Drug Development.

Background: Progranulin (PGRN), a glycoprotein secreted by microglia and neurons, regulates lysosomal function, neuroinflammation, and has neurotrophic effects. Variants in the granulin gene (GRN) that cause a reduction of PGRN in plasma and cerebrospinal fluid (CSF) are associated with an increased risk of Alzheimer's disease (AD). The sortilin receptor (SORT1) on neurons and microglia regulates PGRN degradation.

Drug Development.

Background: The increased incidence of Alzheimer's disease (AD) rate represent an unmet medical need and thus critical for the development of novel molecular therapeutics. Recent work focusing on patients with apoE4 alleles has highlighted the association of brain cholesterol dysregulation with elevated pathological burden and neurodegeneration. These studies have highlighted the importance of the nuclear receptor Liver X receptor (LXR) for developing AD therapies.

Drug Development.

Background: Participant dropout from study treatment in a clinical trial can leave a trial underpowered, produce bias in statistical analysis, and limit interpretability of study results. Retaining participants in clinical trials for the full study duration is therefore as important as participant recruitment. This analysis aims to identify the baseline characteristics of participants who discontinued during the blinded phase of one of the first and largest preclinical AD trial completed to date, the Anti-Amyloid treatment in Asymptomatic AD (A4) Study.

Drug Development.

Background: Alzheimer's disease (AD) presents unique challenges in clinical trials involving small molecules. Multifaceted issues plague such trials, emphasizing susceptibility to fraud from clinical sites and "professional patients". The relative ease of simulating Alzheimer's diagnosis, coupled with inadequate oversight by Contract Research Organizations (CROs), creates fertile ground for deceptive practices.

Drug Development.

Background: In a 16-week, 91-patient placebo-controlled clinical study in DLB ("AscenD-LB";NCT04001517), neflamapimod improved outcomes on the CDR Sum-of-Boxes (p = 0.023 vs. placebo) and Timed Up and Go test (p = 0.

Drug Development.

Background: Non-human primates (NHP) serve as an important bridge for testing therapeutic agents that have been previously shown to be effective in transgenic mouse models. Our earlier published data using an NHP model of sporadic AD-related pathology that develops abundant cerebral amyloid angiopathy (CAA), squirrel monkeys (SQMs), indicates that chronic treatment with TLR9 agonist, class B CpG ODN, safely ameliorates CAA while promoting cognitive benefits. In the present study, we intended to delineate alterations in brain metabolome induced by chronic CpG ODN administration in order to provide further insight into CpG ODN immunomodulatory capabilities.

Drug Development.

Background: Neurological disorders are at epidemic levels in the world today. Various proteins are being targeted for the development of novel molecular therapeutics; however, no small-molecule inhibitors have been discovered. Recent studies suggest that there are few molecules in clinical trials for various secretase (α, β, and γ), caspase, and calpain inhibitors.

Drug Development.

Background: In Alzheimer's Disease (AD) trials, clinical scales are used to assess treatment effect in patients. Minimizing statistical uncertainty of trial outcomes is an important consideration to increase statistical power. Machine learning models can leverage baseline data to create AI-generated digital twins - individualized predictions (or prognostic scores) of how each patient's clinical outcomes may change during a trial assuming they received placebo.

Drug Development.

Background: Lecanemab is a humanized IgG1 monoclonal antibody binding with high affinity to protofibrils of amyloid-beta (Aβ) protein. In clinical studies, lecanemab has been shown to reduce markers of amyloid in early symptomatic Alzheimer's disease (AD) and slow decline on clinical endpoints of cognition and function. Herein, a modeling approach was used to correlate amyloid reduction with change in rate of AD progression.

Drug Development.

Background: Major contributors to AD pathogenesis include aggregates of amyloid-β (Aβ) peptides, hyperphosphorylated tau protein, and neuroinflammation. No currently approved treatment stops or significantly slows the progression of AD. Nevertheless, one class of agents that has shown promise is metal chelators.

Drug Development.

Background: A new era of Alzheimer's disease (AD) research is beginning now that multiple monoclonal antibodies (mABs) are on the market. Their use may not be widespread initially but will be more common in clinical sites likely to participate in clinical trials and will continue to grow. Many AD investigational treatments have been studied as add-on to acetylcholinesterase inhibitors; however, putative disease-modifying therapies (DMTs) like mABs are expected to alter the underlying rate of progression, potentially reducing our ability to detect effects of other DMTs on top of mABs.

Drug Development.

Background: Cognitive decline associated with Alzheimer's disease (AD) correlates with hyperphosphorylated tau (pTau) propagating between neurons along networks connected by synapses. It has been hypothesized this transcellular transmission occurs partially by extracellular vesicles (EVs). Both genetic and pharmacological inhibition of nSMase2 has been found to inhibit EV biogenesis and pTau propagation.

Drug Development.

Background: Recruiting large numbers of study participants for Alzheimer's Disease (AD) drug trials remains a significant challenge in need of more effective approaches. Advertising can be an effective way to reach large numbers of prospective participants, but can suffer from low attendance rates. This study examined the relationship between the initial behaviors of prospective AD trial participants who did not attend their first scheduled appointment and their overall likelihood of eventually attending an in-person consultation.

Dementia Care Research and Psychosocial Factors.

Background: Hispanic/Latinx older adults have increased risk of developing Alzheimer's disease, poor access to timely and quality dementia care, as well as limited access to caregiver support and interventions. We addressed these structural barriers at a local level in central Virginia in order to improve disparities in risk, early detection, and care.

Method: Systematic expansion of services was undertaken by establishing a Spanish neuropsychological clinic, providing personalized scheduling services by providers to ensure appropriate follow-up after referral is received, engaging in dementia specific community talks through a broader health system initiative (UVA Latinx Health Initiative), and facilitating dementia care coordination services for caregivers.

Drug Development.

Background: Alzheimer's disease (AD) is characterized by hallmark amyloid plaques and neurofibrillary tangles as well as by a significant loss of myelin in the cerebral cortex and other brain regions, which contributes to neurodegeneration and cognitive decline. Remyelination, of the myelin sheath by oligodendrocytes, is a process that may be impaired in neurodegenerative diseases. Depending on the severity of the disease, there occurs loss or partial damage of the myelin sheath surrounding the neuron leading to memory deficits.

Drug Development.

Alzheimer's disease pathophysiology is believed to involve various abnormalities, including those of amyloid beta (Ab) peptide and tau processing, inflammation, oxidative stress, and vascular risk factors. Aβ peptides exist in a dynamic continuum of conformational states from monomeric Aβ, to soluble progressively larger Aβ assemblies that include a range of low molecular weight oligomers to higher molecular weight protofibrils, and finally to insoluble fibrils (plaques). Various lines of evidence support the "amyloid hypothesis" that Aβ plays a central role in the pathogenesis of AD, and several immunotherapies have been developed to interact with this cascade in various different places which may reduce the number of soluble aggregates and insoluble Aβ fibrils deposited in the brain.

Drug Development.

Background: Dementia with Lewy bodies (DLB) is characterized by the accumulation of α-synuclein (α-syn) as well as Alzheimer's disease (AD) pathology, which includes the accumulation of amyloid beta (Aß) in plaques and phosphorylated tau in tangles, leading to neurodegeneration, cognitive loss and dementia. In DLB and other synucleinopathies, α-syn oligomers and proto-fibrils are thought to be mechanistically linked to the pathogenic neurodegenerative process. AD and related disorders (ADRD) are leading causes of dementia in the aging population and although new approaches are being tested, to date no disease-modifying therapies are available.

Drug Development.

Background: Recruitment challenges in people with and without Down syndrome (DS) can delay research progress and risk sample bias. This study identified and quantified differences in research attitudes across populations of research enrollment decision-makers for individuals with and without DS.

Method: We compared scores on the Research Attitudes Questionnaire (RAQ) of individuals enrolled in two recruitment registries: the UCI Consent to Contact [C2C (N = 4818)] and DS-Connect (N = 976).

Drug Development.

Background: There are no approved oral disease-modifying treatments for Alzheimer disease (AD). This study was intended to assess efficacy and safety of blarcamesine (ANAVEX2-73), an orally available small-molecule activator of the sigma-1 receptor (SIGMAR1) designed to exert neuroprotection through restoration of cellular homeostasis including autophagy enhancement.

Method: ANAVEX2-73-AD-004 is a multicenter (52 medical research centers/hospitals in 5 countries), randomized, double-blind, placebo-controlled, 48-week phase 2b/3 trial that enrolled 508 participants with early AD (mild cognitive impairment/mild dementia) from July 2018 to June 2021 (last patient visit in June 2022).

Drug Development.

Background: Apolipoprotein E4 (apoE4) has been identified as the major genetic risk factor for late onset Alzheimer's disease (AD). Our lab has demonstrated that chronic administration of Aβ12-28P, a synthetic peptide that blocks apoE4/Aβ binding, in middle-aged transgenic AD mice significantly ameliorates pathology progression, resulting in reduced Aβ plaques deposition and cerebral amyloid angiopathy (CAA) along with improved memory and cognition. However, whether blocking apoE4/Aβ interaction by Aβ12-28P also has an ameliorating effect on the neuronal and cognitive function of old AD mice where Aβ pathology has been extensively developed remains unknown.

Drug Development.

Background: Alzheimer's Disease (AD) is a neurodegenerative disorder characterized by the accumulation of neurofibrillary tangles (NFTs) which consist primarily of hyperphosphorylated tau protein. Abnormal phosphorylated tau has been considered as a pathogenic species that impairs cellular function and propagates from neuron to neuron. AD affects millions of people around the world, however, there's no effective drug that can prevent or cure the disease to date.

Drug Development.

Background: Lecanemab is a humanized IgG1 monoclonal antibody that binds with high affinity to Aβ soluble protofibrils. In two clinical study evaluations of lecanemab, Clarity AD (NCT03887455) and lecanemab phase 2 study (Study 201, NCT01767311), the drug showed statistically significant reduction in disease progression during 18 months of treatment relative to placebo. Anti-amyloid immunotherapy can result in higher rates of "pseudo-atrophy" (ie, whole brain volume loss or ventricular enlargement) relative to disease progression observed in placebo-treated subjects.

Drug Development.

Background: OLX-07010 is an oral small molecule inhibitor of tau self-association that prevented the accumulation of tau aggregates in the htau mouse model expressing wild type human CNS tau isoforms and in P301L tau JNPL3 mice using chronic treatment by administration in diet (Davidowitz et al., 2020, PMID: 31771053; 2023 PMID:37556474). A therapeutic study of JNPL3 mice with chronic treatment from 7-12 months of age inhibited the progression of tau aggregation and improved motor coordination.

Dementia Care Research and Psychosocial Factors.

Background: People living with Alzheimer's disease and related dementias confront numerous decisions that affect their wellbeing, as well as that of their family members. Research demonstrates the importance of family involvement in such decision making, yet there is a lack of knowledge about how patients and families work together to make decisions and how families can best provide decisional support.

Methods: Semi-structured interviews were conducted separately with 15 patients diagnosed with mild cognitive impairment (MCI) or mild dementia, identified through a National Institute on Aging-funded Alzheimer's Disease Research Center, and 14 care partners.

Drug Development.

Background: Incretin receptor agonists (IRAs) are synthetic peptides that have beneficial effects within the brain. We investigated IRA brain uptake following two routes of delivery: across the blood-brain barrier (BBB) and following intranasal (IN) delivery.

Method: Radiolabeled IRAs were delivered intravenously or intranasally into CD-1 mice and uptake by or distribution throughout the brain was assessed.