Mild Alzheimer's Disease Dementia Research Articles

Neurofilament Light Chain as a Biomarker of Global Cognition in Individuals With Possible Vascular Mild Cognitive Impairment.

Neurofilament Light Chain (NfL) is a biomarker of axonal injury elevated in mild cognitive impairment (MCI) and Alzheimer's disease dementia. Blood NfL also inversely correlates with cognitive performance in those conditions. However, few studies have assessed NfL as a biomarker of global cognition in individuals demonstrating mild cognitive deficits who are at risk for vascular-related cognitive decline. To assess the relationship between blood NfL and global cognition in individuals with possible vascular MCI (vMCI) throughout cardiac rehabilitation (CR). Additionally, NfL levels were compared to age/sex-matched cognitively unimpaired (CU) controls. Participants with coronary artery disease (vMCI or CU) were recruited at entry to a 24-week CR program. Global cognition was measured using the Montreal Cognitive Assessment (MoCA) and plasma NfL level (pg/ml) was quantified using a highly sensitive enzyme-linked immunosorbent assay. Higher plasma NfL was correlated with worse MoCA scores at baseline (β = -.352, P = .029) in 43 individuals with vMCI after adjusting for age, sex, and education. An increase in NfL was associated with worse global cognition (b[SE] = -4.81[2.06], P = .023) over time, however baseline NfL did not predict a decline in global cognition. NfL levels did not differ between the vMCI (n = 39) and CU (n = 39) groups (F(1, 76) = 1.37, P = .245). Plasma NfL correlates with global cognition at baseline in individuals with vMCI, and is associated with decline in global cognition during CR. Our findings increase understanding of NfL and neurobiological mechanisms associated with cognitive decline in vMCI.

Slovenian Memory Clinic Organization with the Introduction of Potential New Alzheimer's Disease Treatment.

Slovenia, situated in Central Europe with a population of 2.1 million, has an estimated 44,278 individuals with mild cognitive impairment due to Alzheimer's disease or mild Alzheimer's dementia, rendering them potential candidates for disease-modifying treatment (DMT), such as lecanemab. We identified 114 potential candidates whose real-life expenses for diagnostic process surmount to more than €80,000. Treating all potential candidates nationwide would amount to €1.06 billion, surpassing Slovenia's entire annual medication expenditure for 2022 (€743 million). The introduction of DMTs and the associated logistics, along with potential complications, will significantly change societal, professional, and patient approach to treatment of Alzheimer's disease.

Combining neuropsychological assessment and structural neuroimaging to identify early Alzheimer's disease in a memory clinic cohort.

The current study examined the contributions of comprehensive neuropsychological assessment and volumetric assessment of selected mesial temporal subregions on structural magnetic resonance imaging (MRI) to identify patients with amnestic mild cognitive impairment (aMCI) and mild probable Alzheimer's disease (AD) dementia in a memory clinic cohort. Comprehensive neuropsychological assessment and automated entorhinal, transentorhinal, and hippocampal volume measurements were conducted in 40 healthy controls, 38 patients with subjective memory symptoms, 16 patients with aMCI, 16 patients with mild probable AD dementia. Multinomial logistic regression was used to compare the neuropsychological and MRI measures. Combining the neuropsychological and MRI measures improved group membership prediction over the MRI measures alone but did not improve group membership prediction over the neuropsychological measures alone. Comprehensive neuropsychological assessment was an important tool to evaluate cognitive impairment. The mesial temporal volumetric MRI measures contributed no diagnostic value over and above the determinations made through neuropsychological assessment.

Real World Prescribing: Use of Anti-Amyloid Antibodies in Clinical Practice

Anti-amyloid antibody therapy is now available for clinical use in MCI due to Alzheimer's disease and mild Alzheimer's dementia. This symposium will focus on clinical aspects of screening, prescribing and safety monitoring. The first talk will address patient eligibility and therapy implementation. The speaker will discuss disease staging and how to recognize neuroimaging abnormalities and concomitant medications that would exclude patient from eligibility. The speaker will explore use of CSF or amyloid PET to confirm amyloid pathology and use of ApoE genotyping to assess ARIA risk. There will be emphasis on ways to provide treatment specific education to patients and their care partners. Lastly, the speaker will demonstrate infusions orders and utilization of CMS registry for Medicare coverage.The second talk will move to management issues once a patient starts receiving antibody therapy, such as identifying and treating infusion reactions. Our neurologist speaker will define and review the edema and hemorrhage subtypes of Amyloid-Related Imaging Abnormalities (ARIA-E and ARIA-H respectively). The speaker will recommend MRI monitoring schedule and provide strategies to reduce risk and manage ARIA.The final talk will utilize case studies to demonstrate best practices. The speakers will share lessons learned from their collective expertise. The panel acknowledges two different providers on the care spectrum - one being a treating provider and one being a referring provider. Referring providers will learn to create a comprehensive referral, ensuring efficient treatment transition.At time of submission, there are pending issues relevant to this symposium. Commercial insurance and Medicare Advantage plans are currently clarifying their position on drug coverage and patient registry requirement. CMS has proposed a coverage pathway for amyloid PET scans, currently in an open-comment period. There could be an introduction of an AD blood test, but it is unclear if would be acceptable for pathology confirmation. The speakers will address these updates.

Association between T1w/T2w ratio in white matter and cognitive function in Alzheimer’s disease

Loss of myelin in the brain may lead to cognitive decline in Alzheimer's disease (AD). The ratio of T1 weighted/T2 weighted (T1w/T2w) on magnetic resonance imaging has been used as a proxy for myelin content in the brain. Using this approach, we investigated the correlation between the white matter (WM) T1w/T2w ratio and both cognitive scores and disease progression in AD. A total of 93 participants who were cognitively unimpaired or diagnosed with mild cognitive impairment or AD dementia were recruited between March 2021 and November 2022. All participants were assessed using neuropsychological tests, and a subset of the participants was assessed every 1 year to monitor disease progression. We observed significant positive associations between the WM T1w/T2w ratio and executive function within the fornix, sagittal stratum, anterior internal capsule, and body of the corpus callosum (False discovery rate [FDR]-corrected P-value < 0.05). There was a marginal interaction between the WM T1w/T2w ratio of the left anterior internal capsule and the longitudinal change in sum of boxes of the Clinical Dementia Rating Scale (FDR-corrected P-value = 0.05). The present study demonstrated that the WM T1w/T2w ratio was associated with executive function and disease progression, suggesting that it may be a novel neuroimaging marker for AD.

ChatGPT as a Diagnostic Aid in Alzheimer's Disease: An Exploratory Study.

The potential of ChatGPT in medical diagnosis has been explored in various medical conditions. We assessed whether ChatGPT can contribute to the diagnosis of Alzheimer's disease (AD). We provided ChatGPT with four generated cases (mild, moderate, or advanced stage AD dementia, or mild cognitive impairment), including descriptions of their complaints, physical examinations, as well as biomarker, neuroimaging, and neuropsychological data. ChatGPT accurately diagnosed the test cases similarly to two blinded specialists. While the use of generated cases can be a limitation to our study, our findings demonstrate that ChatGPT can be a useful tool for symptom assessment and the diagnosis of AD. However, while the use of ChatGPT in AD diagnosis is promising, it should be seen as an adjunct to clinical judgment rather than a replacement.

Feasibility and usefulness of cognitive monitoring using a new home-based cognitive test in mild cognitive impairment: a prospective single arm study

BackgroundThe risk of dementia is increased in subjects with mild cognitive impairment (MCI). Despite the plethora of in-person cognitive tests, those that can be administered over the phone are lacking. We hypothesized that a home-based cognitive test (HCT) using phone calls would be feasible and useful in non-demented elderly. We aimed to assess feasibility and validity of a new HCT as an optional cognitive monitoring tool without visiting hospitals.MethodsOur study was conducted in a prospective design during 24 weeks. We developed a new HCT consisting of 20 questions (score range 0–30). Participants with MCI (n = 38) were consecutively enrolled and underwent regular HCTs during 24 weeks. Associations between HCT scores and in-person cognitive scores and Alzheimer’s disease (AD) biomarkers were evaluated. In addition, HCT scores in MCI participants were cross-sectionally compared with age-matched cognitively normal (n = 30) and mild AD dementia (n = 17) participants for discriminative ability of the HCT.ResultsHCT had good intra-class reliability (test-retest Cronbach’s alpha 0.839). HCT scores were correlated with the Mini-Mental State Examination (MMSE), verbal memory delayed recall, and Stroop test scores but not associated with AD biomarkers. HCT scores significantly differed among cognitively normal, MCI, and mild dementia participants, indicating its discriminative ability. Finally, 32 MCI participants completed follow-up evaluations, and 8 progressed to dementia. Baseline HCT scores in dementia progressors were lower than those in non-progressors (p = 0.001).ConclusionThe feasibility and usefulness of the HCT were demonstrated in elderly subjects with MCI. HCT could be an alternative option to monitor cognitive decline in early stages without dementia.

A proof of concept phase II study with the PDE-4 inhibitor roflumilast in patients with mild cognitive impairment or mild Alzheimer’s disease dementia (ROMEMA): study protocol of a double-blind, randomized, placebo-controlled, between-subjects trial

BackgroundResearch into the neurobiological underpinnings of learning and memory has demonstrated the cognitive-enhancing effects associated with diverse classes of phosphodiesterase (PDE) inhibitors. Specific PDE inhibitors have been identified to improve neuronal communication through selective inhibition of PDE activity. Roflumilast, a PDE4 inhibitor, has demonstrated efficacy in enhancing episodic memory in healthy adults and elderly participants with pronounced memory impairment, indicative of amnestic mild cognitive impairment (aMCI). In alignment with these findings, the present protocol aims to provide a proof of concept phase II of the potential of roflumilast to aid patients diagnosed with (a)MCI or mild Alzheimer’s disease (AD) dementia.MethodsThe study will be conducted according to a double-blind, randomized placebo-controlled, between-subjects design. Participants with (a)MCI and mild AD dementia will be recruited through the Memory Clinic at the Maastricht University Medical Centre + (MUMC +) in Maastricht, the Netherlands, alongside outreach through regional hospitals, and social media. The study will have three arms: placebo, 50 μg roflumilast, and 100 μg roflumilast, with a treatment duration of 24 weeks. The primary outcome measure will focus on the assessment of episodic memory, as evaluated through participants’ performance on the 15-word Verbal Learning Task (VLT). Our secondary objectives are multifaceted, including an exploration of various cognitive domains. In addition, insights into the well-being and daily functioning of participants will be investigated through interviews with both the participants and their (informal) caregivers, we are interested in the well-being and daily functioning of the participants.DiscussionThe outcomes of the present study aim to elucidate the significance of the PDE4 inhibition mechanism as a prospective therapeutic target for enhancing cognitive function in individuals with (a)MCI and mild AD dementia. Identifying positive effects within these patient cohorts could extend the relevance of this treatment to encompass a broader spectrum of neurological disorders.Trial registrationThe Medical Ethics Committee of MUMC + granted ethics approval for the 4th version of the protocol on September 10th, 2020. The trial was registered at the European Drug Regulatory Affairs Clinical Trials (EudraCT) registered on the 19th of December 2019 (https://www.clinicaltrialsregister.eu/ctr-search/trial/2019-004959-36/NL) and ClinicalTrial.gov (NCT04658654, https://clinicaltrials.gov/study/NCT04658654?intr=roflumilast&cond=mci&rank=1) on the 8th of December 2020. The Central Committee on Research Involving Human Subjects (CCMO) granted approval on the 30th of September 2020.

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.

Polygenic effects on the risk of Alzheimer's disease in the Japanese population.

Polygenic effects have been proposed to account for some disease phenotypes; these effects are calculated as a polygenic risk score (PRS). This score is correlated with Alzheimer's disease (AD)-related phenotypes, such as biomarker abnormalities and brain atrophy, and is associated with conversion from mild cognitive impairment (MCI) to AD. However, the AD PRS has been examined mainly in Europeans, and owing to differences in genetic structure and lifestyle, it is unclear whether the same relationships between the PRS and AD-related phenotypes exist in non-European populations. In this study, we calculated and evaluated the AD PRS in Japanese individuals using genome-wide association study (GWAS) statistics from Europeans. In this study, we calculated the AD PRS in 504 Japanese participants (145 cognitively unimpaired (CU) participants, 220 participants with late mild cognitive impairment (MCI), and 139 patients with mild AD dementia) enrolled in the Japanese Alzheimer's Disease Neuroimaging Initiative (J-ADNI) project. In order to evaluate the clinical value of this score, we (1) determined the polygenic effects on AD in the J-ADNI and validated it using two independent cohorts (a Japanese neuropathology (NP) cohort (n = 565) and the North American ADNI (NA-ADNI) cohort (n = 617)), (2) examined the AD-related phenotypes associated with the PRS, and (3) tested whether the PRS helps predict the conversion of MCI to AD. The PRS using 131 SNPs had an effect independent of APOE. The PRS differentiated between CU participants and AD patients with an area under the curve (AUC) of 0.755 when combined with the APOE variants. Similar AUC was obtained when PRS calculated by the NP and NA-ADNI cohorts was applied. In MCI patients, the PRS was associated with cerebrospinal fluid phosphorylated-tau levels (β estimate = 0.235, p value = 0.026). MCI with a high PRS showed a significantly increased conversion to AD in APOE ε4 noncarriers with a hazard rate of 2.22. In addition, we also developed a PRS model adjusted for LD and observed similar results. We showed that the AD PRS is useful in the Japanese population, whose genetic structure is different from that of the European population. These findings suggest that the polygenicity of AD is partially common across ethnic differences.

Predicting functional decline in aging and Alzheimer's disease with PET-based Braak staging.

The progression of PET-based Braak stages correlates with cognitive deterioration in aging and Alzheimer's disease. Here, we investigate the association between PET-based Braak stages and functional impairment and assess whether PET-based Braak staging predicts a longitudinal decline in the performance of activities of daily living. In this cohort study, we evaluated cognitively unimpaired individuals and individuals with mild cognitive impairment or Alzheimer's disease dementia. Participants underwent [18F]MK6240 tau-PET, were assigned a PET-based Braak stage at baseline and were followed for a mean (SD) of 1.97 (0.66) years. Functional performance was evaluated with the Functional Activities Questionnaire, Everyday Cognition and functional Clinical Dementia Rating sum of boxes. Multiple linear regressions assessed the association of PET-based Braak stages with baseline functionality and with the longitudinal rate of change in functional scores, adjusting for age, sex and amyloid-β load. We employed voxel-based regression models to investigate the association between functionality and tau-PET signal and assessed the voxel overlap with Braak regions of interest. We included 291 individuals (181 cognitively unimpaired, 56 amyloid-β+ mild cognitive impairment and 54 amyloid-β+ Alzheimer's disease) aged 70.60 (7.48) years. At baseline, PET-based Braak stages III-IV (β = 0.43, P = 0.03) and V-VI (β = 1.20, P < 0.0001) showed associations with poorer Functional Activities Questionnaire scores. Similarly, stages III-IV (β = 0.43, P = 0.02) and V-VI (β = 1.15, P < 0.0001) were associated with worse Everyday Cognition scores. Only stages V-VI were associated with higher functional Clinical Dementia Rating sum of boxes (β = 1.17, P < 0.0001) scores. Increased tau-PET signals in all Braak regions of interest were linked to worse performance in all tools. The voxelwise analysis showed widespread cortical associations between functional impairment and tau-PET and high voxel overlap with Braak regions of interest. Baseline PET-based Braak stages V-VI predicted significant longitudinal functional decline as assessed by the Functional Activities Questionnaire (β = 1.69, P < 0.0001), the Everyday Cognition (β = 1.05, P = 0.001) and the functional Clinical Dementia Rating sum of boxes (β = 1.29, P < 0.0001). Our results suggest that functional impairment increases with the severity of tau accumulation. These findings also indicate that PET-based Braak staging is a good predictor of functional impairment in the Alzheimer's disease continuum. Finally, our study provides evidence for the clinical significance of the PET-based Braak staging framework.

Prevalence of mild behavioural impairment and its association with cognitive and functional impairment in normal cognition, mild cognitive impairment, and mild Alzheimer's dementia.

Mild behavioural impairment (MBI) is an emergent and persistent neuropsychiatric symptom (NPS) in subjects aged 50 and older who are at risk for cognitive decline. We examined the prevalence of MBI across the spectrum from cognitively normal (CN), mild cognitive impairment (MCI), to dementia, and further investigated the association between the MBI domain and cognitive and functional impairment. MBI was assessed in 2337 elderly patients in the Alzheimer's Disease Neuroimaging Initiative database (mean age, 73.04 years; 52.8% male). Among the subjects, 868 (37.1%) had normal cognition, 1066 (45.6%) had MCI, and 403 (17.2%) had mild Alzheimer's dementia (AD). MBI was evaluated in accordance with the Alzheimer's Association International Society to Advance Alzheimer's Research and Treatment diagnostic criteria for MBI, utilising the Neuropsychiatric Inventory. We compared the prevalence of the MBI domain with CN using multinominal logistic regression analysis and further quantified the magnitude of the association between MCI/AD and the MBI domains by calculating the population attributable risk (PAR). We assessed the association between the MBI domains and cognitive and functional impairment using simultaneous linear regression analysis. The most common MBI domains in each diagnostic group were affective dysregulation followed by impulse dyscontrol, decreased motivation, social inappropriateness, and abnormal perception or thought content. The PARs for MBI domains in subjects with MCI or AD were respectively: 16.60% and 24.34% for affective dysregulation; 3.72% and 18.06% for impulse dyscontrol; 4.78% and 14.13% for decreased motivation, 1.91% and 2.29% for social inappropriateness; and 0.68% and 3.85% for abnormal perception or thought content. All MBI domains except for social inappropriateness were significantly associated with a higher 11-item Alzheimer's Disease Assessment Scale-Cognitive Subscale total score. All MBI domains were significantly associated with a higher Functional Activities Questionnaire total score. Our findings show that MBI is highly prevalent across subjects with CN, MCI, and AD and is associated with cognitive and functional decline. MBI could be a crucial clinical phenotype relevant to the risk of cognitive and functional impairment, and provides a useful dimension pertinent to diagnostic approaches.

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.

Relationships of change in Clinical Dementia Rating (CDR) on patient outcomes and probability of progression: observational analysis

BackgroundUnderstanding the relationship among changes in Clinical Dementia Rating (CDR), patient outcomes, and probability of progression is crucial for evaluating the long-term benefits of disease-modifying treatments. We examined associations among changes in Alzheimer’s disease (AD) stages and outcomes that are important to patients and their care partners including activities of daily living (ADLs), geriatric depression, neuropsychiatric features, cognitive impairment, and the probabilities of being transitioned to a long-term care facility (i.e., institutionalization). We also estimated the total time spent at each stage and annual transition probabilities in AD.MethodsThe study included participants with unimpaired cognition, mild cognitive impairment (MCI) due to AD, and mild, moderate, and severe AD dementia in the National Alzheimer’s Coordinating Center (NACC) Uniform Data Set (UDS) database. The associations among change in AD stages and change in relevant outcomes were estimated using linear mixed models with random intercepts. The probability of transitioning to long-term care facilities was modeled using generalized estimating equations. The total length of time spent at AD stages and annual transition probabilities were estimated with multistate Markov models.ResultsThe estimated average time spent in each stage was 3.2 years in MCI due to AD and 2.2, 2.0, and 2.8 years for mild, moderate, and severe AD dementia, respectively. The annual probabilities of progressing from MCI to mild, moderate, and severe AD dementia were 20, 4, and 0.7%, respectively. The incremental change to the next stage of participants with unimpaired cognition, MCI, and mild, moderate, and severe AD dementia (to death) was 3.2, 20, 26.6, 31, and 25.3%, respectively. Changes in ADLs, neuropsychiatric features, and cognitive measures were greatest among participants who transitioned from MCI and mild AD dementia to more advanced stages. Participants with MCI and mild and moderate AD dementia had increasing odds of being transitioned to long-term care facilities over time during the follow-up period.ConclusionsThe findings demonstrated that participants with early stages AD (MCI or mild dementia) were associated with the largest changes in clinical scale scores. Early detection, diagnosis, and intervention by disease-modifying therapies are required for delaying AD progression. Additionally, estimates of transition probabilities can inform future studies and health economic modeling.

Genome-Wide Association Studies of ARIA From the Aducanumab Phase 3 ENGAGE and EMERGE Studies.

Amyloid-related imaging abnormalities (ARIA) were the most common adverse events reported in the phase 3 ENGAGE and EMERGE trials of aducanumab, an anti-amyloid monoclonal antibody. APOE ε4 carrier status has been shown to increase risk of ARIA in prior trials of aducanumab and other anti-amyloid therapies; however, the remainder of the human genome has not been evaluated for ARIA risk factors. Therefore, we sought to determine in a hypothesis-free manner whether genetic variants beyond APOE influence risk of ARIA in aducanumab-treated patients. We performed genome-wide association studies (GWAS) of ARIA in participants in the ENGAGE and EMERGE trials. Participants had mild cognitive impairment due to Alzheimer disease or mild Alzheimer disease dementia and were amyloid-positive on PET scans. All participants underwent regular MRI monitoring to detect and diagnose ARIA. Of the 3,285 participants in the intent-to-treat population, this analysis included 1,691 with genotyping array data who received at least one dose of aducanumab with at least one post-baseline MRI. All participants in the study cohort were of European ancestry; 51% were female. The mean age was 70.3 years. 31% had ARIA-E, 19% had ARIA-H microhemorrhage, and 14% had ARIA-H superficial siderosis. We identified one genome-wide significant (p < 5.0 × 10-8) association at the chromosome 19 locus encompassing APOE. The APOE association with ARIA was stronger in ε4/ε4 homozygotes (OR = 4.28, 4.58, 7.84; p < 2.9 × 10-14 for ARIA-E, ARIA-H microhemorrhage, and ARIA-H superficial siderosis, respectively) than in ε3/ε4 heterozygotes (OR = 1.74, 1.46, 3.14; p ≤ 0.03). We found greater odds of radiographically severe ARIA (OR = 7.04-24.64, p ≤ 2.72 × 10-5) than radiographically mild ARIA (OR = 3.19-5.00, p ≤ 1.37 × 10-5) among ε4/ε4 homozygotes. APOE ε4 was also significantly associated with both symptomatic (ε4/ε4 OR = 3.64-9.52; p < 0.004) and asymptomatic (ε4/ε4 OR = 4.20-7.94, p < 1.7 × 10-11) cases, although among ARIA cases, APOE did not appear to modulate symptomatic status. No other genome-wide significant associations were found. We identified a strong, genome-wide significant association between APOE and risk of ARIA. Future, larger studies may be better powered to detect associations beyond APOE. These findings indicate that APOE is the strongest genetic risk factor of ARIA incidence, with implications for patient management and risk-benefit treatment decisions. Both trials (ENGAGE [221AD301]: NCT02477800 and EMERGE [221AD302]: NCT02484547) were registered in June 2015 at clinicaltrials.gov and enrolled patients from August 2015 to July 2018.

Clinical and neuroimaging association between neuropsychiatric symptoms and nutritional status across the Alzheimer's disease continuum: a longitudinal cohort study

ObjectivesTo investigate the association between neuropsychiatric symptoms (NPS) and nutritional status, and explore their shared regulatory brain regions on the Alzheimer’s disease (AD) continuum. DesignA longitudinal, observational cohort study. SettingData were collected from the Chinese Imaging, Biomarkers, and Lifestyle study between June 1, 2021 and December 31, 2022. ParticipantsOverall, 432 patients on the AD continuum, including amnestic mild cognitive impairment and AD dementia, were assessed at baseline, and only 165 patients completed the (10.37 ± 6.08) months’ follow-up. MeasurementsThe Mini-Nutritional Assessment (MNA) and Neuropsychiatric Inventory (NPI) were used to evaluate nutritional status and NPS, respectively. The corrected cerebral blood flow (cCBF) measured by pseudo-continuous arterial spin labeling of the dietary nutrition-related brain regions was analyzed. The association between the NPS at baseline and subsequent change in nutritional status and the association between the changes in the severity of NPS and nutritional status were examined using generalized linear mixed models. ResultsIncreased cCBF in the left putamen was associated with malnutrition, general NPS, affective symptoms, and hyperactivity (P < 0.05). The presence of general NPS (β = −1.317, P = 0.003), affective symptoms (β = −1.887, P < 0.001), and appetite/eating disorders (β = −1.714, P < 0.001) at baseline were associated with a decline in the MNA scores during follow-up. The higher scores of general NPI (β = −0.048), affective symptoms (β = −0.181), and appetite/eating disorders (β = −0.416; all P < 0.001) were longitudinally associated with lower MNA scores after adjusting for confounding factors. ConclusionsWe found that baseline NPS were predictors of a decline in nutritional status on the AD continuum. The worse the severity of affective symptoms and appetite/eating disorders, the poorer the nutritional status. Furthermore, abnormal perfusion of the putamen may regulate the association between malnutrition and NPS, which suggests their potentially common neural regulatory basis.

Multiomics Blood-Based Biomarkers Predict Alzheimer’s Predementia with High Specificity in a Multicentric Cohort Study

BackgroundThe primary criteria for diagnosing mild cognitive impairment (MCI) due to Alzheimer’s Disease (AD) or probable mild AD dementia rely partly on cognitive assessments and the presence of amyloid plaques. Although these criteria exhibit high sensitivity in predicting AD among cognitively impaired patients, their specificity remains limited. Notably, up to 25% of non-demented patients with amyloid plaques may be misdiagnosed with MCI due to AD, when in fact they suffer from a different brain disorder. The introduction of anti-amyloid antibodies complicates this scenario. Physicians must prioritize which amyloid-positive MCI patients receive these treatments, as not all are suitable candidates. Specifically those with non-AD amyloid pathologies are not primary targets for amyloid-modifying therapies. Consequently there is an escalating medical necessity for highly specific blood biomarkers that can accurately detect pre-dementia AD, thus optimizing amyloid antibody prescription.ObjectivesThe objective of this study was to evaluate a predictive model based on peripheral biomarkers to identify MCI and mild dementia patients who will develop AD dementia symptoms in cognitively impaired population with high specificity.DesignPeripheral biomarkers were identified in a gene transfer-based animal model of AD and then validated during a retrospective multi-center clinical study.SettingParticipants from 7 retrospective cohorts (US, EU and Australia).ParticipantsThis study followed 345 cognitively impaired individuals over up to 13 years, including 193 with MCI and 152 with mild dementia, starting from their initial visits. The final diagnoses, established during their last assessments, classified 249 participants as AD patients and 96 as having non-AD brain disorders, based on the specific diagnostic criteria for each disorder subtype. Amyloid status, assessed at baseline, was available for 82.9% of the participants, with 61.9% testing positive for amyloid. Both amyloid-positive and negative individuals were represented in each clinical group. Some of the AD patients had co-morbidities such as metabolic disorders, chronic diseases, or cardiovascular pathologies.MeasurementsWe developed targeted mass spectrometry assays for 81 blood-based biomarkers, encompassing 45 proteins and 36 metabolites previously identified in AAV-AD rats.MethodsWe analyzed blood samples from study participants for the 81 biomarkers. The B-HEALED test, a machine learning-based diagnostic tool, was developed to differentiate AD patients, including 123 with Prodromal AD and 126 with mild AD dementia, from 96 individuals with non-AD brain disorders. The model was trained using 70% of the data, selecting relevant biomarkers, calibrating the algorithm, and establishing cutoff values. The remaining 30% served as an external test dataset for blind validation of the predictive accuracy.ResultsIntegrating a combination of 19 blood biomarkers and participant age, the B-HEALED model successfully distinguished participants that will develop AD dementia symptoms (82 with Prodromal AD and 83 with AD dementia) from non-AD subjects (71 individuals) with a specificity of 93.0% and sensitivity of 65.4% (AUROC=81.9%, p<0.001) during internal validation. When the amyloid status (derived from CSF or PET scans) and the B-HEALED model were applied in association, with individuals being categorized as AD if they tested positive in both tests, we achieved 100% specificity and 52.8% sensitivity. This performance was consistent in blind external validation, underscoring the model’s reliability on independent datasets.ConclusionsThe B-HEALED test, utilizing multiomics blood-based biomarkers, demonstrates high predictive specificity in identifying AD patients within the cognitively impaired population, minimizing false positives. When used alongside amyloid screening, it effectively identifies a nearly pure prodromal AD cohort. These results bear significant implications for refining clinical trial inclusion criteria, facilitating drug development and validation, and accurately identifying patients who will benefit the most from disease-modifying AD treatments.

Association between clinical dementia rating and clinical outcomes in Alzheimer's disease.

We examined associations between the Clinical Dementia Rating Scale (CDR) and function (Functional Assessment Scale [FAS]), neuropsychiatric symptoms (Neuropsychiatric Inventory Questionnaire [NPI-Q]), and cognitive impairment in Alzheimer's disease (AD). We used data from the National Alzheimer's Coordinating Center Uniform Data Set and defined cognitively unimpaired and AD stages using CDR-global. Functional and neuropsychiatric symptoms occur as early as the mild cognitive impairment (MCI) phase. The adjusted lest square mean FAS (95% confidence interval [CI]) was lowest in cognitively unimpaired (3.88 [3.66, 4.11] to 5.01 [4.76, 5.26]) and higher with more advanced AD (MCI: 8.17 [6.92, 9.43] to 20.87 [19.53, 22.20]; mild: 18.54 [17.57, 19.50] to 28.13 [27.14, 29.12]; moderate: 26.01 [25.31, 26.70] to 29.42 [28.73, 30.10]). FAS and NPI-Q scores increased steeply with MCI (NPI-Q: 5.55 [4.89, 6.20] to 7.11 [6.43, 7.78]) and mild AD dementia (NPI-Q: 6.66 [5.72, 7.60] to 8.32 [7.32, 9.33]). CDR-global staged AD by capturing differences in relevant outcomes along AD progression. There were strong associations among CDR and the various outcomes relevant to healthcare providers, patients, and their care givers, such as activities of daily living.Overall, activities of daily living, neuropsychiatric symptoms, and cognitive function outcomes deteriorated over time and can be observed in early stages of AD (MCI or mild dementia).Our findings directly inform the current understanding of AD progression and can aid in care planning and benefit assessments of early AD interventions to delay the progression of AD to more advanced stages.

Bayesian meta-analysis of phase 3 results of aducanumab, lecanemab, donanemab, and high-dose gantenerumab in prodromal and mild Alzheimer's disease.

Phase 3 trials using the anti-amyloid antibodies aducanumab, lecanemab, donanemab, and high-dose gantenerumab in prodromal and mild Alzheimer's disease dementia were heterogeneous in respect to statistical significance of effects. However, heterogeneity of results has not yet directly be quantified. We used Bayesian random effects meta-analysis to quantify evidence for or against a treatment effect, and assessed the size of the effect and its heterogeneity. Data were extracted from published studies where available and Web based data reports, assuming a Gaussian data generation process. We found moderate evidence in favor of a treatment effect (Bayes factor = 13.2). The effect was moderate to small with -0.33 (95% credible interval -0.54 to -0.10) points on the Clinical Dementia Rating - Sum of Boxes (CDR-SB) scale. The heterogeneity parameter was low to moderate with 0.21 (0.04 to 0.45) CDR-SB points. Heterogeneity across studies was moderate despite some trials reaching statistical significance, while others did not. This suggests that the negative aducanumab and gantenerumab trials are in full agreement with the expected effect sizes.

Longitudinal associations of apathy and regional tau in mild cognitive impairment and dementia: Findings from the Alzheimer's Disease Neuroimaging Initiative.

It is important to study apathy in Alzheimer's disease (AD) to better understand its underlying neurobiology and develop effective interventions. In the current study, we sought to examine the relationships between longitudinal apathy and regional tau burden in cognitively impaired older adults from the Alzheimer's Disease Neuroimaging Initiative (ADNI) database. Three hundred and nineteen ADNI participants with mild cognitive impairment (MCI) or AD dementia underwent flortaucipir (FTP) tau positron emission tomography (PET) imaging and clinical assessment with the Neuropsychiatric Inventory (NPI) annually. Longitudinal NPI Apathy (NPI-A) scores were examined in relation to baseline tau PET signal in three a priori selected regions implicated in AD and AD-related apathy (supramarginal gyrus, entorhinal cortex [EC] and rostral anterior cingulate cortex [rACC]). Secondary models were adjusted for global cognition (Mini-Mental State Examination score) and cortical amyloid (florbetapir PET). Higher baseline supramarginal gyrus and EC tau burden were each significantly associated with greater NPI-A over time, while rACC tau was associated with higher NPI-A but did not predict its trajectory over time. These results were retained for supramarginal and EC tau after adjusting models for global cognition and cortical amyloid. Our findings suggest that baseline in vivo tau burden in parietal and temporal brain regions affected in AD, and less so in a medial frontal region involved in motivational control, is associated with increasing apathy over time in older adults with MCI and AD dementia. Future work studying emergent apathy in relation to not only core AD pathology but also circuit level dysfunction may provide additional insight into the neurobiology of apathy in AD and opportunities for intervention. Tau (Flortaucipir PET) in regions implicated in AD was associated with increasing apathy over timeCortical amyloid was also found to be a robust predictor of the trajectory of apathyEvidence of synergy between regional tau and amyloid in overall higher levels of apathy.