potent immunostimulating (adjuvant) activity; Freund's complete adjuvant based on mycobacteria remains the most potent immunopotentiator reported to date. We then discuss whether the beneficial effects of BCG require long-term persistence of live bacteria, before focusing on the specific mycobacterial molecules, notably muramyl dipeptides, that mediate immunopotentiation, as well as the receptors involved. Part II addresses evidence that immunopotentiation by BCG and other vaccines can protect against dementia development.

Review
Charles L. Greenblatt, Richard Lathe
Vaccines and Dementia: Part II. Efficacy of BCG and Other Vaccines Against Dementia
Abstract: There is growing awareness that infections may contribute to the development of senile dementia including Alzheimer's disease (AD), and that immunopotentiation is therefore a legitimate target in the management of diseases of the elderly including AD. In Part I of this work, we provided a historical and molecular background to how vaccines, adjuvants, and their component molecules can elicit broad-spectrum protective effects against diverse agents, culminating in the development of the tuberculosis vaccine strain Bacille Calmette–Guérin (BCG) as a treatment for some types of cancer as well as a prophylactic against infections of the elderly such as pneumonia. In Part II, we critically review studies that BCG and other vaccines may offer a measure of protection against dementia development. Five studies to date have determined that intravesicular BCG administration, the standard of care for bladder cancer, is followed by a mean ~45% reduction in subsequent AD development in these patients. Although this could potentially be ascribed to confounding factors, the finding that other routine vaccines such as against shingles (herpes zoster virus) and influenza (influenza A virus), among others, also offer a degree of protection against AD (mean 29% over multiple studies) underlines the plausibility that the protective effects are real. We highlight clinical trials that are planned or underway and discuss whether BCG could be replaced by key components of the mycobacterial cell wall such as muramyl dipeptide. We conclude that BCG and similar agents merit far wider consideration as prophylactic agents against dementia.

Systematic Review
Xiao-Xue Zhang, He-Ran Wang, Meng-Wei, Ya-Zhuo Hu, Hong-Mei Sun, Yu-Xin Feng, Jian-Jun Jia
Association of Vitamin D Levels with Risk of Cognitive Impairment and Dementia: A Systematic Review and Meta-Analysis of Prospective Studies
Abstract: Background: Emerging evidence suggests the potential relationship between vitamin D deficiency and risk of cognitive impairment or dementia. To what extent the excess risk of dementia conferred by vitamin D deficiency is less clear. Objective: We summarized the current evidence from several aspects and further quantified these associations. Methods: We collected relevant prospective cohort studies by searching PubMed, Embase and Cochrane up to July 2023. The pooled relative risks (RR) were evaluated by random-effects models. Dose-response analyses were conducted by the method of two-stage generalized least squares regression. Results: Of 9,267 identified literatures, 23 were eligible for inclusion in the meta-analyses, among which 9 and 4 literatures were included in the dose-response analyses for the risk of dementia and Alzheimer’s disease (AD). Vitamin D deficiency exhibited a 1.42 times risk for dementia (95% confidence interval (CI) = 1.21-1.65) and a 1.57-fold excess risk for AD (95% CI = 1.15-2.14). And vitamin D deficiency was associated with 34% elevated risk with cognitive impairment (95% CI = 1.19-1.52). Additionally, vitamin D was non-linearly related to the risk of dementia (pnonlinearity = 0.0000) and AD (pnonlinearity = 0.0042). The approximate 77.5-100 nmol/L 25-hydroxyvitamin D [25(OH)D] was optimal for reducing dementia risk. And the AD risk seemed to be decreased when the 25(OH)D level > 40.1 nmol/L. Conclusions: Vitamin D deficiency was a risk factor for dementia, AD, and cognitive impairment. The nonlinear relationships may further provide the optimum dose of 25(OH)D for dementia prevention.

Hypothesis
Jose A. Adams, Arkady Uryash, Jose R. Lopez (Handling Associate Editor: Madeleine Hackney)
Harnessing Passive Pulsatile Shear Stress for Alzheimer's Disease Prevention and Intervention
Abstract: Alzheimer’s disease (AD) affects more than 40 million people worldwide and is the leading cause of dementia. This disease is a challenge for both patients and caregivers and puts a significant strain on the global healthcare system. To address this issue, the Lancet Commission recommends focusing on reducing modifiable lifestyle risk factors such as hypertension, diabetes, and physical inactivity. Passive pulsatile shear stress (PPSS) interventions, which use devices like whole-body periodic acceleration, periodic acceleration along the Z-axis (pGz), and the Jogging Device, have shown significant systemic and cellular effects in preclinical and clinical models which address these modifiable risks factors. Based on this, we propose that PPSS could be a potential non-pharmacological and non-invasive preventive or therapeutic strategy for AD. We perform a comprehensive review of the biologic and physiological basis based on all publications of PPSS using these devices and demonstrate their effects on the various aspects of AD. We draw from this comprehensive analysis to support our hypothesis. We then delve into the possible application of PPSS as an innovative intervention. We discuss how PPSS holds promise in ameliorating hypertension and diabetes while mitigating physical inactivity, potentially offering a holistic approach to AD prevention and management.

Short Communication
Joanna Norton, Laure-Anne Gutierrez, Christian Gourdeau, Hélène Amieva, Patrick Bernier, Claudine Berr (Handling Associate Editor: Petronilla Battista)
Mapping Cognitive Trajectories and Detecting Early Dementia Using the Mini-Mental State Examination Cognitive Charts: Application to the French Three-City Cohort
Abstract: The Cognitive Quotient (QuoCo) classification algorithm monitoring decline on age- and education-adjusted Mini-Mental State Examination (MMSE)-derived cognitive charts has proved superior to the conventionally-used cut-off for identifying incident dementia; however, it remains to be tested in different settings. Data were drawn from the Three-City Cohort to 1) assess the screening accuracy of the QuoCo, and 2) compare its performance to that of serial MMSE tests applying different cut-offs. For the QuoCo, sensitivity was 74.2 (95%CI: 71.4-76.8) and specificity 84.1 (83.6-84.7) and for the MMSE <24, 64.1 (61.1-67.0) and 94.8 (94.4-95.1), respectively; whereas overall accuracy and sensitivity was highest for MMSE cut-offs <25 and < 26. User-friendly charts for mapping cognitive trajectories over visits with an alert for potentially ‘abnormal’ decline can be of practical use and encourage regular monitoring in primary care where the <24 cut-off is still widely used despite its poor sensitivity.

Commentary
Miranda E. Orr
A Need for Refined Senescence Biomarkers and Measures of Senolytics in the Brain
Abstract: Cellular senescence contributes to Alzheimer’s disease (AD) pathogenesis. Treatments that remove senescent cells, senolytics, improve brain outcomes in AD mice with amyloid-β or tau deposition. 3xTgAD mice develop both AD neuropathologies; however, Ng et al. report low p16INK4a-associated senescence in the brain. Senolytic treatment by genetic removal; dasatinib with quercetin (D+Q), which enter the brain; and ABT-263 with limited brain penetrance all reduced AD neuropathology. Refined measures of senescence and brain exposure would help clarify the benefits of senolytics despite low p16INK4a-associated senescence and potential limited brain penetrance.

Commentary
Jesse Ballenger, Daniel R. George, Peter J. Whitehouse
Digging Deeper: What Can We Really Learn about Dementia from History?
Abstract: In response to Finch and Burstein’s provocative argument that the advanced dementias may result from environmental toxins and lifestyle factors associated with post-industrial societies, we call for a more rigorous historical approach, emphasizing the importance of situating ancient texts more fully in their historical and cultural context. Such an approach would also entail consideration of the declining relative rates of dementia in Western countries, which have been linked to population health-level factors and policies that appear to have reduced the risk of dementia by directly and indirectly influencing the social determinants of brain health.

Commentary
Rónán O’Caoimh
Hypertension and Mild Cognitive Impairment: Understanding the Complexities of the Relationship in Understudied Populations
Abstract: The association between hypertension and mild cognitive impairment (MCI) is complex. Both are increasing in prevalence worldwide and will have disproportionate effects on lower income countries across Latin America. Despite this, there is insufficient evidence investigating this relationship in this region or those of Hispanic or Latino ancestry in higher income countries. In this context, the Study of Latinos-Investigation of Neurocognitive Aging represents a unique dataset. Although more research is required, Márquez and colleagues show that hypertension in this population in the United States is associated with decline in cognitive measures and greater odds of MCI over seven years follow-up.

Marco Michelutti*, Daniele Urso*, Valentina Gnoni, Alessia Giugno, Chiara Zecca, Davide Vilella, Maria Accadia, Roberta Barone, Maria Teresa Dell’Abate, Roberto De Blasi, Paolo Manganotti, Giancarlo Logroscino *These authors contributed equally to this work.
Narcissistic Personality Disorder as Prodromal Feature of Early-Onset, GRN-Positive bvFTD: A Case Report
Abstract: Background: Behavioral variant frontotemporal dementia (bvFTD) typically involves subtle changes in personality that can delay a timely diagnosis. Objective: Here, we report the case of a patient diagnosed of GRN-positive bvFTD at the age of 52 presenting with a 7-year history of narcissistic personality disorder, accordingly to DSM-5 criteria. Methods: The patient was referred to neurological and neuropsychological examination. She underwent 3 Tesla magnetic resonance imaging (MRI) and genetic studies. Results: The neuropsychological examination revealed profound deficits in all cognitive domains and 3T brain MRI showed marked fronto-temporal atrophy. A mutation in the GRN gene further confirmed the diagnosis. Conclusions: The present case documents an unusual onset of bvFTD and highlights the problematic nature of the differential diagnosis between prodromal psychiatric features of the disease and primary psychiatric disorders. Early recognition and diagnosis of bvFTD can lead to appropriate management and support for patients and their families. This case highlights the importance of considering neurodegenerative diseases, such as bvFTD, in the differential diagnosis of psychiatric disorders, especially when exacerbations of behavioral traits manifest in adults.

Milou J. Angevaare, Jack A. Pieters, Jos W.R. Twisk, Hein P.J. van Hout
Social Activity and Cognitive Decline in Older Residents of Long-Term Care Facilities: A Cohort Study
Abstract: Background: Cognitive decline is a major reason for dependence and resource use in long-term care. Objective: We explored whether social activities may prevent cognitive decline of older residents of long-term care facilities. Methods: In a routine care cohort, 3,603 residents of long-term care facilities were assessed on average 4.4 times using the InterRAI-Long-Term-Care-Facilities instrument which includes frequency of participation in social activities of long standing interest over the last 30 days and the Cognitive Performance Scale. Linear mixed models repeated measures analyses were performed corrected for age, sex, physical activity, Activities of Daily Living, mood, and health indicators. Results: Social activity was associated with cognitive preservation over time. This association was stronger in those with no or mild cognitive impairment at baseline, relative to those with moderate to severe impairment. Participation in specific social activities such as conversing and helping others showed a similar positive association. The relation between social activity and cognitive impairment appeared to be bi-directional. Conclusions: The protective effects of social activity offer a window of opportunity to preserve cognitive functioning in long-term care residents.

Quinton D. Cotton, Elle Albers, Steph Ingvalson, Emily Skalla, Dionne Bailey, Katie Marx, Keith Anderson, Holly Dabelko-Schoeny, Lauren Parker, Laura N. Gitlin, Joseph E. Gaugler (Handling Associate Editor: Megan Shepherd-Banigan)
Qualitative Analysis of Implementation Factors of an Embedded Caregiver Support Intervention into Adult Day Services
Abstract: Background: Adult day services (ADS) are an important and often underutilized support resource for older adults. For persons living with dementia (PLWD), ADS is an optimal access point to not only receive therapeutic and rehabilitative activities, but as a vehicle for respite/relief for dementia caregivers. Yet, there is currently a lack of research on integrating caregiver interventions into home and community-based services such as ADS. Objective: This paper reports on qualitative findings from the Improving Outcomes for Family Caregivers of Older Adults with Complex Conditions: The Adult Day Plus (ADS Plus) Program Trial. Methods: Drawing from semi-structured interviews conducted with family caregivers and ADS site staff, we conducted a thematic analysis to examine the implementation process of ADS Plus. Results: Themes address the relational nature of the intervention, learning, influence of the administrative infrastructure, and receptivity of ADS Plus. Conclusions: Our analysis determined that implementation of ADS Plus was feasible and accepted by site staff and dementia caregivers but also calls for additional evaluation of embedded caregiver support interventions across different contexts (e.g., staff size, limited technology environments) to further identify and test implementation mechanisms across settings.

Filipa Raposo Pereira, Nathalie George, Gianfranco Dalla Barba, Bruno Dubois, Valentina La Corte, the INSIGHT-preAD study group
The Memory Binding Test Detects Early Subtle Episodic Memory Decline in Preclinical Alzheimer’s Disease: A Longitudinal Study
Abstract: Background: The asymptomatic at-risk phase might be the optimal time-window to establish clinically meaningful endpoints in Alzheimer’s disease (AD). Objective: We investigated whether, compared with the Free and Cued Selective Reminding Test (FCSRT), the Memory Binding Test (MBT) can anticipate the diagnosis of emergent subtle episodic memory (EM) deficits to an at-risk phase. Methods: Five-year longitudinal FCSRT and MBT scores from 45 individuals matched for age, education, and gender, were divided into 3 groups of 15 subjects: Aβ-/controls, Aβ+/stable, and Aβ+/progressors (preclinical-AD). The MBT adds an associative memory component (binding), particularly sensitive to subtle EM decline. Results: In the MBT, EM decline started in the Aβ+/progressors (preclinical-AD) up to 4 years prior to diagnosis in delayed free recall (FR), followed by decline in binding-associated scores 1 year later. Conversely, in the FCSRT, EM-decline began later, up to 3 years prior to diagnosis, in the same group on both immediate and delayed versions of FR, while on total recall (TR) and intrusions decline started only 1 year prior to diagnosis. Conclusions: The MBT seems more sensitive than the FCSRT for early EM-decline detection, regarding the year of diagnosis and the number of scores showing AD-linked EM deficits (associated with the AD-characteristic amnesic hippocampal syndrome). Considering the MBT as a detection tool of early subtle EM-decline in an asymptomatic at-risk phase, and the FCSRT as a classification tool of stages of EM-decline from a preclinical phase, these tests ought to potentially become complementary diagnostic tools that can foster therapies to delay cognitive decline.

Sha Li, Xiaoyong Lan, Yumei Liu, Junhong Zhou, Zian Pei, Xiaolin Su, Yi Guo
Unlocking the Potential of Repetitive Transcranial Magnetic Stimulation in Alzheimer's Disease: A Meta-Analysis of Randomized Clinical Trials to Optimize Intervention Strategies
Abstract: Background: Repetitive transcranial magnetic stimulation (rTMS) is an advanced and noninvasive technology that uses pulse stimulation to treat cognitive impairment. However, its specific effects have always been mixed with those of cognitive training, and the optimal parameter for Alzheimer’s disease (AD) intervention is still ambiguous. Objective: This study aimed to summarize the therapeutic effects of pure rTMS on AD, excluding the influence of cognitive training, and to develop a preliminary rTMS treatment plan. Methods: Between 1 January 2010 and 28 February 2023, we screened randomized controlled clinical trials from five databases (PubMed, Web of Science, Embase, Cochrane, and ClinicalTrials. gov). We conducted a meta-analysis and systematic review of treatment outcomes and rTMS treatment parameters. Result: A total of 4,606 articles were retrieved. After applying the inclusion and exclusion criteria, 16 articles, comprising 655 participants (308 males and 337 females), were included in the final analysis. The findings revealed that rTMS significantly enhances both global cognitive ability (p=0.0002, SMD=0.43, 95% CI=0.20-0.66) and memory (p = 0.009, SMD = 0.37, 95% CI = 0.09–0.65). Based on follow-up periods of at least 6 weeks, the following stimulation protocols have demonstrated efficacy for AD: stimulation sites (single or multiple targets), frequency (20 Hz), stimulation time (1-2 s), interval (20-30 s), single pulses (≤2500), total pulses (>20000), duration (≥3 weeks), and sessions (≥20). Conclusions: This study suggests that rTMS may be an effective treatment option for patients with AD, and its potential therapeutic capabilities should be further developed in the future.

YuanYing Wang*, ShiHao Wang*, JiaXin Wu*, XinLian Liu, LuShun Zhang *These authors contributed equally to this work.
Causal Association Between Allergic Diseases and Dementia: Evidence from Multivariate Mendelian Randomization Study
Abstract: Background: The link between allergic diseases and dementia remains controversial, and the genetic causality of this link is unclear. Objective: This study investigated the causal relationship between allergic diseases and dementia using univariate and multivariate Mendelian randomization (MR) methods. Methods: We selected genome-wide association studies including 66,645 patients with allergic diseases and 12,281 patients with dementia, with statistical datasets derived from the FinnGen Consortium of European origin. After a rigorous screening process for single nucleotide polymorphisms to eliminate confounding effects, MR estimation was performed mainly using the inverse variance weighting method and the MR-Egger method. Sensitivity analyses were performed using Cochran's Q test, MR-PRESSO test, MR Pleiotropy residuals and leave-one-out analysis. Results: Univariate and multivariate MR together demonstrated a causal relationship between atopic dermatitis and reduced vascular dementia (VaD) risk (OR=0.89, 95% CI: 0.81-0.99, p=0.031; OR=0.85, 95% CI: 0.76-0.95, p=0.003). MVMR confirmed asthma was associated with a reduction in the risk of Alzheimer's disease (AD) (OR=0.82, 95% CI: 0.71-0.94, p=0.005) and may be associated with a reduction in the risk of VaD (OR=0.80, 95% CI: 0.65-0.99, p=0.042); allergic rhinitis may be causally associated with an increased risk of AD (OR=1.16, 95% CI: 1.00-1.35, p=0.046) and VaD (OR=1.29, 95% CI: 1.03-1.62, p=0.027). In sensitivity analyses, these findings were reliable. Conclusions: MR methods have only demonstrated that allergic rhinitis dementia is associated with an increased risk of developing dementia. Previously observed associations between other allergic diseases and dementia may be influenced by comorbidities and confounding factors rather than causality.

Jing Wang, I Tek Leong, Min Kyoung Johnson, Yaolin Pei, Kyung Hee Lee, Mary S. Mittelman, Cynthia Epstein, Soyeon Cho, Bei Wu
What Matters to Chinese and Korean American Dementia Caregivers: Navigating Cultural Influences in Dementia Care from Caregivers’ Perspectives
Abstract: Background: Chinese and Korean Americans are among the fastest-growing minority groups in the US but face disparities in income and limited English proficiency, leading to health inequities in Alzheimer's disease and related dementias (ADRD) care. Objective: This study aims to understand cultural influences in ADRD care from the perspectives of Chinese and Korean American caregivers to inform culturally sensitive support for caregivers in Asian immigrant populations. Methods: We conducted a study that was part of a broader project aimed at informing the cultural adaptation of the NYU Caregiver Intervention-Enhanced Support (NYUCI-ES) program specifically for Chinese and Korean American caregivers managing multiple chronic conditions. In our interviews with 14 Chinese American and 11 Korean American caregivers, we focused on how their roles as primary caregivers were influenced by cultural and family expectations, the impact of caregiving on their personal and emotional well-being, and the specific barriers they face in accessing healthcare for themselves and their relatives with dementia. Results: Cultural beliefs and values significantly influenced the perceptions and utilization of support systems among Chinese and Korean American caregivers. Family stigma and adherence to cultural norms impacted their caregiving experiences. The study also highlighted the added burden during the pandemic and the potential benefits of telehealth and information technology in ADRD care. Conclusions: Developing culturally tailored, person-centered programs is crucial to meeting the unique needs of Chinese and Korean American caregivers. This research contributes to understanding and supporting this vulnerable population, promoting healthcare equity for ADRD patients and caregivers.

Hiroshi Kameyama, Kenji Tagai, Emi Takasaki, Tetsuo Kashibayashi, Ryuichi Takahashi, Hideki Kanemoto, Kazunari Ishii, Manabu Ikeda, Masatoshi Shigeta, Shunichiro Shinagawa, Hiroaki Kazui
Examining Frontal Lobe Asymmetry and Its Potential Role in Aggressive Behaviors in Early Alzheimer’s Disease
Abstract: Background: Neuropsychiatric symptoms (NPS) in patients with dementia lead to caregiver burdens and worsen the patient's prognosis. Although many neuroimaging studies have been conducted, the etiology of NPS remains complex. We hypothesize that brain structural asymmetry could play a role in the appearance of NPS. Objective: This study explores the relationship between NPS and brain asymmetry in patients with Alzheimer’s disease (AD). Methods: Demographic and MRI data for 121 mild AD cases were extracted from a multicenter Japanese database. Brain asymmetry was assessed by comparing the volumes of gray matter in the left and right brain regions. NPS was evaluated using the Neuropsychiatric Inventory (NPI). Subsequently, a comprehensive assessment of the correlation between brain asymmetry and NPS was conducted. Results: Among each NPS, aggressive NPS showed a significant correlation with asymmetry in the frontal lobe, indicative of right-side atrophy (r=0.235, p=0.009). This correlation remained statistically significant even after adjustments for multiple comparisons (p<0.01). Post-hoc analysis further confirmed this association (p<0.05). In contrast, no significant correlations were found for other NPS subtypes, including affective and apathetic symptoms. Conclusions: The study suggests frontal lobe asymmetry, particularly relative atrophy in the right hemisphere, may be linked to aggressive behaviors in early AD. These findings shed light on the neurobiological underpinnings of NPS, contributing to the development of potential interventions.

Robert Vera, Nicholas Hong, Bailin Jiang, Ge Liang, Maryellen F. Eckenhoff, Halle J. Kincaid, Veron Browne, Vinolia Chellaraj, Douglas Gisewhite, Michael Greenberg, Sudhir Ranjan, Gaozhong Zhu, Huafeng Wei (Handling Associate Editor: Tao Ma)
Effects of Intranasal Dantrolene Nanoparticles on Brain Concentration and Behavior in PS19 Tau Transgenic Mice
Abstract: Background: Repurposing dantrolene to treat Alzheimer’s disease has been shown to be effective in amyloid transgenic mouse models but has not been examined in a model of tauopathy. Objective: The effects of a nanoparticle intranasal formulation, the Eagle Research Formulation of Ryanodex (ERFR), in young adult and aged wild type and PS19 tau transgenic mice was investigated. Methods: The bioavailability of intranasal ERFR was measured in 2 and 9–11-month-old C57BL/6J mice. Blood and brain samples were collected 20 minutes after a single ERFR dose, and the plasma and brain concentrations were analyzed. Baseline behavior was assessed in untreated PS19 tau transgenic mice at 6 and 9 months of age. PS19 mice were treated with intranasal ERFR, with or without acrolein (to potentiate cognitive dysfunction), for 3 months, beginning at 2 months of age. Animal behavior was examined, including cognition (cued and contextual fear conditioning, y-maze), motor function (rotarod), and olfaction (buried food test). Results: The dantrolene concentration in the blood and brain decreased with age, with the decrease greater in the blood resulting in a higher brain to blood concentration ratio. The behavioral assays showed no significant changes in cognition, olfaction, or motor function in the PS19 mice compared to controls after chronic treatment with intranasal ERFR, even with acrolein. Conclusions: Our studies suggest the intranasal administration of ERFR has higher concentrations in the brain than the blood in aged mice and has no serious systemic side effects with chronic use in PS19 mice.

Carol Sheei-Meei Wang, Po-See Chen, Tsung-Yu Tsai, Nien-Tsen Hou, Chia-Hung Tang, Pai-Lien Chen, Ying-Che Huang, Kuo-Sheng Cheng
Cognitive Effect of Transcranial Direct Current Stimulation on Left Dorsolateral Prefrontal Cortex in Mild Alzheimer’s Disease: A Randomized, Double-Blind, Cross-Over Small-Scale Exploratory Study
Abstract: Background: Transcranial direct current stimulation (tDCS) is considered a potential therapeutic instrument for Alzheimer’s disease (AD) because it affects long-term synaptic plasticity through the processes of long-term potentiation and long-term depression, thereby improving cognitive ability. Nevertheless, the efficacy of tDCS in treating AD is still debated. Dorsal lateral prefrontal cortex is the main role in executive functions. Objective: We investigate the cognitive effects of tDCS on AD patients. Methods: Thirty mild AD patients aged 66-86 years (mean = 75.6) were included in a double-blind, randomized, sham-controlled crossover study. They were randomly assigned to receive 10 consecutive daily sessions of active tDCS (2mA for 30 min) or a sham intervention and switched conditions 3 months later. The anodal and cathodal electrodes were placed on the left dorsal lateral prefrontal cortex and the right supraorbital area, respectively. Subjects underwent various neuropsychological assessments before and after the interventions. Results: The results showed that tDCS significantly improved Cognitive Abilities Screening Instrument scores, especially on the items of “concentration and calculation”, “orientation”, “language ability”, and “categorical verbal fluency”. Mini-Mental State Examination and Wisconsin Card Sorting Test scores in all domains of “concept formation”, “abstract thinking”, “cognitive flexibility”, and “accuracy” also improved significantly after tDCS. For the sham condition, no difference was found between the baseline scores and the after-intervention scores on any of the neuropsychological tests. Conclusions: Using tDCS improves the cognition of AD patients. Further large size clinical trials are necessary to validate the data.

Progress Njomboro, Tlholego Lekhutlile
The Effect of Apathy and Depressive Syndromes on Functional Outcomes in Alzheimer’s Disease
Abstract: Background: Alzheimer’s disease (AD) is the most common cause of dementia. Its initially characterized by progressive short-term memory loss followed by cross-domain cognitive decline in later stages resulting in significant functional deficits and loss of activities of daily living (ADLs) independence. Apathy and depression are frequent neuropsychiatric sequelae in AD, but their contribution to functional deficits is poorly understood. Objective: We aimed to quantitatively investigate if apathy and depressive symptoms predict ADLs in AD. We also wanted to fractionate apathy dimensions by factor-analyzing the apathy evaluation scale (AES) and then investigate the dimensions’ relation to ADLs. Methods: We recruited a sample of 115 patients with probable or possible AD and assessed them for depression, apathy, and ADLs alongside other measures. We hypothesized that apathy and depressive symptoms would predict ADLs and that AES items will load into cognitive, behavioral, and affective factors that would differentially relate to ADLs. Results: Our results indicated that apathy symptoms predict ADLs deficits. The AES items resolved into a three-factor solution but the manner of clustering diverged from that proposed by AES authors. When these factors were regressed simultaneously, only behavioral apathy predicted global ADLs. Distinguishing basic from instrumental ADLs showed that behavioral and cognitive apathy symptoms associate with ADLs deficits while affective symptoms do not. Conclusions: Our results highlight the influence of apathy on ADLs in AD. This has important implications for patient care considering the high prevalence of apathy in AD and other dementing illnesses.

Daniel C. Parker, Heather E. Whitson, Patrick J. Smith, Virginia B. Kraus, Janet L. Huebner, Rebecca North, William E. Kraus, Harvey Jay Cohen, Kim M. Huffman
Anti-CMV IgG Seropositivity Is Associated with Plasma Biomarker Evidence of Amyloid-β Accumulation
Abstract: Background: Some human studies have identified infection with cytomegalovirus (CMV), a member of the alpha herpesvirus family, as a risk factor for Alzheimer’s disease and related dementias (ADRD). To our knowledge, no studies have evaluated associations of CMV seropositivity with plasma biomarkers of ADRD risk in middle-aged adults. Objective: In participants recruited for an exercise study, we evaluated cross-sectional associations of CMV seropositivity with: Aβ42/Aβ40 ratio, a low ratio suggestive of central nervous system Aβ accumulation; glial fibrillary acidic protein (GFAP), a measure of neuroinflammation; and neurofilament light (NfL), a measure of neurodegeneration. Methods: Anti-CMV IgG was quantified by ELISA. Plasma ADRD biomarkers were quantified using the ultrasensitive SIMOA assay. We used linear regression to evaluate associations of CMV seropositivity with the ADRD biomarkers, adjusting for age, sex, and race (n=303; Age=55.7±9.2 years). For ADRD biomarkers significantly associated with CMV seropositivity, we evaluated continuous associations of anti-CMV IgG levels with the ADRD biomarkers, excluding CMV seronegative participants. Results: 53% of participants were CMV seropositive. CMV seropositivity was associated with a lesser Aβ42/Aβ40 ratio (β=-3.02e-03 95%CI [-5.97e-03, -7.18e-05]; p=0.045). In CMV seropositive participants, greater anti-CMV IgG levels were associated with a lesser Aβ42/Aβ40 ratio (β=-4.85e-05 95%CI[-8.45e-05, -1.25e-05]; p=0.009). CMV seropositivity was not associated with plasma GFAP or NfL in adjusted analyses. Conclusions: CMV seropositivity was associated with a lesser plasma Aβ42/Aβ40 ratio. This association may be direct and causally related to CMV neuro-cytotoxicity or may be indirect and mediated by inflammatory factors resulting from CMV infection burden and/or the immune response.

José María García-Alberca*, Itziar de Rojas*, Elisabeth Sanchez-Mejias*, Diego Garrido-Martín, Laura Gonzalez-Palma, Sebastian Jimenez, Almudena Pino-Angeles, Jose Manuel Cruz-Gamero, Silvia Mendoza, Emilio Alarcón-Martín, The GERALD consortium, Clara Muñoz-Castro, Luis Miguel Real, Juan Jesus Tena, Rocio Polvillo, Fernando Govantes, Aroa Lopez, Jose Luis Royo-Aguado, Victoria Navarro, Irene Gonzalez, Maximiliano Ruiz, Armando Reyes-Engel, Esther Gris, Maria Jose Bravo, Lidia Lopez-Gutierrez, Marina Mejias-Ortega, Paz De la Guía, María López de la Rica, Olga Ocejo, Javier Torrecilla, Carmen Zafra, María Dolores Nieto, Concepción Urbano, Rocío Jiménez-Sánchez, Nuria Pareja, Macarena Luque, María García-Peralta, Rosario Carrillejo, María del Carmen Furniet, Lourdes Rueda, Ana Sánchez-Fernández, Tomás Mancilla, Isabel Peña, Natalia García-Casares, Sonia Moreno-Grau, Isabel Hernández, Laura Montrreal, Inés Quintela, Antonio González-Pérez, Miguel Calero, Emilio Franco-Macías, Juan Macías, Manuel Menéndez-González, Ana Frank-García, Raquel Huerto Vilas, Mónica Diez-Fairen, Carmen Lage, Sebastián García-Madrona, Pablo García-González, Sergi Valero, Oscar Sotolongo-Grau, Alba Pérez-Cordón, Alberto Rábano, Alfonso Arias Pastor, Ana Belén Pastor, Ana Espinosa, Anaïs Corma-Gómez, Ángel Martín Montes, Ángela Sanabria, Carmen Martínez Rodríguez, Dolores Buiza-Rueda, Eloy Rodriguez-Rodriguez, Gemma Ortega, Ignacio Alvarez, Irene Rosas Allende, Juan A. Pineda, Maitée Rosende-Roca, María Bernal Sánchez-Arjona, Marta Fernández-Fuertes, Montserrat Alegret, Natalia Roberto, Teodoro del Ser, Guillermo Garcia-Ribas, Pascual Sánchez-Juan, Pau Pastor, Gerard Piñol-Ripoll, María José Bullido, Victoria Álvarez, Pablo Mir, Miguel Medina, Marta Marquié, María Eugenia Sáez, Ángel Carracedo, Marina Laplana, Laura Tomas-Gallardo, Adelina Orellana, Lluís Tárraga, Mercè Boada, Joan Fibla Palazon, Javier Vitorica, Agustín Ruiz, Roderic Guigo, Antonia Gutierrez, Jose Luis Royo (Handling Associate Editor: Steve Estus) *These authors contributed equally to this work.
An Insertion Within SIRPβ1 Shows a Dual Effect Over Alzheimer’s Disease Cognitive Decline Altering the Microglial Response
Abstract: Background: Microglial dysfunction plays a causative role in Alzheimer’s disease (AD) pathogenesis. Here we focus on a germline insertion/deletion variant mapping SIRPβ1, a surface receptor that triggers amyloid-β (Aβ) phagocytosis via TYROBP. Objective: To analyze the impact of this copy-number variant in SIRPβ1 expression and how it affects AD molecular etiology. Methods: Copy-number variant proxy rs2209313 was evaluated in GERALD and GR@ACE longitudinal series. Hippocampal specimens of genotyped AD patients were also examined. SIRPβ1 isoform-specific phagocytosis assays were performed in HEK393T cells. Results: The insertion alters the SIRPβ1 protein isoform landscape compromising its ability to bind oligomeric Aβ and its affinity for TYROBP. SIRPβ1 Dup/Dup patients with mild cognitive impairment show an increased cerebrospinal fluid t-Tau/Aβ ratio (p=0.018) and a higher risk to develop AD (OR=1.678, p=0.018). MRIs showed that Dup/Dup patients exhibited a worse initial response to AD. At the moment of diagnosis, all patients showed equivalent Mini-Mental State Examination scores. However, AD patients with the duplication had less hippocampal degeneration (p<0.001) and fewer white matter hyperintensities. In contrast, longitudinal studies indicate that patients bearing the duplication allele show a slower cognitive decline (p=0.013). Transcriptional analysis also shows that the SIRPβ1 duplication allele correlates with higher TREM2 expression and an increased microglial activation. Conclusions: The SIRPβ1 internal duplication has opposite effects over MCI-to-Dementia conversion risk and AD progression, affecting microglial response to Aβ. Given the pharmacological approaches focused on the TREM2-TYROBP axis, we believe that SIRPβ1 structural variant might be considered as a potential modulator of this causative pathway.

Lynn Chenoweth, Claire Burley, Jacquelene Cook, Seong Leang Cheah, Patricia Reyes, Genevieve Maiden, Jane McGuire, Donna McCade, Henry Brodaty, Mayouri Sukhapure, Fleur Harrison, Anna Williams
Improving Healthcare Quality and Clinical Outcomes for Persons with Dementia in the Sub-Acute Hospital Through Person-Centered Care Practice
Abstract: Background: Person-centered care is considered beneficial for persons with dementia. Objective: To evaluate the impact of a person-centered knowledge translation intervention on the quality of healthcare and outcomes for persons with dementia. Methods: Over nine months, sub-acute hospital nursing, allied health, and medical staff (n=90) participated in online and/or face-to-face person-centered education and were supported by senior nursing, allied health, and medical staff champions (n=8) to implement person-centered healthcare. The quality of healthcare service, ward climate and care delivery were evaluated pre/post study intervention. In the week following hospital admission (Time 1) and week of discharge (Time 3), agitation incidence (co-primary outcome) was assessed in participants with dementia (n=80). Participant delirium (co-primary outcome), accidents/injuries, psychotropic medicines, length of stay, readmission and discharge destination (secondary outcomes) were compared with a retrospective group (n=77) matched on demographics, cognition and function in activities of daily living. Results: Improvements occurred post-intervention in service quality by 17.5% (p=0.369, phi=0.08), ward climate by 18.1% (p=0.291, phi=0.08), and care quality by 50% (p=0.000, phi=0.37). Participant agitation did not change from Time 1 to Time 3 (p=0.223). Relative to the retrospective group, significant reductions occurred in participant delirium (p=0.000, phi=0.73), incidents/injuries (p=0.000, phi=0.99), psychotropic medicine use (p=0.030, phi=0.09), and hospital readmissions within 30 days (p=0.002, phi=0.25), but not in discharge to home (p=0.171). Conclusions: When person-centered healthcare knowledge is translated through staff education and practice support, persons with dementia can experience improved healthcare services and clinical outcomes, while healthcare services can benefit through reductions in unplanned service use.

Hao-Chen Chi*, Ling-Zhi Ma*, Zhi-Bo Wang, Ze-Hu Sheng, Jia-Yao Liu, Yin-Chu Mi, Yan Fu, Yi-Ming Huang, Shuang-Ling Han, Pei-Yang Gao, for the Alzheimer’s Disease Neuroimaging Initiative, Lan Tan, Jin-Tai Yu *These authors contributed equally to this work.
Associations of Frailty with Neuropsychiatric Symptoms of Alzheimer’s Disease: A Longitudinal Study
Abstract: Background: Frailty is a vulnerability state increasing the risk of many adverse health outcomes, but little is known about the effects of frailty on neuropsychiatric health. Objective: To explore the associations between frailty and the risk of neuropsychiatric symptoms (NPSs) in Alzheimer’s disease (AD), especially in its different clinical stages. Methods: We included 2,155 individuals assessed using modified frailty index-11 (mFI-11), Neuropsychiatric Inventory (NPI) and Neuropsychiatric Inventory Questionnaire (NPI-Q) in the Alzheimer’s Disease Neuroimaging Initiative (ADNI). The relationships between frailty and NPSs were explored with logistic regression models and Cox proportional hazard regression models. Causal mediation analyses were conducted to explore the mediation factors between frailty and NPSs. Results: Among mild cognitive impairment (MCI) participants, frailty was cross-sectionally associated with an increased risk of apathy, and longitudinally associated with increased risk of depression and apathy. Among AD participants, frailty was cross-sectionally associated with increased risk of depression and anxiety, and longitudinally associated with an increased risk of apathy. Among participants with cognitive progression, frailty was associated with increased risk of depression and apathy. In MCI participants, the influence of frailty on NPSs was partially mediated by hippocampus volume, whole brain volume, and monocytes, with mediating proportions ranging from 8.40% to 9.29%. Conclusions: Frailty was associated with NPSs such as depression, anxiety, and apathy among MCI, AD, and cognitive progression participants. Atrophy of the hippocampus and whole brain, as well as peripheral immunity may be involved in the potential mechanisms underlying the above associations.

Dhruv Gohel*, Pengyue Zhang*, Amit Kumar Gupta*, Yichen Li, Chien-Wei Chiang, Lang Li, Yuan Hou, Andrew A. Pieper, Jeffrey Cummings, Feixiong Cheng *These authors contributed equally to this work.
Sildenafil as a Candidate Drug for Alzheimer’s Disease: Real-World Patient Data Observation and Mechanistic Observations from Patient-Induced Pluripotent Stem Cell-Derived Neurons
Abstract: Background: Alzheimer’s disease (AD) is a chronic neurodegenerative disease needing effective therapeutics urgently. Sildenafil, one of the approved phosphodiesterase-5 inhibitors, has been implicated as having potential effect in AD. Objective: To investigate the potential therapeutic benefit of sildenafil on AD. Methods: We performed real-world patient data analysis using the MarketScan® Medicare Supplemental and the Clinformatics® databases. We conducted propensity score-stratified analyses after adjusting confounding factors (i.e., sex, age, race, and comorbidities). We used both familial and sporadic AD patient induced pluripotent stem cells (iPSC) derived neurons to evaluate the sildenafil’s mechanism-of-action. Results: We showed that sildenafil usage is associated with reduced likelihood of AD across four new drug compactor cohorts, including bumetanide, furosemide, spironolactone, and nifedipine. For instance, sildenafil usage is associated with a 54% reduced incidence of AD in MarketScan® (hazard ratio [HR] = 0.46, 95% CI 0.32-0.66) and a 30% reduced prevalence of AD in Clinformatics® (HR = 0.70, 95% CI 0.49-1.00) compared to spironolactone. We found that sildenafil treatment reduced tau hyperphosphorylation (pTau181 and pTau205) in a dose-dependent manner in both familial and sporadic AD patient iPSC-derived neurons. RNA-sequencing data analysis of sildenafil-treated AD patient iPSC-derived neurons reveals that sildenafil specifically target AD related genes and pathobiological pathways, mechanistically supporting the beneficial effect of sildenafil in AD. Conclusions: These real-world patient data validation and mechanistic observations from patient iPSC-derived neurons further suggested that sildenafil is a potential repurposable drug for AD. Yet, randomized clinical trials are warranted to validate the causal treatment effects of sildenafil in AD.

Hiroyuki Shimada, Takehiko Doi, Kota Tsutsumimoto, Keitaro Makino, Kenji Harada, Kouki Tomida, Hidenori Arai
Elevated Risk of Dementia Diagnosis in Older Adults with Low Frequencies and Durations of Social Conversation
Abstract: Background: Social networks and social participation have protective effects on cognitive function maintenance and Alzheimer’s disease and general dementia development. Objective: We aimed to investigate the association between conversations and dementia incidence in older adults. Methods: This longitudinal prospective cohort study used population data from the National Center for Geriatric and Gerontology–Study of Geriatric Syndromes (NCGG–SGS) from September 2015 to February 2017. The database included 4,167 individuals in Japan aged ≥60 years who were generally healthy and without major cognitive impairment. Participants were classified into two groups according to six daily conversation measures at baseline. The conversation index was calculated as a composite score for these measures. Participants were tracked monthly over 60 months for new-onset dementia. Results: Data from 2,531 participants were analyzed (72.7 ± 6.7 years; range: 60–96 years). Dementia incidence per 1,000 person-years was 15.7 (95% confidence interval, 13.6–18.1). The Youden index determined the cut-off point for dementia incidence, with a conversation index of 16/17 points. The low conversation group included more participants with new-onset dementia. Cox proportional hazards regression crude models showed remarkable relationships between dementia onset and specific conversation measurements, including conversation index. According to the Cox regression adjusted model, the cut-off point of the conversation index showed only a remarkable relationship with dementia onset. Conclusions: Dementia risk was extensively associated with low daily conversation statuses. The assessment of conversational factors may be useful as a risk indicator for the development of Alzheimer's disease and general dementia.

Sakine Kavoosi, Ali Shahraki, Roghayeh Sheervalilou
Identification of microRNA-mRNA Regulatory Networks with Therapeutic Values in Alzheimer’s Disease by Bioinformatics Analysis
Abstract: Background: Alzheimer’s disease (AD) is the most prevalent neurological disorder worldwide, affecting approximately 24 million individuals. Despite more than a century of research on AD, its pathophysiology is still not fully understood. Objective: Recently, genetic studies of AD have focused on analyzing the general expression profile by employing high-throughput genomic techniques such as microarrays. Current research has leveraged bioinformatics advancements in genetic science to build upon previous efforts. Methods: Data from the GSE118553 dataset used in this investigation, and the analyses carried out using programs such as Limma and BioBase. Differentially expressed genes (DEGs) and differentially expressed microRNAs (DEmiRs) associated with AD identified in the studied areas of the brain. Target genes of the DEmiRs identified using the MultiMiR package. Gene ontology (GO) completed using the Enrichr website, and the protein-protein interaction (PPI) network for these genes drawn using STRING and Cytoscape software. Results: The findings introduced DEGs including CTNNB1, PAK2, MAP2K1, PNPLA6, IGF1R, FOXL2, DKK3, LAMA4, PABPN1, and GDPD5, and DEmiRs linked to AD (miR-106A, miR-1826, miR-1253, miR-10B, miR-18B, miR-101-2, miR-761, miR-199A1, miR-379 and miR-668), (miR-720, miR-218-2, miR-25, miR-602, miR-1226, miR-548K, miR-H1, miR-410, miR-548F2, miR-181A2), (miR-1470, miR-651, miR-544, miR-1826, miR-195, miR-610, miR-599, miR-323, miR-587 and miR-340), and (miR-1282, miR-1914, miR-642, miR-1323, miR-373, miR-323, miR-1322, miR-612, miR-606 and miR-758) in cerebellum, frontal cortex, temporal cortex, and entorhinal cortex, respectively. Conclusions: The majority of the genes and miRNAs identified by our findings may be employed as biomarkers for prediction, diagnosis, or therapy response monitoring.

Loreto Olavarría, Paulo Caramelli, José Lema, Caíssa Bezerra de Andrade, Alejandra Pinto, Lílian Viana dos Santos Azevedo, Daniela Thumala, Maria Carolina Santos Vieira, Adriana Peredo Rossetti, Alana Barroso Generoso, Karoline Carvalho Carmona, Walter Sepúlveda-Loyola, Ludmilla Aparecida Cardoso Pinto, Maira Tonidandel Barbosa, Andrea Slachevsky
Impact of the Pandemic Time on the Mental Health of People with Dementia and Their Family Caregivers in Brazil and Chile: One-Year Follow-Up
Abstract: Background: Previous studies reported the negative impact of social isolation on mental health in people with dementia (PwD) and their caregivers, but longitudinal studies seem scarcer. Objective: To describe a one-year follow-up impact of the COVID-19 pandemic on PwD and their caregivers in both Brazil and Chile. Methods: This study analyzed the impact of the pandemic on the psychological and physical health of PwD and their family caregivers after one year of follow-up in three outpatient clinics in Brazil (n=68) and Chile (n=61). Results: In both countries, PwD reduced their functional capacity after one year of follow-up (p = 0.017 and p = 0.009; respectively) and caregivers reported worse physical and mental health (p = 0.028 and p = 0.039). Only in Chile, caregivers reported more sadness associated with care (p = 0.001), and reduced time sleeping (p = 0.07). Conclusions: In conclusion, the COVID-19 pandemic appears to have had a long-lasting impact on PwD and their caregivers. However, it is essential to acknowledge that the inherent progression of dementia itself may also influence changes observed over a year.

Sakshi Kumari*, Priyajit Kaur*, Abhinay Kumar Singh, Mohd Suhail Ashar, Rashmita Pradhan, Abhijit Rao, Partho Haldar, Avinash Chakrawarty, Prasun Chatterjee, Sharmistha Dey *These authors contributed equally to this work.
Quantification of COX-2 Level in Alzheimer’s Disease Patients to Develop Potential Blood-Based Biomarker for Early Diagnosis and Therapeutic Target
Abstract: Background: Alzheimer’s disease (AD) is progressive neurodegenerative disease and symptoms develop gradually over many years. The current direction for medication development in AD is focused on neuro-inflammation and oxidative stress. Amyloid-β (Aβ) deposition activates microglia leading to neuro-inflammation and neurodegeneration induced by activation of COX-2 via NFκB p50 in glioblastoma cells. Objective: The study aimed to evaluate the concentration of COX-2 and NFκB p50 in serum of AD, mild cognitive impairment (MCI), and geriatric control (GC) and to establish a blood-based biomarker for early diagnosis and its therapeutic implications. Methods: Proteins and their mRNA level in blood of study groups were measured by surface plasmon resonance (SPR) and quantitative polymerase chain reaction (qPCR), respectively. The level of protein was further validated by western blot. The binding study of designed peptide against COX-2 by molecular docking was verified by SPR. The rescue of neurotoxicity by peptide was also checked by MTT assay on SH-SY5Y cells (neuroblastoma cell line). Results: Proteins and mRNA were highly expressed in AD and MCI compared to GC. However, COX-2 decreases with disease duration. The peptide showed binding affinity with COX-2 with low dissociation constant in SPR and rescued the neurotoxicity of SH-SY5Y cells by decreasing the level of Aβ, tau, and pTau proteins. Conclusions: It can be concluded that COX-2 protein can serve as a potential blood-based biomarker for early detection and can be a good platform for therapeutic intervention for AD.

 

Philippe Verwaerde, Cécilia Estrella, Stéphane Burlet, Mathieu Barrier, Andrée-Anne Marotte, Gilbert Clincke
First-In-Human Safety, Tolerability, and Pharmacokinetics of Single and Multiple Doses of AZP2006, a Synthetic Compound for the Treatment of Alzheimer’s Disease and Related Diseases
Abstract: Background: Alzheimer's disease (AD) and progressive supranuclear palsy (PSP) are major neurodegenerative conditions with tau pathology in common but distinct symptoms—AD involves cognitive decline while PSP affects balance and eye movement. Progranulin (PGRN) is a growth factor implicated in neurodegenerative diseases, including AD and PSP. AZP2006, a synthetic compound, targets tauopathies by stabilizing PGRN levels and reducing tau aggregation and neuroinflammation. Objective: Evaluate the safety, tolerability, and pharmacokinetics of AZP2006. Methods: A first-in-Human phase 1 study comprised a single ascending dose (SAD) and a multiple ascending dose study (MAD). The SAD study included 64 healthy male volunteers and tested singles oral doses of 3 to500 mg of AZP2006 free base equivalent or placebo. In the MAD study, 24 healthy male volunteers were administered oral doses of 30, 60, and 120 mg per day of AZP2006 or placebo for 10 days. Results: No serious adverse events were observed. Clinical, biological, and electrocardiogram findings were non-relevant. Nineteen minor adverse events resolved before study completion. The safety profile indicated no specific risks. The multiple ascending dose study was halted, and the optional dose level of 180 mg was not performed due to high levels of M2 metabolite in plasma that necessitated additional preclinical evaluation of M2. Both AZP2006 and its M2 metabolite were quickly absorbed and widely distributed in tissues. Exposure increased more than proportionally with dose. Conclusions: AZP2006 had a favorable safety profile and was rapidly absorbed. Elevated M2 metabolite levels necessitate further studies to clarify excretion and metabolism mechanisms.

Thuy V. Lu, Joshua D. Grill, Daniel L. Gillen, for the Alzheimer’s Disease Cooperative Study (Handling Associate Editor: Russell Swerdlow)
Study Partner Type and Adverse Event Reporting in Mild-to-Moderate Alzheimer’s Disease Clinical Trials
Abstract: Background: In randomized clinical trials (RCTs), monitoring adverse events (AEs) and serious AEs (SAEs) is critical. All Alzheimer’s disease (AD) RCTs require participants to enroll with a study partner. Objective: We examined AE reporting rates in mild-to-moderate AD trials and their associations with study partner type. Methods: We estimated AE reporting rates using placebo data from seven independent RCTs conducted by the Alzheimer’s Disease Cooperative Study. We assessed the heterogeneity of reporting rates as a function of visits using generalized estimating equations. In the primary analysis, we tested the hypotheses that the rates of reporting differed by study partner type and time they spent with the participant weekly using Poisson regression with robust variance estimation. In all regression models, log-transformed total patient years was included. Results: The estimated reporting rates were 2.83 (95% CI: 2.66, 3.02), 1.18 (95% CI: 1.09, 1.28), 0.23 (95% CI: 0.19, 0.27), and 0.28 (95% CI: 0.24, 0.33) events per participant year for grade 1-3 AEs and SAEs, respectively. We estimated that greater number of visits per year was associated with increased reporting for grade 1-2 AEs and SAEs. We did not find evidence to suggest that AE reporting differed by study partner type or by time the study partner spent with the participant. Conclusions: Study partner type and time the study partner spent with the participant did not appear to impact AE reporting. Estimated reporting rates may be useful to evaluate safety in future studies, particularly those with no control arm and similar visit frequencies.