Background Abnormal tau hyperphosphorylation is a central feature of Alzheimer's disease (AD). Tau tubulin kinase 1 (TTBK1) is a key kinase involved in tau phosphorylation, but its upstream regulatory mechanisms remain poorly understood. Objective To identify circRNAs involved in the upstream regulation of TTBK1 and elucidate their molecular mechanisms and functional roles in tau hyperphosphorylation and cognitive impairment in AD. Methods Hippocampal circRNA and miRNA profiles were analyzed in 6-month-old 3×Tg-AD and wild-type mice. The candidate regulatory axis was investigated using qRT-PCR, Western blotting, dual-luciferase reporter and RNA immunoprecipitation assays, cell viability and apoptosis analyses, lentiviral intervention, immunofluorescence, silver staining, and behavioral tests. Results Circ_0004801 was upregulated and miR-7688-5p was downregulated in the hippocampus of 3×Tg-AD mice. Circ_0004801 knockdown enhanced HT22 cell viability, reduced apoptosis, decreased TTBK1 expression, and suppressed tau phosphorylation at Ser199, Ser202, and Ser396. MiR-7688-5p overexpression reduced TTBK1 expression and tau phosphorylation at Ser199 and Ser202, whereas TTBK1 overexpression reversed these effects. Reporter and RNA immunoprecipitation assays supported a sequence-dependent interaction between circ_0004801 and miR-7688-5p and their association with the Ago2 complex. In vivo, circ_0004801 knockdown reduced hippocampal p-tau (Ser199) and improved spatial learning, memory, and object recognition, whereas TTBK1 overexpression attenuated these benefits. Conclusions Circ_0004801 acts as an upstream regulator of TTBK1 by sequestering miR-7688-5p, thereby promoting tau hyperphosphorylation and cognitive impairment in AD. This axis may represent a potential target for tau-directed intervention.
Alzheimer's disease (AD) affects about fifty million people worldwide. Its main characteristics are the formation of amyloid deposits and of neurofibrillary tangles, and cognition loss. To date, no clear etiology for this disease has been identified. Metal ions have been shown to accumulate in amyloid deposits. Moreover, multiple infections have been shown to be risk factors for the development of AD and other dementia, with vaccines playing protective roles. I will here elaborate on the likelihood that amyloid-β is not dominantly a toxic molecule, but a protective protein fragment. A combination of chemical and biological exposures, with metals and infections playing key roles, would be essential factors in late-onset cases of AD. A new, translational mechanistic proposal is presented here, combining abundant experimental results and ideas from the fields of biochemistry, coordination chemistry and immunology.
Background Early detection of amnestic mild cognitive impairment (aMCI), a prodromal stage of Alzheimer's disease (AD), is critical for timely intervention. Declines in olfactory function seem to be a promising, non-invasive indicator of AD pathology, but screening research in underrepresented groups is limited. Objective To evaluate the diagnostic discrimination and exploratory utility of the NIH Toolbox Odor Identification Test (NIHTB-OIT) in distinguishing healthy aging from aMCI in older African American adults. Methods Participants included 93 healthy agers (81.7% female; M age = 73.85, SD age = 5.06) and 52 individuals with aMCI (69.2% female; M age = 74.37, SD age = 5.26). NIHTB-OIT scores were analyzed using two-way ANCOVAs, controlling for age and education. Receiver Operating Characteristic (ROC) analysis assessed diagnostic utility. The optimal cut-off score was determined using the Youden index, which maximizes combined sensitivity and specificity. APOE ε4 status was examined in a subset of participants (64.8%). Results Healthy agers scored significantly higher than participants with aMCI ( p = 0.019), and females performed significantly better than males ( p = 0.031). ROC analysis demonstrated modest but significant discrimination with an Area Under the Curve (AUC) of 0.626 ( p = 0.010). Using a cut-off score of 5.5 resulted in 76.3% specificity and 40.4% sensitivity. No significant differences were observed by APOE ε4 status or diagnosis-by-sex interactions. Conclusions The NIHTB-OIT demonstrated modest discrimination between aMCI and healthy aging in African American older adults. Its brief administration time and high specificity support its potential as a rapid, low-burden adjunctive measure in community-based settings.
The phase 3 EVOKE and EVOKE + trials of oral semaglutide in early Alzheimer's disease missed their primary endpoint and every cognitive or functional secondary endpoint. A recent article by Hölscher revisits extension-phase data and reports partial separation at later timepoints, attributing the failure to limited brain penetration. We argue that attrited extension cohorts bear limited inferential weight and that the biomarker substudy, read in full, complicates a clean disease-modification reading. EVOKE does not refute the cardiometabolic hypothesis but reframes the open questions: which pathways, which patients, and which disease stages are most likely to benefit.
BackgroundWhile amnestic mild cognitive impairment (aMCI) and Alzheimer's disease (AD) are primarily associated with cognitive impairments, motor dysfunction has also consistently been observed. Less is known, however, about the acquisition of new motor sequences along the AD continuum.ObjectiveThis study examined motor sequence learning in individuals with aMCI and AD dementia compared to cognitively normal individuals (CNI), and to what extent such learning is related to AD biomarkers.MethodsA total of 28 individuals with AD dementia, 33 with aMCI, and 52 CNI performed a computerized task that assessed general motor performance and motor sequence learning abilities. Participants also completed a neuropsychological test battery to assess their cognitive abilities. APOE genotyping was used to determine the presence of ɛ4 alleles, amyloid PET imaging to quantify amyloid deposition, and structural MRI scanning to obtain hippocampal volume.ResultsWhile individuals with aMCI or AD dementia generally performed slower and less consistent than CNI, motor sequence learning occurred regardless of cognitive status. The rate of initial learning was slower in individuals with aMCI or AD dementia than in CNI. No significant associations between motor learning and AD biomarkers were observed. A combination of motor and cognitive measures best predicted amyloid burden, whereas a model with cognitive measures only best predicted hippocampal volume and APOE allele count.ConclusionsOverall, individuals with aMCI and AD dementia showed relatively preserved motor sequence learning abilities, despite some decrements in the initial rate of learning. Combining measures of motor and cognitive functioning may enhance the prediction of amyloid burden. Future studies should use more complex sequential movements and further explore the value of integrating motor measures in AD/aMCI assessment and monitoring.
