Alzheimer's Research & Therapy最新文献

Background: Dementia poses a significant burden on healthcare systems. Early identification of individuals at risk for cognitive decline is crucial. The retina, an extension of the central nervous system, reflects neurodegenerative changes. Optical coherence tomography (OCT) is a non-invasive tool for assessing retinal health and has shown promise in predicting cognitive decline. However, prior studies produced mixed results.

Methods: This study investigated a large cohort (n = 490) of Asian individuals attending memory clinics. Participants underwent comprehensive neuropsychological testing annually for five years. Retinal thickness was measured by OCT at baseline. We assessed the association between baseline retinal thickness and subsequent cognitive decline.

Results: Participants with a significantly thinner macular ganglion cell-inner plexiform layer (GCIPL) at baseline (≤ 79 μm) had a 38% greater risk of cognitive decline compared to those who did not (≥ 88 μm; p = 0.037). In a multivariable model accounting for age, education, cerebrovascular disease status, hypertension, hyperlipidemia, diabetes and smoking, thinner GCIPL was associated with an increased risk of cognitive decline (hazard ratio = 1.14, 95% CI = 1.01-1.30, p = 0.035). Retinal nerve fiber layer (RNFL) thickness was not associated with cognitive decline.

Conclusions: This study suggests that OCT-derived macular GCIPL thickness may be a valuable biomarker for identifying individuals at risk of cognitive decline. Our findings highlight GCIPL as a potentially more sensitive marker compared to RNFL thickness for detecting early neurodegenerative changes.

Trial registration number and name of the trial registry: National Healthcare Group Domain-Specific Review Board (NHG DSRB) reference numbers DSRB Ref: 2018/01368. Name of the trial: Harmonisation project.

Objective: To evaluate the association between anti-diabetic agents and the risks of dementia in patients with type 2 diabetes (T2D).

Methods: Literature retrieval was conducted in PubMed, Embase, the Cochrane Central Register of Controlled Trials and Clinicaltrial.gov between January 1995 and October 2024. Observational studies and randomized controlled trials (RCTs) in patients with T2D, which intercompared anti-diabetic agents or compared them with placebo, and reported the incidence of dementia were included. Conventional and network meta-analyses of these studies were implemented. Results were exhibited as the odds ratio (OR) or risk ratio (RR) with 95% confidence interval (CI).

Results: A total of 41 observational studies (3,307,483 participants) and 23 RCTs (155,443 participants) were included. In the network meta-analysis of observational studies, compared with non-users, sodium glucose cotransporter-2 inhibitor (SGLT-2i) (OR = 0.56, 95%CI, 0.45 to 0.69), glucagon-like peptide-1 receptor agonist (GLP-1RA) (OR = 0.58, 95%CI, 0.46 to 0.73), thiazolidinedione (TZD) (OR = 0.68, 95%CI, 0.57 to 0.81) and metformin (OR = 0.89, 95%CI, 0.80 to 0.99) treatments were all associated with reduced risk of dementia in patients with T2D. The surface under the cumulative ranking curve (SUCRA) evaluation conferred a rank order as SGLT-2i > GLP-1RA > TZD > dipeptidyl peptidase-4 inhibitor (DPP-4i) > metformin > α-glucosidase inhibitor (AGI) > glucokinase activator (GKA) > sulfonylureas > glinides > insulin in terms of the cognitive benefits. Meanwhile, compared with non-users, SGLT-2i (OR = 0.43, 95%CI, 0.30 to 0.62), GLP-1RA (OR = 0.54, 95%CI, 0.30 to 0.96) and DPP-4i (OR = 0.73, 95%CI, 0.57 to 0.93) were associated with a reduced risk of Alzheimer's disease while a lower risk of vascular dementia was observed in patients receiving SGLT-2i (OR = 0.42, 95%CI, 0.22 to 0.80) and TZD (OR = 0.52, 95%CI, 0.36 to 0.75) treatment. In the network meta-analysis of RCTs, the risks of dementia were comparable among anti-diabetic agents and placebo.

Conclusion: Compared with non-users, SGLT-2i, GLP-1RA, TZD and metformin were associated with the reduced risk of dementia in patients with T2D. SGLT-2i, and GLP-1RA may serve as the optimal choice to improve the cognitive prognosis in patients with T2D.

Background: Cerebrospinal fluid (CSF) biomarkers of synaptic dysfunction, neuroinflammation, and glial response, complementing Alzheimer's disease (AD) core biomarkers, have improved the pathophysiological characterization of the disease. Here, we tested the hypothesis that the co-expression of multiple CSF biomarkers will help the identification of AD-like phenotypes when biomarker positivity thresholds are not met yet.

Methods: Two hundred and seventy cognitively unimpaired adults with family history (FH) of sporadic AD (mean age = 60.6 ± 4.85 years, 64.8% women) underwent lumbar puncture, magnetic resonance imaging (n = 266) and positron emission tomography imaging (n = 239) protocols, and clinical evaluations. CSF Aβ₄₂, Aβ₄₀, p-tau₁₈₁, p-tau_217, p-tau_231, NfL, neurogranin, sTREM2, YKL40, GFAP, S100, α-Synuclein, SYT1, and SNAP25 were measured. Participants were clustered based on CSF biomarker co-expression with an agglomerative algorithm. The predictive value of the classification against brain and cognitive outcomes was evaluated.

Results: Three clusters (C) were identified. Higher Aβ burden and CSF p-tau was the hallmark of C1. The other two clusters showed lower Aβ burden but higher expression of glial (C2) or synaptic markers (C3). Participants in C1 showed an AD-like clinical phenotype, comprising participants with the overall highest percentage of two parent FH and APOE-ε4 carriers, in addition to comprising more females compared to C2. C3 displayed better vascular health compared to C1. C2 were older and comprised a lower percentage of females compared to C3. C1 showed an AD-like gray matter reduction in medial temporal (notably hippocampus) and frontal regions that were not observed in Aβ_42/40 + compared with Aβ_42/40 - . Furthermore, Aβ_42/40 - participants in C1 showed GM reduction in inferior temporal areas compared with Aβ_42/40 + participants overall. C1 membership also predicted cognitive decline in executive function, but not memory, beyond Aβ + status, overall suggesting a better prognosis in Aβ_42/40 + participants without C1 membership. Additionally, C1 displayed a higher rate of conversion to Aβ + (25%) over time.

Conclusions: Our results suggest that examining multiple CSF biomarkers reflecting diverse pathological pathways may complement and/or outperform AD core biomarkers and thresholding approaches to identify individuals showing a clinical and cognitive AD-like phenotype, including higher conversion to Aβ + , GM reductions and cognitive decline. The clinical utility of this approach warrants further investigation and replication in other cohorts.

Background: Recent research has postulated that the activation of cGAS-STING-interferon signalling pathways could be implicated in the pathogenesis of Alzheimer's disease (AD). However, the precise types of interferons and related cytokines, both from the brain and periphery, responsible for cognitive impairment in patients with AD remain unclear.

Methods: A total of 131 participants (78 [59.5%] female and 53 [40.5%] male; mean [SD] age, 61.5 [7.6] years) with normal cognition and cognitive impairment from the China Aging and Neurodegenerative Initiative cohort were included. CSF and serum IFNα-2a, IFN-β, IFN-γ, TNF-α, IL-6, IL-10, MCP-1and CXCL-10 were tested. The correlation between these interferons and related cytokines with AD core biomarkers in the CSF and plasma, cognition performance, and brain MRI measures were analysed.

Results: We found that only CSF IFN-β levels were significantly elevated in Alzheimer's disease compared to normal cognition. Furthermore, CSF IFN-β levels were significantly associated with AD core biomarkers (CSF P-tau and Aβ42/Aβ40 ratio) and cognitive performance (MMSE and CDR score). Additionally, the CSF IFN-β levels were significantly correlated with the typical pattern of brain atrophy in AD (such as hippocampus, amygdala, and precuneus). In contrast, CSF IL-6 levels were significantly elevated in non-AD cognitively impaired patients compared to other groups. Moreover, CSF IL-6 levels were significantly associated with cognitive performance in non-AD individuals and correlated with the vascular cognitive impairment-related MRI markers (such as white matter hyperintensity).

Conclusion: Our findings demonstrate that distinct inflammatory molecules are associated with different cognitive disorders. Notably, CSF IFN-β levels are significantly linked to the pathology and cognitive performance of AD, identifying this interferon as a potential target for AD therapy.

Background: Alzheimer's disease neuropathologic change (ADNC) and Lewy pathology (LP) often coexist in cognitively impaired individuals. These pathologies' relative distribution and severity may modify these individuals' clinical presentation, cognitive profile, and prognosis. Therefore, we examined the contributions of LP and concomitant ADNC to disease survival and profiles of cognitive decline in preclinical and clinical stages in a large neuropathologically diagnosed group.

Methods: We evaluated 597 participants with LP and 491 participants with intermediate/high ADNC in the absence of LP from the National Alzheimer Coordinating Center (NACC) database. At baseline, 237 participants were cognitively normal (CN), 255 were diagnosed with mild cognitive impairment (MCI), and 596 with dementia. Cognition was assessed using three cognitive domain scores (i.e., Memory, Executive, and Language) from the NACC Uniform Dataset (UDS) neuropsychological test battery, MMSE, and Clinical Dementia Rating (CDR). Multivariate adaptive regression splines were used to evaluate associations between baseline cognitive scores and mean annual rate of change over two years. The likelihood of progression to MCI or dementia was assessed using Cox hazard models.

Results: Neocortical LP, independent of the clinical diagnosis, was associated with lower Executive and higher Language and Memory scores at baseline, whereas Braak V-VI neurofibrillary tangle pathology was associated with lower Memory and Language scores. Similarly, neocortical LP was associated with faster Executive decline, whereas Braak V-VI neurofibrillary tangle pathology was associated with faster Memory and Language decline. A clinical diagnosis of Lewy Body Dementia (i.e., a strong LP phenotype) was associated with the LP cognitive profile and shorter disease duration. Progression to incident MCI or dementia was primarily associated with the degree of tau pathology; neocortical LP or a diagnosis of Lewy Body Dementia only predicted progression when those with intermediate/high ADNC were excluded.

Conclusions: LP and ADNC differentially affected cross-sectional and longitudinal cognitive profiles in a large autopsy sample. Concomitant Braak V-VI neurofibrillary tangle pathology had a strong impact on clinical progression in those with LP, regardless of the initial stage. Thus, LB and ADNC co-pathology interact to affect cognitive domains that may be used to track Lewy Body disease longitudinally and as outcome measures in therapeutic trials.

Background: Accumulation of critically short telomeres (CST) is implicated in decreased tissular regenerative capacity and increased susceptibility to degenerative diseases such as Alzheimer's disease (AD). Telomere shortening has also been associated with age-related brain changes. However, it remains unclear whether CST accumulation is directly associated with AD markers or instead amplifies age-related effects, potentially increasing susceptibility of developing AD in cognitively healthy older adults.

Methods: This cross-sectional study used baseline data of 129 community-dwelling cognitively healthy older adults from the Age-Well trial (NCT02977819), aged 65 years and older enrolled between 2016 and 2018, in France. Using linear regressions, we analyzed the relationship between an innovative marker of telomere shortening, the percentage of CST (%CST), structural, functional and molecular neuroimaging outcomes, and multiple blood-based biomarkers related to AD pathophysiology. The effect of apolipoprotein E ε4 genotype (APOE4) was assessed on these relationships using interaction analysis.

Results: A higher %CST was associated with lower global kurtosis fractional anisotropy (β = -.230; P = .010), particularly in frontal and temporal regions. A higher %CST was also related to higher plasma levels of Neurofilament light chain (β = .195; P = .020) and a lower subiculum volume (β = -.206; P = .020), although these associations did not meet the threshold for multiple comparisons. %CST was not associated with AD-related neuroimaging markers, including the AD-sensitive gray matter pattern (β = -.060; P = .441), glucose metabolism pattern (β = -.099; P = .372), brain perfusion pattern (β = -.106; P = .694) or hippocampus volume (β = -.106; P = .194). In APOE4 carriers, higher %CST was associated with lower subiculum (β = -.423; P = 0.003), DG (β = -.410; P = 0.018) and CA1 volumes (β = -.373; P = 0.024), even though associations with DG and CA1 volumes did not survive multiple comparison.

Conclusions: Although an increase in %CST does not appear to be directly linked to the pathophysiology of AD in cognitively healthy older adults, it could heighten the susceptibility of APOE4 carriers to develop AD plausibly due to greater vulnerability to age-related effects. However, longitudinal studies would be necessary to determine whether %CST influences the development and progression of AD later in life.

Background: The advent of Alzheimer's disease-modifying drugs requires accurate biological diagnosis to identify candidates for these therapies. So far, the most promising single plasma biomarker is phosphorylated tau at threonine 217 (p-tau217). To understand its biological features, it is essential to know its longitudinal trajectory and factors influencing it in cognitively unimpaired subjects with no brain pathology.

Methods: We analyzed longitudinal plasma p-tau217 values (mean follow-up time = 768.3 days) in a cohort of 209 healthy volunteers. We have studied factors associated with plasma p-tau217 changes by using different linear mixed-effects models.

Results: In amyloid-negative cognitively healthy subjects (n = 151) carriers of ApoE ε4 allele had significantly higher p-tau217 values than non-carriers (0.85 pg/mL; p-value < 0.001) and also a greater rate of change (0.01 pg/mL/year; p-value < 0.001). In the overall sample, including subjects with amyloid and tau pathology we have seen that amyloid positive subjects had higher predicted baseline plasma p-tau217 values than amyloid negative subjects (0.16 pg/mL; p-value < 0.001) and a greater rate of change (0.00004 pg/mL/day; p-value < 0.001). Subjects considered tau positive also showed a greater rate of change of p-tau217 with respect to tau negative (0.00005 pg/mL/day; p-value < 0.001). A + T + N + participants showed a higher baseline p-tau217 levels than A-T-N- subjects (0.2 pg/mL; p-value < 0.001) and also a greater rate of change (0.00006 pg/mL/day; p-value = 0.002). ApoE ε4 carriers had a greater rate of change than non-carriers (0.00003 pg/mL/day; p-value = 0.03).

Conclusion: In amyloid-negative cognitively unimpaired subjects, ApoE4 status influenced both baseline levels and rate of change of plasma p-tau217. Other factors such as age, sex or glomerular filtration rate have not shown significant influence on plasma p-tau217 levels in this group.

Objective: Report a case of an apolipoprotein E (APOE)ε2 carrier receiving lecanemab who developed late onset intracerebral hemorrhage (ICH) following amyloid-related imaging abnormalities-hemorrhage (ARIA-H).

Method: We detail the history and neuroimaging findings of a 73-year-old male with Alzheimer's disease (APOEε2/ε3 status) who developed ICH after mild ARIA-H and suffering a fall.

Results: The patient developed mild ARIA-H after his 13th infusion that was proceeded by left temporo-occipital hemorrhage following his 14th infusion.

Discussion: Although APOE ε2 is known to be protective against Alzheimer's disease, it has also been shown to increase risk for hemorrhage with cerebral amyloid angiopathy. This case serves as an opportunity to examine the complex role that APOE ε2 plays in both protection against Alzheimer's disease and contribution to increased hemorrhagic risk with lecanemab.

Background: Although there is growing evidence of the association between gender and early diagnosis of preclinical Alzheimer's disease, little attention has been given to the enrolment ratio of men and women in clinical trials and data reporting.

Methods: This study aims to analyze gender differences in sociodemographic factors associated with the willingness to participate in clinical trials and undergo specific procedures in the context of an Alzheimer's disease prevention research cohort. 2544 cognitively unimpaired participants from the ALFA parent cohort (age 45-75 years) of the Barcelonaβeta Brain Research Center were contacted through a structured phone call to determine their willingness to participate in Alzheimer's disease clinical trials and undergo trial-related procedures (magnetic resonance imaging, lumbar puncture, positron emission tomography, and cognitive assessment). Sociodemographic data on education, occupational attainment, civil and caregiver status were gathered. Stepwise logistic regression models were performed in order to study the interaction between gender and sociodemographic factors in the willingness to participate in clinical trials and to undergo clinical trial-related procedures.

Results: 1,606 out of the 2,544 participants were women (63.1%). Women were significantly younger and had lower educational attainment compared with men. In addition, women were more likely to be caregivers, single and unemployed. Women showed a significantly lower willingness than men to participate in a clinical trial (p = 0.003) and to undergo a lumbar puncture (p < 0.001). Single women were less willing to participate in clinical trials than single men (p = 0.041). Regarding clinical trial-related procedures, women with higher years of education were significantly less willing to undergo a lumbar puncture (p = 0.031).

Conclusion: We found gender differences regarding the sociodemographic factors that predict the willingness to participate in clinical trials and to undergo clinical trial-related procedures. Our results highlight the urgent need to design recruitment strategies accounting for gender-related factors, particularly those related to marital status and education.