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European Neuropsychopharmacology : the... Nov 2023Alzheimer's Disease (AD) is a currently incurable but increasingly prevalent fatal and progressive neurodegenerative disease, demanding consideration of therapeutically... (Review)
Review
Alzheimer's Disease (AD) is a currently incurable but increasingly prevalent fatal and progressive neurodegenerative disease, demanding consideration of therapeutically relevant natural products and their synthetic analogues. This paper reviews evidence for effectiveness of natural and synthetic psychedelics in the treatment of AD causes and symptoms. The plastogenic effects of serotonergic psychedelics illustrate that they have efficacy for addressing multiple facets of AD pathology. We review findings illustrating neuroplasticity mechanisms of classic (serotonergic) and non-classic psychedelics that indicate their potential as treatments for AD and related dementias. Classic psychedelics modulate glutamatergic neurotransmission and stimulate synaptic and network remodeling that facilitates synaptic, structural and behavioral plasticity. Up-regulation of neurotrophic factors enable psychedelics to promote neuronal survival and glutamate-driven neuroplasticity. Muscimol modulation of GABAR reduces Aβ-induced neurotoxicity and psychedelic Sig-1R agonists provide protective roles in Aβ toxicity. Classic psychedelics also activate mTOR intracellular effector pathways in brain regions that show atrophy in AD. The potential of psychedelics to treat AD involves their ability to induce structural and functional neural plasticity in brain circuits and slow or reverse brain atrophy. Psychedelics stimulate neurotrophic pathways, increase neurogenesis and produce long-lasting neural changes through rewiring pathological neurocircuitry. Psychedelic effects on 5-HT receptor target genes and induction of synaptic, structural, and functional changes in neurons and networks enable them to promote and enhance brain functional connectivity and address diverse mechanisms underlying degenerative neurological disorders. These findings provide a rationale for immediate investigation of psychedelics as treatments for AD patients.
Topics: Humans; Alzheimer Disease; Hallucinogens; Neurodegenerative Diseases; Brain; Atrophy
PubMed: 37451163
DOI: 10.1016/j.euroneuro.2023.07.003 -
Alzheimer's Research & Therapy Dec 2023Modifiable lifestyle behaviors account for a large proportion of dementia risk. However, the combined contributions of multidomain lifestyle patterns to cognitive aging...
BACKGROUND
Modifiable lifestyle behaviors account for a large proportion of dementia risk. However, the combined contributions of multidomain lifestyle patterns to cognitive aging are poorly understood, as most studies have examined individual lifestyle behaviors in isolation and without neuropathological characterization. This study examined data-driven patterns of lifestyle behaviors across multiple domains among older adults and tested their associations with disease-specific neuropathological burden and cognitive decline.
METHODS
Participants included 2059 older adults enrolled in the longitudinal Memory and Aging Project (MAP) at the Rush Alzheimer's Disease Center; none of whom had dementia at baseline (73% no cognitive impairment (NCI), 27% mild cognitive impairment [MCI]). All participants completed cognitive testing annually. Lifestyle factors were measured during at least one visit and included (1) actigraphy-measured physical activity, as well as self-reported (2) sleep quality, (3) life space, (4) cognitive activities, (5) social activities, and (6) social network. A subset of participants (n = 791) had autopsy data for which burden of Alzheimer's disease (AD), cerebrovascular disease (CVD), Lewy body disease, and hippocampal sclerosis/TDP-43 was measured. Latent profile analysis across all 2059 participants identified distinct subgroups (i.e., classes) of lifestyle patterns. Linear mixed-effects models examined relationships between lifestyle classes and global cognitive trajectories, with and without covarying for all neuropathologies. Classes were also compared on rates of incident MCI/dementia.
RESULTS
Five classes were identified: Class 1 (lowest lifestyle engagement), Class 2 (high physical activity), Class 3 (low to average lifestyle engagement), Class 4 (high average lifestyle engagement), and Class 5 (large social network). Classes 4 and 5 had the lowest AD burden, and Class 2 had the lowest CVD burden. Classes 2-5 had significantly less steep global cognitive decline compared to Class 1, with comparable effect sizes before and after covarying for neuropathological burden. Classes 4 and 5 exhibited the lowest rates of incident MCI/dementia.
CONCLUSIONS
Lifestyle behavior patterns among older adults account for differential rates of cognitive decline and clinical progression. Those with at least average engagement across all lifestyle domains exhibit greater cognitive stability after adjustment for neuropathology, highlighting the importance of engagement in multiple healthy lifestyle behaviors for later life cognitive health.
Topics: Humans; Aged; Alzheimer Disease; Cognitive Dysfunction; Life Style; Cerebrovascular Disorders; Cognition
PubMed: 38111051
DOI: 10.1186/s13195-023-01365-9 -
Frontiers in Endocrinology 2023Alzheimer's disease (AD) is a neurodegenerative disorder that is the major cause of dementia in the aged population. Recent researches indicate that patients with AD... (Review)
Review
BACKGROUND
Alzheimer's disease (AD) is a neurodegenerative disorder that is the major cause of dementia in the aged population. Recent researches indicate that patients with AD have a significantly increased fracture risk, but the pathological mechanisms are still unclear.
OBJECTIVE
We systematically reviewed studies regarding bone fracture risk in AD to uncover links between the pathologies of osteoporosis and AD.
METHODS
We searched the literature using the databases of PubMed, Web of Science, Embase and Cochrane Library. Studies were included if they evaluated bone fracture risk in AD patients and if they explored the pathogenesis and prevention of bone fractures in these patients.
RESULTS
AD patients had a significantly higher risk of bone fractures than age-matched controls. Multiple factors contributed to the increased risk of bone fractures in AD patients, including the direct effects of amyloid pathology on bone cells, abnormal brain-bone interconnection, Wnt/β-catenin signalling deficits, reduced activity, high risk of falls and frailty, and chronic immune activity. Exercise, prevention of falls and fortified nutrition were beneficial for reducing the fracture risk in AD patients. However, the efficacy of anti-osteoporotic agents in preventing bone fractures should be further evaluated in AD patients as corresponding clinical studies are very scarce.
CONCLUSION
Alzheimer's disease patients have increased bone fracture risk and decreased bone mineral density owing to multiple factors. Assessment of anti-osteoporotic agents' efficacy in preventing bone fractures of AD patients is urgently needed.
Topics: Humans; Aged; Alzheimer Disease; Fractures, Bone; Osteoporosis; Amyloidogenic Proteins; Brain
PubMed: 37635980
DOI: 10.3389/fendo.2023.1190762 -
BMC Geriatrics Dec 2023Evidence-based interventions to protect against cognitive decline among older adults at risk for Alzheimer's disease and related dementias (ADRD) are urgently needed.... (Comparative Study)
Comparative Study Randomized Controlled Trial
Memory support training and lifestyle modifications to promote healthy aging in persons at risk for Alzheimer's disease: a digital application supported intervention (Brain Boosters).
BACKGROUND
Evidence-based interventions to protect against cognitive decline among older adults at risk for Alzheimer's disease and related dementias (ADRD) are urgently needed. Rehabilitation approaches to support memory and behavioral/lifestyle interventions are recognized as promising strategies for preserving or improving cognitive health, although few previous interventions have combined both approaches. This paper describes the protocol of the Brain Boosters intervention, which synergistically combines training in compensatory and healthy lifestyle behaviors and supports implementation and tracking of new behaviors with a digital application.
METHODS
The study utilizes a single-site, single-blinded, randomized controlled design to compare a structured lifestyle and compensatory aid intervention to an education-only self-guided intervention. We plan to enroll 225 community-dwelling adults (25% from underrepresented groups) aged 65 + who endorse subjective cognitive decline (SCD) and low baseline levels of healthy lifestyle behaviors. Both interventions will be administered in group format, consisting of 15 two-hour classes that occur weekly for ten weeks and taper to bi-monthly and monthly, for an intervention duration of 6 months. Participants in both interventions will receive education about a variety of memory support strategies and healthy lifestyle behaviors, focusing on physical and cognitive activity and stress management. The structured intervention will also receive support in adopting new behaviors and tracking set goals aided by the Electronic Memory and Management Aid (EMMA) digital application. Primary outcomes include global cognition (composite of memory, attention, and executive function tests) and everyday function (Everyday Cognition Questionnaire). Data will be collected at baseline and outcome visits, at approximately 6, 12, and 18 months. Qualitative interviews, self-report surveys (e.g., indicators of self-determination, health literacy) and EMMA data metrics will also be used to identify what components of the intervention are most effective and for whom they work.
DISCUSSION
Successful project completion will provide valuable information about how individuals with SCD respond to a compensation and preventative lifestyle intervention assisted by a digital application, including an understanding of factors that may impact outcomes, treatment uptake, and adherence. The work will also inform development, scaling, and personalization of future interventions that can delay disability in individuals at risk for ADRD.
TRIAL REGISTRATION
ClinicalTrials.gov. (NCT05027789, posted 8/30/2021).
Topics: Aged; Humans; Alzheimer Disease; Brain; Cognition; Cognitive Dysfunction; Healthy Aging; Life Style; Single-Blind Method
PubMed: 38129775
DOI: 10.1186/s12877-023-04574-x -
International Journal of Molecular... Sep 2023This review is devoted to the problems of the common features linking metabolic disorders and type 2 diabetes with the development of Alzheimer's disease. The... (Review)
Review
This review is devoted to the problems of the common features linking metabolic disorders and type 2 diabetes with the development of Alzheimer's disease. The pathogenesis of Alzheimer's disease closely intersects with the mechanisms of type 2 diabetes development, and an important risk factor for both pathologies is aging. Common pathological mechanisms include both factors in the development of oxidative stress, neuroinflammation, insulin resistance, and amyloidosis, as well as impaired mitochondrial dysfunctions and increasing cell death. The currently available drugs for the treatment of type 2 diabetes and Alzheimer's disease have limited therapeutic efficacy. It is important to note that drugs used to treat Alzheimer's disease, in particular acetylcholinesterase inhibitors, show a positive therapeutic potential in the treatment of type 2 diabetes, while drugs used in the treatment of type 2 diabetes can also prevent a number of pathologies characteristic for Alzheimer's disease. A promising direction in the search for a strategy for the treatment of type 2 diabetes and Alzheimer's disease may be the creation of complex multi-target drugs that have neuroprotective potential and affect specific common targets for type 2 diabetes and Alzheimer's disease.
Topics: Humans; Alzheimer Disease; Diabetes Mellitus, Type 2; Acetylcholinesterase; Mitochondria; Oxidative Stress
PubMed: 37833898
DOI: 10.3390/ijms241914450 -
Ageing Research Reviews Jul 2024Alzheimer's disease (AD) is the most common type of cognitive impairment. AD is closely related to orthopedic diseases, such as osteoporosis and osteoarthritis, in terms... (Review)
Review
Alzheimer's disease (AD) is the most common type of cognitive impairment. AD is closely related to orthopedic diseases, such as osteoporosis and osteoarthritis, in terms of epidemiology and pathogenesis. Brain and bone tissues can regulate each other in different manners through bone-brain axis. This article reviews the research progress of the relationship between AD and orthopedic diseases, bone-brain axis mechanisms of AD, and AD therapy by targeting bone-brain axis, in order to deepen the understanding of bone-brain communication, promote early diagnosis and explore new therapy for AD patients.
Topics: Alzheimer Disease; Humans; Brain; Bone and Bones; Animals; Osteoporosis; Osteoarthritis
PubMed: 38759893
DOI: 10.1016/j.arr.2024.102341 -
Zhejiang Da Xue Xue Bao. Yi Xue Ban =... Aug 2023Alzheimer's disease (AD) is a multifactorial and heterogenic disorder. MiRNA is a class of non-coding RNAs with 19-22 nucleotides in length that can regulate the... (Review)
Review
Alzheimer's disease (AD) is a multifactorial and heterogenic disorder. MiRNA is a class of non-coding RNAs with 19-22 nucleotides in length that can regulate the expression of target genes in the post-transcriptional level. It has been found that the miRNAome in AD patients is significantly altered in brain tissues, cerebrospinal fluid and blood circulation, as compared to healthy subjects. Experimental studies have suggested that expression changes in miRNA could drive AD onset and development via different mechanisms. Therefore, targeting miRNA expression to regulate the key genes involved in AD progression is anticipated to be a promising approach for AD prevention and treatment. Rodent AD models have demonstrated that targeting miRNAs could block biogenesis and toxicity of amyloid β, inhibit the production and hyper-phosphorylation of τ protein, prevent neuronal apoptosis and promote neurogenesis, maintain neural synaptic and calcium homeostasis, as well as mitigate neuroinflammation mediated by microglia. In addition, animal and human studies support the view that miRNAs are critical players contributing to the beneficial effects of cell therapy and lifestyle intervention to AD. This article reviews the most recent advances in the roles, mechanisms and applications of targeting miRNA in AD prevention and treatment based on rodent AD models and human intervention studies. The potential opportunities and challenges in clinical application of targeting miRNA for AD patients are also discussed.
Topics: Animals; Humans; MicroRNAs; Alzheimer Disease; Amyloid beta-Peptides; Apoptosis; Microglia
PubMed: 37643982
DOI: 10.3724/zdxbyxb-2023-0324 -
BMC Psychiatry Oct 2023Alzheimer's disease (AD) is a progressive neurological disorder and the most common cause of dementia. The clinical continuum of AD ranges from asymptomatic disease to...
BACKGROUND
Alzheimer's disease (AD) is a progressive neurological disorder and the most common cause of dementia. The clinical continuum of AD ranges from asymptomatic disease to mild cognitive impairment (MCI), followed by AD dementia, categorized as mild, moderate, or severe. Almost one-third of patients suspected of having MCI or mild AD dementia are referred to specialists including psychiatrists. We sought to better understand the role that psychiatrists play in the diagnosis, treatment, and management of patients with all-cause MCI or mild AD dementia.
METHODS
We conducted an anonymous, online survey among physicians in the United States between February 4, 2021, and March 1, 2021. We surveyed psychiatrists, primary care physicians (PCPs), geriatricians, and neurologists who treat patients with all-cause MCI or mild AD dementia.
RESULTS
A total of 301 physicians participated in the survey, 50 of whom were psychiatrists. Of their patients with all-cause MCI or mild AD dementia, psychiatrists reported personally diagnosing two-thirds (67%). Psychiatrists used various methods to diagnose MCI or mild AD dementia including mental status testing (94%), review of patient medical history (86%), and neurological exams (61%). Upon diagnosis, psychiatrists reported most commonly discussing treatments (86%), management strategies (80%), disease progression (72%), and etiology of MCI or mild AD dementia (72%) with their patients. Most psychiatrists surveyed (82%) reported receiving advanced formal training in MCI and AD dementia care, primarily via residency training (38%), continuing medical education (22%) or fellowship (18%). Additionally, almost all psychiatrists (92%) reported receiving referrals for ongoing management of patients with MCI or mild AD dementia, primarily from PCPs or neurologists. However, only 46% of psychiatrists viewed themselves as the coordinator of care for their patients with MCI or mild AD dementia.
CONCLUSIONS
Many psychiatrists indicated that they were well-informed about MCI and AD dementia and have a strong interest in providing care for these patients. They can provide timely and accurate diagnosis of clinical MCI and mild AD dementia and develop optimal treatment plans for patients. Although many psychiatrists consider other physicians to be the care coordinators for patients with MCI and mild AD dementia, psychiatrists can play a key role in diagnosing and managing patients with MCI and mild AD dementia.
Topics: Humans; Alzheimer Disease; Cross-Sectional Studies; Dementia; Cognitive Dysfunction; Psychiatry; Disease Progression
PubMed: 37794326
DOI: 10.1186/s12888-023-05129-5 -
EBioMedicine Mar 2024Psychiatric disorders have been associated with higher risk for future dementia. Understanding how pre-dementia psychiatric disorders (PDPD) relate to established...
BACKGROUND
Psychiatric disorders have been associated with higher risk for future dementia. Understanding how pre-dementia psychiatric disorders (PDPD) relate to established dementia genetic risks has implications for dementia prevention.
METHODS
In this retrospective cohort study, we investigated the relationships between polygenic risk scores for Alzheimer's disease (AD PRS), PDPD, alcohol use disorder (AUD), and subsequent dementia in the UK Biobank (UKB) and tested whether the relationships are consistent with different causal models.
FINDINGS
Among 502,408 participants, 9352 had dementia. As expected, AD PRS was associated with greater risk for dementia (odds ratio (OR) 1.62, 95% confidence interval (CI), 1.59-1.65). A total of 94,237 participants had PDPD, of whom 2.6% (n = 2519) developed subsequent dementia, compared to 1.7% (n = 6833) of 407,871 participants without PDPD. Accordingly, PDPD were associated with 73% greater risk of incident dementia (OR 1.73, 1.65-1.83). Among dementia subtypes, the risk increase was 1.5-fold for AD (n = 3365) (OR 1.46, 1.34-1.59) and 2-fold for vascular dementia (VaD, n = 1823) (OR 2.08, 1.87-2.32). Our data indicated that PDPD were neither a dementia prodrome nor a mediator for AD PRS. Shared factors for both PDPD and dementia likely substantially account for the observed association, while a causal role of PDPD in dementia could not be excluded. AUD could be one of the shared causes for PDPD and dementia.
INTERPRETATION
Psychiatric diagnoses were associated with subsequent dementia in UKB participants, and the association is orthogonal to established dementia genetic risks. Investigating shared causes for psychiatric disorders and dementia would shed light on this dementia pathway.
FUNDING
US NIH (K08AG054727).
Topics: Humans; UK Biobank; Biological Specimen Banks; Retrospective Studies; Mental Disorders; Alzheimer Disease; Risk Factors; Alcoholism
PubMed: 38320878
DOI: 10.1016/j.ebiom.2024.104978 -
Journal of Cerebral Blood Flow and... Oct 2023Aging-related cognitive decline can be accelerated by a combination of genetic factors, cardiovascular and cerebrovascular dysfunction, and amyloid-β burden. Whereas...
Aging-related cognitive decline can be accelerated by a combination of genetic factors, cardiovascular and cerebrovascular dysfunction, and amyloid-β burden. Whereas cerebral blood flow (CBF) has been studied as a potential early biomarker of cognitive decline, its normal variability in healthy elderly is less known. In this study, we investigated the contribution of genetic, vascular, and amyloid-β components of CBF in a cognitively unimpaired (CU) population of monozygotic older twins. We included 134 participants who underwent arterial spin labeling (ASL) MRI and [F]flutemetamol amyloid-PET imaging at baseline and after a four-year follow-up. Generalized estimating equations were used to investigate the associations of amyloid burden and white matter hyperintensities with CBF. We showed that, in CU individuals, CBF: 1) has a genetic component, as within-pair similarities in CBF values were moderate and significant (ICC > 0.40); 2) is negatively associated with cerebrovascular damage; and 3) is positively associated with the interaction between cardiovascular risk scores and early amyloid-β burden, which may reflect a vascular compensatory response of CBF to early amyloid-β accumulation. These findings encourage future studies to account for multiple interactions with CBF in disease trajectory analyses.
Topics: Humans; Aged; Cerebrovascular Circulation; Amyloid beta-Peptides; Magnetic Resonance Imaging; Amyloid; Positron-Emission Tomography; Cognitive Dysfunction; Alzheimer Disease
PubMed: 37231665
DOI: 10.1177/0271678X231178993