Prodromal Alzheimer's Disease Research Articles

Differentiating Prodromal Dementia with Lewy Bodies from Prodromal Alzheimer's Disease: A Pragmatic Review for Clinicians.

This pragmatic review synthesises the current understanding of prodromal dementia with Lewy bodies (pDLB) and prodromal Alzheimer's disease (pAD), including clinical presentations, neuropsychological profiles, neuropsychiatric symptoms, biomarkers, and indications for disease management. The core clinical features of dementia with Lewy bodies (DLB)-parkinsonism, complex visual hallucinations, cognitive fluctuations, and REM sleep behaviour disorder are common prodromal symptoms. Supportive clinical features of pDLB include severe neuroleptic sensitivity, as well as autonomic and neuropsychiatric symptoms. The neuropsychological profile in mild cognitive impairment attributable to Lewy body pathology (MCI-LB) tends to include impairment in visuospatial skills and executive functioning, distinguishing it from MCI due to AD, which typically presents with impairment in memory. pDLB may present with cognitive impairment, psychiatric symptoms, and/or recurrent episodes of delirium, indicating that it is not necessarily synonymous with MCI-LB. Imaging, fluid and other biomarkers may play a crucial role in differentiating pDLB from pAD. The current MCI-LB criteria recognise low dopamine transporter uptake using positron emission tomography or single photon emission computed tomography (SPECT), loss of REM atonia on polysomnography, and sympathetic cardiac denervation using meta-iodobenzylguanidine SPECT as indicative biomarkers with slowing of dominant frequency on EEG among others as supportive biomarkers. This review also highlights the emergence of fluid and skin-based biomarkers. There is little research evidence for the treatment of pDLB, but pharmacological and non-pharmacological treatments for DLB may be discussed with patients. Non-pharmacological interventions such as diet, exercise, and cognitive stimulation may provide benefit, while evaluation and management of contributing factors like medications and sleep disturbances are vital. There is a need to expand research across diverse patient populations to address existing disparities in clinical trial participation. In conclusion, an early and accurate diagnosis of pDLB or pAD presents an opportunity for tailored interventions, improved healthcare outcomes, and enhanced quality of life for patients and care partners.

Cognitive dysfunction characteristics of multiple sclerosis with aging

BackgroundWe aimed to investigate the characteristics of cognitive impairment in older people with multiple sclerosis (MS). MethodsCross-sectional study that included participants that were examined with a common and comprehensive neuropsychological protocol. The subjects were matched by sociodemographic variables and the following groups were generated for comparisons: young MS versus healthy controls (HC) (n = 246), old MS versus HC (n = 198), young MS vs old MS (n = 226), MS vs Alzheimer's disease (AD)(n = 70), and MS vs Parkinson's disease (PD) (n = 62). The ICCoDiMS criteria were used to define cognitive impairment in MS. ResultsCognitive impairment was more frequent in young than old patients (70.8 % vs 52.2 %). Attention and speed processing is the most frequent cognitive domain impaired in MS (54.9 % of young MS vs 32.7 % of old MS). The frequency of impairment in attention/processing speed (54.9 % vs 32.7 %) and episodic memory (27.9 % vs 14.3) was higher in the young group than in the old group. There were no statistically significant differences in the distribution of impairment in executive function (46.0 % vs 35.3 %), visuospatial (17.9 % vs 9.5 %), and language (12.4 % vs 17.7 %). In those patients meeting the criteria for cognitive impairment, young MS patients showed lower performance in attention/processing speed tests. Conversely, old MS patients showed lower performance in episodic memory, verbal fluency, and planning. There were no differences in the correlations between SDMT and other neuropsychological tests in young and old patients, which suggests similar cognitive processes underlying SDMT performance in both groups. There were differences between old MS and prodromal AD, especially in episodic memory, while the cognitive profile of old MS was largely shared with PD. ConclusionsOur study found that the cognitive profile of MS is defined by a characteristic impairment in attention and processing speed, which is present during the lifespan. The impairment in processing speed is less prominent in old age, whereas the impairment of other cognitive functions becomes more relevant. These findings suggest potential differences in the pathophysiological processes associated with cognitive impairment between young and old ages that warrant further investigation.

Exploration of neuroanatomical characteristics to differentiate prodromal Alzheimer’s disease from cognitively unimpaired amyloid-positive individuals

Differentiating clinical stages based solely on positive findings from amyloid PET is challenging. We aimed to investigate the neuroanatomical characteristics at the whole-brain level that differentiate prodromal Alzheimer’s disease (AD) from cognitively unimpaired amyloid-positive individuals (CU A+) in relation to amyloid deposition and regional atrophy. We included 45 CU A+ participants and 135 participants with amyloid-positive prodromal AD matched 1:3 by age, sex, and education. All participants underwent 18F-florbetaben positron emission tomography and 3D structural T1-weighted magnetic resonance imaging. We compared the standardized uptake value ratios (SUVRs) and volumes in 80 regions of interest (ROIs) between CU A+ and prodromal AD groups using independent t-tests, and employed the least absolute selection and shrinkage operator (LASSO) logistic regression model to identify ROIs associated with prodromal AD in relation to amyloid deposition, regional atrophy, and their interaction. After applying False Discovery Rate correction at < 0.1, there were no differences in global and regional SUVR between CU A+ and prodromal AD groups. Regional volume differences between the two groups were observed in the amygdala, hippocampus, entorhinal cortex, insula, parahippocampal gyrus, and inferior temporal and parietal cortices. LASSO logistic regression model showed significant associations between prodromal AD and atrophy in the entorhinal cortex, inferior parietal cortex, both amygdalae, and left hippocampus. The mean SUVR in the right superior parietal cortex (beta coefficient = 0.0172) and its interaction with the regional volume (0.0672) were also selected in the LASSO model. The mean SUVR in the right superior parietal cortex was associated with an increased likelihood of prodromal AD (Odds ratio [OR] 1.602, p = 0.014), particularly in participants with lower regional volume (OR 3.389, p < 0.001). Only regional volume differences, not amyloid deposition, were observed between CU A+ and prodromal AD. The reduced volume in the superior parietal cortex may play a significant role in the progression to prodromal AD through its interaction with amyloid deposition in that region.

Association of Basal Forebrain Volume with Amyloid, Tau, and Cognition in Alzheimer's Disease.

Degeneration of cholinergic basal forebrain (BF) neurons characterizes Alzheimer's disease (AD). However, what role the BF plays in the dynamics of AD pathophysiology has not been investigated precisely. To investigate the baseline and longitudinal roles of BF along with core neuropathologies in AD. In this retrospective cohort study, we enrolled 113 subjects (38 amyloid [Aβ]-negative cognitively unimpaired, 6 Aβ-positive cognitively unimpaired, 39 with prodromal AD, and 30 with AD dementia) who performed brain MRI for BF volume and cortical thickness, 18F-florbetaben PET for Aβ, 18F-flortaucipir PET for tau, and detailed cognitive testing longitudinally. We investigated the baseline and longitudinal association of BF volume with Aβ and tau standardized uptake value ratio and cognition. Cross-sectionally, lower BF volume was not independently associated with higher cortical Aβ, but it was associated with tau burden. Tau burden in the orbitofrontal, insular, lateral temporal, inferior temporo-occipital, and anterior cingulate cortices were associated with progressive BF atrophy. Lower BF volume was associated with faster Aβ accumulation, mainly in the prefrontal, anterior temporal, cingulate, and medial occipital cortices. BF volume was associated with progressive decline in language and memory functions regardless of baseline Aβ and tau burden. Tau deposition affected progressive BF atrophy, which in turn accelerated amyloid deposition, leading to a vicious cycle. Also, lower baseline BF volume independently predicted deterioration in cognitive function.

Frontal Cortex Lipid Alterations During the Onset of Alzheimer's Disease.

Although sporadic Alzheimer's disease (AD) is a neurodegenerative disorder of unknown etiology, familial AD is associated with specific gene mutations. A commonality between these forms of AD is that both display multiple pathogenic events including cholinergic and lipid dysregulation. We aimed to identify the relevant lipids and the activity of their related receptors in the frontal cortex and correlating them with cognition during the progression of AD. MALDI-mass spectrometry imaging (MSI) and functional autoradiography was used to evaluate the distribution of phospholipids/sphingolipids and the activity of cannabinoid 1 (CB1), sphingosine 1-phosphate 1 (S1P1), and muscarinic M2/M4 receptors in the frontal cortex (FC) of people that come to autopsy with premortem clinical diagnosis of AD, mild cognitive impairment (MCI), and no cognitive impairment (NCI). MALDI-MSI revealed an increase in myelin-related lipids, such as diacylglycerol (DG) 36:1, DG 38:5, and phosphatidic acid (PA) 40:6 in the white matter (WM) in MCI compared to NCI, and a downregulation of WM phosphatidylinositol (PI) 38:4 and PI 38:5 levels in AD compared to NCI. Elevated levels of phosphatidylcholine (PC) 32:1, PC 34:0, and sphingomyelin 38:1 were observed in discrete lipid accumulations in the FC supragranular layers during disease progression. Muscarinic M2/M4 receptor activation in layers V-VI decreased in AD compared to MCI. CB1 receptor activity was upregulated in layers V-VI, while S1P1 was downregulated within WM in AD relative to NCI. FC WM lipidomic alterations are associated with myelin dyshomeostasis in prodromal AD, suggesting WM lipid maintenance as a potential therapeutic target for dementia.

Multi-pathological contributions toward atrophy patterns in the Alzheimer's disease continuum.

Heterogeneity in downstream atrophy in Alzheimer's disease (AD) is predominantly investigated in relation to pathological hallmarks (Aβ, tau) and co-pathologies (cerebrovascular burden) independently. However, the proportional contribution of each pathology in determining atrophy pattern remains unclear. We assessed heterogeneity in atrophy using two recently conceptualized dimensions: typicality (typical AD atrophy at the center and deviant atypical atrophy on either extreme including limbic predominant to hippocampal sparing patterns) and severity (overall neurodegeneration spanning minimal atrophy to diffuse typical AD atrophy) in relation to Aβ, tau, and cerebrovascular burden. We included 149 Aβ + individuals on the AD continuum (cognitively normal, prodromal AD, AD dementia) and 163 Aβ- cognitively normal individuals from the ADNI. We modeled heterogeneity in MRI-based atrophy with continuous-scales of typicality (ratio of hippocampus to cortical volume) and severity (total gray matter volume). Partial correlation models investigated the association of typicality/severity with (a) Aβ (global Aβ PET centiloid), tau (global tau PET SUVR), cerebrovascular (total white matter hypointensity volume) burden (b) four cognitive domains (memory, executive function, language, visuospatial composites). Using multiple regression, we assessed the association of each pathological burden and typicality/severity with cognition. (a) In the AD continuum, typicality (r = -0.31, p < 0.001) and severity (r = -0.37, p < 0.001) were associated with tau burden after controlling for Aβ, cerebrovascular burden and age. Findings imply greater tau pathology in limbic predominant atrophy and diffuse atrophy. (b) Typicality was associated with memory (r = 0.49, p < 0.001) and language scores (r = 0.19, p = 0.02). Severity was associated with memory (r = 0.26, p < 0.001), executive function (r = 0.24, p = 0.003) and language scores (r = 0.29, p < 0.001). Findings imply better cognitive performance in hippocampal sparing and minimal atrophy patterns. Beyond typicality/severity, tau burden but not Aβ and cerebrovascular burden explained cognition. In the AD continuum, atrophy-based severity was more strongly associated with tau burden than typicality after accounting for Aβ and cerebrovascular burden. Cognitive performance in memory, executive function and language domains was explained by typicality and/or severity and additionally tau pathology. Typicality and severity may differentially reflect burden arising from tau pathology but not Aβ or cerebrovascular pathologies which need to be accounted for when investigating AD heterogeneity.

Glymphatic system dysfunction predicts amyloid deposition, neurodegeneration, and clinical progression in Alzheimer's disease.

Although glymphatic function is involved in Alzheimer's disease (AD), its potential for predicting the pathological and clinical progression of AD and its sequential association with core AD biomarkers is poorly understood. Whole-brain glymphatic activity was measured by diffusion tensor image analysis along the perivascular space (DTI-ALPS) in participants with AD dementia (n=47), mild cognitive impairment (MCI; n=137), and normal controls (n=235) from the Alzheimer's Disease Neuroimaging Initiative. ALPS index was significantly lower in AD dementia than in MCI or controls. Lower ALPS index was significantly associated with faster changes in amyloid positron emission tomography (PET) burden and AD signature region of interest volume, higher risk of amyloid-positive transition and clinical progression, and faster rates of amyloid- and neurodegeneration-related cognitive decline. Furthermore, the associations of the ALPS index with cognitive decline were fully mediated by amyloid PET and brain atrophy. Glymphatic failure may precede amyloid pathology, and predicts amyloid deposition, neurodegeneration, and clinical progression in AD. The analysis along the perivascular space (ALPS) index is reduced in patients with Alzheimer's disease (AD) dementia, prodromal AD, and preclinical AD. Lower ALPS index predicted accelerated amyloid beta (Aβ) positron emission tomography (PET) burden and Aβ-positive transition. The decrease in the ALPS index occurs before cerebrospinal fluid Aβ42 reaches the positive threshold. ALPS index predicted brain atrophy, clinical progression, and cognitive decline. Aβ PET and brain atrophy mediated the link of ALPS index with cognitive decline.

Diagnosis of Alzheimer's disease: Towards accuracy and accessibility

Alzheimer’s disease (AD) is a serious dementia afflicting aging population and is characterized by cognitive decline, amyloid-β plaques, and neurofibrillary tangles. AD substantially impairs the life quality of the victims and poses a heavy burden on the society at large. The number of people with dementia due to AD, prodromal AD, and preclinical AD is estimated to stand at roughly 3.2, 69, and 315 million worldwide, respectively. Current clinical diagnosis is based on clinical symptoms, and clinical research demonstrated that positron emission tomography (PET) and cerebrospinal fluid (CSF) biomarkers had excellent diagnostic performance. However, the application of CSF biomarker tests and PET are restricted by the invasiveness and high cost. The presence of clinical symptoms means that AD pathology has been progressing for many years, and only a few drugs have been approved for the traetemnt of AD. Therefore, early diagnosis is extremely important for controlling the outcomes caused by AD. In this review, we provided an overview of developing clinical diagnostic criteria, diagnostic strategies under clinical research, developing blood based-biomarker assays, and promising nanotechnologically-based assays.

A cell autonomous regulator of neuronal excitability modulates tau in Alzheimer's disease vulnerable neurons.

Neurons from layer II of the entorhinal cortex (ECII) are the first to accumulate tau protein aggregates and degenerate during prodromal Alzheimer's disease (AD). Gaining insight into the molecular mechanisms underlying this vulnerability will help reveal genes and pathways at play during incipient stages of the disease. Here, we use a data-driven functional genomics approach to model ECII neurons in silico and identify the proto-oncogene DEK as a regulator of tau pathology. We show that epigenetic changes caused by Dek silencing alter activity-induced transcription, with major effects on neuronal excitability. This is accompanied by gradual accumulation of tau in the somatodendritic compartment of mouse ECII neurons in vivo, reactivity of surrounding microglia, and microglia-mediated neuron loss. These features are all characteristic of early AD. The existence of a cell-autonomous mechanism linking AD pathogenic mechanisms in the precise neuron type where the disease starts provides unique evidence that synaptic homeostasis dysregulation is of central importance in the onset of tau pathology in AD.

Exploring the potential of fully automated LUMIPULSE G plasma assays for detecting Alzheimer’s disease pathology

BackgroundLUMIPULSE G-automated immunoassays represent a widely used method for the quantification of Alzheimer’s disease (AD) biomarkers in the cerebrospinal fluid (CSF). Less invasive blood-based markers confer a promising tool for AD diagnosis at prodromal stages (mild cognitive impairment (MCI)). Highly sensitive assays for the quantification of amyloid-beta (Aβ) and phosphorylated Tau-181 (p-Tau181) in the blood are showing promising results. In this study, we evaluated the clinical performance of the recently available fully automated LUMIPULSE plasma marker assays for detecting brain AD pathology and for predicting progression from MCI to AD dementia stage.MethodsA retrospective exploratory cohort of 138 individuals (22 neurological controls [NC], 72 MCI, and 44 AD dementia patients) was included. Data regarding baseline CSF concentrations of Aβ42, Aβ40, t-Tau, and p-Tau181 was available and used to establish the presence of AD brain pathology. Baseline Aβ42, Aβ40, and p-Tau181 concentrations were determined in stored plasma samples using high-throughput fully automated LUMIPULSE assays. Progression from MCI to AD dementia was evaluated during follow-up (mean 6.4 ± 2.5 years). Moreover, a prospective validation cohort of 72 individuals with memory complaints underwent AD biomarker quantification, closely mirroring typical clinical practice. This cohort aimed to confirm the study’s main findings.ResultsIn the exploratory cohort, correlations between CSF and plasma were moderate for p-Tau181 (ρ = 0.61, p < 0.001) and weak for Aβ42/Aβ40 ratio (ρ = 0.39, p < 0.001). Plasma p-Tau181 and p-Tau181/Aβ42 concentrations were significantly increased while Aβ42/Aβ40 was significantly decreased (p < 0.001) in patients with AD dementia and prodromal AD, as well as in individuals with CSF abnormal amyloid concentrations (A +). Plasma p-Tau181 showed a robust performance in differentiating patients clinically diagnosed as AD (AUC = 0.89; 95% CI 0.83–0.94); A + vs. A − (AUC = 0.84, 95% CI 0.77–0.91) and also in predicting conversion to AD dementia in MCI patients (AUC = 0.89, 95% CI 0.81–0.96). When tested in the validation cohort, plasma p-Tau181 displayed 83.3% of the overall percentage of agreement according to amyloid status.ConclusionsOur results show that the measurement of p-Tau181 in plasma has great potential as a non-invasive prognostic screening tool for implementation in a clinical setting.

Behavioral Disorders of Spatial Cognition in Patients with Mild Cognitive Impairment due to Alzheimer's Disease: Preliminary Findings from the BDSC-MCI Project.

(1) Background: Spatial cognition (SC) is one of the earliest cognitive domains to be impaired in the course of Alzheimer's disease (AD), resulting in spatial disorientation and becoming lost even in familiar surroundings as later dementia symptoms. To date, few studies have identified initial alterations of spatial navigation (SN) in the premorbid AD phase by real-world paradigms, and none have adopted an innovative technological apparatus to better detect gait alterations as well as physiological aspects correlated to spatial disorientation (SD). The present study aimed at exploring initial SN defects in patients with prodromal AD via a naturalistic task by using a sensory garment. (2) Methods: 20 community-dwelling patients with Mild Cognitive Impairment (MCI) due to AD and 20 age/education controls were assessed on their sequential egocentric and allocentric navigation abilities by using a modified version of the Detour Navigation Test (DNT-mv). (3) Results: When compared to controls, patients with MCI due to AD exhibited higher wrong turns (WT) and moments of hesitation (MsH) in the DNT-mv, reflecting difficulties both in sequential egocentric and allocentric navigation, depending on hippocampal deterioration. Moreover, they reported more complaints about their SN competencies and lower long-term visuospatial memory abilities than controls. Remarkably, WTs and MsH manifested in the allocentric naturalistic task of the DNT-mv were associated with autonomic nervous system alteration pertaining to cardiac functioning in the whole sample. (4) Conclusions: Naturalistic navigation tests of hippocampal function using a continuous non-invasive monitoring device can provide early markers of spatial disorientation in patients with MCI due to AD. Future studies should develop cognitive remediation techniques able to enhance SC residual abilities in patients at high risk of conversion into dementia and ecological paradigms to be replicated on a large scale.

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.

Vortioxetine Treatment for Depression in Patients with Prodromal vs Mild Alzheimer’s Disease: A Six-Month, Open-Label, Observational Study

BackgroundDepressive symptoms are common in Alzheimer disease (AD) from the prodromal stage. The benefits of antidepressants have been investigated in patients with AD dementia with mixed results.ObjectivesThis study aimed to compare the efficacy of vortioxetine in prodromal and mild-to-moderate AD patients with depression, and to assess the comparative effect on secondary measures, including behavioral disturbances, cognitive function, and activities of daily living.ParticipantsAll subjects with AD at a single-center dementia center underwent a standard evaluation with mini-mental state examination (MMSE), basic and instrumental activities of daily living (BADL and IADL), geriatric depression scale (CDS), neuropsychiatrie inventory (NPI), and clinical evaluation every six months.MeasurementsThe study specifically assessed patients on vortioxetine with available six-month follow-up data. The changes in CDS, NPI, MMSE, BADL/IADL at six months in the entire AD population and mild-to-moderate AD vs prodromal population were analyzed using repeated measure multivariate analyses. Linear regression analyses were implemented to evaluate baseline demographics and clinical characteristics associated with depressive and cognitive improvements at six months.ResultsOut of 680 AD patients, 115 were treated with vortioxetine, and 89 with six-month follow-up data were included in the analyses. A significant improvement at follow-up was observed for CDS, NPI total and sub score items (mood, anxiety, apathy, sleep disturbances, eating abnormalities). Both mild-to-moderate and prodromal AD showed a positive CDS response, whereas mild-to-moderate AD showed a better improvement on total NPI and apathy/nighttime behaviors subitems compared to prodromal AD. Higher baseline CDS score was the only variable associated with higher responses in linear regression analyses. MMSE showed a significant improvement at six months in the entire cohort, with a greater effect in prodromal vs mild-to-moderate AD. Cognitive improvement (i.e., MMSE changes) was associated with cognitive status at baseline but independent of the antidepressant/behavioral changes (i.e., GDS/NPI).ConclusionsOur results suggest that vortioxetine is highly tolerable and clinically effective in both prodromal and mild-to-moderate AD with depression. Patients with mild-to-moderate AD benefited more from a wide range of behavioral disturbances. The study also showed significant improvement in global cognitive measures, especially in prodromal AD subjects. Further studies are needed to investigate the independent beneficial effect of vortioxetine on depression and cognition in AD.

The spatial extent of tauopathy on [18F]MK-6240 tau PET shows stronger association with cognitive performances than the standard uptake value ratio in Alzheimer’s disease

Purpose[18F]MK-6240, a second-generation tau PET tracer, is increasingly used for the detection and the quantification of in vivo cerebral tauopathy in Alzheimer’s disease (AD). Given that neurological symptoms are better explained by the topography rather than by the nature of brain lesions, our study aimed to evaluate whether cognitive impairment would be more closely associated with the spatial extent than with the intensity of tau-PET signal, as measured by the standard uptake value ratio (SUVr).Methods[18F]MK6240 tau-PET data from 82 participants in the AD spectrum were quantified in three different brain regions (Braak ≤ 2, Braak ≤ 4, and Braak ≤ 6) using SUVr and the extent of tauopathy (EOT, percentage of voxels with SUVr ≥ 1.3). PET data were first compared between diagnostic categories, and ROC curves were computed to evaluate sensitivity and specificity. PET data were then correlated to cognitive performances and cerebrospinal fluid (CSF) tau values.ResultsThe EOT in the Braak ≤ 2 region provided the highest diagnostic accuracies, distinguishing between amyloid-negative and positive clinically unimpaired individuals (threshold = 9%, sensitivity = 79%, specificity = 82%) as well as between prodromal AD and preclinical AD (threshold = 38%, sensitivity = 81%, specificity = 93%). The EOT better correlated with cognition than SUVr (∆R2 + 0.08–0.09) with the best correlation observed for EOT in the Braak ≤ 4 region (R2 = 0.64). Cognitive performances were more closely associated with PET metrics than with CSF values.ConclusionsQuantifying [18F]MK-6240 tau PET in terms of EOT rather than SUVr significantly increases the correlation with cognitive performances. Quantification in the mesiotemporal lobe is the most useful to diagnose preclinical AD or prodromal AD.

Combination strategy employing BACE1 inhibitor and memantine to boost cognitive benefits in Alzheimer's disease therapy.

The β-secretase BACE1 initiates amyloid-β (Aβ) generation and represents a long-standing prime therapeutic target for the treatment of Alzheimer's disease (AD). However, BACE1 inhibitors tested to date in clinical trials have yielded no beneficial outcomes. In fact, prior BACE1 inhibitor trials targeted at ~ 50-90% Aβ reductions in symptomatic or prodromal AD stages have ended in the discontinuation due to futility and/or side effects, including cognitive worsening rather than expected improvement at the highest dose. We tested whether a combination strategy with the selective BACE1 inhibitor GRL-8234 and the FDA-approved symptomatic drug memantine may provide synergistic cognitive benefits within their safe dose range. The drug effects were evaluated in the advanced symptomatic stage of 5XFAD mice that developed extensive cerebral Aβ deposition. Chronic combination treatment with 33.4-mg/kg GRL-8234 and 10-mg/kg memantine, but not either drug alone, rescued cognitive deficits in 5XFAD mice at 12months of age (the endpoint after 60-day drug treatment), as assessed by the contextual fear conditioning, spontaneous alternation Y-maze and nest building tasks. Intact baseline performances of wild-type control mice on three cognitive paradigms demonstrated that combination treatment did not augment potential cognitive side effects of individual drugs. Biochemical and immunohistochemical examination showed that combination treatment did not synergistically reduce the β-amyloidogenic processing of amyloid precursor protein or Aβ levels in 5XFAD mouse brains. A combination strategy with BACE1 inhibitors and memantine may be able to increase the effectiveness of individual drugs within their safe dose range in AD therapy.

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.

Prodromal Alzheimer's disease can affect activities of daily living for adults with Down syndrome.

Alzheimer's disease (AD) affecting adults with Down syndrome (DS-AD), like late-onset AD (LOAD) in the neurotypical population, has preclinical, prodromal, and more advanced stages. Only tasks placing high demands on cognition are expected to be affected during the prodromal stage, with activities of daily living (ADLs) typically being spared. However, cognitive demands of ADLs could be high for adults with DS and may be affected during prodromal DS-AD. Cognitively stable cases that subsequently developed prodromal DS-AD were identified within a set of archived data from a previous longitudinal study. Measures of ADLs and multiple cognitive domains were examined over time. Clear declines in ADLs accompanied cognitive declines with prodromal DS-AD while stability in all measures was verified during preclinical DS-AD. Operationally defining prodromal DS-AD is essential to disease staging in this high-risk population and for informing treatment options and timing as new disease-modifying drugs become available. Cognitive and functional stability were demonstrated prior to the onset of prodromal DS-AD.ADL declines accompanied cognitive declines as adults with DS transitioned to prodromal AD.Declines in ADLs should be a defining feature of prodromal AD for adults with DS.Better characterization of prodromal DS-AD can improve AD diagnosis and disease staging.Improvements in DS-AD diagnosis and staging could also inform the timing of interventions.

Disintegration at the syntax-semantics interface in prodromal Alzheimer's disease: New evidence from complex sentence anaphora in amnestic Mild Cognitive Impairment (aMCI)

Although diverse language deficits have been widely observed in prodromal Alzheimer's disease (AD), the underlying nature of such deficits and their explanation remains opaque. Consequently, both clinical applications and brain-language models are not well-defined. In this paper we report results from two experiments which test language production in a group of individuals with amnestic Mild Cognitive Impairment (aMCI) in contrast to healthy aging and healthy young. The experiments apply factorial designs informed by linguistic analysis to test two forms of complex sentences involving anaphora (relations between pronouns and their antecedents). Results show that aMCI individuals differentiate forms of anaphora depending on sentence structure, with selective impairment of sentences which involve construal with reference to context (anaphoric coreference). We argue that aMCI individuals maintain core structural knowledge while evidencing deficiency in syntax-semantics integration, thus locating the source of the deficit in the language-thought interface of the Language Faculty.

Comparing Symmetric Dimethylarginine and Amyloid-β42 as Predictors of Alzheimer's Disease Development.

Physicians may soon be able to diagnose Alzheimer's disease (AD) in its early stages using fluid biomarkers like amyloid. However, it is acknowledged that additional biomarkers need to be characterized which would facilitate earlier monitoring of AD pathogenesis. To determine if a potential novel inflammation biomarker for AD, symmetric dimethylarginine, has utility as a baseline serum biomarker for discriminating prodromal AD from cognitively unimpaired controls in comparison to cerebrospinal fluid amyloid-β42 (Aβ42). Data including demographics, magnetic resonance imaging and fluorodeoxyglucose-positron emission tomography scans, Mini-Mental State Examination and Functional Activities Questionnaire scores, and biomarker concentrations were obtained from the Alzheimer's Disease Neuroimaging Initiative for a total of 146 prodromal AD participants and 108 cognitively unimpaired controls. Aβ42 (p = 0.65) and symmetric dimethylarginine (p = 0.45) were unable to predict age-matched cognitively unimpaired controls and prodromal AD participants. Aβ42 was negatively associated with regional brain atrophy and hypometabolism as well as cognitive and functional decline in cognitively unimpaired control participants (p < 0.05) that generally decreased in time. There were no significant associations between Aβ42 and symmetric dimethylarginine with imaging or neurocognitive biomarkers in prodromal AD patients. Correlations were smaller between Aβ42 and neuropathological biomarkers over time and were absent in prodromal AD participants, suggesting a plateau effect dependent on age and disease stage. Evidence supporting symmetric dimethylarginine as a novel biomarker for AD as a single measurement was not found.

Contributions of amyloid beta and cerebral small vessel disease in clinical decline.

We assessed whether co-morbid small vessel disease (SVD) has clinical predictive value in preclinical or prodromal Alzheimer's disease. In 1090 non-demented participants (65.4±10.7 years) SVD was assessed with magnetic resonance imaging and amyloid beta (Aβ) with lumbar puncture and/or positron emission tomography scan (mean follow-up for cognitive function 3.1±2.4 years). Thirty-nine percent had neither Aβ nor SVD (A-V-), 21% had SVD only (A-V+), 23% Aβ only (A+V-), and 17% had both (A+V+). Pooled cohort linear mixed model analyses demonstrated that compared to A-V- (reference), A+V- had a faster rate of cognitive decline. Co-morbid SVD (A+V+) did not further increase rate of decline. Cox regression showed that dementia risk was modestly increased in A-V+ (hazard ratio [95% confidence interval: 1.8 [1.0-3.2]) and most strongly in A+ groups. Also, mortality risk was increased in A+ groups. In non-demented persons Aβ was predictive of cognitive decline, dementia, and mortality. SVD modestly predicts dementia in A-, but did not increase deleterious effects in A+. Amyloid beta (Aβ; A) was predictive for cognitive decline, dementia, and mortality. Small vessel disease (SVD) had no additional deleterious effects in A+. SVD modestly predicted dementia in A-. Aβ should be assessed even when magnetic resonance imaging indicates vascular cognitive impairment.