Growth-associated protein 43 is associated with faster functional decline among amyloid-positive individuals with objectively defined subtle cognitive decline and mild cognitive impairment.

Decision letter: Stage-dependent differential influence of metabolic and structural networks on memory across Alzheimer’s disease continuum

To test the associations between the presynaptic growth-associated protein 43 (GAP-43), quantified in CSF, and biomarkers of Alzheimer disease (AD) pathophysiology, cross-sectionally and longitudinally. In this retrospective study, GAP-43 was measured in participants from the AD Neuroimaging Initiative (ADNI) cohort using an in-house ELISA method, and levels were compared between groups, both cross-sectionally and longitudinally. Linear regression models tested the associations between biomarkers of AD (amyloid beta [Aβ] and tau pathologies, neurodegeneration, and cognition) adjusted by age, sex, and diagnosis. Linear mixed-effect models evaluated how baseline GAP-43 predicts brain hypometabolism, atrophy, and cognitive decline over time. Cox proportional hazard regression models tested how GAP-43 levels and Aβ status, at baseline, increased the risk of progression to AD dementia over time. This study included 786 participants from the ADNI cohort, which were further classified in cognitively unimpaired (CU) Aβ-negative (nCU- = 197); CU Aβ-positive (nCU+ = 55), mild cognitively impaired (MCI) Aβ-negative (nMCI- = 228), MCI Aβ-positive (nMCI+ = 193), and AD dementia Aβ-positive (nAD = 113). CSF GAP-43 levels were increased in Aβ-positive compared with Aβ-negative participants, independent of the cognitive status. In Aβ-positive participants, high baseline GAP-43 levels led to worse brain metabolic decline (p = 0.01), worse brain atrophy (p = 8.8 × 10-27), and worse MMSE scores (p = 0.03) over time, as compared with those with low GAP-43 levels. Similarly, Aβ-positive participants with high baseline GAP-43 had the highest risk to convert to AD dementia (hazard ratio [HR = 8.56, 95% CI 4.94-14.80, p = 1.5 × 10-14]). Despite the significant association with Aβ pathology (η2 Aβ PET = 0.09, P Aβ PET < 0.001), CSF total tau (tTau) and phosphorylated tau (pTau) had a larger effect size on GAP43 than Aβ PET (η2 pTau-181 = 0.53, P pTau-181 < 0.001; η2 tTau = 0.59, P tTau < 0.001). High baseline levels of CSF GAP-43 are associated with progression in Aβ-positive individuals, with a more aggressive neurodegenerative process, faster rate of cognitive decline, and increased risk of converting to dementia.

Growth-associated protein 43 (GAP-43), a key regulator of synaptic plasticity, neuronal growth, and memory, has recently been identified as a crucial biomarker for synaptic dysfunction in mild cognitive impairment (MCI) and Alzheimer's disease (AD) dementia. This study aimed to explore the mechanisms underlying GAP-43's role in cognitive impairment by examining the relationship between CSF GAP-43 levels and amyloid-β (Aβ) accumulation in brain regions like the frontal, temporal, and parietal lobes. This study included 332 participants sourced from the Alzheimer's Disease Neuroimaging Initiative (ADNI), categorized into three groups: 93 cognitively normal (CN), 218 with MCI, and 21 with AD dementia. Cognitive status was assessed with ADAS-Cog 13, CSF GAP-43 levels via ELISA, and Aβ accumulation using florbetapir PET imaging and Syngo.PET for SUVr values in key brain regions. The results revealed that CSF GAP-43 levels were highest in the AD dementia group, followed by the MCI group, and lowest in the CN group, with a significant difference (p < 0.001), indicating a link between elevated CSF GAP-43 and cognitive impairment. In MCI group, CSF GAP-43 positively correlated with Aβ accumulation in all regions: Globally (β = 0.362, p < 0.001), frontal (β = 0.388, p < 0.001), temporal (β = 0.382, p < 0.001), and parietal lobes (β = 0.344, p < 0.001). In contrast, the AD dementia group exhibited negative correlations between CSF GAP-43 levels and Aβ accumulation, significantly in the frontal (β = - 0.513, p = 0.035) and parietal lobes (β = - 0.513, p = 0.035), suggesting a shift in the CSF GAP-43-Aβ relationship in AD dementia. Mediation analysis, adjusted for age, gender, education, and ApoE ɛ4 status, revealed that elevated CSF GAP-43 is linked to increased cognitive impairment via increasing Aβ accumulation solely in MCI, with significant effects in global (β = 0.0894, CI: [0.0427, 0.1457]), frontal (β = 0.0895, CI: [0.0422, 0.1443]), temporal (β = 0.0941, CI: [0.0466, 0.1522]), and parietal (β = 0.0499, CI: [0.0100, 0.0945]) regions. Thus, elevated CSF GAP-43 may contribute to cognitive impairment by promoting Aβ accumulation in individuals with MCI, while in AD dementia, it may be associated with reduced Aβ accumulation, potentially reflecting a compensatory or disease-stage-dependent effect. This dynamic relationship suggests that GAP-43 could play a dual role in neurodegeneration, influencing Aβ pathology differently across disease stages.

Synaptic degeneration has been suggested as an early pathological event that strongly correlates with severity of dementia in Alzheimer's disease (AD). However, changes in longitudinal cerebrospinal fluid (CSF) growth-associated protein 43 (GAP-43) as a synaptic biomarker in the AD continuum remain unclear. To assess the trajectory of CSF GAP-43 with AD progression and its association with other AD hallmarks. CSF GAP-43 was analyzed in 788 participants from the Alzheimer's Disease Neuroimaging Initiative (ADNI), including 246 cognitively normal (CN) individuals, 415 individuals with mild cognitive impairment (MCI), and 127 with AD dementia based on cognitive assessments. The associations between a multimodal classification scheme with amyloid-β (Aβ), tau, and neurodegeneration, and changes in CSF GAP-43 over time were also analyzed. CSF GAP-43 levels were increased at baseline in MCI and dementia patients, and increased significantly over time in the preclinical (Aβ-positive CN), prodromal (Aβ-positive MCI), and dementia (Aβ-positive dementia) stages of AD. Higher levels of CSF GAP-43 were also associated with higher CSF phosphorylated tau (p-tau) and total tau (t-tau), cerebral amyloid deposition and hypometabolism on positron emission tomography, the hippocampus and middle temporal atrophy, and cognitive performance deterioration at baseline and follow-up. Furthermore, CSF GAP-43 may assist in effectively predicting the probability of dementia onset at 2- or 4-year follow-up. CSF GAP-43 can be used as a potential biomarker associated with synaptic degeneration in subjects with AD; it may also be useful for tracking the disease progression and for monitoring the effects of clinical trials.

ABSTRACTBackground and AimsAlzheimer's disease (AD) is a widespread neurodegenerative condition that has a growing impact on a global scale. This study aims to examine the relationship between cerebral blood flow (CBF) and the synaptic biomarker growth‐associated protein 43 (GAP‐43) through the utilization of arterial spin labeling (ASL). The research identified noteworthy correlations between cerebrospinal fluid (CSF) GAP‐43 levels, CBF, and cognitive composite scores, especially among participants with mild cognitive impairment (MCI) who possess the APOE‐ε4 gene.MethodsThe study examined 92 participants from the Alzheimer's Disease Neuroimaging Initiative (ADNI) database, including 36 cognitively normal (CN) and 56 MCI. The cognitive status of 42 participants was evaluated using ADNI composite scores. Independent t‐tests and Mann‐Whitney tests were used for the comparison of continuous variables between groups, and multiple linear regression analysis with adjustments for confounding factors was used to assess the relationship between GAP‐43 and CBF values.ResultsSignificant positive correlations were observed between GAP‐43 levels and (A) the executive function composite score (ADNI_EF) in CN individuals, as well as (B) the language composite score (ADNI_LAN) in individuals with MCI. CSF biomarkers and ASL regions did not show statistical significance between diagnostic groups after correction for multiple comparisons. No significant differences in baseline characteristics were found between diagnostic groups. However, associations were observed between ROI CBF and Mini Mental State Examination in various subgroups.ConclusionThe findings indicate a potential function for ASL perfusion in identifying early AD‐related alterations and gaining insight into the pathophysiology of AD and mild cognitive impairment.The study revealed associations between CBF, cognitive scores, and APOE‐ε4 gene status. This study contributes to the comprehension of the correlation between CSF biomarkers, regional brain perfusion, and cognitive function in individuals with AD using ASL as a noninvasive approach.

Search for Clinical Markers Could? Transform Alzheimer's Drug Research

To examine whether the presence of sleep-disordered breathing (SDB) is associated with an earlier age at mild cognitive impairment (MCI) or Alzheimer disease (AD)-dementia onset in participants from the Alzheimer's Disease Neuroimaging Initiative (ADNI) cohort. We also examined whether continuous positive airway pressure (CPAP) use is associated with delayed onset of cognitive decline. From the ADNI cohort, 3 subsets with progressively stringent criteria were created in a step-wise manner. Age at MCI or AD-dementia onset was the main outcome variable. Analyses were performed separately for each subset in untreated SDB+ vs SDB- and untreated SDB+ vs CPAP+ groups. Chi-square and t tests were performed to examine between-group differences. Survival analyses were performed using the Kaplan-Meier method, compared by the log-rank test, and assessed by multivariate Cox regression adjusting for potential confounders. SDB+ patients had a younger age at MCI onset in all subsets (MC1: 72.63 vs 83.67; MC2: 72.15 vs 83.45; MC3: 77.40 vs 89.89; p < 0.01). SDB+ patients had a younger age at AD-dementia onset only in our most conservative subset (AC3: 83.46 vs 88.13; p < 0.05). In a combined outcome analysis, SDB+ patients had a younger age at onset to MCI or AD-dementia in all subsets. In subsets 1 and 2, CPAP use delayed the age at MCI onset (CMC1: 72.63 vs 82.10; CMC2: 72.11 vs 82.10; p < 0.01). Consistent with our hypothesis, the presence of SDB was associated with an earlier age at cognitive decline. Our findings in CPAP+ participants suggest that CPAP treatment of SDB may delay progression of cognitive impairment.

BackgroundAlzheimer’s disease (AD) is the most common cause of dementia, characterized by a considerable decline in memory. The aggregation of amyloid-beta (Aβ) plaques and tau tangles is the primary pathology of AD. Recently, growth-associated protein 43 (GAP-43) has been suggested as a reliable biomarker in the early diagnosis of patients with AD continuum.ObjectivesIn this study, we aimed to observe the association of white matter (WM) features detected by diffusion tensor imaging (DTI) with the cerebrospinal fluid (CSF) level of GAP-43 in patients with cognitive impairment.MethodsInformation from 132 participants from different ATN groups, including 62 with A−/TN−, 16 with A+/TN−, 30 with A−/TN+, and 24 with A+/TN + pathology were enrolled from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) database. We observed the association of CSF GAP-43 with DTI findings among patients with AD spectrum by using a linear regression model adjusted for age, sex, period of education, and APOE ε4 status.ResultsOur findings suggested a significant association for CSF GAP-43 concentration with WM features in the inferior cerebellar peduncle in the A−/TN− group as well as WM in the cerebral peduncle, anterior corona radiata, and the left sagittal stratum of patients with A+/TN− pathology. In addition, a significant relation was reported between DTI findings in the cingulum cingulate, fornix, body, and splenium of the corpus callosum of patients with A−/TN + with CSF GAP-43 concentration. A similar significant association was shown in the posterior limb of the internal capsule of the A+/TN + group. Moreover, a significant association was found between CSF level of GAP-43 and the performance of A+/TN + and A+/TN−groups in cognitive tests.ConclusionsOur study observed a significant association between CSF GAP-43 concentration and WM microstructural findings in different brain tracts of patients with various ATN groups, suggesting GAP-43 as a reliable and accurate biomarker in the early detection of patients with cognitive decline. Further longitudinal investigations with other imaging methods can provide more evidence on the role of GAP-43 in the detection of brain damage among patients with AD spectrum.

Battle against Alzheimer's Disease: The Scope and Potential Value of Magnetic Resonance Imaging Biomarkers

Structural magnetic resonance imaging (sMRI) can provide morphological information about the structure and function of the brain in the same scanning process. It has been widely used in the diagnosis of Alzheimer's disease (AD) and mild cognitive impairment (MCI). To capture the anatomical changes in the brain caused by AD/MCI, deep learning-based MRI image analysis methods have been proposed in recent years. However, it is observed that the performance of most existing methods is limited as they only construct a single type of deep network and ignore the significance of other clinicalinformation. To make up for these defects, an ensemble framework that incorporates three types of dedicatedly-designed convolutional neural networks (CNNs) and a multilayer perceptron (MLP) network is proposed, where three CNNs with entropy-based multi-instance learning pooling layers have more reliable feature selection abilities. The dedicatedly-designed base classifiers can make use of the heterogeneous data, and empower the framework with enhanced diversity and robustness. In particular, to consider the interactions among the base classifiers, a novel multi-head self-attention voting scheme is designed. Moreover, considering the chance that MCI can be transformed to AD, the proposed framework is designed to diagnose AD and predict MCI conversion simultaneously, with the aid of the transfer learning technique. For performance evaluation and comparison, extensive experiments are conducted on the public dataset of the Alzheimer's Disease Neuroimaging Initiative (ADNI). The results show that the proposed ensemble framework provides superior performance under most of the evaluation metrics. Especially, the proposed framework achieves state-of-the-art diagnostic accuracy (98.61% for the AD diagnosis task, and 84.49% for the MCI conversion prediction task). These promising results demonstrate the proposed ensemble framework can accurately diagnose AD patients and predict the conversion of MCI patients, which has the potential of clinical practice for diagnosing AD andMCI.

Synchronized sigmoidal mixed‐effects model for dynamics of cognitive decline relative to onset of Alzheimer’s disease in aging adults in the Alzheimer’s Disease Neuroimaging Initiative (ADNI) study.

INTRODUCTIONHearing loss is identified as one of the largest modifiable risk factors for cognitive impairment and dementia. Studies evaluating this relationship have yielded mixed results.METHODSWe investigated the longitudinal relationship between self‐reported hearing loss and cognitive/functional performance in 695 cognitively normal (CN) and 941 participants with mild cognitive impairment (MCI) enrolled in the Alzheimer's Disease Neuroimaging Initiative.RESULTSWithin CN participants with hearing loss, there was a significantly greater rate of cognitive decline per modified preclinical Alzheimer's cognitive composite. Within both CN and MCI participants with hearing loss, there was a significantly greater rate of functional decline per the functional activities questionnaire (FAQ). In CN and MCI participants, hearing loss did not significantly contribute to the risk of progression to a more impaired diagnosis.DISCUSSIONThese results confirm previous studies demonstrating a significant longitudinal association between self‐reported hearing loss and cognition/function but do not demonstrate an increased risk of conversion to a more impaired diagnosis.CLINICAL TRIAL REGISTRATION INFORMATIONNCT00106899 (ADNI: Alzheimer's Disease Neuroimaging Initiative, clinicaltrials.gov), NCT01078636 (ADNI‐GO: Alzheimer's Disease Neuroimaging Initiative Grand Opportunity, clinicaltrials.gov), NCT01231971 (ADNI2: Alzheimer's Disease Neuroimaging Initiative 2, clinicaltrials.gov), NCT02854033 (ADNI3: Alzheimer's Disease Neuroimaging Initiative 3, clinicaltrials.gov).HighlightsHearing loss is a potential modifiable risk factor for dementia.We assessed the effect of self‐reported hearing loss on cognition and function in the ADNI cohort.Hearing loss contributes to significantly faster cognitive and functional decline.Hearing loss was not associated with conversion to a more impaired diagnosis.

Inflammatory changes are among the key markers of Alzheimer's disease (AD) related pathological changes. Pro-inflammatory analytes have been related to cognitive decline while others have been related to attenuating neuronal death. Among them, changes in cerebrospinal fluid (CSF) levels of soluble triggering receptor expressed on myeloid cells 2 (sTREM2) and soluble tumor necrosis factor receptor 2 (sTNFR2) have been described as impacting favorable clinical outcomes in AD. We therefore evaluate the effect of CSF sTREM2 and sTNFR2 when taken together on AD biomarkers and longitudinal clinical decline to understand their relative role on impacting AD clinical biomarkers and subsequent clinical outcomes. This longitudinal observational cohort study included 168 amyloid-positive (A+) and p-tau-positive (T+) participants with mild cognitive impairment (MCI) or AD dementia from the Alzheimer's Disease Neuroimaging Initiative (ADNI) with 109 of them having concomitant CSF sTREM2 and sTNFR2 data and 48 A+ T+ participants with MCI from a tertiary memory clinic cohort. An exploratory analysis was performed using data from 86 cognitively normal (CN) participants from ADNI with 72 of them having concomitant CSF AD biomarkers and CSF sTREM2 and sTNFR2 data. General linear models were used to evaluate the effect of sTREM2 and sTNFR2 levels on baseline CSF Aβ42, t-tau, and p-tau, and a linear mixed-effects model was used to assess longitudinal cognitive change after controlling for well-known covariates. Among ADNI A+ T+ MCI and AD dementia participants, CSF sTNFR2 had a stronger association, than CSF sTREM2, with CSF t-tau and p-tau. This was replicated among A+ T+ MCI participants from the memory clinic cohort. On the contrary, among A+ T+ CN participants, CSF sTREM2 explained significant variance in CSF t-tau and p-tau, while CSF sTNFR2 did not. When the effects of CSF sTNFR2 and t-tau on longitudinal cognitive change were taken into account, higher CSF sTREM2 predicted slower cognitive decline in A+ T+ AD dementia participants and faster decline in A+ T+ CN participants. Our results show that given the dynamic changes in sTREM2 and sTNFR2, the clinical impact of these distinct inflammation related biomarkers in tracking AD temporal progression across disease stages are likely to differ.

Effects of sex, educational background, and chronic kidney disease grading on longitudinal cognitive and functional decline in patients in the Japanese Alzheimer's Disease Neuroimaging Initiative study

Background: Ongoing research is focusing on the identification of those individuals with mild cognitive impairment (MCI) who are most likely to convert to Alzheimer's disease (AD). We investigated whether recognition memory tasks in combination with delayed recall measure of episodic memory and CSF biomarkers can predict MCI to AD conversion at 24-month follow-up.Methods: A total of 397 amnestic-MCI subjects from Alzheimer's disease Neuroimaging Initiative were included. Logistic regression modeling was done to assess the predictive value of all RAVLT measures, risk factors such as age, sex, education, APOE genotype, and CSF biomarkers for progression to AD. Estimating adjusted odds ratios was used to determine which variables would produce an optimal predictive model, and whether adding tests of interaction between the RAVLT Delayed Recall and recognition measures (traditional score and d-prime) would improve prediction of the conversion from a-MCI to AD.Results: 112 (28.2%) subjects developed dementia and 285 (71.8%) subjects did not. Of the all included variables, CSF Aβ1-42 levels, RAVLT Delayed Recall, and the combination of RAVLT Delayed Recall and d-prime were predictive of progression to AD (χ2 = 38.23, df = 14, p < 0.001).Conclusions: The combination of RAVLT Delayed Recall and d-prime measures may be predictor of conversion from MCI to AD in the ADNI cohort, especially in combination with amyloid biomarkers. A predictive model to help identify individuals at-risk for dementia should include not only traditional episodic memory measures (delayed recall or recognition), but also additional variables (d-prime) that allow the homogenization of the assessment procedures in the diagnosis of MCI.