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Alzheimer's Research & Therapy Jun 2024Posttraumatic stress disorder (PTSD) and traumatic brain injury (TBI) are associated with self-reported problems with cognition as well as risk for Alzheimer's disease...
BACKGROUND
Posttraumatic stress disorder (PTSD) and traumatic brain injury (TBI) are associated with self-reported problems with cognition as well as risk for Alzheimer's disease and related dementias (ADRD). Overlapping symptom profiles observed in cognitive disorders, psychiatric disorders, and environmental exposures (e.g., head injury) can complicate the detection of early signs of ADRD. The interplay between PTSD, head injury, subjective (self-reported) cognitive concerns and genetic risk for ADRD is also not well understood, particularly in diverse ancestry groups.
METHODS
Using data from the U.S. Department of Veterans Affairs (VA) Million Veteran Program (MVP), we examined the relationship between dementia risk factors (APOE ε4, PTSD, TBI) and subjective cognitive concerns (SCC) measured in individuals of European (n = 140,921), African (n = 15,788), and Hispanic (n = 8,064) ancestry (EA, AA, and HA, respectively). We then used data from the VA electronic medical record to perform a retrospective survival analysis evaluating PTSD, TBI, APOE ε4, and SCC and their associations with risk of conversion to ADRD in Veterans aged 65 and older.
RESULTS
PTSD symptoms (B = 0.50-0.52, p < 1E-250) and probable TBI (B = 0.05-0.19, p = 1.51E-07 - 0.002) were positively associated with SCC across all three ancestry groups. APOE ε4 was associated with greater SCC in EA Veterans aged 65 and older (B = 0.037, p = 1.88E-12). Results of Cox models indicated that PTSD symptoms (hazard ratio [HR] = 1.13-1.21), APOE ε4 (HR = 1.73-2.05) and SCC (HR = 1.18-1.37) were positively associated with risk for ADRD across all three ancestry groups. In the EA group, probable TBI also contributed to increased risk of ADRD (HR = 1.18).
CONCLUSIONS
The findings underscore the value of SCC as an indicator of ADRD risk in Veterans 65 and older when considered in conjunction with other influential genetic, clinical, and demographic risk factors.
Topics: Humans; Veterans; Stress Disorders, Post-Traumatic; Male; Female; Aged; Apolipoprotein E4; Dementia; Risk Factors; United States; Brain Injuries, Traumatic; Aged, 80 and over; Retrospective Studies
PubMed: 38951900
DOI: 10.1186/s13195-024-01512-w -
BMC Medicine Jul 2024Benzodiazepine use is common, particularly in older adults. Benzodiazepines have well-established acute adverse effects on cognition, but long-term effects on...
BACKGROUND
Benzodiazepine use is common, particularly in older adults. Benzodiazepines have well-established acute adverse effects on cognition, but long-term effects on neurodegeneration and dementia risk remain uncertain.
METHODS
We included 5443 cognitively healthy (MMSE ≥ 26) participants from the population-based Rotterdam Study (57.4% women, mean age 70.6 years). Benzodiazepine use from 1991 until baseline (2005-2008) was derived from pharmacy dispensing records, from which we determined drug type and cumulative dose. Benzodiazepine use was defined as prescription of anxiolytics (ATC-code: N05BA) or sedative-hypnotics (ATC-code: N05CD) between inception of pharmacy records and study baseline. Cumulative dose was calculated as the sum of the defined daily doses for all prescriptions. We determined the association with dementia risk until 2020 using Cox regression. Among 4836 participants with repeated brain MRI, we further determined the association of benzodiazepine use with changes in neuroimaging markers using linear mixed models.
RESULTS
Of all 5443 participants, 2697 (49.5%) had used benzodiazepines at any time in the 15 years preceding baseline, of whom 1263 (46.8%) used anxiolytics, 530 (19.7%) sedative-hypnotics, and 904 (33.5%) used both; 345 (12.8%) participants were still using at baseline assessment. During a mean follow-up of 11.2 years, 726 participants (13.3%) developed dementia. Overall, use of benzodiazepines was not associated with dementia risk compared to never use (HR [95% CI]: 1.06 [0.90-1.25]), irrespective of cumulative dose. Risk estimates were somewhat higher for any use of anxiolytics than for sedative-hypnotics (HR 1.17 [0.96-1.41] vs 0.92 [0.70-1.21]), with strongest associations for high cumulative dose of anxiolytics (HR [95% CI] 1.33 [1.04-1.71]). In imaging analyses, current use of benzodiazepine was associated cross-sectionally with lower brain volumes of the hippocampus, amygdala, and thalamus and longitudinally with accelerated volume loss of the hippocampus and to a lesser extent amygdala. However, imaging findings did not differ by type of benzodiazepines or cumulative dose.
CONCLUSIONS
In this population-based sample of cognitively healthy adults, overall use of benzodiazepines was not associated with increased dementia risk, but potential class-dependent adverse effects and associations with subclinical markers of neurodegeneration may warrant further investigation.
Topics: Humans; Female; Dementia; Male; Aged; Benzodiazepines; Middle Aged; Magnetic Resonance Imaging; Netherlands; Aged, 80 and over; Neuroimaging; Brain; Prospective Studies; Neurodegenerative Diseases; Hypnotics and Sedatives; Risk Factors
PubMed: 38951846
DOI: 10.1186/s12916-024-03437-5 -
Alzheimer's Research & Therapy Jun 2024The Amyloid precursor protein (APP) is a transmembrane glycoprotein from which amyloid-β (Aβ) peptides are generated after proteolytic cleavage. Aβ peptides are the... (Review)
Review
The Amyloid precursor protein (APP) is a transmembrane glycoprotein from which amyloid-β (Aβ) peptides are generated after proteolytic cleavage. Aβ peptides are the main constituent of amyloid plaques in Alzheimer's Disease (AD). The physiological functions of APP in the human adult brain are very diverse including intracellular signaling, synaptic and neuronal plasticity, and cell adhesion, among others. There is growing evidence that APP becomes dysfunctional in AD and that this dyshomeostasis may impact several APP functions beyond Aβ generation. The vast majority of current anti-amyloid approaches in AD have focused on reducing the synthesis of Aβ or increasing the clearance of brain Aβ aggregates following a paradigm in which Aβ plays a solo in APP dyshomeostasis. A wider view places APP at the center stage in which Aβ is an important, but not the only, factor involved in APP dyshomeostasis. Under this paradigm, APP dysfunction is universal in AD, but with some differences across different subtypes. Little is known about how to approach APP dysfunction therapeutically beyond anti-Aβ strategies. In this review, we will describe the role of APP dyshomeostasis in AD beyond Aβ and the potential therapeutic strategies targeting APP.
Topics: Humans; Alzheimer Disease; Amyloid beta-Protein Precursor; Animals; Amyloid beta-Peptides; Brain
PubMed: 38951839
DOI: 10.1186/s13195-024-01504-w -
Alzheimer's & Dementia : the Journal of... Jul 2024Vascular contributions to cognitive impairment and dementia (VCID) represent a major factor in cognitive decline in older adults. The present study examined the...
INTRODUCTION
Vascular contributions to cognitive impairment and dementia (VCID) represent a major factor in cognitive decline in older adults. The present study examined the relationship between cerebrovascular reactivity (CVR) measured by magnetic resonance imaging (MRI) and cognitive function in a multi-site study, using a predefined hypothesis.
METHODS
We conducted the study in a total of three analysis sites and 263 subjects. Each site performed an identical CVR MRI procedure using 5% carbon dioxide inhalation. A global cognitive measure of Montreal Cognitive Assessment (MoCA) and an executive function measure of item response theory (IRT) score were used as outcomes.
RESULTS
CVR and MoCA were positively associated, and this relationship was reproduced at all analysis sites. CVR was found to be positively associated with executive function.
DISCUSSION
The predefined hypothesis on the association between CVR and a global cognitive score was validated in three independent analysis sites, providing support for CVR as a biomarker in VCID.
HIGHLIGHTS
This study measured a novel functional index of small arteries referred to as cerebrovascular reactivity (CVR). CVR was positively associated with global cognition in older adults. This finding was observed in three independent cohorts at three sites. Our statistical analysis plan was predefined before beginning data collection.
PubMed: 38951718
DOI: 10.1002/alz.13888 -
Nature Cell Biology Jul 2024α-Synuclein (α-Syn) aggregation is closely associated with Parkinson's disease neuropathology. Physiologically, α-Syn promotes synaptic vesicle (SV) clustering and...
α-Synuclein (α-Syn) aggregation is closely associated with Parkinson's disease neuropathology. Physiologically, α-Syn promotes synaptic vesicle (SV) clustering and soluble N-ethylmaleimide-sensitive factor attachment protein receptor (SNARE) complex assembly. However, the underlying structural and molecular mechanisms are uncertain and it is not known whether this function affects the pathological aggregation of α-Syn. Here we show that the juxtamembrane region of vesicle-associated membrane protein 2 (VAMP2)-a component of the SNARE complex that resides on SVs-directly interacts with the carboxy-terminal region of α-Syn through charged residues to regulate α-Syn's function in clustering SVs and promoting SNARE complex assembly by inducing a multi-component condensed phase of SVs, α-Syn and other components. Moreover, VAMP2 binding protects α-Syn against forming aggregation-prone oligomers and fibrils in these condensates. Our results suggest a molecular mechanism that maintains α-Syn's function and prevents its pathological amyloid aggregation, the failure of which may lead to Parkinson's disease.
PubMed: 38951706
DOI: 10.1038/s41556-024-01456-1 -
Communications Chemistry Jun 2024The neuroprotective transcription factor nuclear receptor-related 1 (Nurr1) has shown great promise as a therapeutic target in Parkinson's and Alzheimer's disease as...
The neuroprotective transcription factor nuclear receptor-related 1 (Nurr1) has shown great promise as a therapeutic target in Parkinson's and Alzheimer's disease as well as multiple sclerosis but high-quality chemical tools for pharmacological target validation of Nurr1 are rare. We have employed the weak Nurr1 modulator amodiaquine (AQ) and AQ-derived fragments as templates to design a new Nurr1 agonist chemotype by scaffold hopping and fragment growing strategies. Systematic structural optimization of this scaffold yielded Nurr1 agonists with nanomolar potency and binding affinity. Comprehensive in vitro profiling revealed efficient cellular target engagement and compliance with the highest probe criteria. In human midbrain organoids bearing a Parkinson-driving LRRK2 mutation, a novel Nurr1 agonist rescued tyrosine hydroxylase expression highlighting the potential of the new Nurr1 modulator chemotype as lead and as a chemical tool for biological studies.
PubMed: 38951694
DOI: 10.1038/s42004-024-01224-0 -
Scientific Reports Jul 2024Overly restrictive clinical trial eligibility criteria can reduce generalizability, slow enrollment, and disproportionately exclude historically underrepresented...
Overly restrictive clinical trial eligibility criteria can reduce generalizability, slow enrollment, and disproportionately exclude historically underrepresented populations. The eligibility criteria for 196 Alzheimer's Disease and Related Dementias (AD/ADRD) trials funded by the National Institute on Aging were analyzed to identify common criteria and their potential to disproportionately exclude participants by race/ethnicity. The trials were categorized by type (48 Phase I/II pharmacological, 7 Phase III/IV pharmacological, 128 non-pharmacological, 7 diagnostic, and 6 neuropsychiatric) and target population (51 AD/ADRD, 58 Mild Cognitive Impairment, 25 at-risk, and 62 cognitively normal). Eligibility criteria were coded into the following categories: Medical, Neurologic, Psychiatric, and Procedural. A literature search was conducted to describe the prevalence of disparities for eligibility criteria for African Americans/Black (AA/B), Hispanic/Latino (H/L), American Indian/Alaska Native (AI/AN) and Native Hawaiian/Pacific Islander (NH/PI) populations. The trials had a median of 15 criteria. The most frequent criterion were age cutoffs (87% of trials), specified neurologic (65%), and psychiatric disorders (61%). Underrepresented groups could be disproportionately excluded by 16 eligibility categories; 42% of trials specified English-speakers only in their criteria. Most trials (82%) contain poorly operationalized criteria (i.e., criteria not well defined that can have multiple interpretations/means of implementation) and criteria that may reduce racial/ethnic enrollment diversity.
Topics: Humans; Alzheimer Disease; Clinical Trials as Topic; Cognitive Dysfunction; Dementia; Eligibility Determination; Ethnicity; National Institute on Aging (U.S.); Patient Selection; United States; Black or African American; Hispanic or Latino; American Indian or Alaska Native; Native Hawaiian or Other Pacific Islander
PubMed: 38951633
DOI: 10.1038/s41598-024-65767-x -
Inflammopharmacology Jun 2024Alzheimer's disease (AD) is a most prevalent neurologic disorder characterized by cognitive dysfunction, amyloid-β (Aβ) protein accumulation, and excessive... (Review)
Review
Alzheimer's disease (AD) is a most prevalent neurologic disorder characterized by cognitive dysfunction, amyloid-β (Aβ) protein accumulation, and excessive neuroinflammation. It affects various life tasks and reduces thinking, memory, capability, reasoning and orientation ability, decision, and language. The major parts responsible for these abnormalities are the cerebral cortex, amygdala, and hippocampus. Excessive inflammatory markers release, and microglial activation affect post-synaptic neurotransmission. Various mechanisms of AD pathogenesis have been explored, but still, there is a need to debate the role of NF-κB, Nrf2, inflammatory markers, CREB signaling, etc. In this review, we have briefly discussed the signaling mechanisms and function of the NF-ĸB signaling pathway, inflammatory mediators, microglia activation, and alteration of autophagy. NF-κB inhibition is a current strategy to counter neuroinflammation and neurodegeneration in the brain of individuals with AD. In clinical trials, numbers of NF-κB modulators are being examined. Recent reports revealed that molecular and cellular pathways initiate complex pathological competencies that cause AD. Moreover, this review will provide extensive knowledge of the cAMP response element binding protein (CREB) and how these nuclear proteins affect neuronal plasticity.
PubMed: 38951436
DOI: 10.1007/s10787-024-01502-2 -
Environmental Science and Pollution... Jun 2024Alzheimer's disease (AD) is a condition initiated by the assimilation of β-amyloid plaques (Aβ) and tau tangles, leading to neurodegeneration. It involves frequently... (Review)
Review
Alzheimer's disease (AD) is a condition initiated by the assimilation of β-amyloid plaques (Aβ) and tau tangles, leading to neurodegeneration. It involves frequently cognitive decline as well as memory impairment in patients. Efforts in therapeutic interventions are currently facing challenges in identifying targets within this scaffold that can significantly alter the clinical course for individuals with AD. Moreover, in AD, neurons release a protein called endostatin, which accumulates in Aβ plaques and enhances AD. This accumulation of Aβ in the triggers a cascade of events leading to synaptic dysfunction, neuroinflammation, and ultimately neuronal death. Environmental factors nowadays increase the risk of AD with prolonged exposure of heavy metals such as copper (Cu), lead (Pb), mercury (Hg), cadmium (Cd), and other pesticides. It has been observed that these factors can cause the aggregation of Aβ and tau which initiates the plaque formation and hence leads to enhanced pathogenesis of AD. This review summarizes the interlinking between heavy metals, environmental factors, pesticides, endostatin, and progression of AD has been deliberated with recent findings.
PubMed: 38951391
DOI: 10.1007/s11356-024-34113-z -
Inflammation Jun 2024This study investigates the role of autophagy regulation in modulating neuroinflammation and cognitive function in an Alzheimer's disease (AD) mouse model with chronic...
This study investigates the role of autophagy regulation in modulating neuroinflammation and cognitive function in an Alzheimer's disease (AD) mouse model with chronic cerebral hypoperfusion (CCH). Using the APP23/PS1 mice plus CCH model, we examined the impact of autophagy regulation on cognitive function, neuroinflammation, and autophagic activity. Our results demonstrate significant cognitive impairments in AD mice, exacerbated by CCH, but mitigated by treatment with the autophagy inhibitor 3-methyladenine (3-MA). Dysregulation of autophagy-related proteins, accentuated by CCH, underscores the intricate relationship between cerebral blood flow and autophagy dysfunction in AD pathology. While 3-MA restored autophagic balance, rapamycin (RAPA) treatment did not induce significant changes, suggesting alternative therapeutic approaches are necessary. Dysregulated microglial polarization and neuroinflammation in AD+CCH were linked to cognitive decline, with 3-MA attenuating neuroinflammation. Furthermore, alterations in M2 microglial polarization and the levels of inflammatory markers NLRP3 and MCP1 were observed, with 3-MA treatment exhibiting potential anti-inflammatory effects. Our findings shed light on the crosstalk between autophagy and neuroinflammation in AD+CCH and suggest targeting autophagy as a promising strategy for mitigating neuroinflammation and cognitive decline in AD+CCH.
PubMed: 38951357
DOI: 10.1007/s10753-024-02043-0