Journal of Alzheimer's Disease - Volume 96, issue 4

Authors: Tetzloff, Katerina A. | Duffy, Joseph R. | Clark, Heather M. | Pham, Nha Trang Thu | Machulda, Mary M. | Botha, Hugo | Jack Jr., Clifford R. | Dickson, Dennis W. | Lowe, Val J. | Josephs, Keith A. | Whitwell, Jennifer L. | Utianski, Rene L.

Article Type: Research Article

Abstract: Background: The agrammatic variant of primary progressive aphasia (PAA), primary progressive apraxia of speech (PPAOS), or a combination of both (AOS-PAA) are neurodegenerative disorders characterized by speech-language impairments and together compose the AOS-PAA spectrum disorders. These patients typically have an underlying 4-repeat tauopathy, although they sometimes show evidence of amyloid-β and tau deposition on PET, suggesting Alzheimer’s disease (AD). Given the growing number of pharmacologic treatment options for AD, it is important to better understand the incidence of AD pathology in these patients. Objective: This study aimed to evaluate the frequency of amyloid-β and tau positivity in AOS-PAA …spectrum disorders. Sixty-five patients with AOS-PAA underwent a clinical speech-language battery and PiB PET and flortaucipir PET imaging. Methods: Global PiB PET standardized uptake value ratios (SUVRs) and flortaucipir PET SUVRs from the temporal meta region of interest were compared between patient groups. For 19 patients who had died and undergone autopsy, their PET and pathology findings were also compared. Results: The results showed that although roughly half of the patients are positive for at least one biomarker, their clinical symptoms and biomarker status were not related, suggesting that AD is not the primary cause of their neurodegeneration. All but one patient in the autopsy subset had a Braak stage of IV or less, despite four being positive on tau PET imaging. Conclusions: Inclusion criteria for clinical trials should specify clinical presentation or adjust the evaluation of such treatments to be specific to disease diagnosis beyond the presence of certain imaging biomarkers. Show more

Keywords: Alzheimer’s disease, biomarkers, amyloid-β protein, tau protein

DOI: 10.3233/JAD-230912

Citation: Journal of Alzheimer's Disease, vol. 96, no. 4, pp. 1759-1765, 2023

Authors: Short, Meghan I. | Fohner, Alison E. | Skjellegrind, Håvard K. | Beiser, Alexa | Gonzales, Mitzi M. | Satizabal, Claudia L. | Austin, Thomas R. | Longstreth Jr., W.T. | Bis, Joshua C. | Lopez, Oscar | Hveem, Kristian | Selbæk, Geir | Larson, Martin G. | Yang, Qiong | Aparicio, Hugo J. | McGrath, Emer R. | Gerszten, Robert E. | DeCarli, Charles S. | Psaty, Bruce M. | Vasan, Ramachandran S. | Zare, Habil | Seshadri, Sudha

Article Type: Research Article

Abstract: Background: Alzheimer’s disease and related dementias (ADRD) involve biological processes that begin years to decades before onset of clinical symptoms. The plasma proteome can offer insight into brain aging and risk of incident dementia among cognitively healthy adults. Objective: To identify biomarkers and biological pathways associated with neuroimaging measures and incident dementia in two large community-based cohorts by applying a correlation-based network analysis to the plasma proteome. Methods: Weighted co-expression network analysis of 1,305 plasma proteins identified four modules of co-expressed proteins, which were related to MRI brain volumes and risk of incident dementia over a …median 20-year follow-up in Framingham Heart Study (FHS) Offspring cohort participants (n = 1,861). Analyses were replicated in the Cardiovascular Health Study (CHS) (n = 2,117, mean 6-year follow-up). Results: Two proteomic modules, one related to protein clearance and synaptic maintenance (M2) and a second to inflammation (M4), were associated with total brain volume in FHS (M2: p = 0.014; M4: p = 4.2×10–5 ). These modules were not significantly associated with hippocampal volume, white matter hyperintensities, or incident all-cause or AD dementia. Associations with TCBV did not replicate in CHS, an older cohort with a greater burden of comorbidities. Conclusions: Proteome networks implicate an early role for biological pathways involving inflammation and synaptic function in preclinical brain atrophy, with implications for clinical dementia. Show more

Keywords: Alzheimer’s disease, biomarkers, dementia, endophenotypes, magnetic resonance imaging, proteomics

DOI: 10.3233/JAD-230145

Citation: Journal of Alzheimer's Disease, vol. 96, no. 4, pp. 1767-1780, 2023

Authors: White, Joshua P. | Schembri, Adrian | Prenn-Gologranc, Carmen | Ondrus, Matej | Katina, Stanislav | Novak, Petr | Lim, Yen Ying | Edgar, Chris | Maruff, Paul

Article Type: Research Article

Abstract: Background: The Cogstate Brief Battery (CBB) is a computerized cognitive test battery used commonly to identify cognitive deficits related to Alzheimer’s disease (AD). However, AD and normative samples used to understand the sensitivity of the CBB to AD in the clinic have been limited, as have the outcome measures studied. Objective: This study investigated the sensitivity of CBB outcomes, including potential composite scores, to cognitive impairment in mild cognitive impairment (MCI) and dementia due to AD, in carefully selected samples. Methods: Samples consisted of 4,871 cognitively unimpaired adults and 184 adults who met clinical criteria for …MCI (Clinical Dementia Rating (CDR) = 0.5) or dementia (CDR > 0.5) due to AD and CBB naive. Speed and accuracy measures from each test were examined, and theoretically- and statistically-derived composites were created. Sensitivity and specificity of classification of cognitive impairment were compared between outcomes. Results: Individual CBB measures of learning and working memory showed high discriminability for AD-related cognitive impairment for CDR 0.5 (AUCs ∼ 0.79–0.88), and CDR > 0.5 (AUCs ∼ 0.89–0.96) groups. Discrimination ability for theoretically derived CBB composite measures was high, particularly for the Learning and Working Memory (LWM) composite (CDR 0.5 AUC = 0.90, CDR > 0.5 AUC = 0.97). As expected, statistically optimized linear composite measures showed strong discrimination abilities albeit similar to the LWM composite. Conclusions: In older adults, the CBB is effective for discriminating cognitive impairment due to MCI or AD-dementia from unimpaired cognition with the LWM composite providing the strongest sensitivity. Show more

Keywords: Alzheimer’s disease, cogstate brief battery, composites, dementia, discriminability, mild cognitive impairment

DOI: 10.3233/JAD-230352

Citation: Journal of Alzheimer's Disease, vol. 96, no. 4, pp. 1781-1799, 2023

Authors: Yoon, Jieun | Sasaki, Kazunori | Tateoka, Korin | Arai, Tetsuaki | Isoda, Hiroko | Okura, Tomohiro

Article Type: Research Article

Abstract: Background: The amyloid-β1-42 (Aβ42 ) level is a biomarker that is widely used to evaluate individual cognitive dysfunction early in neurodegenerative diseases, as well as differentiate between normal cognitive function, mild cognitive impairment, Alzheimer’s disease, and vascular cognitive impairment. Objective: Our cross-sectional study evaluated the association between daily exercise and physical and cognitive function and Aβ42 levels among a subsample of 325 older adults from the Kasama Study. Methods: Participants (age: 74.5 [range 65–90] years) were classified into three exercise groups: the dual-task (DEG, n = 128), single-task (SEG, n = 122), …and non-exercise (NEG, n = 75) groups. The main outcomes were the plasma Aβ42 levels and the scores of the five cognitive (5-COG) tests and five cognition-related physical function (5-PHYS) tests. Results: The Aβ42 levels and 5-COG and 5-PHYS scores were higher in the SEG and DEG than in the NEG. The Aβ42 levels were higher in the DEG than in the NEG (p = 0.008). Conclusions: Physical activities such as regular exercise may benefit older adults, improving their cognitive and physical function. Show more

Keywords: Alzheimer’s disease, amyloid-β, cognitive function, dual-task exercise, physical function, single-task exercise

DOI: 10.3233/JAD-230675

Citation: Journal of Alzheimer's Disease, vol. 96, no. 4, pp. 1801-1812, 2023

Authors: Zhao, Bing | Ou, Ya-Nan | Zhang, Xuan-Yue | Fu, Yan | Tan, Lan

Article Type: Research Article

Abstract: Background: The APOE genotype has emerged as the major genetic factor for AD but differs among different alleles. Objective: To investigate the discrepant effects of APOE genotype on AD cerebrospinal fluid (CSF) biomarkers. Methods: A total of 989 non-demented ADNI participants were included. The associations of APOE ɛ 2 and APOE ɛ 4 with CSF biomarkers were investigated using linear regression models. Interaction and subgroup analyses were used to investigate the effects of sex and age on these associations. Furthermore, we used mediation analyses to assess whether Aβ mediated the associations between …APOE genotypes and tau. Results: APOE ɛ 2 carriers only showed higher Aβ levels (β [95% CI] = 0.07 [0.01, 0.13], p  = 0.026). Conversely, APOE ɛ 4 carriers exhibited lower Aβ concentration (β [95% CI] = –0.27 [–0.31, –0.24], p  < 0.001), higher t-Tau (β [95% CI] = 0.25 [0.08, 0.18], p  < 0.001) and higher p-Tau (β [95% CI] = 0.31 [0.25, 0.37], p  < 0.001). Subgroup analysis showed that APOE ɛ 2 was significantly positively associated with Aβ only in females (β [95% CI] = 0.12 [0.04, 0.21], p  = 0.005) and older people (β [95% CI] = 0.06 [0.001, 0.12], p  = 0.048). But the effects of APOE ɛ 4 were independent of gender and age. Besides, the associations of APOE ɛ 4 with t-Tau and p-Tau were both mediated by baseline Aβ. Conclusions: Our data suggested that APOE ɛ 2 could promote Aβ clearance, while the process could be modified by sex and age. However, APOE ɛ 4 might cause the accumulation of Aβ and tau pathology independent of sex and age. Show more

Keywords: Age interaction, Alzheimer’s disease, amyloid-β , APOE , sex interaction, tau

DOI: 10.3233/JAD-230761

Citation: Journal of Alzheimer's Disease, vol. 96, no. 4, pp. 1813-1825, 2023

Authors: Spampinato, Maria Vittoria | Ulber, Jenny L. | Fayyaz, Habiba | Sullivan, Allison | Collins, Heather R.

Article Type: Research Article

Abstract: Background: Neuropsychiatric symptoms (NPS) carry an increased risk of progression from mild cognitive impairment (MCI) to Alzheimer’s disease (AD). There is a need to understand how to integrate NPS into the paradigm outlined in the 2018 NIA-AA Research Framework. Objective: To evaluate a prediction model of MCI-AD progression using a collection of variables, including NPS, cognitive testing, apolipoprotein E4 status (APOE4 ), imaging and laboratory AD biomarkers. Methods: Of 300 elderly subjects, 219 had stable MCI and 81 MCI-AD progression over a 5-year follow-up. NPS were measured using the Neuropsychiatric Inventory (NPI). A multivariate Cox Proportional …Hazards Regression Analysis assessed the effects of APOE4 , baseline NPI, baseline CSF amyloid-β, phosphorylated and total tau, baseline AD-signature MRI biomarker, baseline memory and executive function on MCI-AD progression. Results: 27% progressed to dementia (median follow-up = 43 months). NPS were found in stable MCI (62.6%) and MCI-AD converters (70.3%). The Cox model exhibited a good fit (p  < 0.001), and NPS (HR = 1.033, p  = 0.027), phosphorylated tau (HR = 1.011, p  = 0.025), total tau (HR = 1.005, p  = 0.024), AD-signature MRI biomarker (HR = 0.111, p  = 0.002), executive function (HR = 0.727, p  = 0.045), and memory performance (HR = 0.387, p  < 0.001) were significantly associated with dementia. Conclusions: NPS may inform dementia risk assessment in conjunction with cognitive testing and imaging and laboratory AD biomarkers. NPS is independently associated with the risk of MCI-dementia progression, over and beyond the contributions of CSF biomarkers. Show more

Keywords: Alzheimer’s disease, amyloid, cerebrospinal fluid, cognitive dysfunction, magnetic resonance imaging, neuropsychiatric symptoms

DOI: 10.3233/JAD-220835

Citation: Journal of Alzheimer's Disease, vol. 96, no. 4, pp. 1827-1836, 2023

Article Type: Other

DOI: 10.3233/JAD-239012

Citation: Journal of Alzheimer's Disease, vol. 96, no. 4, pp. 1837-1850, 2023