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Alzheimer's Research & Therapy Oct 2023Development of in vivo biomarkers has shifted the diagnosis of Alzheimer's disease (AD) from the later dementia stages of disease towards the earlier stages and has... (Review)
Review
BACKGROUND
Development of in vivo biomarkers has shifted the diagnosis of Alzheimer's disease (AD) from the later dementia stages of disease towards the earlier stages and has introduced the potential for pre-symptomatic diagnosis. The International Working Group recommends that AD diagnosis is restricted in the clinical setting to people with specific AD phenotypes and supportive biomarker findings.
MAIN BODY
In this review, we discuss the phenotypic presentation and use of biomarkers for the early diagnosis of typical and atypical AD and describe how this can support clinical decision making, benefit patient communication, and improve the patient journey. Early diagnosis is essential to optimize the benefits of available and emerging treatments. As atypical presentations of AD often mimic other dementias, differential diagnosis can be challenging and can be facilitated using AD biomarkers. However, AD biomarkers alone are not sufficient to confidently diagnose AD or predict disease progression and should be supplementary to clinical assessment to help inform the diagnosis of AD.
CONCLUSIONS
Use of AD biomarkers with incorporation of atypical AD phenotypes into diagnostic criteria will allow earlier diagnosis of patients with atypical clinical presentations that otherwise would have been misdiagnosed and treated inappropriately. Early diagnosis is essential to guide informed discussion, appropriate care and support, and individualized treatment. It is hoped that disease-modifying treatments will impact the underlying AD pathology; thus, determining the patient's AD phenotype will be a critical factor in guiding the therapeutic approach and the assessment of the effects of interventions.
Topics: Humans; Alzheimer Disease; Diagnosis, Differential; Biomarkers; Recognition, Psychology; Disease Progression
PubMed: 37833762
DOI: 10.1186/s13195-023-01314-6 -
Alzheimer's & Dementia : the Journal of... Nov 2020Development of disease-modifying treatments for Alzheimer's disease (AD) has been challenging, with no drugs approved to date. The failures of several amyloid-targeted... (Review)
Review
Development of disease-modifying treatments for Alzheimer's disease (AD) has been challenging, with no drugs approved to date. The failures of several amyloid-targeted programs have led many to dismiss the amyloid beta (Aβ) hypothesis of AD. An antiamyloid antibody aducanumab recently showed modest but significant efficacy in a phase 3 trial, providing important validation of amyloid as a therapeutic target. However, the inconsistent results observed with aducanumab may be explained by the limited brain penetration and lack of selectivity for the soluble Aβ oligomers, which are implicated as upstream drivers of neurodegeneration by multiple studies. Development of agents that can effectively inhibit Aβ oligomer formation or block their toxicity is therefore warranted. An ideal drug would cross the blood-brain barrier efficiently and achieve sustained brain levels that can continuously prevent oligomer formation or inhibit their toxicity. A late-stage candidate with these attributes is ALZ-801, an oral drug with a favorable safety profile and high brain penetration that can robustly inhibit Aβ oligomer formation. An upcoming phase 3 trial with ALZ-801 in APOE4/4 homozygous patients with early AD will effectively test this amyloid oligomer hypothesis.
Topics: Alzheimer Disease; Amyloid beta-Peptides; Antibodies, Monoclonal, Humanized; Drug Discovery; Humans; Taurine; Valine
PubMed: 31706733
DOI: 10.1016/j.jalz.2019.09.075 -
Journal of Internal Medicine Aug 2021The critical role of primary care clinicians (PCCs) in Alzheimer's disease (AD) prevention, diagnosis and management must evolve as new treatment paradigms and... (Review)
Review
The critical role of primary care clinicians (PCCs) in Alzheimer's disease (AD) prevention, diagnosis and management must evolve as new treatment paradigms and disease-modifying therapies (DMTs) emerge. Our understanding of AD has grown substantially: no longer conceptualized as a late-in-life syndrome of cognitive and functional impairments, we now recognize that AD pathology builds silently for decades before cognitive impairment is detectable. Clinically, AD first manifests subtly as mild cognitive impairment (MCI) due to AD before progressing to dementia. Emerging optimism for improved outcomes in AD stems from a focus on preventive interventions in midlife and timely, biomarker-confirmed diagnosis at early signs of cognitive deficits (i.e. MCI due to AD and mild AD dementia). A timely AD diagnosis is particularly important for optimizing patient care and enabling the appropriate use of anticipated DMTs. An accelerating challenge for PCCs and AD specialists will be to respond to innovations in diagnostics and therapy for AD in a system that is not currently well positioned to do so. To overcome these challenges, PCCs and AD specialists must collaborate closely to navigate and optimize dynamically evolving AD care in the face of new opportunities. In the spirit of this collaboration, we summarize here some prominent and influential models that inform our current understanding of AD. We also advocate for timely and accurate (i.e. biomarker-defined) diagnosis of early AD. In doing so, we consider evolving issues related to prevention, detecting emerging cognitive impairment and the role of biomarkers in the clinic.
Topics: Alzheimer Disease; Humans; Primary Health Care; Time Factors
PubMed: 33458891
DOI: 10.1111/joim.13244 -
Journal of Alzheimer's Disease : JAD 2022Female sex, subjective cognitive decline (SCD), and cardiovascular risk factors (CVRFs) are known risk factors for developing Alzheimer's disease (AD). We previously... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
Female sex, subjective cognitive decline (SCD), and cardiovascular risk factors (CVRFs) are known risk factors for developing Alzheimer's disease (AD). We previously demonstrated that yoga improved depression, resilience, memory and executive functions, increased hippocampal choline concentrations, and modulated brain connectivity in older adults with mild cognitive impairment.
OBJECTIVE
In this study (NCT03503669), we investigated brain gray matter volume (GMV) changes in older women with SCD and CVRFs following three months of yoga compared to memory enhancement training (MET).
METHODS
Eleven women (mean age = 61.45, SD = 6.58) with CVRF and SCD completed twelve weeks of Kundalini Yoga and Kirtan Kriya (KY + KK) while eleven women (mean age = 64.55, SD = 6.41) underwent MET. Anxiety, resilience, stress, and depression were assessed at baseline and 12 weeks, as were T1-weighted MRI scans (Siemens 3T Prisma scanner). We used Freesurfer 6.0 and tested group differences in GMV change, applying Monte-Carlo simulations with alpha = 0.05. Region-of-interest analysis was performed for hippocampus and amygdala.
RESULTS
Compared to KY + KK, MET showed reductions in GMV in left prefrontal, pre- and post-central, supramarginal, superior temporal and pericalcarine cortices, right paracentral, postcentral, superior and inferior parietal cortices, the banks of the superior temporal sulcus, and the pars opercularis. Right hippocampal volume increased after yoga but did not survive corrections.
CONCLUSION
Yoga training may offer neuroprotective effects compared to MET in preventing neurodegenerative changes and cognitive decline, even over short time intervals. Future analyses will address changes in functional connectivity in both groups.
Topics: Aged; Alzheimer Disease; Atrophy; Cognitive Dysfunction; Female; Gray Matter; Humans; Magnetic Resonance Imaging; Yoga
PubMed: 35275541
DOI: 10.3233/JAD-215563 -
Alzheimer's & Dementia : the Journal of... Jan 2021The LipiDiDiet trial investigates the effects of the specific multinutrient combination Fortasyn Connect on cognition and related measures in prodromal Alzheimer's... (Randomized Controlled Trial)
Randomized Controlled Trial
INTRODUCTION
The LipiDiDiet trial investigates the effects of the specific multinutrient combination Fortasyn Connect on cognition and related measures in prodromal Alzheimer's disease (AD). Based on previous results we hypothesized that benefits increase with long-term intervention.
METHODS
In this randomized, double-blind, placebo-controlled trial, 311 people with prodromal AD were recruited using the International Working Group-1 criteria and assigned to active product (125 mL once-a-day drink) or an isocaloric, same tasting, placebo control drink. Main outcome was change in cognition (Neuropsychological Test Battery [NTB] 5-item composite). Analyses were by modified intention-to-treat, excluding (ie, censoring) data collected after the start of open-label active product and/or AD medication.
RESULTS
Of the 382 assessed for eligibility, 311 were randomized, of those 162 participants completed the 36-month study, including 81 with 36-month data eligible for efficacy analysis. Over 36 months, significant reductions in decline were observed for the NTB 5-item composite (-60%; between-group difference 0.212 [95% confidence interval: 0.044 to 0.380]; P = 0.014), Clinical Dementia Rating-Sum of Boxes (-45%; P = 0.014), memory (-76%; P = 0.008), and brain atrophy measures; small to medium Cohen's d effect size (0.25-0.31) similar to established clinically relevant AD treatment.
DISCUSSION
This multinutrient intervention slowed decline on clinical and other measures related to cognition, function, brain atrophy, and disease progression. These results indicate that intervention benefits increased with long-term use.
Topics: Aged; Aged, 80 and over; Alzheimer Disease; Atrophy; Cognition; Cognitive Dysfunction; Double-Blind Method; Female; Humans; Magnetic Resonance Imaging; Male; Mental Status and Dementia Tests; Middle Aged; Neuropsychological Tests; Nutrition Therapy; Prodromal Symptoms; Risk Factors
PubMed: 32920957
DOI: 10.1002/alz.12172 -
Alzheimer's & Dementia : the Journal of... Nov 2019Several microRNAs (miRNAs) have been implicated in Alzheimer's disease pathogenesis, but the evidence from individual case-control studies remains inconclusive. (Meta-Analysis)
Meta-Analysis
INTRODUCTION
Several microRNAs (miRNAs) have been implicated in Alzheimer's disease pathogenesis, but the evidence from individual case-control studies remains inconclusive.
METHODS
A systematic literature review was performed, followed by standardized multistage data extraction, quality control, and meta-analyses on eligible data for brain, blood, and cerebrospinal fluid specimens. Results were compared with miRNAs reported in the abstracts of eligible studies or recent qualitative reviews to assess novelty.
RESULTS
Data from 147 independent data sets across 107 publications were quantitatively assessed in 461 meta-analyses. Twenty-five, five, and 32 miRNAs showed studywide significant differential expression (α < 1·08 × 10) in brain, cerebrospinal fluid, and blood-derived specimens, respectively, with 5 miRNAs showing differential expression in both brain and blood. Of these 57 miRNAs, 13 had not been reported in the abstracts of previous original or review articles.
DISCUSSION
Our systematic assessment of differential miRNA expression is the first of its kind in Alzheimer's disease and highlights several miRNAs of potential relevance.
Topics: Alzheimer Disease; Biomarkers; Brain; Case-Control Studies; Epigenomics; Humans; MicroRNAs
PubMed: 31495604
DOI: 10.1016/j.jalz.2019.06.4952 -
Journal of Alzheimer's Disease : JAD 2020The progressive aging of the population will dramatically increase the burden of dementia related to Alzheimer's disease (AD) and other neurodegenerative disorders in... (Review)
Review
BACKGROUND
The progressive aging of the population will dramatically increase the burden of dementia related to Alzheimer's disease (AD) and other neurodegenerative disorders in the future. Because of the absence of drugs that can modify the neuropathological substrate of AD, research is focusing on the application of preemptive and disease-modifying strategies in the pre-symptomatic period of the disease. In this perspective, the identification of people with cognitive frailty (CF), i.e., those individuals with higher risk of developing dementia, on solid pathophysiological bases and with clear operational clinical criteria is of paramount importance.
OBJECTIVE/METHODS
This hypothesis paper reviews the current definitions of CF, presents and discusses some of their limitations, and proposes a framework for updating and improving the conceptual and operational definition of the CF construct.
RESULTS
The potential for reversibility of CF should be supported by the assessment of amyloid, tau, and neuronal damage biomarkers, especially in younger patients. Physical and cognitive components of frailty should be considered as separate entities, instead of part of a single macro-phenotype. CF should not be limited to the geriatric population, because trajectories of amyloid accumulation are supposed to start earlier than 65 years in AD. Operational criteria are needed to standardize assessment of CF.
CONCLUSION
Based on the limitations of current CF definitions, we propose a revised one according to a multidimensional subtyping. This new definition might help stratifying CF patients for future trials to explore new lifestyle interventions or disease-modifying pharmacological strategies for AD and dementia.
Topics: Aging; Alzheimer Disease; Amyloidosis; Biomarkers; Cognition; Cognitive Dysfunction; Frailty; Humans
PubMed: 32568197
DOI: 10.3233/JAD-200137 -
European Journal of Medicinal Chemistry Jul 2023Alzheimer's Disease (AD) remains one of the most challenging health-related issues for our society. It is becoming increasingly prevalent, especially in developed... (Review)
Review
Alzheimer's Disease (AD) remains one of the most challenging health-related issues for our society. It is becoming increasingly prevalent, especially in developed countries, due to the rising life expectancy and, moreover, represents a considerable economic burden worldwide. All efforts at the discovery of new diagnostic and therapeutic tools in the last decades have invariably met with failure, making AD an incurable illness and underscoring the need for new approaches. In recent years, theranostic agents have emerged as an interesting strategy. They are molecules able to simultaneously provide diagnostic information and deliver therapeutic activity, allowing for the assessment of the molecule activity, the organism response and the pharmacokinetics. This makes these compounds promising for streamlining research on AD drugs and for their application in personalized medicine. We review here the field of small-molecule theranostic agents as promising tools for the development of novel diagnostic and therapeutic resources against AD, highlighting the positive and significant impact that theranostics can be expected to have in the near future in clinical practice.
Topics: Humans; Alzheimer Disease; Precision Medicine; Amyloid beta-Peptides
PubMed: 37141706
DOI: 10.1016/j.ejmech.2023.115382 -
Biomolecules Feb 2022Alzheimer's disease (AD) incidence is increasing worldwide at an alarming rate. Considering this increase, prevention efforts, stemming from scientific research, health... (Review)
Review
Alzheimer's disease (AD) incidence is increasing worldwide at an alarming rate. Considering this increase, prevention efforts, stemming from scientific research, health education, and public policies, are critical. Clinical studies evidenced that healthy lifestyles along with natural multitarget and disease-modifying agents have a preventative impact on AD or mitigate symptoms in diagnosed patients. The pathological alterations of AD start 30 years before symptoms, and it is essential to develop the capacity to detect those changes. In this regard, molecular biomarkers that detect early pathological manifestations are helpful. Based on markers data, early preventive interventions could reduce more than 40% of AD cases. Protective actions include exercise, shown to induce neurogenesis, cognitive stimulation, intellectual-social activity, and nutrition among others. Mediterranean diet, preprobiotics, and nutraceuticals containing bioactive molecules with antioxidant and anti-inflammatory properties are relevant. Antiprotein aggregation molecules whose mechanisms were described are important. Anti-inflammatory agents with anti-aggregation properties that help to control cognitive impairment, include quercetin, biocurcumin, rosemarinic acid, and Andean . Anthocyanidins, e.g., delphinidin, malvidin, and natural flavonoids, are also included. Quercetin and hydroxy-tyrosol are antiaging molecules and could have anti-AD properties. We emphasize the relevance of nutraceuticals as a main actor in the prevention and/or control of dementia and particularly AD.
Topics: Alzheimer Disease; Antioxidants; Cognitive Dysfunction; Diet, Mediterranean; Dietary Supplements; Humans
PubMed: 35204750
DOI: 10.3390/biom12020249 -
Alzheimer's & Dementia : the Journal of... Jan 2024
Topics: Humans; Alzheimer Disease; Mendelian Randomization Analysis; Sleep; Risk Factors; Genome-Wide Association Study
PubMed: 37828703
DOI: 10.1002/alz.13505