Lessons learned from the failure of solanezumab as a prospective treatment strategy for Alzheimer's disease.

INTRODUCTION: In the last decade, the efforts conducted for discovering Alzheimer's Disease (AD) treatments targeting the best-known pathogenic factors [amyloid-ß (Aß), tau protein, and neuroinflammation] were mostly unsuccessful. Given that a systemic failure of Aß clearance was supposed to primarily contribute to AD development and progression, disease-modifying therapies with anti-Aß monoclonal antibodies (e.g. solanezumab, bapineuzumab, gantenerumab, aducanumab, lecanemab and donanemab) are ongoing in randomized clinical trials (RCTs) with contrasting results. AREAS COVERED: The present Drug Discovery Case History analyzes the failures of RCTs of solanezumab on AD. Furthermore, the authors review the pharmacokinetics, pharmacodynamics, and tolerability effect of solanezumab from preclinical studies with its analogous m266 in mice. Finally, they describe the RCTs with cognitive, cerebrospinal fluid and neuroimaging findings in mild-to-moderate AD (EXPEDITION studies) and in secondary prevention studies (A4 and DIAN-TU). EXPERT OPINION: Solanezumab was one of the first anti-Aß monoclonal antibodies to be tested in preclinical and clinical AD showing to reduce brain Aß level by acting on soluble monomeric form of Aß peptide without significant results on deposits. Unfortunately, this compound showed to accelerate cognitive decline in both asymptomatic and symptomatic trial participants, and this failure of solanezumab further questioned the Aß cascade hypothesis of AD.

How can we manage progressive supranuclear palsy syndrome with pharmacotherapy?

INTRODUCTION: Tauopathies are a spectrum of clinicopathological neurodegenerative disorders with increased aggregates included in glia and/or neurons of hyperphosphorylated insoluble tau protein, a microtubule-associated protein. Progressive supranuclear palsy (PSP) is an atypical dopaminergic-resistant parkinsonian syndrome, considered as a primary tauopathy with possible alteration of tau isoform ratio, and tau accumulations characterized by 4 R tau species as the main neuropathological lesions. AREAS COVERED: In the present review article, we analyzed and discussed viable disease-modifying and some symptomatic pharmacological therapeutics for PSP syndrome (PSPS). EXPERT OPINION: Pharmacological therapy for PSPS may interfere with the aggregation process or promote the clearance of abnormal tau aggregates. A variety of past and ongoing disease-modifying therapies targeting tau in PSPS included genetic, microtubule-stabilizing compounds, anti-phosphorylation, and acetylation agents, antiaggregant, protein removal, antioxidant neuronal and synaptic growth promotion therapies. New pharmacological gene-based approaches may open alternative prevention pathways for the deposition of abnormal tau in PSPS such as antisense oligonucleotide (ASO)-based drugs. Moreover, kinases and ubiquitin-proteasome systems could also be viable targets.

The epigenetics of frailty.

The conceptual change of frailty, from a physical to a biopsychosocial phenotype, expanded the field of frailty, including social and behavioral domains with critical interaction between different frailty models. Environmental exposures - including physical exercise, psychosocial factors and diet - may play a role in the frailty pathophysiology. Complex underlying mechanisms involve the progressive interactions of genetics with epigenetics and of multimorbidity with environmental factors. Here we review the literature on possible mechanisms explaining the association between epigenetic hallmarks (i.e., global DNA methylation, DNA methylation age acceleration and microRNAs) and frailty, considered as biomarkers of aging. Frailty could be considered the result of environmental epigenetic factors on biological aging, caused by conflicting DNA methylation age and chronological age.

The present narrative review describes the available evidence about epigenetic biological markers of frailty considered aging biomarkers, among others. Aging biomarkers can help in identifying frail and older individuals affected by multiple diseases to further increase the power of composite biomarker panels in the diagnostic and prognostic process. Among combined biomarkers, epigenetic regulators with different methylation patterns and small molecules such as microRNAs are included. Given that frailty involves multiple biological systems, it is possible to define it according to a novel model, including emotional and social domains and the influence of environmental factors, named the biopsychosocial phenotype. Different epigenetic biomarkers of frailty, from the first generation to the more specific and recent second-generation epigenetic aging biomarkers, may account for factors linked to different cellular types, such as heterogeneity, and a reverse causation process that requires integration with gene expression. A better understanding of the relationships among frailty, multimorbidity and overall mortality will help us to identify the best therapeutic targets.

The Impact of Apolipoprotein E (APOE) Epigenetics on Aging and Sporadic Alzheimer's Disease.

Sporadic Alzheimer's disease (AD) derives from an interplay among environmental factors and genetic variants, while epigenetic modifications have been expected to affect the onset and progression of its complex etiopathology. Carriers of one copy of the apolipoprotein E gene (APOE) ε4 allele have a 4-fold increased AD risk, while APOE ε4/ε4-carriers have a 12-fold increased risk of developing AD in comparison with the APOE ε3-carriers. The main longevity factor is the homozygous APOE ε3/ε3 genotype. In the present narrative review article, we summarized and described the role of APOE epigenetics in aging and AD pathophysiology. It is not fully understood how APOE variants may increase or decrease AD risk, but this gene may affect tau- and amyloid-mediated neurodegeneration directly or indirectly, also by affecting lipid metabolism and inflammation. For sporadic AD, epigenetic regulatory mechanisms may control and influence APOE expression in response to external insults. Diet, a major environmental factor, has been significantly associated with physical exercise, cognitive function, and the methylation level of several cytosine-phosphate-guanine (CpG) dinucleotide sites of APOE.

The Relationship between Oral Health-Related Quality of Life and Body Mass Index in an Older Population from Southern Italy: The Salus in Apulia Study.

BACKGROUND: The assessment of oral health-related quality of life (OHRQoL) evaluated the impact of an individual's oral health on the patient's physical and psychosocial status. We evaluated the association between subjective OHRQoL, measured with the Oral Health Impact Profile-14 (OHIP-14) questionnaire, and unfavorable body mass index (BMI) (i.e., too high or too low) in a large population-based study on older adults from Southern Italy. Moreover, we assessed which of the seven OHIP-14 domains was the most strongly associated with an unfavorable BMI. METHODS: We used data on a subpopulation of the Salus in Apulia Study, including 216 older adults. BMI < 18.4 kg/m2 and >30 kg/m2 were classified as unfavorable, while values between 18.5 and 30 kg/m2 were classified as ideal. RESULTS: A higher OHIP-14 total score increased the risk of an unfavorable BMI (odds ratio (OR): 1.08, 95% confidence interval (CI): 1.01-1.15). In the model adjusted for age, sex, education, hypertension, carbohydrate consumption, and alcohol consumption, this finding was confirmed with a higher OHIP-14 total score increasing the risk of an unfavorable BMI (OR: 1.10, 95% CI: 1.01-1.22), and higher age linked to a decreased risk of an unfavorable BMI (OR: 0.89, 95% CI: 0.82-0.97). In a random forest regression model, the most important predictive domains/sub-scales of OHIP-14 in the mean decrease in the Gini coefficient for unfavorable BMI were, in order of decreasing importance, physical pain, functional limitation, psychological discomfort, physical disability, social disability, psychological disability, and handicap. CONCLUSIONS: In older age, negative OHRQoL, particularly linked to the physical pain domain, increased the risk of being underweight or overweight and obesity.

Passive tau-based immunotherapy for tauopathies.

Tauopathies are heterogeneous clinicopathological entities characterized by abnormal neuronal and/or glial inclusions of the microtubule-binding protein tau. In secondary tauopathies, i.e., Alzheimer's disease (AD), tau deposition can be observed, but tau may coexist with another protein, i.e., amyloid-ß. In the last 20 years, little progress has been made in developing disease-modifying drugs for primary and secondary tauopathies and available symptomatic drugs have limited efficacy. Treatments are being developed to interfere with the aggregation process or to promote the clearance of tau protein. Several tau-targeted passive immunotherapy approaches are in development for treating tauopathies. At present, 12 anti-tau antibodies have entered clinical trials, and 7 of them are still in clinical testing for primary tauopathies and AD (semorinemab, bepranemab, E2814, JNJ-63733657, Lu AF87908, PNT00, and APNmAb005). However, none of these seven agents have reached Phase III. The most advanced anti-tau monoclonal antibody for treating AD is semorinemab, while bepranemab is the only anti-tau monoclonal antibody still in clinical testing for treating progressive supranuclear palsy syndrome. Two other anti-tau monoclonal antibodies have been discontinued for the treatment of primary tauopathies, i.e., gosuranemab and tilavonemab. Further evidence will come from ongoing Phase I/II trials on passive immunotherapeutics for treating primary and secondary tauopathies.

Clinical development of passive tau-based immunotherapeutics for treating primary and secondary tauopathies.

INTRODUCTION: Tauopathies are clinicopathological entities with increased and pathological deposition in glia and/or neurons of hyperphosphorylated aggregates of the microtubule-binding protein tau. In secondary tauopathies, i.e. Alzheimer's disease (AD), tau deposition can be observed, but tau coexists with another protein (amyloid-ß). In the last 20 years, little progress has been made in developing disease-modifying drugs for primary and secondary tauopathies and available symptomatic drugs have limited efficacy. AREAS COVERED: The present review summarized recent advances about the development and challenges in treatments for primary and secondary tauopathies, with a focus on passive tau-based immunotherapy. EXPERT OPINION: Several tau-targeted passive immunotherapeutics are in development for treating tauopathies. At present, 14 anti-tau antibodies have entered clinical trials, and 9 of them are still in clinical testing for progressive supranuclear palsy syndrome and AD (semorinemab, bepranemab, E2814, JNJ-63733657, Lu AF87908, APNmAb005, MK-2214, PNT00, and PRX005). However, none of these nine agents have reached Phase III. The most advanced anti-tau monoclonal antibody for treating AD is semorinemab, while bepranemab is the only anti-tau monoclonal antibody still in clinical testing for treating progressive supranuclear palsy syndrome. Further evidence on passive immunotherapeutics for treating primary and secondary tauopathies will come from ongoing Phase I/II trials.

Temporomandibular Disorders as Contributors to Primary Headaches: A Systematic Review.

AIMS: To systematically review the literature assessing associations between TMDs and primary headaches. METHODS: Using validated clinical criteria, studies on TMDs and primary headaches published up to January 10, 2023 were identified using six electronic databases. This review adhered to the PRISMA 2020 guidelines and 27-item checklist and is registered on PROSPERO (CRD42021256391). Risk of bias was evaluated using the National Institutes of Health Quality Assessment Toolkits for Observational Cohort and Cross-Sectional Studies. RESULTS: Two independent investigators rated 7,697 records against the primary endpoint and found 8 records meeting the eligibility requirements. Migraine was found to be the most common primary headache related to TMDs (61.5%), followed by episodic tension-type headache (ETTH; 38.5%). A moderate association was found for mixed TMDs with migraine and ETTH, with a large sample size and multiple studies included (n = 8). A very low-quality association was found for myalgia-related TMDs with migraine and ETTH (included studies, n = 2). CONCLUSION: The association between TMDs and primary headaches is of great interest given the possible effectiveness of TMD management in reducing headache intensity/frequency in patients with TMDs and headache comorbidity. A moderate association was found for mixed TMDs with primary headaches, in particular migraine and ETTH. However, owing to the overall moderate certainty of evidence of the present findings, further longitudinal studies with larger samples investigating possible associated factors and using accurate TMD and headache category assignment are needed.

Exploring the Association of Burning Mouth Syndrome with Depressive and Anxiety Disorders in Middle-Aged and Older Adults: A Systematic Review.

BACKGROUND: Burning Mouth Syndrome (BMS) is an idiopathic condition mainly affecting middle-aged and older individuals with hormonal disturbances or psychiatric disorders and is characterized by chronic pain. The etiopathogenesis of this multifactorial syndrome is largely unknown. The objective of the present systematic review was therefore to evaluate the relationship of BMS with depressive and anxiety disorders in middle-aged and older individuals. METHODS: We selected studies evaluating BMS and depressive and anxiety disorders assessed with validated tools, published from their inception up to April 2023, using PubMed, MEDLINE, EMBASE, Scopus, Ovid, and Google Scholar databases and adhering to the PRISMA 2020 guidelines/PRISMA 2020 27-item checklist. This study is registered on PROSPERO (CRD42023409595). The National Institutes of Health Quality Assessment Toolkits for Observational Cohort and Cross-Sectional Studies were used to examine the risk of bias. RESULTS: Two independent investigators rated 4322 records against the primary endpoint and found 7 records meeting the eligibility requirements. Anxiety disorders were found to be the most common psychiatric disorders related to BMS (63.7%), followed by depressive disorders (36.3%). We found a moderate association of BMS with anxiety disorders, with multiple studies included (n = 7). Moreover, we found a low association of BMS with depressive disorders (included studies, n = 4). The role of pain appeared to be controversial in explaining these associations. CONCLUSIONS: In middle-aged and older subjects, anxiety and depressive disorders may be potentially related to the development of BMS. Furthermore, also in these age groups, females showed higher risk of developing BMS than males, even when taking into account multimorbidity such as sleep disorders, personality traits, and biopsychosocial changes as suggested by study-specific findings.

Depressive and Biopsychosocial Frailty Phenotypes: Impact on Late-life Cognitive Disorders.

In older age, frailty is a detrimental transitional status of the aging process featuring an increased susceptibility to stressors defined by a clinical reduction of homoeostatic reserves. Multidimensional frailty phenotypes have been associated with all-cause dementia, mild cognitive impairment (MCI), Alzheimer's disease (AD), AD neuropathology, vascular dementia, and non-AD dementias. In the present article, we reviewed current evidence on the existing links among depressive and biopsychosocial frailty phenotypes and late-life cognitive disorders, also examining common pathways and mechanisms underlying these links. The depressive frailty phenotype suggested by the construct of late-life depression (LLD) plus physical frailty is poorly operationalized. The biopsychosocial frailty phenotype, with its coexistent biological/physical and psychosocial dimensions, defines a biological aging status and includes motivational, emotional, and socioeconomic domains. Shared biological pathways/substrates among depressive and biopsychosocial frailty phenotypes and late-life cognitive disorders are hypothesized to be inflammatory and cardiometabolic processes, together with multimorbidity, loneliness, mitochondrial dysfunction, dopaminergic neurotransmission, specific personality traits, lack of subjective/objective social support, and neuroendocrine dysregulation. The cognitive frailty phenotype, combining frailty and cognitive impairment, may be a risk factor for LLD and vice versa, and a construct of depressive frailty linking physical frailty and LLD may be a good dementia predictor. Frailty assessment may enable clinicians to better target the pharmacological and psychological treatment of LLD. Given the epidemiological links of biopsychosocial frailty with dementia and MCI, multidomain interventions might contribute to delay the onset of late-life cognitive disorders and other adverse health-related outcomes, such as institutionalization, more frequent hospitalization, disability, and mortality.

Dementia, infections and vaccines: 30 years of controversy.

This paper reports the proceedings of a virtual meeting convened by the European Interdisciplinary Council on Ageing (EICA), to discuss the involvement of infectious disorders in the pathogenesis of dementia and neurological disorders leading to dementia. We recap how our view of the infectious etiology of dementia has changed over the last 30 years in light of emerging evidence, and we present evidence in support of the implication of infection in dementia, notably Alzheimer's disease (AD). The bacteria and viruses thought to be responsible for neuroinflammation and neurological damage are reviewed. We then review the genetic basis for neuroinflammation and dementia, highlighting the genes that are currently the focus of investigation as potential targets for therapy. Next, we describe the antimicrobial hypothesis of dementia, notably the intriguing possibility that amyloid beta may itself possess antimicrobial properties. We further describe the clinical relevance of the gut-brain axis in dementia, the mechanisms by which infection can move from the intestine to the brain, and recent findings regarding dysbiosis patterns in patients with AD. We review the involvement of specific pathogens in neurological disorders, i.e. SARS-CoV-2, human immunodeficiency virus (HIV), herpes simplex virus type 1 (HSV1), and influenza. Finally, we look at the role of vaccination to prevent dementia. In conclusion, there is a large body of evidence supporting the involvement of various infectious pathogens in the pathogenesis of dementia, but large-scale studies with long-term follow-up are needed to elucidate the role that infection may play, especially before subclinical or clinical disease is present.

The development of peptide- and oligonucleotide-based drugs to prevent the formation of abnormal tau in tauopathies.

INTRODUCTION: Tauopathies represent clinicopathological entities with increased and abnormal glial and/or neuronal inclusions of tau, a microtubule-binding protein. Antisense oligonucleotides (ASOs) are a promising therapeutic approach for treating tauopathies as they can target tau mRNA to reduce total human tau expression or tau exon 10 expression and 4 R tau. Additionally, targeting the tau specifically with peptides may be a unique pharmacological approach, between small molecules and proteins. AREAS COVERED: The present review investigates the chemical basis of designing ASOs and peptides currently known to treat tauopathies. Among ASOs targeting tau expression, BIIB080 was the first to enter clinical trial development for treating mild Alzheimer's disease (AD). Furthermore, the therapeutic potential of peptide 021 (P021, Ac-DGGLAG-NH2) in tauopathies is discussed based on preclinical studies. EXPERT OPINION: ASOs are a promising therapeutic approach for tauopathies, particularly because ASOs may suppress the expression of harmful genes and are directly delivered to the brain, showing little systemic side effects. However, whether a generalized brain tau decrease will produce positive clinical effects remains unclear. A Phase II trial of BIIB080 is ongoing in mild AD. Neurotrophic and neurogenic peptide mimetic compounds have also shown potential as treatment options for AD and other tauopathies.

Associations of a biopsychosocial frailty phenotype with all-cause dementia, Alzheimer's disease, vascular dementia, and other dementias: the Italian PRoject on the Epidemiology of Alzheimer's disease (IPREA).

Frailty is a critical intermediate status of the aging process including physical, cognitive, and psychosocial domains/phenotypes. We operationalized a new biopsychosocial frailty construct, estimating its impact on the odds of all-cause dementia, Alzheimer's disease (AD), vascular dementia (VaD), and other dementias in 2838 older individuals from the population-based Italian PRoject on the Epidemiology of Alzheimer's disease (IPREA). Biopsychosocial frailty operationalization was based on the results of a previous comprehensive geriatric assessment and the presence of physical frailty. In this cross-sectional study, participants with biopsychosocial frailty showed an increased odds ratio of all-cause dementia [odds ratio (OR): 5.55, 95% confidence interval (CI): 3.72-8.28, p < 0.001], in particular for probable AD (OR: 3.62, 95% CI: 1.55-8.45, p < 0.001), probable VaD (OR: 10.05, 95% CI: 5.05-19.97, p < 0.001), and possible VaD (OR: 17.61, 95% CI: 6.42-48.32, p < 0.001). No statistically significant association was found between this biopsychosocial frailty phenotype and possible AD (OR: 2.84, 95% CI: 0.81-9.97, p = 0.09) or other dementias (OR: 1.77, 95% CI: 0.75-0.21, p = 0.19). In conclusion, in a large cohort of Italian older individuals, a biopsychosocial frailty model was associated to all-cause dementia, probable AD, and probable and possible VaD. In the next future, other large and prospective population-based studies evaluating the association between the biopsychosocial frailty phenotype and incident all-cause dementia, AD, and VaD are needed, addressing also potential bias and confounding sources.

Effect of Physical Activity Intervention on Gait Speed by Frailty Condition: A Randomized Clinical Trial.

OBJECTIVES: There is uncertainty about effects of physical activity on physical performance, such as gait speed, among community-dwelling older adults according to their physical frailty status. We determined whether a long-term, moderate-intensity physical activity program was associated with different responses on gait speed over 4 m and 400 m based on physical frailty status. DESIGN: Post hoc analysis from the Lifestyle Interventions and Independence for Elders (LIFE) (NCT01072500), a single-blind randomized clinical trial testing the effect of physical activity intervention compared with health education program. SETTING AND PARTICIPANTS: We analyzed data on 1623 community-dwelling older adults (78.9 ± 5.2 years) at risk for mobility disability. METHODS: Physical frailty was assessed at baseline using the Study of Osteoporotic Fractures frailty index. Gait speed over 4 m and 400 m was measured at baseline, and 6, 12, and 24 months. RESULTS: We estimated significantly better 400-m gait speed at 6, 12, and 24 months for nonfrail older adults in the physical activity group, but not for frail participants. Among frail participants, physical activity showed a potentially clinically meaningful benefit on 400-m gait speed at 6 months (0.055; 95% CI 0.016-0.094; P = .005), compared with the healthy educational intervention, only in those who, at baseline, were able to rise from a chair 5 times without using their arms. CONCLUSIONS AND IMPLICATIONS: A well-structured physical activity program produced a faster 400-m gait speed potentially able to prevent mobility disability among physically frail individuals with preserved muscle strength in lower limbs.

Biopsychosocial frailty and mild cognitive impairment subtypes: Findings from the Italian project on the epidemiology of Alzheimer's disease (IPREA).

INTRODUCTION: Frailty is a critical intermediate status of the aging process including physical, cognitive, and psychosocial phenotypes. We operationalized a biopsychosocial frailty construct, estimating its association with mild cognitive impairment (MCI) and its subtypes. METHODS: In 1980, older individuals from the population-based Italian PRoject on the Epidemiology of Alzheimer's disease (IPREA), we investigated cross-sectional associations among biopsychosocial frailty, MCI, and its subtypes. RESULTS: Participants with biopsychosocial frailty showed an increased odds ratio (OR) of MCI [OR: 4.36; 95% confidence interval (CI): 2.60-7.29; Fisher's exact p < 0.01], particularly for nonamnestic MCI single domain (naMCI-SD, OR:3.28; 95% CI: 1.35-7.97; Fisher's exact p = 0.02) and for nonamnestic MCI multiple domain (naMCI-MD, OR:6.92; 95% CI: 3.37-14.21; Fisher's exact p < 0.01). No statistically significant associations between amnestic MCI single or multiple domain and biopsychosocial frailty were observed. DISCUSSION: In a large, older Italian cohort, a biopsychosocial frailty phenotype was associated with MCI, in particular, could be associated with some of its subtypes, that is, naMCI-SD, and naMCI-MD.

Late-Onset Depression but not Early-Onset Depression may Increase the Risk of All-Cause Mortality in Older Age: 8-Year Follow-Up of the Salus in Apulia Study.

OBJECTIVES: Individuals with late-life depression (LLD) may have shorter survival, but there is a lack of findings in population-based settings about health-related outcomes of LLD and its subtypes: early-onset depression (EOD) and late-onset depression (LOD). We aimed to evaluate the risk of all-cause mortality of individuals with LLD and its subtypes in an older population-based cohort. Moreover, we investigated whether inflammatory, cognitive, genetic features and multimorbidity could modify the effect of this association. DESIGN: Longitudinal population-based study with 8-year follow-up. SETTING AND PARTICIPANTS: We analyzed data on a sample of 1479 participants, all aged >65 years, in the Salus in Apulia Study. METHODS: LLD was diagnosed through DSM-IV-TR criteria and LOD and EOD according to the age of onset. Multimorbidity status was defined as the copresence of 2 or more chronic diseases. RESULTS: The overall prevalence of LLD in this older sample from Southern Italy was 10.2%, subdivided into 3.4% EOD and 6.8% LOD. In multivariable Cox models adjusted for age, gender, education, global cognition, apolipoprotein E ε4 allele, physical frailty, interleukin-6, and multimorbidity, LLD showed a greater risk of all-cause mortality. LOD differed from EOD regarding gender, education, cognitive dysfunctions, and diabetes mellitus. There was a significantly increased risk of all-cause mortality for participants with LOD (hazard ratio:1.99; 95% CI 1.33-2.97) in the time of observation between enrollment date and death date (7.31 ± 2.17 months). CONCLUSIONS AND IMPLICATION: In older age, individuals with LOD but not with EOD had a significantly decreased survival, probably related to increased inflammation, multimorbidity, and cognitive impairments.

Effect of change of interleukin-6 over time on gait speed response: Results from the lifestyle interventions and independence for elders study.

Interleukin (IL)-6 is a well-accepted biomarker of chronic low-grade inflammation possibly conditioning the effect of physical activity (PA) intervention on physical performance in mobility-limited older adults. We evaluated PA intervention effects on 400 m gait speed by yearly change of IL-6 levels in a post-hoc analysis from Lifestyle Interventions and Independence for Elders (LIFE) Study, a multicenter single-blind randomized clinical trial on 1300 sedentary older adults (mean age:78.85 ± 5.23,65.85 % women) at risk for mobility disability. We compared the intervention effects on 400 m gait speed at 12 months follow-up, according to yearly IL-6 change categorized for 1 pg/ml increase or decrease, and subsequently for larger range of yearly variation. Among subjects with yearly IL-6 change between -1 and + 2 pg/ml, we observed a significant difference of gait speed in PA intervention group compared to healthy educational intervention group [0.041 m/s,95 % confidence interval (CI):0.008-0.074,p = 0.006;Cohen's d:0.26, 95 % CI:0.12-0.41). No effects were observed on 400 m gait speed for wider range of variation of plasma IL-6 levels. Limiting change of IL-6 levels under this specific hormetic window could be an important goal to achieve better benefit from PA intervention in terms of gait speed change and prevention of mobility disability.

Oral frailty indicators to target major adverse health-related outcomes in older age: a systematic review.

A well-preserved oral function is key to accomplishing essential daily tasks. However, in geriatric medicine and gerodontology, as age-related physiological decline disrupts several biological systems pathways, achieving this objective may pose a challenge. We aimed to make a systematic review of the existing literature on the relationships between poor oral health indicators contributing to the oral frailty phenotype, defined as an age-related gradual loss of oral function together with a decline in cognitive and physical functions, and a cluster of major adverse health-related outcomes in older age, including mortality, physical frailty, functional disability, quality of life, hospitalization, and falls. Six different electronic databases were consulted by two independent researchers, who found 68 eligible studies published from database inception to September 10, 2022. The risk of bias was evaluated using the National Institutes of Health Quality Assessment Toolkits for Observational Cohort and Cross-Sectional Studies. The study is registered on PROSPERO (CRD42021241075). Eleven different indicators of oral health were found to be related to adverse outcomes, which we grouped into four different categories: oral health status deterioration; decline in oral motor skills; chewing, swallowing, and saliva disorders; and oral pain. Oral health status deterioration, mostly number of teeth, was most frequently associated with all six adverse health-related outcomes, followed by chewing, swallowing, and saliva disorders associated with mortality, physical frailty, functional disability, hospitalization, and falls, then decline in oral motor skills associated with mortality, physical frailty, functional disability, hospitalization, and quality of life, and finally oral pain was associated only with physical frailty. The present findings could help to assess the contribution of each oral health indicator to the development of major adverse health-related outcomes in older age. These have important implications for prevention, given the potential reversibility of all these factors.

Does the imbalance in the apolipoprotein E isoforms underlie the pathophysiological process of sporadic Alzheimer's disease?

Human apolipoprotein E (apoE) is a 299-amino acid secreted glycoprotein binding cholesterol and phospholipids, and with three common isoforms (APOE ε2, APOE ε3, and APOE ε4). The exact mechanism by which APOE gene variants increase/decrease Alzheimer's disease (AD) risk is not fully understood, but APOE isoforms differently affect brain homeostasis and neuroinflammation, blood-brain barrier (BBB) permeability, glial function, synaptogenesis, oral/gut microbiota, neural networks, amyloid beta (Aß) deposition, and tau-mediated neurodegeneration. In this perspective, we propose a comprehensive interpretation of APOE-mediated effects within AD pathophysiology, describing some specific cellular, biochemical, and epigenetic mechanisms and updating the different APOE-targeting approaches being developed as potential AD therapies. Intracisternal adeno-associated viral-mediated delivery of APOE ε2 is being tested in AD APOE ε4/ε4 carriers, while APOE mimetics are being used in subjects with perioperative neurocognitive disorders. Other approaches including APOE ε4 antisense oligonucleotides, anti-APOE ε4 monoclonal antibodies, APOE ε4 structure correctors, and APOE-Aß interaction inhibitors produced positive results in transgenic AD mouse models.