Contribution of Alzheimer's biomarkers and risk factors to cognitive impairment and decline across the Alzheimer's disease continuum.

Introduction: Amyloid beta (Aβ), tau, and neurodegeneration jointly with the Alzheimer's disease (AD) risk factors affect the severity of clinical symptoms and disease progression.

Methods: Within 248 Aβ-positive elderly with and without cognitive impairment and dementia, partial least squares structural equation pathway modeling was used to assess the direct and indirect effects of imaging biomarkers (global Aβ-positron emission tomography [PET] uptake, regional tau-PET uptake, and regional magnetic resonance imaging-based atrophy) and risk-factors (age, sex, education, apolipoprotein E [APOE], and white-matter lesions) on cross-sectional cognitive impairment and longitudinal cognitive decline.

Results: Sixteen percent of variance in cross-sectional cognitive impairment was accounted for by Aβ, 46% to 47% by tau, and 25% to 29% by atrophy, although 53% to 58% of total variance in cognitive impairment was explained by incorporating mediated and direct effects of AD risk factors.

-Jacksonville (V236E) variant reduces self-aggregation and risk of dementia.

Apolipoprotein E () genetic variants have been shown to modify Alzheimer’s disease (AD) risk. We previously identified an variant (3-V236E), named -Jacksonville (-Jac), associated with healthy brain aging and reduced risk for AD and dementia with Lewy bodies (DLB). Herein, we resolved the functional mechanism by which APOE3-Jac reduces APOE aggregation and enhances its lipidation in human brains, as well as in cellular and biochemical assays.

Using the Alzheimer's Disease Neuroimaging Initiative to improve early detection, diagnosis, and treatment of Alzheimer's disease.

Introduction: The Alzheimer's Disease Neuroimaging Initiative (ADNI) has accumulated 15 years of clinical, neuroimaging, cognitive, biofluid biomarker and genetic data, and biofluid samples available to researchers, resulting in more than 3500 publications. This review covers studies from 2018 to 2020.

Methods: We identified 1442 publications using ADNI data by conventional search methods and selected impactful studies for inclusion.

Associations of amyloid and neurodegeneration plasma biomarkers with comorbidities.

Introduction: Blood-based biomarkers of amyloid pathology and neurodegeneration are entering clinical use. It is critical to understand what factors affect the levels of these markers.

Methods: Plasma markers (Aβ42, Aβ40, NfL, T-tau, Aβ42/40 ratio) were measured on the Quanterix Simoa HD-1 analyzer for 996 Mayo Clinic Study of Aging (MCSA) participants, aged 51 to 95 years.

Relationship of APOE, age at onset, amyloid and clinical phenotype in Alzheimer disease.

The apolipoprotein E (APOE) ε4 allele is the most well-established risk factor for Alzheimer's disease (AD), although its relationship to age at onset and clinical phenotype is unclear. We aimed to assess relationships between APOE genotype and age at onset, amyloid-beta (Aβ) deposition and typical versus atypical clinical presentations in AD. Frequency of APOE ε4 carriers by age at onset was assessed in 447 AD patients, 138 atypical AD patients recruited by the Neurodegenerative Research Group at Mayo Clinic, and 309 with typical AD from ADNI.

Cerebral Amyloid Angiopathy Pathology and Its Association With Amyloid-β PET Signal.

Background And Objectives: To determine the contribution of cerebral amyloid angiopathy (CAA) to Pittsburgh compound B (PiB)-PET tracer retention.

Methods: Participants from the Mayo Clinic Study of Aging and Mayo Clinic Alzheimer's Disease Research Center with antemortem PiB-PET imaging for β-amyloid (Aβ) who later underwent autopsy were included in this study. Pathologic regional leptomeningeal, parenchymal, capillary CAA, and Aβ plaque burden were calculated from one hemisphere.

Chronic Kidney Disease Associated with Worsening White Matter Disease and Ventricular Enlargement.

Background: Chronic kidney disease (CKD), a growing public health issue in the elderly, is associated with increased risk of cognitive impairment.

Objective: To investigate the mechanisms through which CKD impacts brain health using longitudinal imaging.

Methods: We identified 97 participants (74 CKD and 23 non-CKD) from the BRINK (BRain IN Kidney Disease), a longitudinal study of CKD with two MRI scans (baseline and 3-year follow-up).

Brain White Matter Structure and Amyloid Deposition in Black and White Older Adults: The ARIC-PET Study.

Background White matter abnormalities are a common feature of aging and Alzheimer disease, and tend to be more severe among Black individuals. However, the extent to which white matter abnormalities relate to amyloid deposition, a marker of Alzheimer pathology, remains unclear. This cross-sectional study examined the association of white matter abnormalities with cortical amyloid in a community sample of older adults without dementia and examined the moderating effect of race.

Gray and White Matter Correlates of Dysphagia in Progressive Supranuclear Palsy.

Background: Dysphagia is a common symptom of progressive supranuclear palsy often leading to aspiration pneumonia and death.

Objective: The aim of this study was to examine how impairments of the oral and pharyngeal phases of the swallow and airway incursion during liquid swallows relate to gray and white matter integrity.

Methods: Thirty-eight participants with progressive supranuclear palsy underwent videofluorographic swallowing assessment and structural and diffusion tensor head magnetic resonance imaging.

Sex Difference in the Relation Between Marital Status and Dementia Risk in Two Population-Based Cohorts.

Background: The modifying effect of sex on the relation between marital status and dementia has yet to be determined.

Objective: To examine if sex modifies the association between marital status and incident dementia.

Methods: Population-based samples from the Mayo Clinic Study of Aging (MCSA, N = 3,471) and the Gothenburg H70 Birth Cohort Study (H70-study, N = 913) were used.

A Comparison of Cross-Sectional and Longitudinal Methods of Defining Objective Subtle Cognitive Decline in Preclinical Alzheimer's Disease Based on Cogstate One Card Learning Accuracy Performance.

Background: Longitudinal, but not cross-sectional, cognitive testing is one option proposed to define transitional cognitive decline for individuals on the Alzheimer's disease continuum.

Objective: Compare diagnostic accuracy of cross-sectional subtle objective cognitive impairment (sOBJ) and longitudinal objective decline (ΔOBJ) over 30 months for identifying 1) cognitively unimpaired participants with preclinical Alzheimer's disease defined by elevated brain amyloid and tau (A+T+) and 2) incident mild cognitive impairment (MCI) based on Cogstate One Card Learning (OCL) accuracy performance.

Methods: Mayo Clinic Study of Aging cognitively unimpaired participants aged 50 + with amyloid and tau PET scans (n = 311) comprised the biomarker-defined sample.

Relationships between β-amyloid and tau in an elderly population: An accelerated failure time model.

Using positron emission tomography (PET)-derived amyloid and tau measurements from 1,495 participants, we explore the evolution of these values over time via an accelerated failure time (AFT) model. The AFT model assumes a shared pattern of progression, but one which is shifted earlier or later in time for each individual; an individual's time shift for amyloid and for tau are assumed to be linked. The resulting pattern for each outcome consists of an earlier indolent phase followed by sharp progression of the accumulation rate.

Comparing amyloid-β plaque burden with antemortem PiB PET in autosomal dominant and late-onset Alzheimer disease.

Pittsburgh compound B (PiB) radiotracer for positron emission tomography (PET) imaging can bind to different types of amyloid-β plaques and blood vessels (cerebral amyloid angiopathy). However, the relative contributions of different plaque subtypes (diffuse versus cored/compact) to in vivo PiB PET signal on a region-by-region basis are incompletely understood. Of particular interest is whether the same staging schemes for summarizing amyloid-β burden are appropriate for both late-onset and autosomal dominant forms of Alzheimer disease (LOAD and ADAD).

Comparison of CSF phosphorylated tau 181 and 217 for cognitive decline.

Introduction: The prognostic utility of cerebrospinal fluid (CSF) phosphorylated tau 217 (p-tau217) and p-tau181 is not understood.

Methods: Analyses included 753 Mayo Clinic Study on Aging participants (median age = 71.6; 57% male).

Detection of Alzheimer's disease amyloid beta 1-42, p-tau, and t-tau assays.

Introduction: We aimed to provide cut points for the automated Elecsys Alzheimer's disease (AD) cerebrospinal fluid (CSF) biomarkers.

Methods: Cut points for Elecsys amyloid beta 42 (Aβ42), total tau (t-tau), hyperphosphorylated tau (p-tau), and t-tau/Aβ42 and p-tau/Aβ42 ratios were evaluated in Mayo Clinic Study of Aging (n = 804) and Mayo Clinic Alzheimer's Disease Research Center (n = 70) participants.

Results: The t-tau/Aβ42 and p-tau/Aβ42 ratios had a higher percent agreement with normal/abnormal amyloid positron emission tomography (PET) than the individual CSF markers.

Comparison of Plasma Phosphorylated Tau Species With Amyloid and Tau Positron Emission Tomography, Neurodegeneration, Vascular Pathology, and Cognitive Outcomes.

Importance: Cerebrospinal fluid phosphorylated tau (p-tau) 181, p-tau217, and p-tau231 are associated with neuropathological outcomes, but a comparison of these p-tau isoforms in blood samples is needed.

Objective: To conduct a head-to-head comparison of plasma p-tau181 and p-tau231 measured on the single-molecule array (Simoa) platform and p-tau181 and p-tau217 measured on the Meso Scale Discovery (MSD) platform on amyloid and tau positron emission tomography (PET) measures, neurodegeneration, vascular pathology, and cognitive outcomes.

Design, Setting, And Participants: This study included data from the Mayo Clinic Study on Aging collected from March 1, 2015, to September 30, 2017, and analyzed between December 15, 2020, and May 17, 2021.

Phonological Errors in Posterior Cortical Atrophy.

Background: Posterior cortical atrophy (PCA) is an atypical variant of Alzheimer's disease (AD) that presents with visuospatial/perceptual deficits. PCA is characterized by atrophy in posterior brain regions, which overlaps with atrophy occurring in logopenic variant of primary progressive aphasia (lvPPA), another atypical AD variant characterized by language difficulties, including phonological errors. Language abnormalities have been observed in PCA, although the prevalence of phonological errors is unknown.

FDG PET metabolic signatures distinguishing prodromal DLB and prodromal AD.

Background And Purpose: Patients with dementia with Lewy bodies (DLB) are characterized by hypometabolism in the parieto-occipital cortex and the cingulate island sign (CIS) on F-fluorodeoxyglucose (FDG) PET. Whether this pattern of hypometabolism is present as early as the prodromal stage of DLB is unknown. We investigated the pattern of hypometabolism in patients with mild cognitive impairment (MCI) who progressed to probable DLB compared to MCI patients who progressed to Alzheimer's disease (AD) dementia and clinically unimpaired (CU) controls.

Developing the ATX(N) classification for use across the Alzheimer disease continuum.

Breakthroughs in the development of highly accurate fluid and neuroimaging biomarkers have catalysed the conceptual transformation of Alzheimer disease (AD) from the traditional clinical symptom-based definition to a clinical-biological construct along a temporal continuum. The AT(N) system is a symptom-agnostic classification scheme that categorizes individuals using biomarkers that chart core AD pathophysiological features, namely the amyloid-β (Aβ) pathway (A), tau-mediated pathophysiology (T) and neurodegeneration (N). This biomarker matrix is now expanding towards an ATX(N) system, where X represents novel candidate biomarkers for additional pathophysiological mechanisms such as neuroimmune dysregulation, synaptic dysfunction and blood-brain barrier alterations.

A trial of gantenerumab or solanezumab in dominantly inherited Alzheimer's disease.

Dominantly inherited Alzheimer's disease (DIAD) causes predictable biological changes decades before the onset of clinical symptoms, enabling testing of interventions in the asymptomatic and symptomatic stages to delay or slow disease progression. We conducted a randomized, placebo-controlled, multi-arm trial of gantenerumab or solanezumab in participants with DIAD across asymptomatic and symptomatic disease stages. Mutation carriers were assigned 3:1 to either drug or placebo and received treatment for 4-7 years.

Diffusion models reveal white matter microstructural changes with ageing, pathology and cognition.

White matter microstructure undergoes progressive changes during the lifespan, but the neurobiological underpinnings related to ageing and disease remains unclear. We used an advanced diffusion MRI, Neurite Orientation Dispersion and Density Imaging, to investigate the microstructural alterations due to demographics, common age-related pathological processes (amyloid, tau and white matter hyperintensities) and cognition. We also compared Neurite Orientation Dispersion and Density Imaging findings to the older Diffusion Tensor Imaging model-based findings.

Cerebrovascular disease, neurodegeneration, and clinical phenotype in dementia with Lewy bodies.

We investigated whether cerebrovascular disease contributes to neurodegeneration and clinical phenotype in dementia with Lewy bodies (DLB). Regional cortical thickness and subcortical gray matter volumes were estimated from structural magnetic resonance imaging (MRI) in 165 DLB patients. Cortical and subcortical infarcts were recorded and white matter hyperintensities (WMHs) were assessed.

Selecting software pipelines for change in flortaucipir SUVR: Balancing repeatability and group separation.

Since tau PET tracers were introduced, investigators have quantified them using a wide variety of automated methods. As longitudinal cohort studies acquire second and third time points of serial within-person tau PET data, determining the best pipeline to measure change has become crucial. We compared a total of 415 different quantification methods (each a combination of multiple options) according to their effects on a) differences in annual SUVR change between clinical groups, and b) longitudinal measurement repeatability as measured by the error term from a linear mixed-effects model.

Dementia with Lewy bodies: association of Alzheimer pathology with functional connectivity networks.

Dementia with Lewy bodies (DLB) is neuropathologically defined by the presence of α-synuclein aggregates, but many DLB cases show concurrent Alzheimer's disease pathology in the form of amyloid-β plaques and tau neurofibrillary tangles. The first objective of this study was to investigate the effect of Alzheimer's disease co-pathology on functional network changes within the default mode network (DMN) in DLB. Second, we studied how the distribution of tau pathology measured with PET relates to functional connectivity in DLB.