Journal of Alzheimer's Disease - Volume 100, issue s1

Authors: Perry, George

Article Type: Introduction

DOI: 10.3233/JAD-249015

Citation: Journal of Alzheimer's Disease, vol. 100, no. s1, pp. S1-S1, 2024

Authors: Merrick, Richard | Brayne, Carol

Article Type: Research Article

Abstract: Background: There is renewed interest in whether sex differences in dementia risk exist, and what influence social and biological factors have. Objective: To review evidence from the Cognitive Function and Ageing Studies (CFAS), a multi-center population-representative cohort study in the UK; focusing on dementia and cognition, incorporating findings on participants’ health and social circumstances. Methods: After identifying all CFAS publications, the results of all sex-stratified primary analyses of CFAS data were narratively reviewed. Results: Of 337 publications, 94 report results by sex (including null findings), which are summarized by theme: dementia epidemiology, cognition, mental …health, health expectancy, social context and biological resource (including neuropathology). Conclusions: Where differences are found they most commonly favor men; however, greater mortality in men may confound associations with age-related outcomes. This ‘survival bias’ may explain findings of greater risk of dementia and faster cognitive decline in women. Age-specific dementia incidence was similar between sexes, although reduced incidence across study generations was more pronounced in men. Mood disorders were more prevalent in women, but adjusting for disability and deprivation attenuated the association. Prominent findings from other cohorts that women have more Alzheimer’s disease pathology and greater risk of dementia from the Apolipoprotein E ɛ 4 allele were not observed, warranting further investigation. The ‘male-female health-survival paradox’ is demonstrated whereby women live longer but with more comorbidity and disability. Examining why health expectancies changed differently over two decades for each sex (interacting with deprivation) may inform population interventions to improve cognitive, mental and physical health in later life. Show more

Keywords: Aging, Alzheimer’s disease, cognitive decline, dementia, epidemiology, gender, healthy life expectancy, mental health, sex differences

DOI: 10.3233/JAD-240358

Citation: Journal of Alzheimer's Disease, vol. 100, no. s1, pp. S3-S12, 2024

Authors: Sittig, Johannes | Pickert, Lena | Weigert, Hannah | Deelen, Joris | Polidori, M. Cristina | Nelles, Gereon

Article Type: Research Article

Abstract: Background: With advancing age, cognitive decline is frequently associated with endothelial dysfunction, but data on vascular performance prior to the onset of mild cognitive impairment (MCI) is scarce. Objective: To investigate the relationship between endothelial function, vital parameters and cognitive performance in older adults with subjective cognitive decline (SCD). Methods: Forty-five volunteers aged 65 years and older with SCD underwent comprehensive geriatric assessment-based prognosis evaluation by means of the Multidimensional Prognostic Index (MPI), full neuropsychological examination and peripheral arterial tonometry measurement by means of EndoPAT™ 2000 to evaluate endothelial flexibility and vital parameters. Six months after …initial evaluation, participants were contacted by phone and a telephone-administered version of the MPI (TELE-MPI) was conducted. Results: Fifteen study participants scored below the cutoff score of 26 on the Montreal Cognitive Assessment, suggesting MCI (26.56±2.23). Nominal significant correlations were found between heart rate (HR) and trail making test (TMT) A (β= –0.49, p  = 0.03), between heart rate variability (HRV) and TMT B (β= 0.78, p  = 0.041), between power of low-frequency band (LF) HRV and Mini Nutritional Assessment-Short Form (β= 0.007, p  = 0.037) as well as between augmentation index (AI) and CogState Detection Test (β= 0.002, p  = 0.034). Conclusions: HR, HRV, and AI, but not endothelial flexibility are associated with cognitive performance in SCD and suspected MCI patients and may serve as clinical biomarkers in the early diagnosis of neurodegenerative disorders with advancing age. Show more

Keywords: Alzheimer’s disease, augmentation index, dementia, endothelial function, heart-brain syndrome, heart rate, heart rate variability, mild cognitive impairment, Multidimensional Prognostic Index, subjective cognitive decline

DOI: 10.3233/JAD-240661

Citation: Journal of Alzheimer's Disease, vol. 100, no. s1, pp. S13-S24, 2024

Authors: Kaltsa, Maria | Tsolaki, Anthoula | Lazarou, Ioulietta | Mittas, Ilias | Papageorgiou, Mairi | Papadopoulou, Despina | Tsimpli, Ianthi Maria | Tsolaki, Magda

Article Type: Research Article

Abstract: Background: The assessment of language deficits can be valuable in the early clinical diagnosis of neurodegenerative disorders, including Alzheimer’s disease (AD). Objective: The present study aims to explore whether language markers at the macrostructural level could assist with the placement of an individual across the dementia continuum employing production data from structured narratives. Methods: We administered a Picture Sequence Narrative Discourse Task to 170 speakers of Greek: young healthy controls (yHC), cognitively intact healthy elders (eHC), elder participants with subjective cognitive impairment (SCI), with mild cognitive impairment (MCI), and with AD dementia at the mild/moderate stages. …Structural MRIs, medical history, neurological examination, and neuropsychological/cognitive screening determined the status of each speaker to appropriately groupthem. Results: The data analysis revealed that the Macrostructure Index, Irrelevant Info, and Narration Density markers can track cognitive decline and AD (p  < 0.001; Macrostructural Index: eHC versus AD Sensitivity 93.8%, Specificity 74.4%, MCI versus AD Sensitivity 93.8%, Specificity 66.7%; Narration Density: eHC versus AD Sensitivity 90.6%, Specificity 71.8%, MCI versus AD Sensitivity 93.8%, Specificity 66.7%). Moreover, Narrative Complexity was significantly affected for subjects with AD, Irrelevant Info increased in the narrations of speakers with MCI and AD, while Narration Length did not appear to indubitably differentiate between the cognitively intact groups and the clinical ones. Conclusions: Narrative Macrostructure Indices provide valuable information on the language profile of speakers with(out) intact cognition revealing subtle early signs of cognitive decline and AD suggesting that the inclusion of language-based assessment tools would facilitate the clinical process. Show more

Keywords: Alzheimer’s disease, Greek, healthy aging, macrostructure skills, mild cognitive impairment, narratives, picture sequence discourse tasks, subjective cognitive impairment

DOI: 10.3233/JAD-240496

Citation: Journal of Alzheimer's Disease, vol. 100, no. s1, pp. S25-S43, 2024

Authors: Amaral-Carvalho, Viviane | Bento Lima-Silva, Thais | Inácio Mariano, Luciano | Cruz de Souza, Leonardo | Cerqueira Guimarães, Henrique | Santoro Bahia, Valéria | Nitrini, Ricardo | Tonidandel Barbosa, Maira | Sanches Yassuda, Mônica | Caramelli, Paulo

Article Type: Research Article

Abstract: Background: The Addenbrooke’s Cognitive Examination-Revised (ACE-R) is an accessible cognitive tool that supports the early detection of mild cognitive impairment (MCI), Alzheimer’s disease (AD), and behavioral variant frontotemporal dementia (bvFTD). Objective: To investigate the diagnostic efficacy of the ACE-R in MCI, AD, and bvFTD through the identification of novel coefficients for differentiation between these diseases. Methods: We assessed 387 individuals: 102 mild AD, 37 mild bvFTD, 87 with amnestic MCI patients, and 161 cognitively unimpaired controls. The Mokken scaling technique facilitated the extraction out of the 26 ACE-R items that exhibited a common latent trait, thereby …generating the Mokken scales for the AD group and the MCI group. Subsequently, we performed logistic regression, integrating each Mokken scales with sociodemographic factors, to differentiate between AD and bvFTD, as well as between AD or MCI and control groups. Ultimately, the Receiver Operating Characteristic curve analysis was employed to assess the efficacy of the coefficient’s discrimination. Results: The AD-specific Mokken scale (AD-MokACE-R) versus bvFTD exhibited an Area Under the Curve (AUC) of 0.922 (88% sensitivity and specificity). The AD-MokACE-R versus controls achieved an AUC of 0.968 (93% sensitivity, 94% specificity). The MCI-specific scale (MCI-MokACE-R) versus controls demonstrated an AUC of 0.859 (78% sensitivity, 79% specificity). Conclusions: The ACE-R’s capacity is enhanced through statistical methods and demographic integration, allowing for accurate differentiation between AD and bvFTD, as well as between MCI and controls. This new method not only reinforces its clinical value in early diagnosis but also surpasses traditional approaches noted in prior studies. Show more

Keywords: Aging, Alzheimer’s disease, cognition, dementia, frontotemporal dementia, mild cognitive impairment, neuropsychological tests

DOI: 10.3233/JAD-240554

Citation: Journal of Alzheimer's Disease, vol. 100, no. s1, pp. S45-S55, 2024

Authors: Lozupone, Madia | Dibello, Vittorio | Sardone, Rodolfo | Altamura, Mario | Bellomo, Antonello | Daniele, Antonio | Solfrizzi, Vincenzo | Resta, Emanuela | Panza, Francesco

Article Type: Editorial

Abstract: Social dysfunction is a maladaptive process of coping, problem solving, and achieving one’s goals. A new definition of apathy was cross-linked to social dysfunction, with a reduced goal-directed behavior and social interaction as a separate dimension. We hypothesized that these two neuropsychiatric symptoms may be included in the mild behavioral impairment diagnostic framework, operationalizing and standardizing late-life neuropsychiatric symptom assessment, to improve risk determination of dementia. Social dysfunction and apathy were transdiagnostic and prodromic for late-life cognitive disorders. A transdiagnostic approach could provide a useful mean for a better understanding of apathy and related conditions such as social behavior.

Keywords: Alzheimer’s disease, apathy, biopsychosocial frailty, dementia, depression, late-life cognitive disorders, mild behavioral impairment, mild cognitive impairment, social dysfunction, social withdrawal

DOI: 10.3233/JAD-240556

Citation: Journal of Alzheimer's Disease, vol. 100, no. s1, pp. S57-S61, 2024

Authors: Petersen, Melissa E. | Zhang, Fan | Hall, James R. | Julovich, David | Rissman, Robert A. | Meeker, Karin L. | Phillips, Nicole | Large, Stephanie | Ances, Beau M. | O’Bryant, Sid E.

Article Type: Research Article

Abstract: Background: Examination of Alzheimer’s disease (AD) related biomarkers among diverse communities has remained limited. Objective: The aim of this study was to expand on prior work to provide a characterization of ptau181 among a diverse community sample. Consideration was taken regarding the impact of comorbidities on ptau181 levels including medical. Methods: 3,228 (n  = 770 African American [AA], n  = 1,231 Hispanic, and n  = 1,227 non-Hispanic white [NHW]) Health and Aging Brain Study- Health Disparities (HABS-HD) participants were included in this study. ANCOVAs were conducted to examine differences in ptau181 levels across race and ethnic groups. Violin plots …were also generated stratified by APOE ɛ 4 carrier status, Amyloid PET positivity status, medical comorbidity (hypertension, dyslipidemia, chronic kidney disease [CKD], and diabetes) and by cognitive diagnosis. Results: Ptau181 levels were found to differ between Hispanics and NHW after covarying for age, sex, and APOE ɛ 4 status. Amyloid PET positivity was associated with higher ptau181 levels across all groups. APOE ɛ 4 positivity status was only significantly associated with ptau181 levels among AAs. Across all race and ethnic groups, those with a diagnosis of CKD had higher levels of ptau181. When stratified by cognitive diagnosis, cognitively unimpaired Hispanics had higher ptau181 if they also had a diagnosis of CKD or diabetes. p -values ≤0.01. Conclusions: Differences in ptau181 levels were shown in a diverse community sample. Medical comorbidities had a differing effect on ptau181 levels particularly among Hispanics even without cognitive impairment. Findings support the need for future work to consider comorbid conditions when examining the utility of ptau181. Show more

Keywords: Alzheimer’s disease, biomarkers, diverse, plasma, ptau181

DOI: 10.3233/JAD-240633

Citation: Journal of Alzheimer's Disease, vol. 100, no. s1, pp. S63-S73, 2024

Authors: Gogola, Alexandra | Cohen, Ann D. | Snitz, Beth | Minhas, Davneet | Tudorascu, Dana | Ikonomovic, Milos D. | Shaaban, C. Elizabeth | Doré, Vincent | Matan, Cristy | Bourgeat, Pierrick | Mason, N. Scott | Leuzy, Antoine | Aizenstein, Howard | Mathis, Chester A. | Lopez, Oscar L. | Lopresti, Brian J. | Villemagne, Victor L.

Article Type: Research Article

Abstract: Background: Tau accumulation in Alzheimer’s disease is associated with short term clinical progression and faster rates of cognitive decline in individuals with high amyloid-β deposition. Defining an optimal threshold of tau accumulation predictive of cognitive decline remains a challenge. Objective: We tested the ability of regional tau PET sensitivity and specificity thresholds to predict longitudinal cognitive decline. We also tested the predictive performance of thresholds in the proposed new NIA-AA biological staging for Alzheimer’s disease where multiple levels of tau positivity are used to stage participants. Methods: 18 F-flortaucipir scans from 301 non-demented participants were processed …and sampled. Four cognitive measures were assessed longitudinally. Regional standardized uptake value ratios were split into infra- and suprathreshold groups at baseline using previously derived thresholds. Survival analysis, log rank testing, and Generalized Estimation Equations assessed the relationship between the application of regional sensitivity/specificity thresholds and change in cognitive measures as well as tau threshold performance in predicting cognitive decline within the new NIA-AA biological staging. Results: The meta temporal region was best for predicting risk of short-term cognitive decline in suprathreshold, as compared to infrathreshold participants. When applying multiple levels of tau positivity, each subsequent level of tau identified cognitive decline at earlier timepoints. Conclusions: When using 18 F-flortaucipir, meta temporal suprathreshold classification was associated with increased risk of cognitive decline, suggesting that abnormal tau deposition in the cortex predicts decline. Likewise, the application of multiple levels of tau clearly predicts the distinctive cognitive trajectories in the new NIA-AA biological staging framework. Show more

Keywords: Alzheimer’s disease, 18F-flortaucipir, PET, tau

DOI: 10.3233/JAD-240543

Citation: Journal of Alzheimer's Disease, vol. 100, no. s1, pp. S75-S92, 2024

Authors: Egebäck Arulf, Sofia | Ziyue Zhou, Robin | Kirsebom, Bjørn-Eivind | Jejcic, Alenka | Fladby, Tormod | Winblad, Bengt | Tjernberg, Lars | Schedin-Weiss, Sophia

Article Type: Research Article

Abstract: Background: The N-glycan structure bisecting N-acetylglucosamine (bisecting GlcNAc) is present on several N-glycans that are elevated in Alzheimer’s disease (AD), and previous studies have shown that bisecting GlcNAc levels correlate with total tau and phospho-tau181 in cerebrospinal fluid at early stages of AD. A recent population-based study showed that bisecting GlcNAc correlates with total tau also in blood and that this correlation could predict conversion to dementia. Objective: In this study, we have further investigated how bisecting GlcNAc relates to total tau and phospho-tau 181 in cerebrospinal fluid samples from controls and cases with early cognitive deficits, stratified …by amyloid/tau status and gender. Methods: Relative levels of bisecting GlcNAc in cerebrospinal fluid were measured by an enzyme-linked lectin assay in individuals with subjective cognitive decline, mild cognitive impairment and controls from the Norwegian Dementia Disease Initiation cohort. Results: As in our previous study, the correlation between bisecting GlcNAc and total tau or phospho-tau181 was particularly strong in the subjective cognitive decline group. The correlation was observed in amyloid negative and tau negative as well as amyloid positive and tau positive individuals, both in females and in males. Interestingly, among the amyloid negative and tau negative individuals, the correlation was observed in individuals with subjective cognitive decline but not in the controls. Conclusions: Thus, bisecting GlcNAc could be a biomarker for early cognitive decline. Show more

Keywords: Alzheimer’s disease, bisecting N-acetylglucosamine, dementia, mild cognitive impairment, N-glycosylation, phospho-tau, subjective cognitive decline, total tau

DOI: 10.3233/JAD-240628

Citation: Journal of Alzheimer's Disease, vol. 100, no. s1, pp. S93-S101, 2024

Authors: Duits, Flora H. | Nilsson, Johanna | Zetterberg, Henrik | Blennow, Kaj | van der Flier, Wiesje M. | Teunissen, Charlotte E. | Brinkmalm, Ann

Article Type: Research Article

Abstract: Background: Synaptic dysfunction is closely associated with cognitive function in Alzheimer’s disease (AD), and is present already in an early stage of the disease. Objective: Using serial cerebrospinal fluid (CSF) sampling, we aimed to investigate slopes of CSF synaptic proteins, and their relation with cognition along the AD continuum. Methods: We included subjects with subjective cognitive decline (SCD) or mild cognitive impairment (MCI) (n  = 50 amyloid-β+ [A  +], n  = 50 A–) and 50 patients with AD dementia from the Amsterdam dementia cohort, with CSF at two time points (median[IQR] 2.1[1.4–2.7] years). We analyzed 17 synaptic proteins …and neurofilament light (NfL). Using linear mixed models we assessed trajectories of protein levels, and associations with cognitive decline (repeated Mini-Mental State Examination). We used Cox regression models to assess predictive value of protein levels for progression to AD dementia. Results: At baseline most proteins showed increased levels in AD dementia compared to the other groups. In contrast NPTX2 levels were lower in AD dementia. Higher baseline levels of SNAP25, β-syn, and 14-3-3 proteins were associated with faster cognitive decline (St.B[SE] –0.27[0.12] to –0.61[0.12]). Longitudinal analyses showed that SYT1 and NPTX levels decreased over time in AD dementia (st.B[SE] –0.10[0.04] to –0.15[0.05]) and SCD/MCI-A+ (St.B[SE] –0.07[0.03] to –0.12[0.03]), but not in SCD/MCI-A- (pinteraction  < 0.05). Increase over time in NfL levels was associated with faster cognitive decline in AD dementia (St.B[SE] –1.75[0.58]), but not in the other groups (pinteraction  < 0.05). Conclusions: CSF synaptic proteins showed different slopes over time, suggesting complex synaptic dynamics. High levels of especially SNAP-25 may have value for prediction of cognitive decline in early AD stages, while increase in NfL over time correlates better with cognitive decline in later stages. Show more

Keywords: Alzheimer’s disease, biomarkers, cognitive decline, mass spectrometry, synapses

DOI: 10.3233/JAD-240610

Citation: Journal of Alzheimer's Disease, vol. 100, no. s1, pp. S103-S114, 2024