Robust Pharmacodynamic Effect of LY3202626, a Central Nervous System Penetrant, Low Dose BACE1 Inhibitor, in Humans and Nonclinical Species

Background: The development of beta-site amyloid-beta precursor protein cleaving enzyme (BACE) 1 inhibitors for the treatment of Alzheimer’s disease requires optimization of inhibitor potency, selectivity, and brain penetration. Moreover, there is a need for low-dose compounds since liver toxicity was found with some BACE inhibitors. Objective: To determine whether the high in vitro potency and robust pharmacodynamic effect of the BACE inhibitor LY3202626 observed in nonclinical species translated to humans. Methods: The effect of LY3202626 versus vehicle on amyloid-β (Aβ) levels was evaluated in a series of in vitro assays, as well as in in vivo and multi-part clinical pharmacology studies. Aβ levels were measured using analytical biochemistry assays in brain, plasma, and cerebrospinal fluid (CSF) of mice, dogs and humans. Nonclinical data were analyzed using an ANOVA followed by Tukey’s post hoc test and clinical data used summary statistics. Results: LY3202626 exhibited significant human BACE1 inhibition, with an IC50 of 0.615±0.101 nM in a fluorescence resonance energy transfer assay and an EC50 of 0.275±0.176 nM for lowering Aβ 1–40 and 0.228±0.244 nM for Aβ 1–42 in PDAPP neuronal cultures. In dogs, CSF Aβ 1hboxx concentrations were significantly reduced by ∼80% at 9 hours following a 1.5 mg/kg dose. In humans, CSF Aβ 1–42 was reduced by 73.1±7.96 % following administration of 6 mg QD. LY3202626 was found to freely cross the blood-brain barrier in dogs and humans. Conclusion: LY3202626 is a potent BACE1 inhibitor with high blood-brain barrier permeability. The favorable safety and pharmacokinetic/pharmacodynamic profile of LY3202626 supports further clinical development.

Perspectives on the Role of APOE4 as a Therapeutic Target for Alzheimer’s Disease

Alzheimer’s disease (AD) is a neurodegenerative disease that is coupled with chronic cognitive dysfunction. AD cases are mostly late onset, and genetic risk factors like the Apolipoprotein E (APOE) play a key role in this process. APOE ɛ2, APOE ɛ3, and APOE ɛ4 are three key alleles in the human APOE gene. For late onset, APOE ɛ4 has the most potent risk factor while APOE ɛ2 plays a defensive role. Several studies suggests that APOE ɛ4 causes AD via different processes like neurofibrillary tangle formation by amyloid-β accumulation, exacerbated neuroinflammation, cerebrovascular disease, and synaptic loss. But the pathway is still unclear as to what actions of APOE ɛ4 leads to AD development. Since APOE was found to contribute to many AD pathways, targeting APOE ɛ4 can lead to a hopeful plan of action in development of new drugs to target AD. In this review, we focus on recent studies and perspectives, focusing on APOE ɛ4 as a key molecule in therapeutic strategies.

Severe Gestational Low-Protein Intake Impacts Hippocampal Cellularity, Tau, and Amyloid-β Levels, and Memory Performance in Male Adult Offspring: An Alzheimer-Simile Disease Model?

Background: Maternal undernutrition has been associated with psychiatric and neurological disorders characterized by learning and memory impairment. Objective: Considering the lack of evidence, we aimed to analyze the effects of gestational protein restriction on learning and memory function associated with hippocampal cell numbers and neurodegenerative protein content later in life. Methods: Experiments were conducted in gestational low- (LP, 6% casein) or regular-protein (NP, 17% casein) diet intake offspring. Behavioral tests, isolated hippocampal isotropic fractionator cell studies, immunoblotting, and survival lifetime were observed. Results: The birthweight of LP males is significantly reduced relative to NP male progeny, and hippocampal mass increased in 88-week-old LP compared to age-matched NP offspring. The results showed an increased proximity measure in 87-week-old LP compared to NP offspring. Also, LP rats exhibited anxiety-like behaviors compared to NP rats at 48 and 86-wk of life. The estimated neuron number was unaltered in LP rats; however, non-neuron cell numbers increased compared to NP progeny. Here, we showed unprecedented hippocampal deposition of brain-derived neurotrophic factor, amyloid-β peptide (Aβ), and tau protein in 88-week-old LP relative to age-matched NP offspring. Conclusion: To date, no predicted studies showed changes in hippocampal morphological structure in maternal protein-restricted elderly offspring. The current data suggest that gestational protein restriction may accelerate hippocampal function loss, impacting learning/memory performance, and supposedly developing diseases similar to Alzheimer’s disease (AD) in elderly offspring. Thus, we propose that maternal protein restriction could be an elegant and novel method for constructing an AD-like model in adult male offspring.

Depression Mediates the Association Between Occupational Complexity and Late-Life Cognition in Hispanics

There is a dearth of research in Latin America regarding risk and protective factors affecting older adults’ cognition. This study aimed to investigate the factors mediating the association between occupational complexity and late-life cognition and daily function in a sample of Hispanic older adults. Participants (n = 588) aged 65 years and older underwent clinical, functional, and cognitive assessments. Mediation analyses revealed that depressive symptoms mediated the relationship between occupational complexity and cognitive as well as functional outcomes. Results provide evidence that depression may act as a risk factor for worse outcomes, even if older adults had a cognitively demanding occupation.

Use of Benzodiazepines and Z-Drugs in Nursing Home Residents with Dementia: Prevalence and Appropriateness

Background: Guidelines worldwide recommend restricted prescription of benzodiazepine receptor agonists (BZRAs), i.e., benzodiazepines and Z-drugs, for the treatment of dementia-associated behavioral and psychological symptoms and insomnia. Objective: To assess the prevalence and appropriateness of BZRA use among nursing home residents with dementia. Methods: This is a post-hoc analysis of BZRA prescriptions from two intervention studies on psychotropic drug use, conducted from 2016 to 2018. It includes 1,111 residents of dementia special care units from 24 Dutch long-term care organizations. We assessed the prevalence of use of continuous and as-needed BZRA prescriptions and their association with registered symptoms. Continuous BZRA prescriptions were evaluated for appropriateness, i.e., whether indication, dosage, duration, and evaluation accorded with guidelines for the treatment of challenging behavior in dementia and sleep disorders. Results: The prevalence of BZRA use is 39.2%(95%CI: 36.3%–42.0%): continuous 22.9%; only as-needed 16.3%. Combinations of preferred BZRAs and appropriate indications occur in 19.0%of continuous anxiolytic prescriptions and 44.8%of hypnotic prescriptions. Frequently registered inappropriate indications are aggression/agitation for anxiolytics (continuous: 75.7%; as-needed: 75.2%) and nighttime agitation for hypnotics (continuous: 40.3%; as-needed: 26.7%). None of the continuous prescriptions with appropriate indications were appropriate for all other items. For most of the prescriptions, duration and time to evaluation exceeded 4 weeks. Conclusion: BZRA use in nursing home residents with dementia is highly frequent. A large proportion of prescriptions do not follow the guidelines with regard to indication, exceed the recommended duration and are not evaluated in a timely manner. The discrepancy between evidence-based guidelines and daily practice calls for an exploration of factors maintaining inappropriate use.

Molecular Investigation of the Unfolded Protein Response in Select Human Tauopathies

Background: Tauopathies are a group of neurodegenerative diseases associated with the accumulation of misfolded tau protein. The mechanisms underpinning tau-dependent proteinopathy remain to be elucidated. A protein quality control pathway within the endoplasmic reticulum, the unfolded protein response (UPR), has been suggested as a possible pathway modulating cellular responses in a range of neurodegenerative diseases, including those associated with misfolded cytosolic tau. Objective: In this study we investigated three different clinically defined tauopathies to establish whether these diseases are accompanied by the activation of UPR. Methods: We used PCR and western blotting to probe for the modulation of several reliable UPR markers in mRNA and proteins extracted from three distinct tauopathies: 20 brain samples from Alzheimer’s disease patients, 11 from Pick’s disease, and 10 from progressive supranuclear palsy. In each disease samples from these patients were compared with equal numbers of age-matched non-demented controls. Results: Our investigation showed that different markers of UPR are not changed at the late stage of any of the human tauopathies investigated. Interestingly, UPR signatures were often observed in non-demented controls. Conclusion: These data from late-stage human cortical tissue report an activation of UPR markers within the aged brain across all cohorts investigated and further support the emerging evidence that the accumulation of misfolded cytosolic tau does not drive a diseased-associated activation of UPR.

A Novel Intervention for Management of Behavioral and Psychological Symptoms of Dementia in Nursing Home Communal Areas: Results of a Small-Scale Pilot Trial

Background: Behavioral and psychological symptoms of dementia (BPSD) exhibited by persons with dementia (PwD) in nursing home communal areas are generally managed by segregation and/or pharmacological interventions. Objective: This study trialed MindfulGarden (MG), a novel digital calming device, in a Canadian nursing home. Methods: Participants were 15 PwD (mean age = 87.67; 5m,10f; mean MMSE = 11.64±7.85). Each was observed by a research assistant (RA) for an average of 8–10 hours on two separate days. The RA followed them during time spent in communal areas of the nursing home including their unit’s dining space, lounges, and corridors and spaces shared with other units (e.g., gym and gift shop) and documented any BPSD exhibited. Day-1 provided baseline data; on Day-2, residents were exposed to MG if nursing staff considered their BPSD were sufficiently intense or sustained to warrant intervention. Staff rated the impact as positive, neutral, or negative. Results: On Day-1, 9 participants exhibited both aggressive and non-aggressive behaviors, 4 non-aggressive behaviors only, and 2 no BPSD. On Day-2, 7 exhibiting aggressive behaviors were exposed to MG. Staff reported MG as having distracting/calming effects and gave positive impact ratings to 6/13 exposures; there were no negative ratings. The most common aggressive BPSD on days of observation were pushing/shoving and screaming. Conclusion: MG may have value as a “psychiatric crash cart” in de-escalating agitation and aggression in care home settings.

A Non-Invasive Determination of Ketosis-Induced Elimination of Chronic Daytime Somnolence in a Patient with Late-Stage Dementia (Assessed with Type 3 Diabetes): A Potential Role of Neurogenesis

Background: The study involved a female patient diagnosed with late-stage dementia, with chronic daytime somnolence (CDS) as a prominent symptom. Objective: To explore whether her dementia resulted from Type 3 diabetes, and whether it could be reversed through ketosis therapy. Methods: A ketogenic diet (KD) generating low-dose 100 μM Blood Ketone Levels (BKL) enhanced by a brief Ketone Mono Ester (KME) regimen with high-dose 2–4 mM BKLs was used. Results: Three sets of data describe relief (assessed by % days awake) from CDS: 1) incremental, slow, time-dependent KD plus KME-induced sigmoid curve responses which resulted in partial wakefulness (0–40% in 255 days) and complete wakefulness (40–85% in 50 days); 2) both levels of wakefulness were shown to be permanent; 3) initial permanent relief from CDS with low-dose ketosis from 6.7% to 40% took 87 days. Subsequent low-dose recovery from illness-induced CDS (6.9% to 40%) took 10 days. We deduce that the first restoration involved permanent repair, and the second energized the repaired circuits. Conclusion: The results suggest a role for ketosis in the elimination of CDS with the permanent functional restoration of the awake neural circuits of the Sleep-Wake cycle. We discuss whether available evidence supports ketosis-induced bioenergetics alone or whether other mechanisms of functional renewal were the basis for the elimination of CDS. Given evidence for permanent repair, two direct links between ketosis and neurogenesis in the adult mammalian brain are discussed: Ketosis-induced 1) brain-derived neurotrophic factor, resulting in neural progenitor/stem cell proliferation, and 2) mitochondrial bioenergetics-induced stem cell biogenesis.

Computational Approaches for Supporting Combination Therapy in the Post-Aducanumab Era in Alzheimer’s Disease

With the approval of aducanumab on the “Accelerated Approval Pathway” and the recognition of amyloid load as a surrogate marker, new successful therapeutic approaches will be driven by combination therapy as was the case in oncology after the launch of immune checkpoint inhibitors. However, the sheer number of therapeutic combinations substantially complicates the search for optimal combinations. Data-driven approaches based on large databases or electronic health records can identify optimal combinations and often using artificial intelligence or machine learning to crunch through many possible combinations but are limited to the pharmacology of existing marketed drugs and are highly dependent upon the quality of the training sets. Knowledge-driven in silico modeling approaches use multi-scale biophysically realistic models of neuroanatomy, physiology, and pathology and can be personalized with individual patient comedications, disease state, and genotypes to create ‘virtual twin patients’. Such models simulate effects on action potential dynamics of anatomically informed neuronal circuits driving functional clinical readouts. Informed by data-driven approaches this knowledge-driven modeling could systematically and quantitatively simulate all possible target combinations for a maximal synergistic effect on a clinically relevant functional outcomer. This approach seamlessly integrates pharmacokinetic modeling of different therapeutic modalities. A crucial requirement to constrain the parameters is the access to preferably anonymized individual patient data from completed clinical trials with various selective compounds. We believe that the combination of data- and knowledge driven modeling could be a game changer to find a cure for this devastating disease that affects the most complex organ of the universe.

Is There Any Evidence of Monocytes Involvement in Alzheimer’s Disease? A Pilot Study on Human Postmortem Brain

Background: The role of neuroinflammation has become more evident in the pathogenesis of neurodegenerative diseases. Increased expression of microglial markers is widely reported in Alzheimer’s disease (AD), but much less is known about the role of monocytes in AD pathogenesis. In AD animal models, bone marrow-derived monocytes appear to infiltrate the parenchyma and contribute to the phagocytosis of amyloid-β depositions, but this infiltration has not been established in systematic studies of the human brain postmortem. Objective: In addition to assessing the distribution of different subtypes of microglia by immunostaining for CD68, HLA-DR, CD163, and CD206, we focused on the involvement of C-chemokine receptor type2 (CCR2) positive monocytes during the AD course. Methods: We used formalin-fixed and paraffin-embedded tissue from four vulnerable brain regions (hippocampus, occipital lobe, brainstem, and cerebellum) from neuropathologically characterized AD cases at different Braak stages and age-matched controls. Results: Only singular migrated CCR2-positive cells were found in all brain regions and stages. The brainstem showed the highest number of positive cells overall, followed by the hippocampus. This mechanism of recruitment seems to work less efficiently in the human brain at an advanced age, and the ingress of monocytes obviously takes place in much reduced numbers or not at all. Conclusion: In contrast to studies on animal models, we observed only a quite low level of myeloid monocytes associated with AD pathology. Furthermore, we provide evidence associating early microglial reactions carried out in particular by pro-inflammatory cells with early effects on tangle- and plaque-positive vulnerable brain regions.