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In two phase 3 placebo-controlled, randomized trials in 1012 and 1040 patients with mild-to-moderate Alzheimer's disease, solanezumab, a humanized monoclonal antibody that preferentially binds soluble forms of amyloid, did not improve cognition or functional status. Alzheimer's disease is associated with the accumulation of aggregated amyloid-beta (Aβ) peptide in the cerebral cortex and hippocampus. One approach to reducing brain amyloid involves increasing the clearance of Aβ by means of prolonged treatment with monoclonal antibodies directed against this peptide. In preclinical studies, a murine antibody that targeted the central domain of Aβ and was selective for soluble forms slowed Aβ deposition in a transgenic mouse model 1 ; in another transgenic murine model, Aβ–antibody complexes were present in the cerebrospinal fluid (CSF) and plasma, and behavioral deficits were reversed without a decrease in amyloid plaques, as assessed by . . .

•Tau deposition is associated with white-matter (WM) degeneration along connecting tracts.•Tau-related WM degeneration demonstrates distinct spatial pattern, similar to Braak staging.•WM degeneration is characterized by increased mean diffusivity and decreased axon density.•WM plays an important role in the deposition of tau pathology. Progressive accumulation of tau neurofibrillary tangles in the brain is a defining pathologic feature of Alzheimer's disease (AD). Tau pathology exhibits a predictable spatiotemporal spreading pattern, but the underlying mechanisms of this spread are poorly understood. Although AD is conventionally considered a disease of the gray matter, it is also associated with pronounced and progressive deterioration of the white matter (WM). A link between abnormal tau and WM degeneration is suggested by findings from both animal and postmortem studies, but few studies demonstrated their interplay in vivo. Recent advances in diffusion magnetic resonance imaging and the availability of tau positron emission tomography (PET) have made it possible to evaluate the association of tau and WM degeneration (tau-WM) in vivo. In this study, we explored the spatial pattern of tau-WM associations across the whole brain to evaluate the hypothesis that tau deposition is associated with WM microstructural alterations not only in isolated tracts, but in continuous structural connections in a stereotypic pattern. Sixty-two participants, including 22 cognitively normal subjects, 22 individuals with subjective cognitive decline, and 18 with mild cognitive impairment were included in the study. WM characteristics were inferred by classic diffusion tensor imaging (DTI) and a complementary diffusion compartment model – neurite orientation dispersion and density imaging (NODDI) that provides a proxy for axonal density. A data-driven iterative searching (DDIS) approach, coupled with whole-brain graph theory analyses, was developed to continuously track tau-WM association patterns. Without applying prior knowledge of the tau spread, we observed a distinct spatial pattern that resembled the typical propagation of tau pathology in AD. Such association pattern was not observed between diffusion and amyloid-β PET signal. Tau-related WM degeneration is characterized by an increase in the mean diffusivity (with a dominant change in the radial direction) and a decrease in the intra-axonal volume fraction. These findings suggest that cortical tau deposition (as measured in tau PET) is associated with a lower axonal packing density and greater diffusion freedom. In conclusion, our in vivo findings using a data-driven method on cross-sectional data underline the important role of WM alterations in the AD pathological cascade with an association pattern similar to the postmortem Braak staging of AD. Future studies will focus on longitudinal analyses to provide in vivo evidence of tau pathology spreads along neuroanatomically connected brain areas.

In this placebo-controlled trial, the γ-secretase inhibitor semagacestat did not improve cognitive status in patients with Alzheimer's disease and was associated with more adverse events than placebo, including skin cancers and infections. Alzheimer's disease begins decades before the appearance of clinical symptoms, with the deposition of aggregated amyloid-beta (Aβ) peptide plaques in the cortex and hippocampus. This protein is cleaved from the amyloid precursor protein (APP) by the sequential action of β- and γ-secretases, producing fragments that include Aβ1-40 and Aβ1-42. Since the accumulation of aggregated Aβ is associated with disease progression, both β-secretase and γ-secretase represent potential therapeutic targets. Multiple small molecules can inhibit γ-secretase in vitro, 1 – 4 but Notch and other transmembrane proteins are also substrates for γ-secretase, 1 – 4 and studies have raised concern that the inhibition of γ-secretase could . . .

The brains of people with advanced Alzheimer’s disease often look older than expected based on the patients’ actual age. This ‘brain age gap’ (how old a brain appears compared to the person’s chronological age) can be calculated thanks to machine learning algorithms which analyse images of the organ to detect changes related to aging. Traditionally, these models have relied on images of the brain structure, such as the size and thickness of various brain areas; more recent models have started to use activity data, such as how different brain regions work together to form functional networks. While the brain age gap is a useful measure for researchers who investigate aging and disease, it is not yet helpful for clinicians. For example, it is unclear whether the machine learning algorithm could detect changes in the brains of individuals in the initial stages of Alzheimer’s disease, before they start to manifest cognitive symptoms. Millar et al. explored this question by testing whether models which incorporate structural and activity data could be more sensitive to these early changes. Three machine learning algorithms (relying on either structural data, activity data, or combination of both) were used to predict the brain ages of participants with no sign of disease; with biological markers of Alzheimer’s disease but preserved cognitive functions; and with marked cognitive symptoms of the condition. Overall, the combined model was slightly better at predicting the brain age of healthy volunteers, and all three models indicated that patients with dementia had a brain which looked older than normal. For this group, the model based on structural data was also able to make predictions which reflected the severity of cognitive decline. Crucially, the algorithm which used activity data predicted that, in individuals with biological markers of Alzheimer’s disease but no cognitive impairment, the brain looked in fact younger than chronological age. Exactly why this is the case remains unclear, but this signal may be driven by neural processes which unfold in the early stages of the disease. While more research is needed, the work by Millar et al. helps to explore how various types of machine learning models could one day be used to assess and predict brain health.

Background: Currently approved Alzheimer's disease (AD) treatments have been reported to provide symptomatic benefit, without proven impact on clinical progression. We hypothesized that the loss of initial therapeutic benefit over time may be mitigated by higher doses of a cholinesterase inhibitor. Objective: The aim of this study was to determine the effectiveness and tolerability of increasing donepezil from 10 to 23 mg/d in patients with moderate to severe AD. Methods: This randomized, double-blind study was conducted at 219 sites in Asia, Europe, Australia, North America, South Africa, and South America from June 6, 2007, to March 27, 2009. Patients aged 45 to 90 years with probable AD, Mini-Mental State Examination score 0 to 20 (moderate to severe impairment), and who were receiving donepezil 10 mg once daily for ≥12 weeks before the start of the study were eligible. Patients (n = 1467) were randomly assigned to receive high-dose donepezil (23 mg once daily) or standard-dose donepezil (10 mg once daily) for 24 weeks. Coprimary effectiveness measures were changes in cognition and global functioning, as assessed using least squares mean changes from baseline (LSM [SE] A) scores (last observation carried forward) on the Severe Impairment Battery (SIB; cognition) and the Clinician's Interview-Based Impression of Change Plus Caregiver Input scale (CIBIC+; global function rating) overall change score (mean [SD]) at week 24. Treatmentemergent adverse events (TEAEs) were assessed using spontaneous patient/caregiver reporting and open-ended questioning; clinical laboratory testing (hematology, biochemistry, and urinalysis panels analyzed by a central laboratory); 12-lead ECG; and physical and neurologic examinations, including vital sign measurements. Results: The effectiveness analyses included 1371 patients (mean age, 73.8 years; 62.8% female; 73.5% white; weight range, 34.0–138.7 kg). A total of 296 of 981 patients (30.2%) withdrew from the donepezil 23-mg/d group; 87 of 486 patients (17.9%) withdrew from the donepezil 10-mg/d group. At study end (week 24), the LSM (SE) Δ in SIB score was significantly greater with donepezil 23 mg/d than with donepezil 10 mg/d (+2.6 [0.58] vs +0.4 [0.66], respectively; difference, 2.2; P < 0.001). The between-treatment difference in CIBIC+ score was nonsignificant (4.23 [1.07] vs 4.29 [1.07]). In post hoc analysis, LSM Δ in SIB score and CIBIC+ treatment effect at end point were greater with donepezil 23 mg/d than 10 mg/d in patients with more advanced AD compared with less impaired patients (SIB, +1.6 [0.78] vs −1.5 [0.88], respectively [ P < 0.001]; CIBIC+, 4.31 [1.09] vs 4.42 [1.10] [ P = 0.028]). TEAEs were reported in 710 of 963 patients (73.7%) who received donepezil 23 mg/d and in 300 of 471 patients (63.7%) who received donepezil 10 mg/d. With donepezil 23 mg/d, mild, moderate, and severe TEAEs were reported in 297 (30.8%), 332 (34.5%), and 81 (8.4%) patients, respectively; with donepezil 10 mg/d, these proportions were 147 (31.2%), 119 (25.3%), and 34 (7.2%). The 3 most common severe AEs reported with the 23-mg/d dose were nausea (9 patients [0.9%] vs 1 [0.2%] with the 10-mg/d dose), dizziness (7 [0.7%] vs 1 [0.2%]), and vomiting (6 [0.6%] vs 0). The most commonly reported TEAEs considered probably related to treatment with the 23-mg/d dose were nausea (59 patients [6.1%] vs 9 [1.9%] with the 10-mg/d dose), vomiting (48 [5.0%] vs 4 [0.8%]), and diarrhea (31 [3.2%] vs 7 [1.5%]).Thirteen deaths were reported during the study or within 30 days of study discontinuation (23 mg/d, 8 patients [0.8%]; 10 mg/d, 5 patients [1.1%]); all were considered unrelated to the study medication. Conclusions: In this study in patients with moderate to severe AD, donepezil 23 mg/d was associated with greater benefits in cognition compared with donepezil 10 mg/d. The between-treatment difference in global functioning was not significant in the overall population. Patients with more advanced AD appeared to benefit from donepezil 23 mg/d on the assessment of global functioning, but this observation requires additional studies for confirmation. ClinicalTrials.gov identifier: NCT00478205.

Autosomal dominant familial Alzheimer’s disease (ADAD) is a rare disorder with non-amnestic neurological symptoms in some clinical presentations. We aimed to compile and compare data from symptomatic participants in the Dominantly Inherited Alzheimer Network observational study (DIAN-OBS) with those reported in the literature to estimate the prevalences of non-amnestic neurological symptoms in participants with ADAD. We prospectively collected data from the DIAN-OBS database, which recruited participants from study centres in the USA, Europe, and Australia, between Feb 29, 2008, and July 1, 2014. We also did a systematic review of publications to extract individual-level clinical data for symptomatic participants with ADAD. We used data for age of onset (from first report of cognitive decline), disease course from onset to death, and the presence of 13 neurological findings that have been reported in association with ADAD. Using multivariable linear regression, we investigated the prevalences of various non-amnestic neurological symptoms and the contributions of age of onset and specific mutation type on symptoms. The DIAN-OBS dataset included 107 individuals with detailed clinical data (forming the DIAN-OBS cohort). Our systematic review yielded 188 publications reporting on 1228 symptomatic individuals, with detailed neurological examination descriptions available for 753 individuals (forming the published data cohort). The most prevalent non-amnestic cognitive manifestations in participants in the DIAN-OBS cohort were those typical of mild to moderate Alzheimer’s disease, including visual agnosia (55·1%, 95% CI 45·7–64·6), aphasia (57·9%, 48·6–67·3), and behavioural changes (61·7%, 51·5–70·0). Non-amnestic cognitive manifestations were less prevalent in the published data cohort (eg, visual agnosia [5·6%, 3·9–7·2], aphasia [23·0%, 20·0–26·0], and behavioural changes [31·7%, 28·4–35·1]). Prevalence of non-cognitive neurological manifestations in the DIAN-OBS cohort was low, including myoclonus and spasticity (9·3%, 95% CI 3·8–15·0), and seizures (2·8%, 0·5–5·9) and moderate for parkinsonism (11·2%, 5·3–17·1). By constrast, prevalence was higher in the published data cohort for myoclonus and spasticity (19·4%, 16·6–22·2 and 15·0%, 12·5–17·6, respectively), parkinsonism (12·5%, 10·1–15·0), and seizures (20·3%, 17·4–23·2). In an analysis of the published data cohort, ischaemic stroke was more prevalent at older ages of onset of symptoms of ADAD (odds ratio 1·09 per 1 year increase in age of onset, 95% CI 1·04–1·14, p=0·0003); and motor symptoms were more common at younger age of onset (myoclonus 0·93, 0·90–0·97, p=0·0007; seizures 0·95, 0·92–0·98, p=0·0018; corticobulbar deficits 0·91, 0·86–0·96, p=0·0012; and cerebellar ataxia 0·82, 0·74–0·91, p=0·0002). In the DIAN-OBS cohort, non-cognitive symptoms were more common at more severe stages of disease. The non-cognitive clinical manifestations of Alzheimer’s disease seem to affect a small proportion of participants with mild to moderate ADAD, and are probably influenced by disease severity, environmental, and genetic factors. When evaluating patients with potential ADAD, clinicians should note that cognitive symptoms typical of sporadic Alzheimer’s disease are the most consistent finding, with some patients manifesting non-cognitive neurological symptoms. Future work is needed to determine the environmental and genetic factors that cause these neurological symptoms. National Institutes of Health and German Center for Neurodegenerative Diseases.

Two genetic variants in strong linkage disequilibrium (rs9536314 and rs9527025) in the Klotho ( KL ) gene, encoding a transmembrane protein, implicated in longevity and associated with brain resilience during normal aging, were recently shown to be associated with Alzheimer disease (AD) risk in cognitively normal participants who are APOE ε4 carriers. Specifically, the participants heterozygous for this variant (KL-SV HET+ ) showed lower risk of developing AD. Furthermore, a neuroprotective effect of KL-VS HET+ has been suggested against amyloid burden for cognitively normal participants, potentially mediated via the regulation of redox pathways. However, inconsistent associations and a smaller sample size of existing studies pose significant hurdles in drawing definitive conclusions. Here, we performed a well-powered association analysis between KL-VS HET+ and five different AD endophenotypes; brain amyloidosis measured by positron emission tomography (PET) scans (n = 5,541) or cerebrospinal fluid Aβ42 levels (CSF; n = 5,093), as well as biomarkers associated with tau pathology: the CSF Tau (n = 5,127), phosphorylated Tau (pTau181; n = 4,778) and inflammation: CSF soluble triggering receptor expressed on myeloid cells 2 (sTREM2; n = 2,123) levels. Our results found nominally significant associations of KL-VS HET+ status with biomarkers for brain amyloidosis (e.g., CSF Aβ positivity; odds ratio [OR] = 0.67 [95% CI, 0.55–0.78], β = 0.72, p = 0.007) and tau pathology (e.g., biomarker positivity for CSF Tau; OR = 0.39 [95% CI, 0.19–0.77], β = -0.94, p = 0.007, and pTau; OR = 0.50 [95% CI, 0.27–0.96], β = -0.68, p = 0.04) in cognitively normal participants, 60–80 years old, who are APOE e4-carriers. Our work supports previous findings, suggesting that the KL-VS HET+ on an APOE ε4 genotype background may modulate Aβ and tau pathology, thereby lowering the intensity of neurodegeneration and incidence of cognitive decline in older controls susceptible to AD.

Genetic studies of Alzheimer disease (AD) have prioritized variants in genes related to the amyloid cascade, lipid metabolism, and neuroimmune modulation. However, the cell-specific effect of variants in these genes is not fully understood. Here, we perform single-nucleus RNA-sequencing (snRNA-seq) on nearly 300,000 nuclei from the parietal cortex of AD autosomal dominant ( APP and PSEN1 ) and risk-modifying variant ( APOE, TREM2 and MS4A ) carriers. Within individual cell types, we capture genes commonly dysregulated across variant groups. However, specific transcriptional states are more prevalent within variant carriers. TREM2 oligodendrocytes show a dysregulated autophagy-lysosomal pathway, MS4A microglia have dysregulated complement cascade genes, and APOE ε4 inhibitory neurons display signs of ferroptosis. All cell types have enriched states in autosomal dominant carriers. We leverage differential expression and single-nucleus ATAC-seq to map GWAS signals to effector cell types including the NCK2 signal to neurons in addition to the initially proposed microglia. Overall, our results provide insights into the transcriptional diversity resulting from AD genetic architecture and cellular heterogeneity. The data can be explored on the online browser ( http://web.hararilab.org/SNARE/ ). Mutations in amyloid precursor protein (APP) and presenilin 1 (PSEN1) cause autosomal dominant AD (ADAD). Here, the authors perform single-nucleus RNA-sequencing of ADAD and other disease risk modifying variant carriers and report altered expression states of specific brain cell types.

Available cholinergic drugs for treating Alzheimer's disease (AD) provide modest symptomatic benefit. We hypothesized that co-administration of a peripheral anticholinergic to reduce dose-limiting adverse effects (AEs) would enable the safe/tolerable use of higher cholinesterase inhibitor doses and thus improve their antidementia efficacy. A modified single-blind, ascending-dose, phase IIa study of donepezil plus solifenacin (CPC-201) lasting 26 weeks was conducted in 41 patients with probable AD of moderate severity. Entry criteria included the use of donepezil at a dose of 10 mg/day during the preceding 3 months. The primary outcome measure was the maximum tolerated dose (MTD) of donepezil achieved (to protocol limit of 40 mg/day) when administered with the anticholinergic solifenacin 15 mg/day. Secondary measures included assessments of cognitive and global function, as well as of AEs. The mean ± SD donepezil MTD increased to 38 ± 0.74 mg/day (median 40 mg/day; p < 0.001); 88% of the study population safely attained this dose at the end of titration. Markedly reduced donepezil AE frequency, especially gastrointestinal, allowed this dose increase. There were no drug-related serious AEs or clinically significant laboratory abnormalities. At 26 weeks, Alzheimer's Disease Assessment Scale Cognitive Component scores in the efficacy evaluable population improved by 0.35 ± 0.85 points over baseline (p < 0.05), an estimated 2.5 ± 0.84 points above 10 mg/day donepezil and 5.4 ± 0.84 points above historic placebo (both p < 0.05). Clinical Global Impression of Improvement scores improved by 0.94 ± 0.20 to 3.1 ± 0.20 points (p < 0.001). The findings suggest that limiting donepezil AEs by co-administration of solifenacin allows the safe administration of substantially higher cholinesterase inhibitors doses that may augment cognitive and global benefits in patients with AD.

Diffusion magnetic resonance imaging may allow for microscopic characterization of white matter degeneration in early stages of Alzheimer's disease. Multishell Diffusion magnetic resonance imaging data were acquired from 100 participants (40 cognitively normal, 38 with subjective cognitive decline, and 22 with mild cognitive impairment [MCI]). White matter microscopic degeneration in 27 major tracts of interest was assessed using diffusion tensor imaging (DTI), neurite orientation dispersion and density imaging, and q-space imaging. Lower DTI fractional anisotropy and higher radial diffusivity were observed in the cingulum, thalamic radiation, and forceps major of participants with MCI. These tracts of interest also had the highest predictive power to discriminate groups. Diffusion metrics were associated with cognitive performance, particularly Rey Auditory Verbal Learning Test immediate recall, with the highest association observed in participants with MCI. While DTI was the most sensitive, neurite orientation dispersion and density imaging and q-space imaging complementarily characterized reduced axonal density accompanied with dispersed and less restricted white matter microstructures. •Mild cognitive decline poses microstructural alterations in white matter tracts.•The alterations include higher axonal dispersion and lower tissue restriction.•Diffusion metrics are associated with cognitive outcomes in AD continuum.