Alzheimer's Research & Therapy最新文献

Background: In this two-part investigation, we examined whether Alzheimer's disease (AD) phenotypes are distinct clinical entities or represent positions within a graded multidimensional space.

Methods: First, using a large retrospective dataset of past research participants (n = 413) from memory clinics, we examined the comparative distributions of cognitive performance in people diagnosed with typical amnestic AD (tAD), logopenic variant of primary progressive aphasia (lvPPA), and posterior cortical atrophy (PCA), across a broad range of disease severities. Secondly, a prospective deep phenotyping study of lvPPA (n = 18) compared to typical AD (n = 9) addressed the following questions: (1) Does the multidimensional cognitive pattern of impairment only emerge in advanced lvPPA, and how does it compare to tAD? (2) Do memory deficits in lvPPA appear in a simple clinic-level cognitive assessment or require in-depth neuropsychological investigation? (3) To what extent is performance on verbal episodic memory attributable to language impairment? (4) Do the patterns of decline in lvPPA and tAD stay categorical or multidimensional over time? We explored the associations between scores derived from a principal component analysis of cognitive measures, and grey matter volumes in key memory- and language-related brain regions, at baseline and longitudinally.

Results: The clinic-level assessment revealed similar results in both the prospective and retrospective data: (i) patients showed graded distinctions (e.g., predominant visual versus language impairment in people with PCA versus lvPPA) and overlap (e.g., shared weakness in domains such as memory); and (ii) people with lvPPA and tAD were equally impaired on both verbal and non-verbal memory tests. Longitudinal assessment showed phenotypic dispersion: (i) people with tAD showed varied patterns of phenotypic differentiation; and (ii) people with lvPPA and lvPPA + exhibited a multidimensional pattern of decline with decreasing principal component scores and worsening multi-domain cognitive performance. The results of Bayesian linear regressions showed evidence for the association of grey matter volumes in language and memory networks with principal component analysis derived scores.

Conclusions: The graded distinctions amongst typical amnestic and atypical (language and visual) phenotypes of AD support the proposal for a transdiagnostic, multidimensional phenotype geometry that spans all AD subtypes.

Background: Alzheimer's disease (AD) clinical trials enroll participants at various site types including research-focused academic institutions and independent non-academic sites. Limited research has examined the impact of site type on recruitment and retention outcomes.

Methods: To evaluate potential differences between site types, we used data from the Anti-Amyloid Treatment for Asymptomatic AD (A4) trial, the largest completed preclinical AD trial to date. We first compared the frequency of varying recruitment sources between site types. We then examined potential differences in participant- and site-level characteristics. To assess potential site type differences in retention, we fit a multivariable logistic regression model adjusting for variables associated with site type. For participants who prematurely discontinued, we examined potential differences by site type in reasons for dropout.

Results: One thousand and fifty-eight participants were randomized at 50 academic (N = 835) and 15 non-academic (N = 223) sites in North America. Academic sites had higher proportions of participants recruited through earned media and organizational referrals and lower proportions recruited through internal referrals and advertisements, compared to non-academic sites. Participant-level characteristics differed between site types. Compared to non-academic sites, academic sites had higher proportions of participants with a family history of dementia and a professional degree (highest education category), but lower proportions of individuals with a history of diabetes, a CDR-SB score above 0, and belonging to a racial and ethnic underrepresented group. Though the results were not statistically significant, non-academic sites had a higher screening rate (number of participants screened/site/month), but a lower randomization rate (randomized/screened) compared to academic sites. No site type differences in completion rates were observed. When examining reasons for discontinuation, we found that among the 72 participants who discontinued the trial at non-academic sites, 56 (77.8%) withdrew consent or were lost to follow up. In contrast, 140 out of 243 (57.6%) participants who discontinued the trial in academic sites withdrew consent or were lost to follow up.

Conclusion: Our findings shed light on important site type differences that investigators should consider when making choices around site, design, and conduct in multisite preclinical AD trials.

Background: Antemortem plasma and structural MRI biomarkers of Alzheimer's disease (AD) are increasingly utilized for diagnosis and prognosis but their ability to predict regional tau burden remains relatively unexplored. We aimed to evaluate predictive models based on antemortem AD plasma and structural MRI for prediction of regional tau pathology in postmortem brain tissue.

Methods: Autopsy data from 62 participants in the Mayo Clinic Study of Aging (MCSA) were analyzed (mean age of 84.6 years; 32% female; 1.4 years of mean time of last plasma draw to death). Tau pathology in the hippocampus and parietal cortex was quantified using two immunohistochemical markers: AT8, an early tangle maturity marker, and 2E9, an advanced tangle maturity marker. Three antemortem plasma markers including phosphorylated tau protein at threonine 181 (p-tau181), total amyloid-β (Aβ) 42 relative to Aβ40 ratio (Aβ42/40), and glial fibrillary acidic protein (GFAP) and three regional structural MRI markers including the hippocampus volume adjusted for total intracranial volume (HVA), parietal thickness (PTH) and parietal volume divided by total intracranial volume (PVTIV) were utilized as predictors. Weighted linear regression models using weights based on time from last plasma draw to death were adjusted for age, sex and cardiovascular and metabolic conditions (CMC) score for patients. We report estimated adjusted R² and partial R² for predicting postmortem tau pathology in the hippocampus and parietal cortex stained by AT8 and 2E9.

Results: MRI models (adjusted R² of 0.28-0.66) showed better performance at predicting tau pathology than plasma models (adjusted R² of 0.19-0.36). The highest adjusted R² was 0.66 for predicting hippocampal 2E9 using HVA, followed by an adjusted R² of 0.6 for hippocampal AT8. Predictions for parietal AT8 and 2E9 were lower with an adjusted R² of 0.28-0.29 based on MRI biomarkers and 0.24-0.36 based on plasma biomarkers. The adjusted R² values for both regions were higher for AT8 compared to 2E9 prediction for plasma biomarker models.

Conclusions: Our study demonstrates the greater sensitivity of regional MRI to tau pathology in comparison to plasma biomarkers. Future studies should explore newer MRI methods and additional plasma biomarkers more specific to tau pathology such as microtubule binding region for prediction of antemortem tau pathology.

Background: Tauopathies share common features, including tau aggregation, which plays a central role in neurodegeneration. However, these disorders are highly heterogeneous, particularly in the spread of pathological tau species between cells. In Alzheimer's disease, intracellular tau aggregation is followed by a propagation between cells leading to a hierarchical pathway of neurodegeneration, whereas in other tauopathies, such as progressive supranuclear palsy (PSP), pathological tau remains largely confined within neurons and exhibits more limited spread. This variability raises the question of whether tailored treatments for each tauopathy might offer more therapeutic benefit. Hence, we designed two different immunological approaches using single domain antibody fragments, also called VHHs, to target intracellular and extracellular tau. This study aims to first evaluate the safety of these immunological tools on physiological tau and then their potential to slow disease progression.

Methods: We selected the pro-aggregative tau hexapeptide PHF6 as a common target for the VHHs. These VHHs were cloned in viral vectors allowing to compare two different expression systems: 1) intracytosolic expression to prevent tau accumulation (intraVHH) and 2) secretion into the interstitial fluid, to prevent tau spreading (extraVHH). By stereotactic injection of viral vectors, these VHHs were expressed in the brain of transgenic or wild-type mice and three readouts were studied: behavior, brain imaging and tau lesions.

Results: We validated the correct addressing of intra- and extraVHHs. These two constructs were not associated with adverse effects, even in the absence of tau overexpression, in wild-type mice. Their efficacy was demonstrated in transgenic mouse tau models, either chronic long-term or in acute seeding with injections of human brain homogenates from Alzheimer's disease patients. They both can slow down several pathological effects (i.e. cognitive deficits, cerebral atrophy and neuronal hyperphosphorylation of tau).

Conclusions: This study is a proof of concept demonstrating that VHHs can be engineered to reduce both intra- and extracellular tau pathologies without major adverse effects, making them of interest for therapeutic applications.

Background: Underlying medical conditions may explain inconsistent reports of the association between sex and dementia risk. The current study aimed to explore the association between sex and the risk of incident dementia, considering a broad range of medical conditions.

Methods: This prospective national birth cohort study consisted of 53,224 members of a nonprofit health maintenance organization. Participants were born between 1922 and 1946 and entered the cohort on January 1, 2002, aged 55 to 80, without a dementia diagnosis. The cohort was followed up for 18 years to January 1, 2020. Dementia was ascertained based on medical diagnoses. Cox regression models were fitted to quantify the association between sex and the risk of incident dementia with hazard ratios (HR) and their 95% confidence intervals (CI), unadjusted and, in the primary model, adjusted for background demographic factors and 33 medical conditions, classified as ten medical domains. Complementary analyses examined adjustment for each medical domain, and sensitivity analyses provided sex-specific estimates for each demographic or medical domain.

Results: The analytic cohort of 53,224 participants had a mean (SD) age at cohort entry of 64.3 (7.08) years (Males: N = 24,489; 46.01%; M=63.47 (6.39); Females: N = 28,735; 53.99%; M=64.35 (6.78)). During follow-up, 8,373 participants (15.73%) were diagnosed with dementia (Females: 17.36%; N = 4,987; Males: 13.83%; N = 3,386). Sex differences in the risk of dementia were null after adjustment for demographic factors and medical conditions (unadjusted HR = 1.08 [95% CI = 1.03-1.13, P = 0.001]; adjusted HR = 1.02 [95% CI, 0.97-1.08; p = 0.38]). Complementary analyses showed that when accounting for some conditions (i.e., circulatory, respiratory, metabolic, digestive, or nervous system diseases; cancer; and injuries), females were at an elevated dementia risk compared to males. However, after accounting for rheumatic and genitourinary diseases, the association between sex and dementia was attenuated to null, and when accounting for psychiatric disorders, males were at greater risk.

Conclusions: In this prospective birth cohort, the association between sex and the risk of incident dementia changed when background medical conditions were considered, possibly explaining previous inconsistent reports. Future dementia risk and prevention studies may wish to adequately explore sex differences in medical history.

Background: Tau-PET binding patterns are heterogenous, with regional binding showing strong cross-sectional correlations with domain-specific cognitive performance and longitudinal correlations with prospective neurodegeneration. Here we evaluated whether regional patterns of baseline tau-PET predict prospective longitudinal decline in specific cognitive domains in early symptomatic Alzheimer's disease (AD), including participants from clinical trial cohorts.

Methods: 731 amyloid-positive participants with a clinical diagnosis of mild cognitive impairment (MCI) or mild AD dementia underwent a flortaucipir F 18 PET (FTP-PET), structural MRI, and neuropsychological testing with the AD Assessment Scale-Cognitive Subscale (ADAS-Cog). Cognitive assessment was repeated after 9-18 or 12-24 months. Sub-scale annualized w-scores at each time point were combined as composite scores according to domains, including episodic memory, semantic memory, executive function, language and praxis. Latent growth curve models were applied to longitudinal composite scores to estimate the rate of annual decline (slope) in each participant. Standardized uptake value ratio (SUVR) images were created using cerebellar crus as the reference region. Regional and voxel-wise correlation analyses were implemented to identify baseline FTP-PET patterns and MRI grey matter volumes associated with longitudinal changes in each cognitive domain, and to evaluate whether MRI mediates the association between FTP-PET and cognitive decline.

Results: Differential FTP-PET signal patterns showed significant negative associations with domain-specific annual rates of decline. Higher temporo-parietal FTP-PET SUVR was associated with faster decline in episodic memory, while higher left anterior temporal SUVR was associated with faster decline in semantic memory. FTP-PET signal in a left-dominant fronto-temporal pattern was associated with faster decline in language, while FTP-PET signal in a right-dominant fronto-parietal pattern was associated with faster decline in praxis. Executive decline showed limited spatial associations with FTP-PET. Overall, regional and voxel-wise analyses identified similar pairwise associations between FTP-PET signal and domain-specific longitudinal decline. Baseline MRI showed weaker associations with domain-specific cognitive decline than FTP-PET, and did not mediate the predictive effect of the latter.

Conclusion: Differential regional tau-PET signal patterns were associated with domain-specific cognitive decline in MCI and early AD dementia. Tau-PET may be a useful precision medicine tool to support individualized predictions of cognitive decline trajectories in early symptomatic AD.

Background: ADappt is a digital toolkit for both memory clinic professionals and patients to support communication on diagnosis and prognosis in memory clinics. We aimed to evaluate ADappt's usability and feasibility in clinical practice.

Methods: In this mixed-methods study, we first assessed usability via think-aloud sessions with ten memory clinic professionals from eight memory clinics, six patients, and one care partner. Think-aloud comments were deductively categorized into: content, navigation, and design. Second, we conducted a feasibility study in four memory clinics. Eight memory clinic professionals recruited 21 patients and 21 care partners. Professionals were instructed to integrate the ADappt-toolkit in their routine. Before their visit, patients received information about the ADappt-patient tools: two video-animations and a question prompt list (QPL). Participants completed questionnaires on usability, satisfaction, and feasibility either after the first consultation (n = 14 patients; n = 15 care partners), after the disclosure consultation (n = 4 patients; n = 5 care partners), or after both consultations (n = 3 patients; n = 1 care partner). Interviews with professionals were conducted and analyzed using thematic content analysis. Third, together with Alzheimer Europe, we co-organized a patient and public involvement (PPI) session with citizens, patients, and care partners to further improve the patient tools.

Results: Professionals found ADappt relevant, easy-to-navigate, and visually appealing. Most think-aloud comments focused on content and navigation, especially regarding the risk calculation tool. Patients indicated the patient tools to be helpful in preparing for consultations. After use in practice, professionals reported acceptable usability (68 ± 14, scale 0-100) and satisfaction (71 ± 10, scale 0-100) with ADappt. Professionals most often used the tool that provides an overview of diagnostic tests with pros and cons (in 15/24(63%) consultations), which they also deemed most helpful (median(IQR): 4(3.75-4), scale 1-5). About half to two-thirds of patients and care partners reported to have received the patient tools (video-animations: n = 23/46(50%)); QPL: n = 30/46(65%)), of whom a majority used (video-animations: n = 16/23(70%)); QPL: n = 21/30(70%)) and would recommend them (video-animations: n = 15/16(94%); QPL: n = 20/21(95%)). The tools helped to express themselves more effectively. The PPI session highlighted the importance of widespread dissemination of the patient tools and through multiple channels.

Conclusions: Our study demonstrates the potential of digital tools to improve medical communication in memory clinics. Taking feedback into account, ADappt is further improved and steps towards implementation are being taken.

Background: A subset of older adults develops high neurofibrillary tangle burden with minimal amyloid, a biomarker profile consistent with suspected non-Alzheimer's pathophysiology or primary age-related tauopathy. Yet its cognitive correlates are unclear, particularly when vascular neuropathologies coexist. We examined whether vascular neuropathologies are linked to cognitive impairment proximate to death and pre-mortem cognitive decline among decedents with intermediate-to-high Braak stage (III-VI) and absent/low neuritic plaques.

Methods: In 579 autopsied participants from the National Alzheimer's Coordinating Center cohort (Braak III-VI; CERAD C0-C1), we evaluated arteriolosclerosis, atherosclerosis of the circle of Willis, cerebral amyloid angiopathy, gross infarcts/lacunes, and microinfarcts effect on harmonized memory, executive function, and language z-scores proximate to death using multivariable linear regression (adjusted for age, sex, education, APOE ε4 status). Linear mixed-effects models assessed interactions between each vascular neuropathology and years-to-death on pre-mortem longitudinal decline.

Results: At the last assessment, microinfarcts were associated with lower memory (β=-0.28, 95% CI - 0.51 - - 0.05; p = 0.02), executive function (β=-0.24, 95% CI - 0.44 - - 0.04; p = 0.02), and language (β=-0.21, 95% CI - 0.38 - - 0.04; p = 0.02). These associations remained after controlling for cardiovascular risk, neuritic plaques and Braak stage, last assessment and death interval, and co-existing vascular neuropathologies. Microinfarcts were not associated with the rates of pre-mortem cognitive decline.

Conclusions: Microinfarcts are contributors to domain-specific cognitive deficits in tangle-predominant, low-amyloid older adults. These findings underscore a vascular-neurodegenerative pathway distinct from classic Alzheimer's disease. Thus, targeting microvascular injury may mitigate impairment in this underrecognized phenotype.