New perspectives in attentional control theory

Importance There are limitations in current diagnostic testing approaches for Alzheimer disease (AD). Objective To examine plasma tau phosphorylated at threonine 217 (P-tau217) as a diagnostic biomarker for AD. Design, Setting, and Participants Three cross-sectional cohorts: an Arizona-based neuropathology cohort (cohort 1), including 34 participants with AD and 47 without AD (dates of enrollment, May 2007-January 2019); the Swedish BioFINDER-2 cohort (cohort 2), including cognitively unimpaired participants (n = 301) and clinically diagnosed patients with mild cognitive impairment (MCI) (n = 178), AD dementia (n = 121), and other neurodegenerative diseases (n = 99) (April 2017-September 2019); and a Colombian autosomal-dominant AD kindred (cohort 3), including 365PSEN1E280A mutation carriers and 257 mutation noncarriers (December 2013-February 2017). Exposures Plasma P-tau217. Main Outcomes and Measures Primary outcome was the discriminative accuracy of plasma P-tau217 for AD (clinical or neuropathological diagnosis). Secondary outcome was the association with tau pathology (determined using neuropathology or positron emission tomography [PET]). Results Mean age was 83.5 (SD, 8.5) years in cohort 1, 69.1 (SD, 10.3) years in cohort 2, and 35.8 (SD, 10.7) years in cohort 3; 38% were women in cohort 1, 51% in cohort 2, and 57% in cohort 3. In cohort 1, antemortem plasma P-tau217 differentiated neuropathologically defined AD from non-AD (area under the curve [AUC], 0.89 [95% CI, 0.81-0.97]) with significantly higher accuracy than plasma P-tau181 and neurofilament light chain (NfL) (AUC range, 0.50-0.72;P   .15). In cohort 3, plasma P-tau217 levels were significantly greater amongPSEN1mutation carriers, compared with noncarriers, from approximately 25 years and older, which is 20 years prior to estimated onset of MCI among mutation carriers. Plasma P-tau217 levels correlated with tau tangles in participants with (Spearman ρ = 0.64;P  Conclusions and Relevance Among 1402 participants from 3 selected cohorts, plasma P-tau217 discriminated AD from other neurodegenerative diseases, with significantly higher accuracy than established plasma- and MRI-based biomarkers, and its performance was not significantly different from key CSF- or PET-based measures. Further research is needed to optimize the assay, validate the findings in unselected and diverse populations, and determine its potential role in clinical care.

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Discriminative Accuracy of Plasma Phospho-tau217 for Alzheimer Disease vs Other Neurodegenerative Disorders.

Background The APOE e4 allele is associated with the risk of late-onset Alzheimer's disease. The age at which memory decline diverges among persons who are homozygous for the APOE e4 allele, those who are heterozygous for the allele, and noncarriers is unknown. Methods Using local advertisements, we recruited cognitively normal subjects between the ages of 21 and 97 years, who were grouped according to their APOE e4 status. We then followed the subjects with longitudinal neuropsychological testing. Anyone in whom mild cognitive impairment or dementia developed during follow-up was excluded. We compared the rates of decline in predetermined cognitive measures between carriers and noncarriers of the APOE e4 allele, using a mixed model for longitudinal change with age. Results We analyzed 815 subjects: 317 APOE e4 carriers (79 who were homozygous for the APOE e4 allele and 238 who were heterozygous) and 498 noncarriers. Carriers, as compared with noncarriers, were generally younger (mean age, 58.0 vs. 61.4 y...

/pdf/longitudinal-modeling-of-age-related-memory-decline-and-the-2d6i1motmy.pdf

Longitudinal Modeling of Age-Related Memory Decline and the APOE ε4 Effect

Our understanding of Alzheimer's disease (AD) pathophysiology remains incomplete. Here we used quantitative mass spectrometry and coexpression network analysis to conduct the largest proteomic study thus far on AD. A protein network module linked to sugar metabolism emerged as one of the modules most significantly associated with AD pathology and cognitive impairment. This module was enriched in AD genetic risk factors and in microglia and astrocyte protein markers associated with an anti-inflammatory state, suggesting that the biological functions it represents serve a protective role in AD. Proteins from this module were elevated in cerebrospinal fluid in early stages of the disease. In this study of >2,000 brains and nearly 400 cerebrospinal fluid samples by quantitative proteomics, we identify proteins and biological processes in AD brains that may serve as therapeutic targets and fluid biomarkers for the disease.

Large-scale proteomic analysis of Alzheimer’s disease brain and cerebrospinal fluid reveals early changes in energy metabolism associated with microglia and astrocyte activation

Diverse Brain Myeloid Expression Profiles Reveal Distinct Microglial Activation States and Aspects of Alzheimer’s Disease Not Evident in Mouse Models

Symposium: B rain B ank Arizona Study of Aging and Neurodegenerative Disorders and Brain and Body Donation Program

We correlated measures of problem solving (Wisconsin Card Sorting Test [WCST] categories, total errors, and perseverative errors) and chronic anxiety (Personality Assessment Inventory Anxiety Scale [ANX]) in asymptomatic apolipoprotein E (APOE) e4 homozygotes (HMZs), heterozygotes, and noncarriers (NC) (n = 42 in each group) matched for age, education, and gender. Differences between HMZ and NC in the slope of the regression of WCST scores on ANX reached statistical significance on all three WCST measures. Chronic anxiety adversely affects cognitive skills in all groups, and is associated with significantly greater decline in problem solving skills in cognitively normal APOE e4 HMZ.

https://neuro.psychiatryonline.org/doi/pdfplus/10.1176/jnp.16.3.320

Joseph G. Hentz

Papers

Symposium: B rain B ank Arizona Study of Aging and Neurodegenerative Disorders and Brain and Body Donation Program

A Distinctive Interaction Between Chronic Anxiety and Problem Solving in Asymptomatic APOE e4 Homozygotes