Chronic psychological stress has been implicated as a risk factor for Alzheimer’s disease (AD), potentially through cortisol-mediated acceleration of disease progression. However, the molecular pathways underlying this relationship remain poorly understood. Epigenetic regulation of the glucocorticoid and mineralocorticoid receptor genes (NR3C1 and NR3C2), which encode receptors for cortisol, may play an important role, but has not been examined in relation to AD progression. Therefore, this study investigated associations between DNA methylation of NR3C1/NR3C2 and AD-related phenotypes, including cognition, brain amyloid-β (Aβ) burden, and regional brain volumes. These associations were examined in two independent cohorts of cognitively unimpaired individuals with accumulating brain Aβ (n = 89–298 across outcomes) using linear regression and meta-analyses. The study also explored whether DNA methylation within NR3C1 and NR3C2 interacted with depression symptoms to influence relationships with AD-related phenotypes. While only nominal associations were observed in direct analyses, stronger associations emerged in interaction with depressive symptoms. Interaction analyses showed that relationships between DNA methylation and AD-related phenotypes (cognition, hippocampal volume and ventricular expansion) differed depending on the presence of depression symptoms. Consistent patterns across cohorts were observed, with associations primarily evident among individuals with clinically relevant depressive symptoms. One site (NR3C1 cg24052866) was associated with cognitive decline, one (NR3C1 cg08845721) with cross-sectional hippocampal volume, and eight (NR3C1 cg21979215, cg16594263; NR3C2 cg27460943, cg17253842, cg04867484, cg10993059, cg25672354, cg27234800) with ventricular expansion. These exploratory findings suggest epigenetic variation within cortisol receptor genes may influence AD-related neurodegeneration in a depression-dependent manner.

OBJECTIVE:Episodic memory is one of the cognitive domains most affected after a traumatic brain injury (TBI), and memory decline is a hallmark of both normal aging and Alzheimer disease (AD). Although TBI is reported to accelerate age-related cognitive decline and brain atrophy, it is unclear how this trajectory is shaped by frequent co-occurring factors such as post-traumatic stress disorder (PTSD) and psychotropic medication use. This study tested whether age-related decline in delayed verbal memory is more pronounced among adults with a history of TBI than those without TBI. Analyses also explored PTSD status and use of selective serotonin reuptake inhibitors or serotonin-norepinephrine reuptake inhibitors (SSRIs/SNRIs) as independent moderators of verbal memory performance. SETTING:VA Medical Center and surrounding community. PARTICIPANTS:Sixty-two Veterans and civilians, ages 30-65, were enrolled. Participants who performed below established cutoffs on performance validity testing were excluded. Analyses (n = 56) included 28 adults with a history of TBI (82% mild, 18% moderate) and 28 demographically matched controls without TBI. MAIN MEASURES:Delayed recall on a standardized verbal memory task was the primary outcome measure. Analyses tested for main effects of TBI status, age, and their interaction, as well as interactions with the moderator variables (PTSD status and SSRI/SNRI use). DESIGN:Observational, cross-sectional design. RESULTS:Participants with a TBI history did not significantly differ from those without TBI in verbal memory performance. There was a trend toward poorer memory performance with age among participants with a TBI history not taking SSRIs/SNRIs, while participants with PTSD and TBI taking SSRIs/SNRIs demonstrated better performance with age. CONCLUSION:The findings underscore the importance of considering psychiatric comorbidities and medication use when examining cognition and aging effects in individuals with TBI. Larger, longitudinal studies are warranted to clarify how traumatic stress and psychotropic medications may mediate cognitive aging trajectories after TBI.

BACKGROUND:In Apathy in Dementia Methylphenidate Trial 2 (ADMET2), apathy in Alzheimer's disease improved with methylphenidate (MPH) in a randomized, placebo-controlled trial, though response varied. Here we evaluated serum biomarkers for their association with apathy and with treatment response. METHODS:All ADMET2 participants with available blood samples were included. Markers of inflammation [interleukin (IL)-6, IL-10, Tumor Necrosis Factor (TNF)], oxidative stress [lipid hydroperoxide (LPH), 4-hydroxynonenal (4-HNE), 8-isoprostane (8-ISO)] and neuronal injury [neurofilament light (NfL), S100B] were assessed and values log-transformed. Neuropsychiatric Inventory-apathy (NPI-A) measured apathy. Least Absolute Shrinkage and Selection Operator (LASSO) regression was performed for feature selection of baseline markers predicting NPI-A at Month-6 (M6). Univariate analyses examined individual biomarker effects and multivariable models evaluated their combined effects. Treatment interactions, baseline and change in biomarker levels in treatment responders (≥4 change in NPI-A) and remitters (M6 NPI-A=0) were explored. RESULTS:In the ADMET2 biomarker subset (n = 44, MPH:21, age:75 years, MMSE:20.2), higher baseline TNF was associated with higher M6 NPI-A [B(SE)= 6.86 (1.71), p = .0003], and multivariable models found lower baseline TNF [B(SE)= 8.28(1.61), p < .001] and higher baseline S100B [B(SE)= -6.41(1.95), p = .002] were associated with lower M6 NPI-A. Exploratory analyses suggested that higher baseline NfL significantly interacted with treatment to predict lower M6 NPI-A [B(SE)= -8.36(4.21), p = .05], only when adjusting for cognition. MPH remitters had lower baseline TNF [B(SE)= -0.27(0.10), p = .02], higher baseline NfL [B(SE)= 0.33(0.14), p = .03], and a greater decrease in IL-6 [B(SE)= -0.44 (0.17), p = .02]. CONCLUSIONS:Inflammatory and neuronal injury biomarkers may have prognostic value and may potentially inform treatment response and remission outcomes in apathy. Apathy in Dementia Methylphenidate Trial 2 (ADMET2), NCT02346201, https://clinicaltrials.gov/study/NCT02346201.

Non-specific Alzheimer's Disease (AD) biomarkers like glial fibrillary acidic protein (GFAP) and neurofilament light chain (Nfl) are now included in the diagnosis and staging of AD, but more work is needed to fully understand their utility in early detection of AD. The present study examined plasma GFAP, Nfl, amyloid beta (Aβ) 40, and Aβ42 in individuals with AD, mild cognitive impairment (MCI) and subjective cognitive decline (SCD) who were either amyloid positive (A+) or negative (A-) according to florbetapir positron emission tomography scan neuroradiological read. The goal was to determine whether individuals with preclinical AD (SCD/A+) show biomarker profiles similar to those expected in AD and MCI (i.e., higher GFAP and Nfl and lower Aβ40 and Aβ42) compared to SCD individuals at lower risk (SCD/A-). Individuals with AD (24 A+, 5 A-), MCI (21 A+, 17 A-) and SCD (5 A+, 11 A-), as determined by clinician referral, completed a blood draw and neuropsychological testing. Blood samples were collected, processed, and stored per previously published guidelines. Plasma samples were assayed using the Neurology 4-Plex E+ assay on the HD-X analyzer (Quanterix, MA). Coefficients of variation for all assays were ≤5%. Generalized linear models (GLMs) with false discovery rate correction examined the effects of diagnosis severity (AD, MCI, SCD) and amyloid status (A+, A-) on plasma levels for each biomarker and the Aβ42/Aβ40 ratio, with covariates of age and sex. Associations between biomarkers and global cognitive functioning, as measured by the Montreal Cognitive Assessment (MoCA), were also examined. The Severity x Amyloid status interaction indicated that GFAP was higher (χ 2 (2)=6.9, p  = .032) and Aβ42/Aβ40 was lower (χ 2 (2)=13.1, p  = .001) in AD/A+ versus AD/A- and in SCD/A+ versus SCD/A-, but amyloid status did not moderate GFAP or Aβ42/Aβ40 in MCI. GLMs for Nfl, Aβ 40, and Aβ 42 did not yield significant effects. GFAP was negatively correlated with MoCA for MCI (ρ=-.61, p  <.001) and SCD (rρ=-.59, p  = .016) groups but not for AD (ρ =-.15, p  = .45). Individuals with preclinical AD (SCD/A+) showed biomarker profiles consistent with AD (higher GFAP; lower Aβ42/Aβ40) and GFAP was associated with poorer global cognition in MCI and SCD.

Apathy is a prevalent neuropsychiatric symptom (NPS) in Alzheimer’s disease (AD), linked to functional impairment and reduced quality of life. The Apathy in Dementia Methylphenidate Trial 2 (ADMET-2) found methylphenidate (MPH) had modest efficacy for treating apathy, but treatment responses varied. MPH blocks dopamine and noradrenaline transporters, inhibiting dopamine and noradrenaline reuptake. Lipids are closely tied to monamine transporter function through their structural and signaling roles in neurotransmission, neuroinflammation, and synaptic plasticity. This study aimed to identify lipid species associated with MPH response and explore lipid pathway disruptions in responders versus non-responders. Participants from ADMET-2 with baseline lipidomic data were included. Responders were defined by a ≥4-point improvement on the Neuropsychiatric Inventory Apathy subscale (NPI-A), or moderate-to-marked improvement on the ADCS-Clinicians Global Impression-Change (ADCS-CGIC). Baseline plasma samples underwent lipidomic profiling. Sparse Partial Least Squares Discriminant Analysis (sPLS-DA) in the MPH group was used to identify lipid species distinguishing responders from non-responders. Model performance was evaluated by area under the curve (AUC). Identified lipid species were analyzed in MetaboAnalyst for pathway enrichment. A secondary analysis in the placebo group assessed specificity of findings to MPH. Of the 43 MPH-treated participants, 28 were NPI-apathy responders, and 10 were ADCS-CGIC responders. The PLS-DA model achieved robust discrimination between responders and non-responders (NPI-apathy: AUC = 0.82 +/- 0.05; ADCS-CGIC: AUC=0.84 +/- 0.07). Pathway analysis revealed disruptions in ceramide, phosphosphingolipid, and glycosphingolipid metabolism for NPI-apathy responders, and ceramide and glycosphingolipid metabolism for ADCS-CGIC responders. In 55 placebo-treated participants (30 NPI-apathy responders), an AUC of 0.79 +/- 0.05 was achieved, with pathway analysis indicating disruption in glycosphingolipid metabolism only. This study demonstrates the utility of lipidomic profiling in identifying biomarkers of response to MPH in AD patients with apathy. The identified lipidomic species are broadly related to monoamine transporter function, reflecting their role in neurotransmission and synaptic plasticity. While glycosphingolipid metabolism appears broadly linked to changes in apathy, disruptions in ceramide and phospholipid metabolism may be specific to MPH treatment. Further study of these pathways may offer insights into the molecular mechanisms underlying apathy and treatment response, and could inform future biomarker-guided interventions.

Alzheimer’s disease (AD) remains irreversible largely because the adult brain cannot replace lost neurons. Here, we present a Nano-ERASER-based Trim-Away system, polypyrimidine tract-binding protein 1 antibody-loaded targeted nanogel (TN-PTBP1), which enables adult neuroregeneration in the AD brain, offering a new strategy to counteract AD progression. TN-PTBP1 penetrates the blood-brain barrier, delivers anti-PTBP1 antibodies into astrocytes, and triggers rapid TRIM21-mediated PTBP1 degradation. This non-genomic protein depletion induces astrocyte-to-neuron conversion, generates functional neurons in vitro and in human brain organoids, and restores hippocampal neurogenesis in AD mice. Importantly, TN-PTBP1 treatment significantly improves cognition, learning, and memory, demonstrating true functional reversal of AD-associated deficits. By resolving the long-standing controversy surrounding PTBP1 reprogramming and establishing a translational biomaterials-based platform for in situ neuronal regeneration, this work introduces a transformative therapeutic paradigm aimed not only at slowing AD but at rebuilding the neuronal circuitry it destroys.

White matter microstructural changes play a crucial role in cognitive decline in aging and neurodegenerative disorders including Alzheimer’s disease (AD). However, the processes underlying white matter microstructural changes and the molecular pathways leading to these changes in AD remain largely unknown. AD involves cortical and juxtacortical microstructural changes, with free water fraction (FWF) as a potential imaging marker. We measured FWF using diffusion magnetic resonance imaging in 68 juxtacortical regions of 153 cognitively normal controls and 194 patients with AD as evidenced by elevated amyloid PET. We estimated the expression of 15,633 genes in the same regions using transcriptomic data from the Allen Human Brain Atlas. The biological processes and cell types associated with the linked genes were evaluated. Mediation analysis was used to examine whether FWF mediates the association between APOE ε4 status and cognitive performance. Gene ontological analyses revealed that these genes were enriched for biological processes relating to lipid metabolic process, ensheathment of neurons, and synaptic signaling and were predominantly expressed in oligodendrocytes, GABAergic neurons, and pyramidal neurons from the hippocampus CA region. These ontological enrichment results were replicated in two additional datasets. Furthermore, mediation analyses revealed a domain-specific role of FWF in the association between APOE ε4 status and cognitive performance. Our findings provide mechanistic insights into regional juxtacortical microstructural changes in AD, particularly the processes involving lipid metabolism, offering potential therapeutic targets.

The convergence of neurological, psychiatric, neurodevelopmental, and public health approaches to brain health is reshaping global strategies for prevention, care, and policy. However, major gaps remain in the integration and implementation of brain and mental health frameworks across healthcare systems and regions.This paper describes the foundation and early development of the International Alliance on Brain Health (IABH), established in Switzerland in 2025 to promote interdisciplinary collaboration, reciprocal innovation, and implementation-oriented exchange between the global North and global South. Drawing on the Alliance's founding meeting in Bern, its contribution as a partner to the World Brain Health Forum organized by the Paris Brain Institute, and its subsequent meeting in Buenos Aires, the paper outlines the Alliance's global positioning and priorities for translating brain health frameworks into practice.Key themes included integrated neurological and mental health approaches, prevention across the life course, digital innovation, brain capital, workforce development, and stronger inclusion of global South perspectives in international policy dialogue. The Alliance also emphasized bidirectional learning and locally adaptable implementation strategies aligned with WHO brain health frameworks.Under the joint patronage of the World Federation of Neurology and the World Psychiatric Association, the IABH represents an emerging platform for cross-continental collaboration in brain health.

BACKGROUND:Diagnostic criteria for apathy in neurocognitive disorders (DCA-NCD) have recently been updated. OBJECTIVES:We investigated whether validated scales measuring apathy severity capture the three dimensions of the DCA-NCD (diminished initiative, diminished interest, diminished emotional expression). MEASUREMENTS:Degree of mapping ("not at all", "weakly", or "strongly") between items on two commonly used apathy scales, the Neuropsychiatric Inventory-Clinician (NPI-C) apathy and Apathy Evaluation Scale (AES), with the DCA-NCD overall and its 3 dimensions was evaluated by survey. DESIGN:Survey participants, either experts (n = 12, DCA-NCD authors) or scientific community members (n = 19), rated mapping for each item and mean scores were calculated. Interrater reliability between expert and scientific community members was assessed using Cohen's kappa. RESULTS:According to experts, 9 of 11 (81.8%) NPI-C apathy items and 6 of 18 (33.3%) AES items mapped strongly onto the DCA-NCD overall. For the scientific community group, 10 of 11 (90.9%) NPI-C apathy items and 7 of 18 (38.8%) AES items mapped strongly onto the DCA-NCD overall. The overall mean mapping scores were higher for the NPI-C apathy compared to the AES for both expert (t (11) = 3.13, p = .01) and scientific community (t (17) = 3.77, p = .002) groups. There was moderate agreement between the two groups on overall mapping for the NPI-C apathy (kappa= 0.74 (0.57, 1.00)) and AES (kappa= 0.63 (0.35, 1.00)). CONCLUSIONS:More NPI-C apathy than AES items mapped strongly and uniquely onto the DCA-NCD and its dimensions. The NPI-C apathy may better capture the DCA-NCD and its dimensions compared with the AES.

Neuropsychiatric syndromes (NPS) such as agitation, psychosis, apathy, and irritability are among the most disabling features of major and mild neurocognitive disorders including Alzheimer's disease, other neurodegenerative disorders (NDD), and vascular cognitive impairment. Clinical trial methodologies for the treatment of these syndromes are evolving and the first agents to reduce NPS severity has been approved. Biomarkers are rapidly becoming available to guide clinical trial decision-making. Biomarkers can confirm the diagnosis of Alzheimer's disease and are playing a larger role in non-Alzheimer trials. The Consolidated Standards for Reporting Trials (CONSORT) specify the elements of clinical trials that must be reported when clinical trials are published. These criteria provide conventions for uniform reporting of all key aspects of a clinical trial and facilitate comparisons across trials. We describe best practices for clinical trials of NPS including research definitions of the NDD, use of biomarkers to support clinical diagnosis, research criteria for NPS, use of rating scales to define the severity of NPS at baseline and as endpoints for the clinical trial, and approaches to data analysis of specific interest in NPS trials. Standards for describing the limitations of trials and their generalizability are provided. The goal is to inform planning and reporting of NPS trials including the use of biomarkers based on CONSORT guidelines for best trial practices.

Apathy in Alzheimer’s disease improves with methylphenidate (MPH) but treatment response was found to vary depending on clinical factors. Here, we explored whether underlying biological factors assessed by blood-based biomarkers of neurodegeneration, inflammation and oxidative stress affect apathy treatment response. A subset of participants from the Apathy in Dementia Methylphenidate Trial 2 (ADMET 2) were included in this study whose blood samples were available at baseline and at the 6-month treatment completion. Apathy was assessed with the Neuropsychiatric Inventory apathy subscale (NPI-A, range: 0-12). Blood concentrations of (i) neuronal damage: neurofilament light (NFL) and S-100B (available at baseline only), (ii) inflammation: interleukin (IL)-6, IL-10, Tumor Necrosis Factor-alpha (TNFα), and (iii) oxidative stress: lipid hydroperoxide (LPH), 4-hydroxynonenal (4-HNE), 8-isoprostane (8-ISO) were obtained with ELISA assays. Biomarkers were normalized by log transformation and pareto scaling. Predictive value of biomarkers was assessed by examining differences in treatment response between each biomarker tertile level. We also assessed whether biomarkers improved predictive models for established clinical predictors. Monitoring value was assessed by linear mixed models with NPI-A as the dependent variable and interaction between biomarker and time or biomarker and treatment as the independent variable. Among 55 participants (MPH: 24, age: 75.4 years [standard deviation (SD): 7.6], MMSE: 19.9 [SD: 4.9]) at baseline and 49 at the 6 month end point, the change in NPI-A showed a greater than 2-point difference between tertiles of NFL (6.8 points), TNFα (4.2 points) and 8-ISO (5.5 points) (Fig. 1). Treatment response prediction improved by adding NFL with cholinesterase use (likelihood ratio test[lrt]: 4.6, p: 0.03), presence of agitation (lrt: 4.4, p: 0.04) or presence of anxiety (lrt: 4.5, p: 0.04); no added value was found with TNFα and 8-ISO. As a monitoring biomarker, TNFα (but not NFL and 8-ISO) levels over time were associated with NPI-A score (t: 2.69, p: 0.009). Blood-based biomarkers of neurodegeneration, inflammation and oxidative stress are associated with apathy and affect treatment response, indicating potential predictive and monitoring value. Peripheral inflammation (TNFα) may have added value along with clinical predictors of response.

INTRODUCTION:Periodontal disease (PD) is a risk factor for stroke and cardiovascular disease. The effect of PD on post-stroke cognitive impairment (PSCI) remains underexplored. METHODS:A cross-sectional analysis of the Periodontal tReatment to Eliminate Minority InEquality and Rural disparities in Stroke (PREMIERS) study participants was conducted. Baseline cognitive function was assessed using the Montreal Cognitive Assessment (MoCA) within 90 days of the index event. MoCA score ≤21 indicated severe PSCI. White matter hyperintensity, indicating cerebral small vessel disease (cSVD), was evaluated using the Fazekas scale on MRI. Due to non-normal MoCA distribution, two analytical approaches were employed: 1) logistic regression using dichotomized MoCA scores based on clinically relevant cutoffs and 2) generalized linear mixed modeling after bootstrap normalization that examined MoCA scores continuously. RESULTS:Among 280 participants with PD, 48% exhibited severe PSCI. Both analytical approaches demonstrated that severe PD, African American (AA) race, and greater stroke severity significantly and independently predicted severe PSCI, while advanced education was protective. Fazekas' scale showed no significant associations with PSCI. CONCLUSIONS:This study identifies PD severity as a novel and independent contributor to early PSCI. Traditional predictors like AA race, educational attainment, and stroke severity remained significant. CLINICAL TRIAL REGISTRATION INFORMATION:https://www. CLINICALTRIALS:gov; Unique identifier: NCT02541032.

Background/Objectives: The goal of this commentary is to highlight several key components of the inflammatory process as it relates to amyloid toxicity in Alzheimer's disease (AD), including the role of neuroinflammatory factors and peripheral inflammatory events. Methods: Google Scholar and PubMed were used to find articles with the following keywords: Alzheimer's disease, amyloids, neuroinflammation, peripheral inflammation, microglia, cytokines, and treatments. Sources that were case reports, not peer-reviewed, or older than 30 years were excluded. Abstracts were reviewed first for their relevance before the full text was considered. Methods sections were reviewed to ensure the interventional papers included were randomized controlled trials, meta-analyses, or systematic reviews; however, several literature reviews were also included due to the relevance of their background information. Results: Based on the literature review, we chose to concentrate on microglia, cytokine signaling, and peripheral inflammation markers. We found that microglia activation and subsequent microglia-driven inflammation play a pivotal role in the pathomechanism of AD. Additionally, cytokines such as interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-a) appear to contribute to amyloid accumulation and cell damage. Finally, the increased permeability of the blood-brain barrier (BBB) allows for the peripheral inflammatory process to contribute to the inflammation of the central nervous system (CNS) and amyloid-beta (Aβ) accumulation. Conclusions: Current evidence suggests that the immune system plays a pivotal role in the pathogenesis of AD, both in the CNS and the periphery.

Despite extensive efforts dedicated to developing therapies for Alzheimer's disease (AD), we still lack effective approaches capable of curing or halting its progression. Mounting evidence highlights the critical roles of dysfunctional microglia, which promote the abnormal accumulation of harmful protein deposits and initiate aggressive neuroinflammation, contributing to both the onset and advancement of AD. Hereby, we develop a brain-targeted ceria nanoparticle (T-CeNP) that exhibits both superoxide dismutase and catalase mimicking activities, for AD therapy. The functionalization of advanced glycation endproducts (RAGE) targeting peptide facilitates the blood-brain barrier (BBB) penetration of T-CeNP, prevents the formation of Aβ fibrils, and boosts Aβ degradation by microglia. By integrating the multifunctional RAGE-targeting ligand and bioactive CeNPs, T-CeNP can effectively cross the BBB, quench elevated reactive oxygen species, attenuate microglial activation, disrupt Aβ aggregation, and promote its clearance in an AD mouse model, thereby slowing the progression of AD.

INTRODUCTION:Psychosis is frequently observed in patients with neurodegenerative disease and may precede onset of cognitive symptoms. Additionally, the presence of psychosis in neurodegenerative disease is often associated with adverse effects including increased progression of cognitive decline and conversion to dementia, increased caregiver burden, and increased rates of placement in long-term care. Moreover, existing pharmacological treatments, which consist principally of off-label antipsychotic medications, may be associated with increased risk of harm, making management of symptoms challenging. OBJECTIVE:We review recent advances in the field of psychosis in neurodegenerative disease, including advances in clinical criteria, biomarkers (neuroimaging, pathology, and genomic and epigenomics), and treatments. METHOD:Under the direction of the International Psychogeriatric Association (IPA), a task force comprised of experts in the field of psychosis in neurodegenerative disease was convened. An in-person meeting was organized in September 2024, coincident with the annual IPA Congress. The task force undertook a review of the literature in the areas of clinical care, biomarkers, and treatment, from which key recommendations for the management and future investigation of psychosis in neurodegenerative disease were derived. RESULTS:It was concluded that psychosis in neurodegenerative disease has a characteristic phenomenology that despite sharing some features with schizophrenia spectrum psychotic disorders, may differ in other clinically meaningful aspects. Etiopathogenesis based on biomarker, genomic, and treatment studies may differ to some extent among neurodegenerative diseases. There is emerging evidence supporting the use of prescriptive non-pharmacological (WHELD intervention) and novel pharmacological (pimavanserin, muscarinic agonists) approaches in the treatment of psychosis in neurodegenerative disease. CONCLUSION:Future directions include the need for the implementation of evidence-based nonpharmacological treatments consistent with the aims of precision medicine, further investigation into novel pharmacological agents, mapping specific psychotic symptoms to specific biomarkers, and further exploration of the link between psychosis in neurodegenerative disease and other late-life psychoses.

Alzheimer’s disease (AD) is an escalating global challenge, with more than 40 million people affected, and this number is projected to increase to more than 100 million by 2050. While amyloid-targeting antibody treatments (lecanemab and donanemab) are a significant step forward, the benefits of these therapies remain limited. This highlights the necessity for safe and effective compounds that offer greater therapeutic benefits to the majority of individuals with or at risk of AD. Drug repurposing allows for a cost-effective, time-efficient strategy to accelerate the availability of treatments, owing to the availability of safety information. This study focuses on the third iteration of the Delphi consensus programme aimed at identifying new high-priority drug candidates for repurposing in AD. An international expert panel comprising academics, clinicians and industry representatives was convened. Through a combination of anonymized drug nominations, systemic evidence reviews, iterative consensus rankings, and lay advisory inputs, drug candidates were evaluated and ranked based on rational, non-clinical, and clinical evidence and overall safety profiles. Among the 80 candidates that were nominated by the expert panel, seven underwent review, with only three candidates meeting the following consensus criteria of relevant mechanisms for targeting neurodegenerative pathways, non-clinical efficacy, and tolerability in older individuals. The three agents were: [1] the live attenuated herpes zoster (HZ) vaccine (Zostavax) [2], sildenafil, a phosphodiesterase-5 (PDE-5) inhibitor, and [3] riluzole, a glutamate antagonist. The HZ vaccine additionally offers potential for population-level dementia risk reduction. This Delphi consensus identified three high-priority drug repurposing candidates for AD with favourable safety profiles and mechanistic plausibility, which are considered suitable for pragmatic clinical trials, including remote or hybrid designs. The PROTECT platform, which supports international cohorts in the UK, Norway, and Canada, offers a well-established means to conduct such trials effectively, thus helping to accelerate the evaluation and potential deployment of these drug candidates to benefit individuals with or at risk for AD.

Apathy in Alzheimer’s disease (AD) is associated with cognitive impairment, particularly executive functions such as selective attention, making it unclear whether apathy should be a separate treatment target. Apathy in Dementia Methylphenidate Trial 2 (ADMET 2) is the largest and most recent trial assessing apathy and cognition. This analysis assessed whether changes in apathy correlated to changes in various cognitive domains in ADMET 2. In this multicentre, randomized, placebo-controlled trial, 200 participants with mild to moderate AD received 20 mg methylphenidate (MPH) or placebo (PLB) for 6 months. The Neuropsychiatric Inventory apathy (NPI-A) subscale measured apathy. Cognitive tests included Mini-Mental State Exam (MMSE), Hopkins Verbal Learning-immediate (HVLT-I) and delayed (HVLT-D), Digit Span forward (DF) and backward (DB), Trail Making (TMT A and B), Action Verbal Fluency (AV), Category Fluency (CF), and Boston Naming Test (BNT). Linear mixed models were conducted with cognitive change scores as the dependent variable and time and change in NPI-A as the independent variable, overall and in each treatment group. All models were adjusted for baseline cognitive test score and NPI-apathy, age, sex, diabetes, and treatment group. 199 ADMET 2 participants (131 (66%) male) were included. For all participants, worsening apathy was associated with worsening MMSE (B (SE) = -0.10 (0.03), p = 0.003), CF (B (SE) = -0.13 (0.04), p = 0.0009), and HVLT-I (B (SE) = -0.13 (0.05), p = 0.005). In the MPH group (n = 98), worsening apathy was associated only with worsening CF (B (SE) = -0.21 (0.06), p = 0.0008). In the PLB group (n = 101), worsening apathy was associated with worsening MMSE (B (SE) = -0.13 (0.05), p = 0.006), HVLT-I (B (SE) = -0.30 (0.06), p = 0.000002), and HVLT-D (B (SE) = -0.06 (0.02), p = 0.002). Changes in apathy were not associated with performance on the remaining cognitive tests. Changes in apathy are associated with changes in cognition as part of the natural history of AD. However, this association is disrupted by MPH treatment and suggests that improvements in apathy in AD with MPH were not driven by cognitive changes. These results are consistent with the view that apathy as a syndrome is related to, but distinct from cognition.

Brain network dynamics have been extensively explored in patients with subjective cognitive decline (SCD). However, these studies are susceptible to individual differences, scanning parameters, and other confounding factors. Therefore, how to reveal subtle SCD-related subtle changes remains unclear. Cross-sectional and longitudinal resting-state functional magnetic resonance imaging data from both Chinese and Western populations were analyzed. We proposed a framework of dynamic proportional loss of functional connectivity (DPLFC). After its stability was validated, the optimal parameters were applied for the clinical diagnosis of SCD. DPLFC yielded a relatively high intraclass correlation coefficient. In particular, the DPLFC of the left superior frontal gyrus (SFG) progressively decreased along the Alzheimer’s disease (AD) continuum. Compared with the traditional index, the DPLFC had better classification performance between cognitively normal controls and patients with SCD. Furthermore, DPLFC was related to Aβ deposition and scale scores. Patients with lower DPLFC values had a greater risk of cognitive decline. Decreased DPLFC in the left SFG may be a potential AD-related neuroimaging biomarker at an early stage.

Most hospice-eligible patients with dementia report agitation with antipsychotics and antidepressants with major side effects predominantly used in this population to control symptoms. Little is known about current evidence on randomized controlled trials (RCTs) on reducing agitation in this population. We aimed to summarize and evaluate the existing literature on RCTs aimed at reducing agitation among hospice-eligible patients with dementia. We conducted a literature review using the following keywords (end-of-life, late-stage dementia, agitation, terminal restless, terminal delirium, randomized controlled trials) on MEDLINE, Pubmed, PyscINFO, Proquest, CINAHL, EBSCO, EMBASE, Cochrane Library, and references of previous publications. This review considered English language RCTs and review articles on RCTs that focus on interventions for reducing agitation among patients who were terminally ill, reported symptoms of agitation, and were diagnosed with dementia. The search included published articles from January 1990 to February 2024. Forty-four articles were identified. Of these articles, sixteen RCTs did not include terminally ill patients with dementia and agitation; seventeen did not focus on reducing agitation; four were not completed trials, two were written in German, and one could not be retrieved. Of the four relevant articles included in this review, three tested a nonpharmacological intervention and one tested a pharmacological intervention. The sample sizes in all four studies were small: ranging from 30 to 90 participants. Of the three studies that reported race, more than 75% of participants were White. None of the studies reported Latino ethnicity. Only one study could apply to the last five-year period, but the use of agitation reduction was the secondary outcome of the study. No interventional trials with a pharmacological approach have been reported in the previous twenty years. Our literature review identified only four RCTs conducted in hospice-eligible patients with agitation in the last four decades with no medication being evaluated in over a decade. Research is urgently needed to identify, develop, and test treatments for end-of-life agitation in patients with dementia.