GRK5 Deficiency Causes Mild Cognitive Impairment due to Alzheimer’s Disease

Prevention of Alzheimer’s disease (AD) is a high priority mission while searching for a disease modifying therapy for AD, a devastating major public health crisis. Clinical observations have identified a prodromal stage of AD for which the patients have mild cognitive impairment (MCI) though do not yet meet AD diagnostic criteria. As an identifiable transitional stage before the onset of AD, MCI should become the high priority target for AD prevention, assuming successful prevention of MCI and/or its conversion to AD also prevents the subsequent AD. By pulling this string, one demonstrated cause of amnestic MCI appears to be the deficiency of G protein-coupled receptor-5 (GRK5). The most compelling evidence is that GRK5 knockout (GRK5KO) mice naturally develop into aMCI during aging. Moreover, GRK5 deficiency was reported to occur during prodromal stage of AD in CRND8 transgenic mice. When a GRK5KO mouse was crossbred with Tg2576 Swedish amyloid precursor protein transgenic mouse, the resulted double transgenic GAP mice displayed exaggerated behavioral and pathological changes across the spectrum of AD pathogenesis. Therefore, the GRK5 deficiency possesses unique features and advantage to serve as a prophylactic therapeutic target for MCI due to AD.

Memory Problems During COVID in Low-Income Older Adults

Prevention, with widespread lifestyle risk reduction at the community-level, is considered an effective method to decrease Alzheimer’s disease (AD). Diverse low-income older adults in Virginia managing either diabetes/cardiovascular symptoms, were offered weekly lifestyle telephone-health coaching for 12-weeks, providing education, motivations, self-efficacy, and referral services for AD lifestyle risk. Participants provided positive anecdotal feedback and the need for continued health coaching during COVID-19. Thirty participants (predominantly African American/Black female) consented for continued health coaching during the pandemic with 47% reporting memory problems. Findings indicated poorer health status associated with reporting memory problems for poor physical health days, poor mental health days, total mental/physical health poor days, sad days, worried days, tired days, feelings of emptiness, feelings of rejection, feelings of failure, little interest/pleasure, and feeling down. This preliminary work creates the impetus for future large-scale AD prevention investigations to improve the lives of AD-risk, low-income, diverse older adults reporting memory problems.

Alzheimer’s Prevention Lifestyle Risk Coaching in Low-income Older Adults

Prevention, with widespread lifestyle risk reduction at the community-level, is currently considered an effective method to decrease Alzheimer’s disease (AD). As part of the Virginia Commonwealth University iCubed Health and Wellness in Aging Core, diverse older adults (60+) living in Richmond, VA, with incomes below $12,000/year and managing either diabetes/cardiovascular symptoms, were offered weekly lifestyle telephone-health coaching for 12-weeks, providing education, motivations, self-efficacy, and referral services for AD lifestyle risk. The study sample (n=40, mean age 68 years (range: 60-77 years) was 88% African American/Black (n=35), 100% Non-Hispanic, and 45% males (n=18)). Thirty-nine (95%) of subjects successfully participated in coaching sessions; on average 91.9% (11) sessions/subject were completed. On a scale of 0-100 (higher scores more positivity), rated their experience 93.3. On a scale of 0-10 (higher scores more improvement), rated their health improved 8.36. Pre/post-test analyses indicated lifestyle improvement trends over 4-months for total lifestyle risk (F=4.69;p=.037;effect=.12), social activity (F=4.63;p=.063;effect =.09), and improvement in certain psychological domains: AD knowledge (F=4.49;p=.041;effect=.11); cognitive functioning (short-term memory (F=4.99;p=.038;effect= .21); delayed memory (F=2.26;p=.154;effect=.11); Trails A (F=5.60;p=.0294;effect=.24); and Trails B (F=2.22;p=.154;effect=.11). Participants provided positive anecdotal feedback and the need for continued health coaching. In conclusion, this preliminary work creates the impetus for future large-scale lifestyle AD prevention investigations to improve the lives of AD-risk, low-income, diverse older adults. These findings demonstrate that telephone-based health coaching is feasible, based on participant engagement, and effective, based on positive trends in reducing AD risk factors.

In vitro Neuroprotective Potential and Lipidomics Study of Olive Leaves Extracts Enriched in Triterpenoids

Alzheimer's Disease (AD) is the most common form of dementia that is associated with extracellular amyloid beta (Aβ) plaque formation. Genetic, environmental, and nutrition factors have been suggested as contributors to oxidative stress and neuroinflammation events that are connected to AD etiology, and secondary metabolites, such as triterpenes, have shown promising results in AD prevention. In this work, the neuroprotective and anti-inflammatory potential of an olive leaves fraction enriched in triterpenoid compounds obtained using supercritical fluid extraction (SFE) and dynamic adsorption/desorption using sea sand as adsorbent has been performed. In addition, a comprehensive lipidomics study of the response of SH-SY5Y neuroblastoma cell line to this fraction was carried out using advanced analytical methodologies, namely, charged-surface hybrid chromatography-quadrupole-time of flight mass spectrometry (CSH-Q-TOF MS/MS). The use of freely available lipidomic annotation tools and databases, and stringent cut-off filters allowed the annotation of more than 250 intracellular lipids. Advanced bioinformatics and statistical tools showed a number of phosphatidylcholines and phosphatidylethanolamines significantly increased, which could explain the protection against the cell death caused by Aβ1–42. Moreover, several triacylglycerols were found decreased. These results suggest triterpenoids from olive leaves as good neuroprotective candidates, and open a new gate for future experiments using in vivo models to corroborate this hypothesis.

Administration of Mucuna Beans (Mucuna Pruriences (L.) DC. Var. Utilis) Improves Cognition and Neuropathology of 3×Tg-AD Mice

Alzheimer’s disease (AD) is a neurodegenerative disorder characterized by the accumulation of extracellular amyloid-beta peptides (Aβ) resulting in senile plaques and intracellular hyperphosphorylated tau protein resulting in neurofibrillary tangles (NFTs). Mucuna beans (Mucuna pruriences (L.) DC. var. utilis) are unique plants containing 3%–9% L-3,4-dihydroxyphenylalanine (L-DOPA). Here we investigated the effect of the administration of Mucuna beans on AD prevention by feeding triple-transgenic mice (3×Tg-AD mice) with a diet containing Mucuna beans for 13 months. The levels of Aβ oligomers and detergent-insoluble phosphorylated tau decreased in the brain of mice fed with Mucuna beans (Mucuna group) compared to those of the Control group. Aβ accumulation and phosphorylated tau accumulation in the brain in the Mucuna group were also reduced. In addition, administration of Mucuna beans improved cognitive function. These results suggest that administration of Mucuna beans may have a preventive effect on AD development in 3×Tg-AD mice.

Adjudicating mild cognitive impairment due to Alzheimer’s disease as a novel endpoint event in the TOMMORROW prevention clinical trial

Background The onset of mild cognitive impairment (MCI) is an essential outcome in Alzheimer’s disease (AD) prevention trials and a compelling milestone for clinically meaningful change. Determining MCI, however, may be variable and subject to disagreement. Adjudication procedures may improve the reliability of these determinations. We report the performance of an adjudication committee for an AD prevention trial. Methods The TOMMORROW prevention trial selected cognitively normal participants at increased genetic risk for AD and randomized them to low-dose pioglitazone or placebo treatment. When adjudication criteria were triggered, a participant’s clinical information was randomly assigned to a three-member panel of a six-member independent adjudication committee. Determination of whether or not a participant reached MCI or AD proceeded through up to three review stages – independent review, collaborative review, and full committee review – requiring a unanimous decision and ratification by the chair. Results Of 3494 participants randomized, the committee adjudicated on 648 cases from 386 participants, resulting in 96 primary endpoint events. Most participants had cases that were adjudicated once (n = 235, 60.9%); the rest had cases that were adjudicated multiple times. Cases were evenly distributed among the eight possible three-member panels. Most adjudicated cases (485/648, 74.8%) were decided within the independent review (stage 1); 14.0% required broader collaborative review (stage 2), and 11.1% needed full committee discussion (stage 3). The primary endpoint event decision rate was 39/485 (8.0%) for stage 1, 29/91 (31.9%) for stage 2, and 28/72 (38.9%) for stage 3. Agreement between the primary event outcomes supported by investigators’ clinical diagnoses and the decisions of the adjudication committee increased from 50% to approximately 93% (after around 100 cases) before settling at 80–90% for the remainder of the study. Conclusions The adjudication process was designed to provide independent, consistent determinations of the trial endpoints. These outcomes demonstrated the extent of uncertainty among trial investigators and agreement between adjudicators when the transition to MCI due to AD was prospectively assessed. These methods may inform clinical endpoint determination in future AD secondary prevention studies. Reliable, accurate assessment of clinical events is critical for prevention trials and may mean the difference between success and failure. Trial registration: NCT01931566

The informed road map to prevention of Alzheimer Disease: A call to arms

Alzheimer disease (AD) prevention trials hold the promise to delay or prevent cognitive decline and dementia onset by intervening before significant neuronal damage occurs. In recent years, the first AD prevention trials have launched and are yielding important findings on the biology of targeting asymptomatic AD pathology. However, there are limitations that impact the design of these prevention trials, including the translation of animal models that recapitulate key stages and multiple pathological aspects of the human disease, missing target validation in asymptomatic disease, uncertain causality of the association of pathophysiologic changes with cognitive and clinical symptoms, and limited biomarker validation for novel targets. The field is accelerating advancements in key areas including the development of highly specific and quantitative biomarker measures for AD pathology, increasing our understanding of the course and relationship of amyloid and tau pathology in asymptomatic through symptomatic stages, and the development of powerful interventions that can slow or reverse AD amyloid pathology. We review the current status of prevention trials and propose key areas of needed research as a call to basic and translational scientists to accelerate AD prevention. Specifically, we review (1) sporadic and dominantly inherited primary and secondary AD prevention trials, (2) proposed targets, mechanisms, and drugs including the amyloid, tau, and inflammatory pathways and combination treatments, (3) the need for more appropriate prevention animal models and experiments, and (4) biomarkers and outcome measures needed to design human asymptomatic prevention trials. We conclude with actions needed to effectively move prevention targets and trials forward.

Forgot to Exercise? Exercise Derived Circulating Myokines in Alzheimer's Disease: A Perspective

Regular exercise plays an essential role in maintaining healthy neurocognitive function and central nervous system (CNS) immuno-metabolism in the aging CNS. Physical activity decreases the risk of developing Alzheimer's Disease (AD), is associated with better AD prognosis, and positively affects cognitive function in AD patients. Skeletal muscle is an important secretory organ, communicating proteotoxic and metabolic stress to distant tissues, including the CNS, through the secretion of bioactive molecules collectively known as myokines. Skeletal muscle undergoes significant physical and metabolic remodeling during exercise, including alterations in myokine expression profiles. This suggests that changes in myokine and myometabolite secretion may underlie the well-documented benefits of exercise in AD. However, to date, very few studies have focused on specific alterations in skeletal muscle-originating secreted factors and their potential neuroprotective effects in AD. In this review, we discuss exercise therapy for AD prevention and intervention, and propose the use of circulating myokines as novel therapeutic tools for modifying AD progression.

The Moringin/α-CD Pretreatment Induces Neuroprotection in an In Vitro Model of Alzheimer’s Disease: A Transcriptomic Study

Alzheimer’s disease (AD) is a progressive neurodegenerative disorder and represents the most common form of senile dementia. Autophagy and mitophagy are cellular processes that play a key role in the aggregation of β-amyloid (Aβ) and tau phosphorylation. As a consequence, impairment of these processes leads to the progression of AD. Thus, interest is growing in the search for new natural compounds, such as Moringin (MOR), with neuroprotective, anti-amyloidogenic, antioxidative, and anti-inflammatory properties that could be used for AD prevention. However, MOR appears to be poorly soluble and stable in water. To increase its solubility MOR was conjugated with α-cyclodextrin (MOR/α-CD). In this work, it was evaluated if MOR/α-CD pretreatment was able to exert neuroprotective effects in an AD in vitro model through the evaluation of the transcriptional profile by next-generation sequencing (NGS). To induce the AD model, retinoic acid-differentiated SH-SY5Y cells were exposed to Aβ1-42. The MOR/α-CD pretreatment reduced the expression of the genes which encode proteins involved in senescence, autophagy, and mitophagy processes. Additionally, MOR/α-CD was able to induce neuronal remodeling modulating the axon guidance, principally downregulating the Slit/Robo signaling pathway. Noteworthy, MOR/α-CD, modulating these important pathways, may induce neuronal protection against Aβ1-42 toxicity as demonstrated also by the reduction of cleaved caspase 3. These data indicated that MOR/α-CD could attenuate the progression of the disease and promote neuronal repair.

COVID-19 and Alzheimer’s disease: how one crisis worsens the other

Alzheimer’s disease (AD) has emerged as a key comorbidity of coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2). The morbidity and mortality of COVID-19 are elevated in AD due to multiple pathological changes in AD patients such as the excessive expression of viral receptor angiotensin converting enzyme 2 and pro-inflammatory molecules, various AD complications including diabetes, lifestyle alterations in AD, and drug-drug interactions. Meanwhile, COVID-19 has also been reported to cause various neurologic symptoms including cognitive impairment that may ultimately result in AD, probably through the invasion of SARS-CoV-2 into the central nervous system, COVID-19-induced inflammation, long-term hospitalization and delirium, and post-COVID-19 syndrome. In addition, the COVID-19 crisis also worsens behavioral symptoms in uninfected AD patients and poses new challenges for AD prevention. In this review, we first introduce the symptoms and pathogenesis of COVID-19 and AD. Next, we provide a comprehensive discussion on the aggravating effects of AD on COVID-19 and the underlying mechanisms from molecular to social levels. We also highlight the influence of COVID-19 on cognitive function, and propose possible routes of viral invasion into the brain and potential mechanisms underlying the COVID-19-induced cognitive impairment. Last, we summarize the negative impacts of COVID-19 pandemic on uninfected AD patients and dementia prevention.