Immunohistochemical evaluation of a trial of gantenerumab or solanezumab in dominantly inherited Alzheimer disease.

Clinical trials of anti-amyloid-β (Aβ) monoclonal antibodies in Alzheimer disease (AD) infer target engagement from Aβ positron emission tomography (PET) and/or fluid biomarkers such as cerebrospinal fluid (CSF) Aβ42/40. However, these biomarkers measure brain Aβ deposits indirectly and/or incompletely. In contrast, neuropathologic assessments allow direct investigation of treatment effects on brain Aβ deposits-and on potentially myriad 'downstream' pathologic features.

Resistance and resilience to Alzheimer's disease in Down syndrome.

Due to the high prevalence of Alzheimer's disease (AD) in adults with Down syndrome (DS), trisomy 21 is now considered a genetic form of AD (DSAD). A better understanding of factors that can prevent or delay AD is vital to improve outcomes for adults with DS. In this narrative review, we apply AD and cognitive aging research frameworks to study resistance and resilience in DSAD.

Evaluation of Serum and Aqueous Humor Neurofilament Light Chain as Markers of Neurodegeneration in Glaucoma.

Purpose: The purpose of this study was to evaluate the relationship between serum and aqueous humor (AH) neurofilament light chain (NfL) and to determine whether serum NfL is elevated in patients undergoing ocular surgery who have glaucoma compared with those who do not.

Methods: In this single-center, case-control study, we enrolled patients with various types and stages of glaucoma undergoing planned ophthalmic surgery as part of their routine care and compared them with patients without glaucoma undergoing phacoemulsification for age-related cataract. We recruited 110 patients with glaucoma and 113 patients without glaucoma and collected AH and blood from these participants.

The pathogenicity of PSEN2 variants is tied to Aβ production and homology to PSEN1.

Introduction: Though recognized as a potential cause of autosomal dominant Alzheimer's disease, the pathogenicity of many PSEN2 variants remains uncertain. We compared amyloid beta (Aβ) production across all missense PSEN2 variants in the AlzForum database and, when possible, to corresponding PSEN1 variants.

Methods: We expressed 74 PSEN2 variants, 21 of which had known, homologous PSEN1 pathogenic variants with the same amino acid substitution, in HEK293 cells lacking presenilin 1/2.

Comparative neurofilament light chain trajectories in CSF and plasma in autosomal dominant Alzheimer's disease.

Disease-modifying therapies for Alzheimer's disease (AD) are likely to be most beneficial when initiated in the presymptomatic phase. To track the benefit of such interventions, fluid biomarkers are of great importance, with neurofilament light chain protein (NfL) showing promise for monitoring neurodegeneration and predicting cognitive outcomes. Here, we update and complement previous findings from the Dominantly Inherited Alzheimer Network Observational Study by using matched cross-sectional and longitudinal cerebrospinal fluid (CSF) and plasma samples from 567 individuals, allowing timely comparative analyses of CSF and blood trajectories across the entire disease spectrum.

γ-Secretase activity, clinical features, and biomarkers of autosomal dominant Alzheimer's disease: cross-sectional and longitudinal analysis of the Dominantly Inherited Alzheimer Network observational study (DIAN-OBS).

Background: Genetic variants that cause autosomal dominant Alzheimer's disease are highly penetrant but vary substantially regarding age at symptom onset (AAO), rates of cognitive decline, and biomarker changes. Most pathogenic variants that cause autosomal dominant Alzheimer's disease are in presenilin 1 (PSEN1), which encodes the catalytic core of γ-secretase, an enzyme complex that is crucial in production of amyloid β. We aimed to investigate whether the heterogeneity in AAO and biomarker trajectories in carriers of PSEN1 pathogenic variants could be predicted on the basis of the effects of individual PSEN1 variants on γ-secretase activity and amyloid β production.

The pathogenicity of variants is tied to Aβ production and homology to .

Introduction: Though recognized as a potential cause of Autosomal Dominant Alzheimer's Disease, the pathogenicity of many variants remains uncertain. We compared Aβ production across all missense variants in the Alzforum database and, when possible, to corresponding variants.

Methods: We expressed 74 variants, 21 of which had homologous variants with the same amino acid substitution, in HEK293 cells lacking PSN1/2.

Presenilin-1 mutation position influences amyloidosis, small vessel disease, and dementia with disease stage.

Introduction: Amyloidosis, including cerebral amyloid angiopathy, and markers of small vessel disease (SVD) vary across dominantly inherited Alzheimer's disease (DIAD) presenilin-1 (PSEN1) mutation carriers. We investigated how mutation position relative to codon 200 (pre-/postcodon 200) influences these pathologic features and dementia at different stages.

Methods: Individuals from families with known PSEN1 mutations (n = 393) underwent neuroimaging and clinical assessments.

Predicting cognitive decline: Which is more useful, baseline amyloid levels or longitudinal change?

The use of biomarkers for the early detection of Alzheimer's disease (AD) is crucial for developing potential therapeutic treatments. Positron Emission Tomography (PET) is a well-established tool used to detect β-amyloid (Aβ) plaques in the brain. Previous studies have shown that cross-sectional biomarkers can predict cognitive decline (Schindler et al.

Etiology of White Matter Hyperintensities in Autosomal Dominant and Sporadic Alzheimer Disease.

Importance: Increased white matter hyperintensity (WMH) volume is a common magnetic resonance imaging (MRI) finding in both autosomal dominant Alzheimer disease (ADAD) and late-onset Alzheimer disease (LOAD), but it remains unclear whether increased WMH along the AD continuum is reflective of AD-intrinsic processes or secondary to elevated systemic vascular risk factors.

Objective: To estimate the associations of neurodegeneration and parenchymal and vessel amyloidosis with WMH accumulation and investigate whether systemic vascular risk is associated with WMH beyond these AD-intrinsic processes.

Design, Setting, And Participants: This cohort study used data from 3 longitudinal cohort studies conducted in tertiary and community-based medical centers-the Dominantly Inherited Alzheimer Network (DIAN; February 2010 to March 2020), the Alzheimer's Disease Neuroimaging Initiative (ADNI; July 2007 to September 2021), and the Harvard Aging Brain Study (HABS; September 2010 to December 2019).

Relation of modifiable lifestyle and mood factors to cognitive concerns among participants and their study partners in the A4 screen data.

Introduction: Subjective cognitive decline (SCD) has been associated with elevated amyloid levels and increased risk of future cognitive decline, as well as modifiable variables, including depression, anxiety, and physical inactivity. Participants generally endorse greater and earlier concerns than their close family and friends (study partners [SPs]), which may reflect subtle changes at the earliest stages of disease among participants with underlying neurodegenerative processes. However, many individuals with subjective concerns are not at risk of Alzheimer's disease (AD) pathology, suggesting that additional factors, such as lifestyle habits, may be contributory.

Experimental evidence for temporal uncoupling of brain Aβ deposition and neurodegenerative sequelae.

Brain Aβ deposition is a key early event in the pathogenesis of Alzheimer´s disease (AD), but the long presymptomatic phase and poor correlation between Aβ deposition and clinical symptoms remain puzzling. To elucidate the dependency of downstream pathologies on Aβ, we analyzed the trajectories of cerebral Aβ accumulation, Aβ seeding activity, and neurofilament light chain (NfL) in the CSF (a biomarker of neurodegeneration) in Aβ-precursor protein transgenic mice. We find that Aβ deposition increases linearly until it reaches an apparent plateau at a late age, while Aβ seeding activity increases more rapidly and reaches a plateau earlier, coinciding with the onset of a robust increase of CSF NfL.

APOE ε4 genotype, amyloid-β, and sex interact to predict tau in regions of high APOE mRNA expression.

The apolipoprotein E () ε4 allele is strongly linked with cerebral β-amyloidosis, but its relationship with tauopathy is less established. We investigated the relationship between ε4 carrier status, regional amyloid-β (Aβ), magnetic resonance imaging (MRI) volumetrics, tau positron emission tomography (PET), messenger RNA (mRNA) expression maps, and cerebrospinal fluid phosphorylated tau (CSF ptau). Three hundred fifty participants underwent imaging, and 270 had ptau.

Cardiorespiratory fitness and cognition in persons at risk for Alzheimer's disease.

Introduction: This study examined the relationship between cardiorespiratory fitness (CRF) and longitudinal cognitive functioning in a cohort enriched with risk factors for Alzheimer's disease (AD).

Methods: A total of 155 enrollees in the Wisconsin Registry for Alzheimer's Prevention completed repeat comprehensive neuropsychological evaluations that assessed six cognitive domains. Peak oxygen consumption (VOpeak) was the primary measure of CRF.

Visually Identified Tau 18F-MK6240 PET Patterns in Symptomatic Alzheimer's Disease.

Background: In Alzheimer's disease, heterogeneity has been observed in the postmortem distribution of tau neurofibrillary tangles. Visualizing the topography of tau in vivo may facilitate clinical trials and clinical practice.

Objective: This study aimed to investigate whether tau distribution patterns that are limited to mesial temporal lobe (MTL)/limbic regions, and those that spare MTL regions, can be visually identified using 18F-MK6240, and whether these patterns are associated with different demographic and cognitive profiles.

Progressive White Matter Injury in Preclinical Dutch Cerebral Amyloid Angiopathy.

Autosomal-dominant, Dutch-type cerebral amyloid angiopathy (D-CAA) offers a unique opportunity to develop biomarkers for pre-symptomatic cerebral amyloid angiopathy (CAA). We hypothesized that neuroimaging measures of white matter injury would be present and progressive in D-CAA prior to hemorrhagic lesions or symptomatic hemorrhage. In a longitudinal cohort of D-CAA carriers and non-carriers, we observed divergence of white matter injury measures between D-CAA carriers and non-carriers prior to the appearance of cerebral microbleeds and >14 years before the average age of first symptomatic hemorrhage.

Variant-dependent heterogeneity in amyloid β burden in autosomal dominant Alzheimer's disease: cross-sectional and longitudinal analyses of an observational study.

Background: Insights gained from studying individuals with autosomal dominant Alzheimer's disease have broadly influenced mechanistic hypotheses, biomarker development, and clinical trials in both sporadic and dominantly inherited Alzheimer's disease. Although pathogenic variants causing autosomal dominant Alzheimer's disease are highly penetrant, there is substantial heterogeneity in levels of amyloid β (Aβ) between individuals. We aimed to examine whether this heterogeneity is related to disease progression and to investigate the association with mutation location within PSEN1, PSEN2, or APP.

Comparison of the Ekblom-Bak Submaximal Test to a Maximal Test in a Cohort of Healthy Younger and Older Adults in the United States.

Cardiorespiratory fitness (CRF) is routinely investigated in diverse populations, including in older adults of varying physical activity levels. Commonly performed maximal exercise testing protocols might be contraindicated and/or inadequate for older individuals who have physical or cognitive impairment. Moreover, early termination of an attempted maximal exercise test could result in underestimation of CRF in this population.

Serum neurofilament light chain levels are associated with white matter integrity in autosomal dominant Alzheimer's disease.

Neurofilament light chain (NfL) is a protein that is selectively expressed in neurons. Increased levels of NfL measured in either cerebrospinal fluid or blood is thought to be a biomarker of neuronal damage in neurodegenerative diseases. However, there have been limited investigations relating NfL to the concurrent measures of white matter (WM) decline that it should reflect.

Plasma neurofilament light chain in the presenilin 1 E280A autosomal dominant Alzheimer's disease kindred: a cross-sectional and longitudinal cohort study.

Background: Neurofilament light chain (NfL) is a promising biomarker of active axonal injury and neuronal degeneration. We aimed to characterise cross-sectional and longitudinal plasma NfL measurements and determine the age at which NfL concentrations begin to differentiate between carriers of the presenilin 1 (PSEN1) E280A (Glu280Ala) mutation and age-matched non-carriers from the Colombian autosomal dominant Alzheimer's disease kindred.

Methods: In this cross-sectional and longitudinal cohort study, members of the familial Alzheimer's disease Colombian kindred aged 8-75 years with no other neurological or health conditions were recruited from the Alzheimer's Prevention Initiative Registry at the University of Antioquia (Medellín, Colombia) between Aug 1, 1995, and Dec 15, 2018.

Association between personality and tau-PET binding in cognitively normal older adults.

Personality traits such as Neuroticism and Conscientiousness are associated with Alzheimer disease (AD) pathophysiology in cognitively normal (CN) and impaired individuals, and may represent potential risk or resilience factors, respectively. This study examined the cross-sectional relationship between personality traits and regional tau deposition using positron emission tomography (PET) in cognitively normal older adults. A cohort of CN (Clinical Dementia Rating (CDR) 0, n = 128) older adults completed the NEO Five-Factor Inventory to assess traits of Neuroticism, Extroversion, Openness, Agreeableness, and Conscientiousness and underwent tau-PET and β-amyloid (Aβ)-PET imaging.

heterozygosity attenuates -related amyloid burden in preclinical AD.

Objective: To examine whether the gene variant KL-VS attenuates associated β-amyloid (Aβ) accumulation in a late-middle-aged cohort enriched with Alzheimer disease (AD) risk factors.

Methods: Three hundred nine late-middle-aged adults from the Wisconsin Registry for Alzheimer's Prevention and the Wisconsin Alzheimer's Disease Research Center were genotyped to determine KL-VS and status and underwent CSF sampling (n = 238) and/or C-Pittsburgh compound B (PiB)-PET imaging (n = 183). Covariate-adjusted regression analyses were used to investigate whether exerted expected effects on Aβ burden.