Alzheimer's Dementia Group Research Articles

알츠하이머병 치매, 혈관성 치매 및 파킨슨병을 동반한 치매 환자의 인지기능 비교를 위한 SNSB-Ⅱ의 유용성

Objective : The purpose of this study was to compare the cognitive function of dementia patients with Alzheimer's disease dementia, vascular dementia and Parkinson's disease using SNSB-II and to investigate the performance differences of three types of dementia patients in five cognitive domains: attention, language, visual-spatial, memory, and frontal-executive function. Methods : The three groups consisted of 393 patients with Alzheimer's disease, 153 patients with vascular dementia, and 26 patients with Parkinson's disease. The differences in performance between the three groups were compared through ANOVA, and Bonferroni adjustment was conducted when significant differences were found. Results : As a result of the analysis, there was no difference in the five cognitive domains of the three groups, but some individual subtests showed differences in the performance variables reflecting the cognitive characteristics of each group: The score of verbal memory recognition was lower in the Alzheimer's disease dementia group than in the Parkinson's disease dementia group, and executive function, planning and control ability, which are frontal lobe functions, were higher in the vascular dementia group and the Parkinson's disease dementia group than in the Alzheimer's disease dementia group. Conclusion : The differences among neuropsychological performance variables of three types of dementia patients, the usefulness of SNSB-II as an assessment tool for dementia, limitations of the study, and points to be considered in follow-up studies were discussed.

Healthcare Resource Utilization Among Patients With Agitation in Alzheimer Dementia

Background: Agitation in Alzheimer dementia is common, but the associated healthcare burden remains unclear. Objective: This retrospective analysis evaluated baseline characteristics, healthcare resource utilization, and costs among patients with agitation in Alzheimer dementia and those without agitation in Alzheimer dementia. Methods: Medicare beneficiaries from 100% of the Medicare Fee-for-Service claims database (2009-2016) with 2 or more claims 30 or more days apart for both Alzheimer’s disease and dementia and continuous enrollment with medical/pharmacy coverage for 6 months before and 12 months after the index diagnosis were included. Patients with agitation in Alzheimer dementia were identified by 2 or more claims 14 or more days apart using International Classification of Diseases-9-CM/-10-CM codes based on the provisional International Psychogeriatric Association agitation definition. Patients with severe psychiatric disorders were excluded. Two cohorts of patients (with and without agitation) were then defined, and patient characteristics, healthcare resource utilization, and costs were compared in a descriptive exploratory analysis. Results: Of 2 684 704 Fee-for-Service patients with Alzheimer dementia, 769 141 met all inclusion criteria; among these, 281 042 (36.5%) had agitation. The mean age in patients with and without agitation in Alzheimer dementia was 83 years. Most patients in both groups were female, but the proportion of males was slightly higher in the agitation in Alzheimer dementia group (30.3% vs 28.2%, respectively). Patients with agitation in Alzheimer dementia were more likely than those without agitation in Alzheimer dementia to have lower socioeconomic status (dual eligibility for Medicaid, 45.0% vs 41.7%, respectively) or be disabled (10.5% vs 9.4%). Overall, healthcare costs were higher in the agitation in Alzheimer dementia population compared with those without agitation in Alzheimer dementia (mean cost PPPY, $32 322 and $30 121, respectively), with the largest differences observed in inpatient and post-acute care costs. Conclusions: These exploratory findings underscore the substantial economic burden of agitation in Alzheimer dementia and highlight the need for treatment options for the agitation in Alzheimer dementia population to improve associated health outcomes.

Healthcare Resource Utilization Among Patients With Agitation in Alzheimer Dementia.

Background: Agitation in Alzheimer dementia is common, but the associated healthcare burden remains unclear. Objective: This retrospective analysis evaluated baseline characteristics, healthcare resource utilization, and costs among patients with agitation in Alzheimer dementia and those without agitation in Alzheimer dementia. Methods: Medicare beneficiaries from 100% of the Medicare Fee-for-Service claims database (2009-2016) with 2 or more claims 30 or more days apart for both Alzheimer's disease and dementia and continuous enrollment with medical/pharmacy coverage for 6 months before and 12 months after the index diagnosis were included. Patients with agitation in Alzheimer dementia were identified by 2 or more claims 14 or more days apart using International Classification of Diseases-9-CM/-10-CM codes based on the provisional International Psychogeriatric Association agitation definition. Patients with severe psychiatric disorders were excluded. Two cohorts of patients (with and without agitation) were then defined, and patient characteristics, healthcare resource utilization, and costs were compared in a descriptive exploratory analysis. Results: Of 2 684 704 Fee-for-Service patients with Alzheimer dementia, 769 141 met all inclusion criteria; among these, 281 042 (36.5%) had agitation. The mean age in patients with and without agitation in Alzheimer dementia was 83 years. Most patients in both groups were female, but the proportion of males was slightly higher in the agitation in Alzheimer dementia group (30.3% vs 28.2%, respectively). Patients with agitation in Alzheimer dementia were more likely than those without agitation in Alzheimer dementia to have lower socioeconomic status (dual eligibility for Medicaid, 45.0% vs 41.7%, respectively) or be disabled (10.5% vs 9.4%). Overall, healthcare costs were higher in the agitation in Alzheimer dementia population compared with those without agitation in Alzheimer dementia (mean cost PPPY, 30 121, respectively), with the largest differences observed in inpatient and post-acute care costs. Conclusions: These exploratory findings underscore the substantial economic burden of agitation in Alzheimer dementia and highlight the need for treatment options for the agitation in Alzheimer dementia population to improve associated health outcomes.

Single-value brain activity scores reflect both severity and risk across the Alzheimer's continuum.

Single-value scores reflecting the deviation from (FADE score) or similarity with (SAME score) prototypical novelty-related and memory-related functional MRI activation patterns in young adults have been proposed as imaging biomarkers of healthy neurocognitive ageing. Here, we tested the utility of these scores as potential diagnostic and prognostic markers in Alzheimer's disease (AD) and risk states like mild cognitive impairment (MCI) or subjective cognitive decline (SCD). To this end, we analysed subsequent memory functional MRI data from individuals with SCD, MCI and AD dementia as well as healthy controls and first-degree relatives of AD dementia patients (AD-rel) who participated in the multi-centre DELCODE study (n = 468). Based on the individual participants' whole-brain functional MRI novelty and subsequent memory responses, we calculated the FADE and SAME scores and assessed their association with AD risk stage, neuropsychological test scores, CSF amyloid positivity and APOE genotype. Memory-based FADE and SAME scores showed a considerably larger deviation from a reference sample of young adults in the MCI and AD dementia groups compared to healthy controls, SCD and AD-rel. In addition, novelty-based scores significantly differed between the MCI and AD dementia groups. Across the entire sample, single-value scores correlated with neuropsychological test performance. The novelty-based SAME score further differed between Aβ-positive and Aβ-negative individuals in SCD and AD-rel, and between ApoE ɛ4 carriers and non-carriers in AD-rel. Hence, FADE and SAME scores are associated with both cognitive performance and individual risk factors for AD. Their potential utility as diagnostic and prognostic biomarkers warrants further exploration, particularly in individuals with SCD and healthy relatives of AD dementia patients.

Synaptic density patterns in early Alzheimer's disease assessed by independent component analysis.

Synaptic loss is a primary pathology in Alzheimer's disease and correlates best with cognitive impairment as found in post-mortem studies. Previously, we observed in vivo reductions of synaptic density with [11C]UCB-J PET (radiotracer for synaptic vesicle protein 2A) throughout the neocortex and medial temporal brain regions in early Alzheimer's disease. In this study, we applied independent component analysis to synaptic vesicle protein 2A-PET data to identify brain networks associated with cognitive deficits in Alzheimer's disease in a blinded data-driven manner. [11C]UCB-J binding to synaptic vesicle protein 2A was measured in 38 Alzheimer's disease (24 mild Alzheimer's disease dementia and 14 mild cognitive impairment) and 19 cognitively normal participants. [11C]UCB-J distribution volume ratio values were calculated with a whole cerebellum reference region. Principal components analysis was first used to extract 18 independent components to which independent component analysis was then applied. Subject loading weights per pattern were compared between groups using Kruskal-Wallis tests. Spearman's rank correlations were used to assess relationships between loading weights and measures of cognitive and functional performance: Logical Memory II, Rey Auditory Verbal Learning Test-long delay, Clinical Dementia Rating sum of boxes and Mini-Mental State Examination. We observed significant differences in loading weights among cognitively normal, mild cognitive impairment and mild Alzheimer's disease dementia groups in 5 of the 18 independent components, as determined by Kruskal-Wallis tests. Only Patterns 1 and 2 demonstrated significant differences in group loading weights after correction for multiple comparisons. Excluding the cognitively normal group, we observed significant correlations between the loading weights for Pattern 1 (left temporal cortex and the cingulate gyrus) and Clinical Dementia Rating sum of boxes (r = -0.54, P = 0.0019), Mini-Mental State Examination (r = 0.48, P = 0.0055) and Logical Memory II score (r = 0.44, P = 0.013). For Pattern 2 (temporal cortices), significant associations were demonstrated between its loading weights and Logical Memory II score (r = 0.34, P = 0.0384). Following false discovery rate correction, only the relationship between the Pattern 1 loading weights with Clinical Dementia Rating sum of boxes (r = -0.54, P = 0.0019) and Mini-Mental State Examination (r = 0.48, P = 0.0055) remained statistically significant. We demonstrated that independent component analysis could define coherent spatial patterns of synaptic density. Furthermore, commonly used measures of cognitive performance correlated significantly with loading weights for two patterns within only the mild cognitive impairment/mild Alzheimer's disease dementia group. This study leverages data-centric approaches to augment the conventional region-of-interest-based methods, revealing distinct patterns that differentiate between mild cognitive impairment and mild Alzheimer's disease dementia, marking a significant advancement in the field.

A network approach to subjective cognitive decline: Exploring multivariate relationships in neuropsychological test performance across Alzheimer's disease risk states

Subjective cognitive decline (SCD) is characterized by subjective concerns of cognitive change despite test performance within normal range. Although those with SCD are at higher risk for developing further cognitive decline, we still lack methods using objective cognitive measures that reliably distinguish SCD from cognitively normal aging at the group level. Network analysis may help to address this by modeling cognitive performance as a web of intertwined cognitive abilities, providing insight into the multivariate associations determining cognitive status. Following previous network studies of mild cognitive impairment (MCI) and Alzheimer's dementia (AD), the current study centered upon the novel visualization and analysis of the SCD cognitive network compared to cognitively normal (CN) older adult, MCI, and AD group networks. Cross-sectional neuropsychological data from CIMA-Q and COMPASS-ND cohorts were used to construct Gaussian graphical models for CN (n = 122), SCD (n = 207), MCI (n = 210), and AD (n = 79) groups. Group networks were explored in terms of global network structure, prominent edge weights, and strength centrality indices. CN and SCD group networks were contrasted using the Network Comparison Test. Results indicate that CN and SCD groups did not differ in univariate cognitive performance or global network structure. However, measures of strength centrality, principally in executive functioning and processing speed, showed a CN-SCD-MCI gradient where subtle differences within the SCD network suggest that SCD is an intermediary between CN and MCI stages. Additional results may indicate a distinctiveness of network structure in AD, a reversal in network influence between age and general cognitive status as clinical impairment increases, and potential evidence for cognitive reserve. Together, these results provide evidence that network-specific metrics are sensitive to cognitive performance changes across the dementia risk spectrum and can help to objectively distinguish SCD group cognitive performance from that of the CN group.

Choroid Plexus Volume, Amyloid Burden, and Cognition in the Alzheimer's Disease Continuum.

As a part of the glymphatic system, the choroid plexus (CP) is involved in the clearance of harmful metabolites from the brain. We investigated the association between CP volume (CPV), amyloid-β (Aβ) burden, and cognition in patients on the Alzheimer's disease (AD) continuum. We retrospectively reviewed the records of 203 patients on the AD continuum and 82 healthy controls who underwent brain magnetic resonance imaging and 18F-florbetaben positron emission tomography. Automatic segmentation was performed, and the CPV was calculated. Cognitive function was assessed using detailed neuropsychological tests, and patients on the AD continuum were categorized into the non-dementia and dementia groups. The relationships between CPV, Aβ burden, and cognitive function were assessed using multivariate linear regression and linear mixed model. CPV was greater in the AD group than in the healthy control group (1.50 vs. 1.30, P < 0.001), but was comparable between the AD non-dementia and dementia groups (1.50 vs. 1.48, P = 0.585). After adjusting for age and sex, a larger CPV was significantly associated with greater global Aβ deposition (β = 0.20, P = 0.002). Larger CPV was also associated with worse general cognitive function assessed using the sum of boxes of the clinical dementia rating scale (β = 0.85, P = 0.034) and lower composite scores for memory (β = -0.68, P = 0.002) and frontal/executive function domains (β = -0.65, P < 0.001). In addition, a larger CPV was associated with a more rapid decline in Mini-Mental State Examination scores in the AD dementia group (β = -0.58, P = 0.004). The present study demonstrated that CP enlargement was associated with increased Aβ deposition and impaired memory and frontal/executive function in patients on the AD continuum.

Alzheimer's Disease Linkage to Real-World Evidence (AD-LINE) Study: Linking Claims Data to Phase 3 GRADUATE Study of Gantenerumab.

Linking data from clinical trials and real-world claims may improve the robustness of trial data and provide information on the health, economic, and societal impacts of a disease. To report on the feasibility of linking trial data to Medicare claims data in early symptomatic Alzheimer's disease (AD) in the US. Alzheimer's Disease Linkage to Real-World Evidence (AD-LINE) was a noninterventional cohort study that included participants recruited from the GRADUATE program whose trial data were linked to their Medicare claims. AD-LINE participants were 66 years and older with early symptomatic AD (ie, mild cognitive impairment [MCI] due to AD or mild AD dementia) and were enrolled in the GRADUATE program and a Medicare fee-for-service or Medicare Advantage plan. The Centers for Medicare and Medicaid Services linked participants' clinical trial identifiers to their Medicare beneficiary identifiers using a deterministic, exact matching process. Demographics and clinical characteristics of the AD-LINE cohort at baseline were collected. Outcomes measured in this study included healthcare resource utilization derived from Medicare claims data. In total, 147 participants across 21 US sites were invited to participate and 111 provided informed consent. Of those, 61 patients had linkable data (ie, Medicare beneficiary identifier), Medicare Parts A/B enrollment, and no health maintenance organization (HMO) enrollment in the year before trial entry. Of the 61 participants whose data were analyzed in this study, 30 had MCI due to AD and 31 had mild AD dementia. Participants in the MCI due to AD group had more healthcare resource utilization on average in the baseline period than those in the mild AD dementia group (29.9 [SD, 20.9] vs 24.5 claims [SD, 12.3]). In an ad hoc analysis, a relatively high concordance (85.3%) was seen between the rates of clinically confirmed AD diagnosis and evidence of AD diagnosis in claims data. This linkage process may serve as a proof of concept for researchers interested in linking clinical trial and real-world claims data. The lessons learned from AD-LINE and innovation of data linkage approaches may encourage key stakeholders to link data in the future.

Relationship between cognitive function and phase angle measured with a bioelectrical impedance system.

The purpose of this study was to investigate the relationship between cognitive function and phase angle (PhA), an indicator of muscle quality. This cross-sectional study enrolled outpatients who visited a memory clinic at the Nagoya University hospital from January 2016 to June 2022. We enrolled 153 participants with body composition measurements. Inclusion criteria were a Mini-Mental State Examination score of 20-30 and a clinical diagnosis of Alzheimer's dementia (AD) or amnesic mild cognitive impairment (aMCI). The background characteristics of the participants were compared according to AD and aMCI. Next, linear regression analysis was performed with PhA as the objective variable. In addition, logistic regression analysis was performed for AD diagnosis. PhA was lower in the AD group (P = 0.009). In linear regression analysis, PhA consistently decreased with worsening ADAS score. In logistic regression analysis, high PhA was associated with absence of AD. Gender-specific analyses showed these associations existed only in men. Our study of patients with AD and aMCI found that PhA decreased with worsening of cognitive function. Compared with aMCI, AD was associated with significantly lower PhA. Our results strengthen the limited evidence in the literature showing that low muscle quality is associated with poor cognitive function.

CSF 14-3-3β is associated with progressive cognitive decline in Alzheimer's disease.

Alzheimer's disease is a neurodegenerative disorder characterized pathologically by amyloid-beta plaques, tau tangles and neuronal loss. In clinical practice, the 14-3-3 isoform beta (β) is a biomarker that aids in the diagnosis of sporadic Creutzfeldt-Jakob disease. Recently, a proteomics study found increased CSF 14-3-3β levels in Alzheimer's disease patients, suggesting a potential link between CSF 14-3-3β and Alzheimer's disease. Our present study aimed to further investigate the role of CSF 14-3-3β in Alzheimer's disease by analysing the data of 719 participants with available CSF 14-3-3β measurements from the Alzheimer's Disease Neuroimaging Initiative. Higher CSF 14-3-3β levels were observed in the mild cognitive impairment group compared to the cognitively normal group, with the highest CSF 14-3-3β levels in the Alzheimer's disease dementia group. This study also found significant associations between CSF 14-3-3β levels and CSF biomarkers of p-tau, t-tau, pTau/Aβ42 ratios and GAP-43, as well as other Alzheimer's disease biomarkers such as Aβ-PET. An early increase in CSF 14-3-3β levels was observed prior to Aβ-PET-positive status, and CSF 14-3-3β levels continued to rise after crossing the Aβ-PET positivity threshold before reaching a plateau. The diagnostic accuracy of CSF 14-3-3β (area under the receiver operating characteristic curve = 0.819) was moderate compared to other established Alzheimer's disease biomarkers in distinguishing cognitively normal Aβ pathology-negative individuals from Alzheimer's disease Aβ pathology-positive individuals. Higher baseline CSF 14-3-3β levels were associated with accelerated cognitive decline, reduced hippocampus volumes and declining fluorodeoxyglucose-PET values over a 4-year follow-up period. Patients with mild cognitive impairment and high CSF 14-3-3β levels at baseline had a significantly increased risk [hazard ratio = 2.894 (1.599-5.238), P < 0.001] of progression to Alzheimer's disease dementia during follow-up. These findings indicate that CSF 14-3-3β may be a potential biomarker for Alzheimer's disease and could provide a more comprehensive understanding of the underlying pathological changes of Alzheimer's disease, as well as aid in the diagnosis and monitoring of disease progression.

Association of Sleep Disturbances With Brain Amyloid and Tau Burden, Cortical Atrophy, and Cognitive Dysfunction Across the AD Continuum.

Patients with Alzheimer disease (AD) frequently suffer from various sleep disturbances. However, how sleep disturbance is associated with AD and its progression remains poorly investigated. We investigated the association of total sleep time with brain amyloid and tau burden, cortical atrophy, cognitive dysfunction, and their longitudinal changes in the AD spectrum. In this retrospective cohort study, we enrolled participants on the AD spectrum who were positive on 18F-florbetaben (FBB) PET. All participants underwent the Pittsburgh Sleep Quality Index, brain MRI, FBB PET, 18F-flortaucipir (FTP) PET, and detailed neuropsychological testing. In addition, a subset of participants completed follow-up assessments. We analyzed the association of total sleep time with the baseline and longitudinal FBB-standardized uptake value ratio (SUVR), FTP-SUVR, cortical thickness, and cognitive domain composite scores. We examined 138 participants on the AD spectrum (15 with preclinical AD, 62 with prodromal AD, and 61 with AD dementia; mean age 73.4 ± 8.0 years; female 58.7%). Total sleep time was longer in the AD dementia group (7.4 ± 1.6 hours) compared with the preclinical (6.5 ± 1.4 hours; p = 0.026) and prodromal groups (6.6 ± 1.4 hours; p = 0.001), whereas other sleep parameters did not differ between groups. Longer total sleep time was not associated with amyloid accumulation but rather with tau accumulation, especially in the amygdala, hippocampus, basal forebrain, insular, cingulate, occipital, inferior temporal cortices, and precuneus. Longer total sleep time predicted faster tau accumulation in Braak regions V-VI (β = 0.016, p = 0.007) and disease progression to mild cognitive impairment or dementia (hazard ratio = 1.554, p = 0.024). Longer total sleep time was also associated with memory deficit (β = -0.19, p = 0.008). Prolonged total sleep time was associated with tau accumulation in sleep-related cortical and subcortical areas as well as memory dysfunction. It also predicted faster disease progression with tau accumulation. Our study highlights the clinical importance of assessing total sleep time as a marker for disease severity and prognosis in the AD spectrum.

Verbal fluency discrepancies as a marker of the prehippocampal stages of Alzheimer's disease.

Prior to evidence of episodic memory decline, a lengthy preclinical phase of Alzheimer's disease (AD) exists characterized by the build-up of tau pathology within extrahippocampal structures. Semantic memory, also impaired in AD, has been linked to degradation within these earliest affected areas. This study aimed to assess the utility of performance discrepancies between letter and category verbal fluency tasks to detect neuronal loss in brain regions affected very early by AD. Whole-brain voxel-based morphometry was used to assess the neural correlates of semantic processing in three patient groups: two groups of mild cognitive impairment (MCI) patients split into mildly (n = 58) and moderately (n = 53) affected and a mild AD dementia group (n = 71). Discrepancies between the level of impairment on the semantic category fluency test and nonsemantic letter fluency test were calculated for each participant and included in regression models measuring the relationship between semantic memory and whole-brain gray matter volume. Patients at all disease stages demonstrated a loss of the normal semantic advantage in fluency tests, showing significantly greater impairments in category relative to letter fluency. Discrepancy scores in mild MCI correlated strongly with the structural integrity of the anterior medial temporal lobes. Correlations in more severely affected groups were weaker and more widespread. Semantic memory appears a useful indicator of even the earliest stages of medial temporal damage in AD. With advancing disease severity, the discrepancy index loses its focal anatomical association, reinforcing its value as an early marker of incipient decline. (PsycInfo Database Record (c) 2023 APA, all rights reserved).

Olfactory Dysfunction Is Associated with Cerebral Amyloid Deposition and Cognitive Function in the Trajectory of Alzheimer's Disease.

Olfactory dysfunction is consistently observed in individuals with Alzheimer's disease (AD), but its association with beta-amyloid (Aβ) deposition remains unclear. This study aimed to investigate the relationship among olfactory function, cerebral Aβ deposition, and neuropsychological profiles in individuals with no cognitive impairment (NCI), mild cognitive impairment (MCI), and AD dementia. A total of 164 participants were included, and olfactory function was assessed using the brief smell identification test (B-SIT). Cerebral Aβ deposition was measured using [18F]-flutemetamol PET imaging (A-PET). The results show a significant group difference in olfactory function, with the highest impairment observed in the Aβ-positive MCI and AD dementia groups, and the impairment was the lowest in Aβ-negative NCI. Olfactory dysfunction was positively associated with cognitive impairments across multiple domains. Furthermore, individuals with Aβ deposition had lower olfactory function compared to those without Aβ, even within the same neuropsychological stage. The association between olfactory dysfunction and Aβ deposition was observed globally and in specific cortical regions. These findings suggest that olfactory dysfunction is associated with both cognitive function and cerebral Aβ pathology in the trajectory of AD. Olfactory deficits may serve as an additional marker for disease progression and contribute to understanding the underlying mechanisms of AD.

Optical Coherence Tomography Assessment of Macular Thickness in Alzheimer's Dementia with Different Neuropsychological Severities.

This retrospective case-control study aimed to investigate associations between disease severity of Alzheimer's dementia (AD) and macular thickness. Data of patients with AD who were under medication (n = 192) between 2013 and 2020, as well as an age- and sex-matched control group (n = 200) with normal cognitive function, were included. AD patients were divided into subgroups according to scores of the Mini-Mental State Examination (MMSE) and Clinical Dementia Rating (CDR). Macular thickness was analyzed via the Early Treatment Diabetic Retinopathy Study (ETDRS) grid map. AD patients had significant reductions in full macula layers, including inner circle, outer inferior area, and outer nasal area of the macula. Similar retinal thinning was noted in ganglion cells and inner plexiform layers. Advanced AD patients (MMSE score < 18 or CDR ≥ 1) showed more advanced reduction of macular thickness than the AD group (CDR = 0.5 or MMSE ≥ 18), indicating that severe cognitive impairment was associated with thinner macular thickness. Advanced AD is associated with significant macula thinning in full retina and inner plexiform layers, especially at the inner circle of the macula. Macular thickness may be a useful biomarker of AD disease severity. Retinal imaging may be a non-invasive, low-cost surrogate for AD.

Association between serum lipid levels and lower-extremity functions in older adults with and without Alzheimer's dementia in South Korea: A cross-sectional analysis

PurposeOlder adults with Alzheimer's dementia (AD) experience lower-extremity dysfunction. High serum lipid levels are a risk factor for AD. We investigated the association between serum lipid levels and lower-extremity function in older individuals with and without AD. MethodsIn this cross-sectional study, we enrolled 33,185 senior citizens (aged 66 years) who participated in the National Geriatric Screening Program, sampled from the Korean National Health Insurance Service-National Health Screening Cohort Database, between 2009 and 2015. Participants were dichotomized into 1) an AD group comprising individuals with the International Classification of Diseases, Tenth Revision, diagnostic codes F00, F00.0–F00.9, and G30, G30.0–G30.9; and 2) a control group comprising individuals without AD.Differences in the Timed Up and Go and One-Leg Standing results among the three levels (low, moderate, and high) of total cholesterol (TC), triglycerides (TG), low-density lipoprotein cholesterol (LDL-C), and high-density lipoprotein cholesterol were evaluated between the groups. Logistic regression analysis was performed to estimate the odds of gait disorder considering clinical and lifestyle variables. ResultsIn participants with low LDL-C levels, increased LDL-C levels correlated with higher gait speed. In the AD group, balancing time with eyes open (BT-EO) was inversely correlated with TG levels in participants with low TG levels. In the control group, BT-EO was negatively correlated with TC levels in participants with low TC levels. ConclusionSerum lipid levels were significantly correlated with lower-extremity function in participants with and without AD but not with gait disorder in participants with AD.

Effects of APOE genotype on amyloid PET positivity according to cognitive status and ethnicity

AbstractBackgroundAmong the various risk factors for Alzheimer disease (AD), apolipoprotein E (APOE) genotype ε4 is known to be a strong factor. On the other hand, ε2 is known to have a protective effect. It is not yet clear how amyloid positivity according to the APOE genotype differs by diagnostic criteria. Also, there were no studies showing the ethnic difference in the effects of APOE genotype on amyloid‐beta (Aβ) between American and Asian. The aim of this study was to investigate how Aβ positivity (Aβ+) according to APOE genotypes differs by ethnicity and cognition.MethodWe recruited 4,203 Korean subjects from multi‐centers in South Korea and 1,069 subjects from Alzheimer’s Disease Neuroimaging Initiative database. All subjects underwent neuropsychological tests, APOE genotype tests, and amyloid PET (FMM/FBB/AV45) scans. Subjects with the ε2/ε4 genotype were excluded due to the opposing effects of the ε4 and ε2 alleles. The degree of influence on amyloid positivity by each factor was analyzed by logistic regression.ResultThe frequency of Aβ+ in normal cognition (NC) group was higher in ADNI than in Korean group (p &lt;0.001). Amnestic mild cognitive impairment and AD dementia (ADD) groups showed no difference in the frequency of Aβ+ between ADNI and Korean groups. Relative to APOE ε3/ε3 group, APOE ε4 carriers showed higher frequent Aβ+ regardless of cognitive status and ethnicity (Figure). ADNI and Korean groups showed APOE ε2 carriers less frequent Aβ+ in ADD but not in NC relative to APOE ε3/ε3 group.ConclusionOur findings suggested that there were no differences in effects of APOE ε4 genotype on Aβ+ between European and Korean. These findings will be helpful in predicting amyloid positivity and AD intervention according to APOE genotype and ethnicity.

Amyloid‐associated increases in soluble tau is a key driver in accumulation of tau aggregates and cognitive decline in early Alzheimer

AbstractBackgroundFor optimal design of anti‐amyloid‐β (Aβ) and anti‐tau clinical trials, it is important to understand how Aβ and soluble phosphorylated tau (p‐tau) relate to the accumulation of tau aggregates assessed with positron emission tomography (PET) and subsequent cognitive decline across the Alzheimer's disease (AD) continuum.MethodWe included 327 participants from the Swedish BioFINDER‐2 cohort with cerebrospinal fluid (CSF) p‐tau217, Aβ‐PET, longitudinal tau‐PET, and longitudinal cognition. The main groups of interest were Aβ‐positive non‐demented participants and AD dementia patients (Table 1 and Figure 1), and analyses were conducted separately in each group. First, we investigated how soluble p‐tau217 and regional Aβ‐PET were associated with tau‐PET rate of change across the 200 brain parcels from the Schaefer atlas. We also tested the mediating effect of p‐tau217 between Aβ‐PET and tau‐PET change. Second, we investigated how soluble p‐tau217 and tau‐PET change related to change in cognition, and mediation between these variables.ResultIn early AD stages (non‐demented participants), increased concentration of soluble p‐tau217 was the main driver of accumulation of insoluble tau aggregates across the brain (measured as tau‐PET rate of change), beyond the effect of regional Aβ‐PET and baseline tau‐PET (Figure 2A‐C). Further, averaged across all regions, soluble p‐tau217 mediated 54% of the association between Aβ and tau aggregation (Figure 2D). Higher soluble p‐tau217 concentrations were also associated with cognitive decline, which was mediated by faster increase of tau aggregates (Figure 3). Repeating the same analyses in the AD dementia group, results were different. In late stage of AD, when Aβ fibrils and soluble p‐tau levels have plateaued, soluble p‐tau217 was not associated with accumulation of tau aggregates beyond baseline tau‐PET (Figure 4A), and cognitive decline was driven by the accumulation rate of insoluble tau aggregates and not soluble p‐tau217 (Figure 4B‐C).ConclusionSoluble p‐tau is a main driver of tau aggregation and future cognitive decline in earlier stages of AD, whereas tau aggregation accumulation is more likely an important driver of disease in later stages. Overall, our data suggest that therapeutic approaches reducing soluble p‐tau levels might be most favorable in early AD.

Amyloid‐associated increases in soluble tau is a key driver in accumulation of tau aggregates and cognitive decline in early Alzheimer

AbstractBackgroundFor optimal design of anti‐amyloid‐β (Aβ) and anti‐tau clinical trials, it is important to understand how Aβ and soluble phosphorylated tau (p‐tau) relate to the accumulation of tau aggregates assessed with positron emission tomography (PET) and subsequent cognitive decline across the Alzheimer's disease (AD) continuum.MethodWe included 327 participants from the Swedish BioFINDER‐2 cohort with cerebrospinal fluid (CSF) p‐tau217, Aβ‐PET, longitudinal tau‐PET, and longitudinal cognition. The main groups of interest were Aβ‐positive non‐demented participants and AD dementia patients (Table 1 and Figure 1), and analyses were conducted separately in each group. First, we investigated how soluble p‐tau217 and regional Aβ‐PET were associated with tau‐PET rate of change across the 200 brain parcels from the Schaefer atlas. We also tested the mediating effect of p‐tau217 between Aβ‐PET and tau‐PET change. Second, we investigated how soluble p‐tau217 and tau‐PET change related to change in cognition, and mediation between these variables.ResultIn early AD stages (non‐demented participants), increased concentration of soluble p‐tau217 was the main driver of accumulation of insoluble tau aggregates across the brain (measured as tau‐PET rate of change), beyond the effect of regional Aβ‐PET and baseline tau‐PET (Figure 2A‐C). Further, averaged across all regions, soluble p‐tau217 mediated 54% of the association between Aβ and tau aggregation (Figure 2D). Higher soluble p‐tau217 concentrations were also associated with cognitive decline, which was mediated by faster increase of tau aggregates (Figure 3). Repeating the same analyses in the AD dementia group, results were different. In late stage of AD, when Aβ fibrils and soluble p‐tau levels have plateaued, soluble p‐tau217 was not associated with accumulation of tau aggregates beyond baseline tau‐PET (Figure 4A), and cognitive decline was driven by the accumulation rate of insoluble tau aggregates and not soluble p‐tau217 (Figure 4B‐C).ConclusionSoluble p‐tau is a main driver of tau aggregation and future cognitive decline in earlier stages of AD, whereas tau aggregation accumulation is more likely an important driver of disease in later stages. Overall, our data suggest that therapeutic approaches reducing soluble p‐tau levels might be most favorable in early AD.

Association of functional connectivity of the executive control network or default mode network with cognitive impairment in older adults with remitted major depressive disorder or mild cognitive impairment.

Major depressive disorder (MDD) is associated with an increased risk of developing dementia. The present study aimed to better understand this risk by comparing resting state functional connectivity (rsFC) in the executive control network (ECN) and the default mode network (DMN) in older adults with MDD or mild cognitive impairment (MCI). Additionally, we examined the association between rsFC in the ECN or DMN and cognitive impairment transdiagnostically. We assessed rsFC alterations in ECN and DMN in 383 participants from five groups at-risk for dementia-remitted MDD with normal cognition (MDD-NC), non-amnestic mild cognitive impairment (naMCI), remitted MDD + naMCI, amnestic MCI (aMCI), and remitted MDD + aMCI-and from healthy controls (HC) or individuals with Alzheimer's dementia (AD). Subject-specific whole-brain functional connectivity maps were generated for each network and group differences in rsFC were calculated. We hypothesized that alteration of rsFC in the ECN and DMN would be progressively larger among our seven groups, ranked from low to high according to their risk for dementia as HC, MDD-NC, naMCI, MDD + naMCI, aMCI, MDD + aMCI, and AD. We also regressed scores of six cognitive domains (executive functioning, processing speed, language, visuospatial memory, verbal memory, and working memory) on the ECN and DMN connectivity maps. We found a significant alteration in the rsFC of the ECN, with post hoc testing showing differences between the AD group and the HC, MDD-NC, or naMCI groups, but no significant alterations in rsFC of the DMN. Alterations in rsFC of the ECN and DMN were significantly associated with several cognitive domain scores transdiagnostically. Our findings suggest that a diagnosis of remitted MDD may not confer functional brain risk for dementia. However, given the association of rs-FC with cognitive performance (i.e., transdiagnostically), rs-FC may help in stratifying this risk among people with MDD and varying degrees of cognitive impairment.

CSF neurofilament light may predict progression from amnestic mild cognitive impairment to Alzheimer's disease dementia

Neurofilament light (NfL) is a promising biomarker of neurodegeneration in Alzheimer's disease (AD). In this study, cerebrospinal fluid (CSF) NfL was measured in a 24-month longitudinal cohort consisting of control (n = 52), amnestic mild cognitive impairment (aMCI) (n = 55), and probable AD dementia (n = 28) individuals. The cohort was reevaluated after 6-10 years. Baseline CSF NfL was significantly elevated in aMCI and probable AD dementia groups compared to controls (p < 0.0001). CSF NfL was significantly lower in stable aMCI patients compared to aMCI patients who converted to probable AD dementia within the 24-month period (p = 0.004). Substituting T-tau for NfL in the core AD biomarkers model (Aβ42/P-tau/T-tau) did not improve ability to separate control and AD, or stable and converter aMCI patients. Our results support that elevated CSF NfL could predict progression in aMCI patients, but its utility cannot improve the core AD biomarkers.