Alzheimer's Research & Therapy最新文献

Background: Cognitive decline with age has heterogeneous, which might be related to the accumulation of protective factors called cognitive reserve, especially intellectual engagement factors over the life course. However, how lifetime intellectual cognitive reserve (LICR) protects cognitive function in the elderly remains unclear. We aimed to examine the relationship between LICR and cognition and the mild cognitive impairment (MCI) risk, as well as the neural mechanism of LICR on cognition.

Methods: A total of 5126 participants completed extensive neuropsychological tests, with LICR indicator encompassing early education, midlife occupational complexity, and mental leisure activities after retirement. Confirmatory factor analysis was performed to derive LICR score and cognitive function scores, then the hierarchical regression analysis was used to explore the relationship between LICR and cognitive functions and the risk of MCI. We further explored the macro- and micro-structural preservation underly LICR in 1117 participants. Multiple regressions and tract-based spatial statistics were used to explore the relationship between LICR and gray matter volume and white matter microstructure (FA value). Finally, using the mediation model to explore the relationship of "LICR-brain-cognition".

Result: The new LICR index, which was more protective than its single indexes, could protect widespread cognitive functions and was associated with a reduction in MCI risk (Odds Ratio, 0.52; 95% CI, 0.47-0.57). For the structure basis of LICR, the higher LICR score was associated with the greater gray matter volume in right fusiform gyrus (t = 4.62, FDR corrected, p < 0.05) and left orbital superior frontal gyrus (t = 4.56, FDR corrected, p < 0.05), and the higher FA values in the frontotemporal related white matter fiber tracts. Furthermore, the right fusiform gyrus partially mediated the relationship between LICR and executive processing ability (β = 0.01, p = 0.02) and general cognitive ability (β = 0.01, p = 0.03).

Conclusions: The new comprehensive cognitive reserve index could promote the temporal macro-structural preservation and thus contribute to maintain better cognitive function. These findings highlight the importance of intellectual CR accumulation over the life course in successful cognitive aging and MCI prevention, thereby contributing to improve the quality of life in the elderly.

Background: Phosphorylated tau (p-tau) and amyloid beta (Aβ) in human plasma may provide an affordable and minimally invasive method to evaluate Alzheimer's disease (AD) pathophysiology. The medial temporal lobe (MTL) is susceptible to changes in structural integrity that are indicative of the disease progression. Among healthy adults, higher dynamic network flexibility within the MTL was shown to mediate better generalization of prior learning, a measure which has been demonstrated to predict cognitive decline and neural changes in preclinical AD longitudinally. Recent developments in cognitive, neural, and blood-based biomarkers of AD risk that may correspond with MTL changes. However, there is no comprehensive study on how these generalization biomarkers, long-term memory, MTL dynamic network flexibility, and plasma biomarkers are interrelated. This study investigated (1) the relationship between long-term memory, generalization performance, and MTL dynamic network flexibility and (2) how plasma p-tau231, p-tau181, and Aβ42/Aβ40 influence generalization, long-term memory, and MTL dynamics in cognitively unimpaired older African Americans.

Methods: 148 participants (Mean_age: 70.88,SD_age: 6.05) were drawn from the ongoing longitudinal study, Pathways to Healthy Aging in African Americans conducted at Rutgers University-Newark. Cognition was evaluated with the Rutgers Acquired Equivalence Task (generalization task) and Rey Auditory Learning Test (RAVLT) delayed recall. MTL dynamic network connectivity was measured from functional Magnetic Resonance Imaging data. Plasma p-tau231, p-tau181, and Aβ42/Aβ40 were measured from blood samples.

Results: There was a significant positive correlation between generalization performance and MTL Dynamic Network Flexibility (t = 3.372, β = 0.280, p < 0.001). There were significant negative correlations between generalization performance and plasma p-tau231 (t = -3.324, β = -0.265, p = 0.001) and p-tau181 (t = -2.408, β = -0.192, p = 0.017). A significant negative correlation was found between plasma p-tau231 and MTL Dynamic Network Flexibility (t = -2.825, β = -0.232, p = 0.005).

Conclusions: Increased levels of p-tau231 are associated with impaired generalization abilities and reduced dynamic network flexibility within the MTL. Plasma p-tau231 may serve as a potential biomarker for assessing cognitive decline and neural changes in cognitively unimpaired older African Americans.

Background: The Finnish Geriatric Intervention Study to Prevent Cognitive Impairment and Disability (FINGER) multimodal lifestyle intervention yielded cognitive and other health benefits in older adults at risk of cognitive decline. The two-year multinational randomized controlled LETHE trial evaluates the feasibility of a digitally supported, adapted FINGER intervention among at-risk older adults. Technology is used to complement in-person activities, streamline the intervention delivery, personalize recommendations, and collect digital biomarkers.

Methods: Trial includes older adults (60-77 years) with digital readiness/experience with smart devices and increased dementia risk but without substantial cognitive impairment. Participants are enrolled at four sites (Austria, Finland, Italy, Sweden). At baseline, participants were randomized 1:1 ratio to 1) intervention i.e., structured multimodal lifestyle program (including diet, exercise, cognitive training, vascular/metabolic risk management, social stimulation, sleep/stress management) where in-person activities led by professionals are supported with an Android mobile phone application developed by the consortium (the LETHE App); or 2) control i.e., self-guided program (regular health advice; simplified App with no personalized/interactive content). All participants wear smartwatches to gather passive data (e.g., physical activity, sleep). Primary outcomes are retention, adherence, and change in validated dementia risk scores. Secondary outcomes include changes in lifestyle, cognition, stress, sleep, health-related quality of life, and health literacy. Additional outcomes (exploratory) include e.g. participant experiences and dementia-related biomarkers (Alzheimer's disease blood markers, neuroimaging). A sub-study explores the feasibility of novel interactive technology (audio glasses, social robot).

Results: Recruitment began in September 2022, and the last participant was randomized in June 2023. In total, 156 individuals were randomized (mean age 69 years, 65% women; balanced recruitment across the four sites). Vascular and lifestyle risk factors were common (e.g., 65% with hypertension, 69% with hypercholesterolemia, 39% physically inactive), indicating successful recruitment of a population with risk reduction potential. Trial will be completed by summer 2025. Retention until the first post-baseline visit at 6 months is high (n = 2 discontinued, retention 98.7%).

Conclusion: LETHE provides crucial information about the feasibility of technology and a digitally supported FINGER lifestyle program to promote brain health. Digital tools specifically designed for older adults could offer potential for large-scale, cost-effective prevention programs.

Trial registration: ClinicalTrials.gov (NCT05565170).

Background: To establish simple screening tests to suspect Alzheimer's disease (AD) pathology, the clinical sign "head-turning sign" (HTS), which is a patient's behavior of turning their head towards their partner to seek assistance with questions posed by the examiner during the interview, and the simple screening questionnaire for dementia named "Neucop-Q" were validated in participants diagnosed with amyloid and tau positron emission tomography (PET).

Methods: We enrolled 155 patients: 47 cognitive normal, 36 with mild cognitive impairment, 64 with dementia, and 8 with psychiatric disorders. All participants underwent Neucop-Q [three questions: Consciousness/self-awareness of cognitive disabilities (C) normal/impaired (nor/imp), Pleasure/pastime (P) nor/imp, and News/knowledge on current topics (N) nor/imp] and amyloid/tau PET. Additionally, we measured plasma amyloid β (Aβ) 42/40 ratio, phosphorylated tau 181 (pTau181), glial fibrillary acidic protein (GFAP), and neurofilament light (NFL) levels and compared with HTS and Neucop-Q results.

Results: The specificity and positive predictive value (PPV) of HTS positivity (HTSpos) were the highest (amyloid PET: 0.930 and 0.870, tau PET: 0.944 and 0.957, respectively), while Cimp and Nimp had a high negative predictive value (NPV) for amyloid PET (negativity) (0.750 and 0.725). Pimp showed high specificity for predicting non-AD tau positivity among non-AD participants without amyloid PET positivity (0.854). To validate these findings with PET results, we examined the correlation between well-established AD blood biomarkers and results obtained from these screening tests. HTSpos, Cimp, and Nimp were strongly associated with Aβ42/40 ratio (P < 0.0001, P = 0.0022, and P = 0.001), pTau181 (P < 0.0001, P = 0.0095, and P = 0.001), GFAP (P = 0.0372, P = 0.0088, and P = 0.0002), and amyloid PET Centiloid (P < 0.0001, P = 0.0210, and P = 0.0006), whereas Pimp increased neuroinflammation (GFAP; P = 0.0061) and was associated with non-AD tauopathy. The combination of Neucop-Q questions showed that Cimp/Pnor/Nimp subjects have the highest specificity and PPV (0.972 and 0.833) and were strongly associated with Aβ42/40 ratio (P = 0.0006), pTau181 (P = 0.0006), and amyloid PET Centiloid (P < 0.0001).

Conclusion: HTSpos, Cimp, and Nimp have diagnostic utility in suspecting MCI due to AD and AD, and Pimp has diagnostic value in non-AD tauopathy. HTSpos, Cimp, and Nimp were associated with biomarkers of Aβ pathology. HTS and Neucop-Q may serve as powerful first-line screening in memory clinics.

Trial registration: UMIN Clinical Trials Registry (UMIN-CTR) under registration numbers 000032027 (Registration date: 2018/03/31) and 000030248 (Registration date: 2018/01/01).

Background: Alzheimer's disease (AD) is the most prevalent neurodegenerative disorder for which no effective therapy is currently available. Given that various attempts to target beta-amyloid (Aβ) have been unsuccessful in clinical trials, other potential pathogenic factors such as brain energy metabolism (EM) have attracted increasing attention. Traditional Chinese medicines, including danggui-shaoyao-san (DSS), play a notable role in AD. However, it remains unclear whether DSS exerts therapeutic effects on AD through EM regulation.

Methods: In this study, we conducted behavioural tests, Nissl staining, haematoxylin and eosin staining, and thioflavin S staining, in APP/PS1 mice to assess the pharmacodynamic effect of DSS on AD. Subsequently, we integrated the drug target network of herbal ingredients in DSS and evaluated their absorption, distribution, metabolism, excretion, and toxicity properties to identify the core ingredients. We used proteomic and metabolomic approaches to explore the potential mechanisms of action of DSS against AD. Consequently, we verified the mechanism underlying EM using qPCR, western blotting, and ELISA.

Results: In vivo experimental results revealed that DSS ameliorated cognitive impairment in APP/PS1 mice, attenuated neuronal apoptosis, and reduced Aβ burden. Furthermore, the drug-target network comprised 6,514 drug-target interactions involving 1,118 herbal ingredients and 218 AD genes, of which 253 were identified as the core ingredients in DSS. The proteomic results implied that DSS could act on EM to alleviate AD, and targeted energy metabolomics suggested that DSS regulated 47 metabolites associated with EM. Mechanistically, we found that DSS could regulate the GSK3β/PGC1α signalling pathway to improve brain glucose uptake and mitigate mitochondrial dysfunction and oxidative stress, ultimately promoting EM to treat AD.

Conclusion: Our study is the first to integrate multi-omics approaches to reveal that DSS could regulate the GSK3β/PGC1α signalling pathway to exert therapeutic effects in AD through the promotion of EM, thereby providing new insights into the mechanism of action of DSS against AD.

Background: The role of Vascular risk factors (VRFs) in the progression of Alzheimer's Disease (AD) and cognitive decline remains to be elucidated, with previous studies resulting in conflicting findings. The possible impact of age-specific mechanisms of resilience/vulnerability is an under addressed issue. We evaluated the association of VRFs with markers of amyloid deposition, neurodegeneration, and blood-brain-barrier (BBB) permeability (Albumin quotient, Qalb), stratifying patients into early-onset (< 65, EOAD), classic late-onset (65-75, cLOAD) and very late-onset (> 75, vLOAD), to evaluate the moderating effect of age of onset. Moreover, we explored the effects of VRFs on cognitive decline at one year follow-up (ΔMMSE).

Methods: For 368 patients with biologically confirmed AD, we computed eight risk factors in a composite measure of cumulative vascular risk (vascular score, VS). Stratifying patients according to age of onset, we regressed VS and main individual VRFs on p-tau/Aβ42, t-tau and Qalb, and used bootstrapped mediation analysis to test direct and indirect associations of VS with t-tau, using Qalb as mediator. In a subset of 105 patients, we performed multivariate backward regressions to assess the effects of sex, APOE, Qalb, VS, p-tau/Aβ42 and t-tau on ΔMMSE.

Results: VS was positively associated with CSF t-tau in more vulnerable groups burdened by more aggressive disease progression (EOAD: β = 0.256, p = 0.019) or aging (vLOAD: β = 0.007, p < 0.001). Conversely, in patients with classic age of onset VS was associated with higher BBB permeability (cLOAD: β = 0.173, p = 0.015), which simultaneously causes the decrease of CSF t-tau, as a possible resilience response. Cognitive decline was not associated with VS in any of the subgroups. Instead, it was affected by both higher CSF t-tau and increased Qalb values in those with very early or very late onset (EOAD and vLOAD), but by Qalb alone in patients with classic age of onset, where CSF t-tau levels might be buffered by BBB permeability.

Conclusions: Our results show that age of onset weighs on the heterogeneous effects played by VRFs in AD, which do not seem to have direct impact on cognitive decline. These findings stress the importance of a tailored patient-centered approach to the application of vascular prevention strategies in AD.

Background: Optical coherence tomography (OCT) enables high-resolution imaging of ocular structures in health and disease. Choroid thickness (CT) is a key vascular retinal parameter that can be assessed by OCT and might be relevant in the evaluation of the vascular component of cognitive decline. We aimed to investigate CT changes in a large cohort of individuals cognitive unimpaired (CU), with mild cognitive impairment due to Alzheimer's (MCI-AD), mild cognitive impairment due to cerebrovascular disease (MCI-Va), Alzheimer's disease dementia (ADD), and vascular dementia (VaD).

Methods: Clinical, demographical, ophthalmological and OCT data from the Neuro-ophthalmological Research at Fundació ACE (NORFACE) project were analyzed. CT was assessed in the macula across nine Early Treatment Diabetic Retinopathy Study (ETDRS) quadrants, average thickness, total volume, and subfoveal choroidal thickness. Differences of CT among the five diagnostic groups were assessed in a multivariate regression model, adjusting for demographic and cardiovascular risk factors and OCT image quality. A comparison between manual and automatic CT measurements in a subset of participants was also performed.

Results: The study cohort comprised 1,280 participants: 301 CU, 196 MCI-AD, 112 MCI-Va, 578 ADD, and 93 VaD. CT was significantly increased in individuals with cognitive impairment compared to those CU, particularly in the VaD and MCI-Va groups and in the peripheral ETDRS regions. No significant differences were found in inner superior, center and subfoveal choroidal thickness. The interaction of sex and diagnosis had no effect in differentiating CT. Mini-Mental State Examination (MMSE) scores were not correlated to CT. Manual and automated CT measurements showed good reliability.

Discussion: Our findings indicated that peripheral choroidal thickening, especially in patients with cerebrovascular disease, may serve as a potential choroidal biomarker for cognitive decline and suggest different pathogenic pathways in AD and VaD. Further research is required to explore CT as a reliable ocular biomarker for cognitive impairment.

Background: Females have a higher age-adjusted incidence of Alzheimer's Disease (AD) than males, even when accounting for longer lifespan and, therefore, stand to benefit the most from dementia prevention efforts. As exposure to many modifiable risk factors for dementia begins in mid-life, interventions must be implemented from middle-age. Building cognitive reserve, particularly through stimulating avocational activities and occupational attainment presents a crucial, underexplored, dementia prevention approach for mid-life. It is currently unknown, however, whether modifiable lifestyle factors can protect against AD processes, from mid-life, differentially for females and males who carry inherited risk for late-life dementia. To address this gap, this study investigated the impact of biological sex and APOE4 carrier status on the relationship between stimulating activities, occupational attainment, and cognition in mid-life.

Methods: We leveraged the PREVENT-Dementia program, the world's largest study investigating the origins and early diagnosis of dementia in mid-life at-risk individuals (N = 700; 40-59 years). Cognitive performance was measured using the Cognito Battery and the Visual Short Term Memory Binding task. Mid-life specific reserve contributors were assessed via the Lifetime of Experiences Questionnaire.

Results: Females had significantly better episodic and relational memory (p < 0.001), and lower occupational attainment than males (p < 0.001). Engagement in stimulating activities was positively associated with episodic and relational memory, regardless of sex and APOE4 status (β = 0.05, CI 0.03-0.07, p < 0.001). APOE4 carriers showed significant sex differences in the association between occupational attainment and episodic and relational memory (β = 0.38, CI 0.12-0.63, p = 0.003). APOE4 carrier females with higher occupational attainment showed better cognition (β = 0.16, CI -0.002-0.32, p = 0.053), whereas APOE4 carrier males showed the opposite effect (β = -0.20, CI -0.40 - -0.001, p = 0.049).

Conclusion: Our findings suggest that occupational attainment in mid-life contributes to cognitive reserve against inherited risk of dementia in females, but not males. They highlight the need for high precision approaches that consider biological sex and APOE4 carrier status to inform Alzheimer's disease prevention strategies and clinical trials.

Background: Facial aging, cognitive impairment, and dementia are all age-related conditions. However, the temporal relation between facial age and future risk of dementia was not systematically examined.

Objectives: To investigate the relationship between facial age (both subjective/perceived and objective) and cognitive impairment and/or dementia risk.

Methods: The study included 195,329 participants (age ≥ 60 y) from the UK Biobank (UKB) with self-perceived facial age and 612 participants from the Nutrition and Health of Aging Population in China Project (NHAPC) study (age ≥ 56 y) with objective assessment of facial age. Cox proportional hazards model was used to prospectively examine the hazard ratios (HRs) and their 95% confidence intervals (CIs) of self-perceived facial age and dementia risk in the UKB, adjusting for age, sex, education, APOE ε4 allele, and other potential confounders. Linear and logistic regressions were performed to examine the cross-sectional association between facial age (perceived and objective) and cognitive impairment in the UKB and NHAPC, with potential confounders adjusted.

Results: During a median follow-up of 12.3 years, 5659 dementia cases were identified in the UKB. The fully-adjusted HRs comparing high vs. low perceived facial age were 1.61 (95% CI, 1.33 ~ 1.96) for dementia (P-trend ≤ 0.001). Subjective facial age and cognitive impairment was also observed in the UKB. In the NHAPC, facial age, as assessed by three objective wrinkle parameters, was associated with higher odds of cognitive impairment (P-trend < 0.05). Specifically, the fully-adjusted OR for cognitive impairment comparing the highest versus the lowest quartiles of crow's feet wrinkles number was 2.48 (95% CI, 1.06 ~ 5.78).

Conclusions: High facial age was associated with cognitive impairment, dementia and its subtypes after adjusting for conventional risk factors for dementia. Facial aging may be an indicator of cognitive decline and dementia risk in older adults, which can aid in the early diagnosis and management of age-related conditions.