Journal of Alzheimer's Disease - Volume 94, issue 1

Authors: Sinha, Neha | Fausto, Bernadette A. | Mander, Bryce | Gluck, Mark A.

Article Type: Research Article

Abstract: Background: Both sleep deficiencies and Alzheimer’s disease (AD) disproportionately affect older African Americans. Genetic susceptibility to AD further compounds risk for cognitive decline in this population. Aside from APOE ɛ4, ABCA7 rs115550680 is the strongest genetic locus associated with late-onset AD in African Americans. While sleep and ABCA7 rs115550680 independently influence late-life cognitive outcomes, we know too little about the interplay between these two factors on cognitive function. Objective: We investigated the interaction between sleep and ABCA7 rs115550680 on hippocampal-dependent cognitive function in older African Americans. Methods: One-hundred fourteen cognitively healthy older African Americans were …genotyped for ABCA7 risk (n  = 57 carriers of risk “G” allele; n  = 57 non-carriers), responded to lifestyle questionnaires, and completed a cognitive battery. Sleep was assessed via a self-reported rating of sleep quality (poor, average, good). Covariates included age and years of education. Results: Using ANCOVA, we found that carriers of the risk genotype who reported poor or average sleep quality demonstrated significantly poorer generalization of prior learning—a cognitive marker of AD—compared to their non-risk counterparts. Conversely, there was no genotype-related difference in generalization performance in individuals who reported good sleep quality. Conclusion: These results indicate that sleep quality may be neuroprotective against genetic risk for AD. Future studies employing more rigorous methodology should investigate the mechanistic role of sleep neurophysiology in the pathogenesis and progression of AD associated with ABCA7. There is also need for the continued development of non-invasive sleep interventions tailored to racial groups with specific AD genetic risk profiles. Show more

Keywords: ABCA7, Alzheimer’s disease, Black or African American, cognition, sleep

DOI: 10.3233/JAD-230043

Citation: Journal of Alzheimer's Disease, vol. 94, no. 1, pp. 281-290, 2023

Authors: Liu, Mingxia | Li, Mo | He, Jing | He, Yi | Yang, Jian | Sun, Zuoli

Article Type: Research Article

Abstract: Background: Alzheimer’s disease (AD) is a complex neurodegenerative disease, and increasing evidence has linked dysregulation of amino acids to AD pathogenesis. However, the existing studies often ignore the chirality of amino acids, and some results are inconsistent and controversial. The changes of amino acid profiles in AD from the perspective of enantiomers remain elusive. Objective: The purpose of this study is to investigate whether the levels of amino acids, especially D-amino acids, are deregulated in the peripheral serum of AD patients, with the ultimate goal of discovering novel biomarkers for AD. Methods: The …chiral amino acid profiles were determined by HPLC-MS/MS with a pre-column derivatization method. Experimental data obtained from 37 AD patients and 34 healthy controls (HC) were statistically analyzed. Results: Among the 35 amino acids detected, D-proline, D/total-proline ratio, D-aspartate, and D/total-aspartate ratio were decreased, while D-phenylalanine was elevated in AD compared to HC. Significant age-dependent increases in D-proline, D/total-proline ratio, and D-phenylalanine were observed in HC, but not in AD. Receiver operator characteristic analyses of the combination of D-proline, D-aspartate, D-phenylalanine, and age for discriminating AD from HC provided satisfactory area under the curve (0.87), specificity (97.0%), and sensitivity (83.8%). Furthermore, the D-aspartate level was significantly decreased with the progression of AD, as assessed by the Clinical Dementia Rating Scale and Mini-Mental State Examination. Conclusion: The panels of D-proline, D-phenylalanine, and D-aspartate in peripheral serum may serve as novel biomarker candidates for AD. The latter parameter is further associated with the severity of AD. Show more

Keywords: Alzheimer’s disease, biomarker, chiral amino acid, serum

DOI: 10.3233/JAD-230142

Citation: Journal of Alzheimer's Disease, vol. 94, no. 1, pp. 291-301, 2023

Authors: Yang, Haimei | Gao, Xia | Lian, Yan | Wu, Tingting | Yang, Zongming | Wu, Qianrong

Article Type: Research Article

Abstract: Background: Leisure activities and sleep duration are correlated and have been linked to cognitive function, but most studies have examined only one of these factors. Objective: To investigate the independent and joint associations of leisure activities and sleep duration with cognitive function among older adults. Methods: We included 7,796 participants aged≥65 years from the Chinese Longitudinal Healthy Longevity Survey during 2008–2018 (waves 5–8). Self-reported leisure activities and sleep duration were assessed at baseline, and cognitive function was measured repeatedly using the Chinese version of the Mini-Mental State Examination (MMSE) at baseline and during …follow-up. We used linear mixed models to estimate regression coefficients (β) and 95% confidence intervals (CI). Results: The median follow-up duration was 5.77 years. After adjusting for each other and potential confounders, both lower leisure activity score (each 1-point decrease β= –0.33, 95% CI: –0.36 to –0.30) and longer sleep duration (each 1-hour increase β= –0.17, 95% CI: –0.22 to –0.11) were independently associated with lower MMSE score. Furthermore, we observed an additive interaction between leisure activities and sleep duration (p interaction  < 0.001). A combination of low leisure activity score and long sleep duration was strongly associated with decreased MMSE score (β= –2.51, 95% CI: –2.85 to –2.16) compared with the group with combined high leisure activity score and normal sleep duration. Conclusion: Both leisure activities and sleep duration were independently associated with cognitive function. Moreover, the combination of leisure inactivity and prolonged sleep duration predicted worse cognitive function (a preclinical hallmark of Alzheimer’s disease) in an additive manner. Show more

Keywords: Alzheimer’s disease, cognition, leisure activities, sleep duration

DOI: 10.3233/JAD-230112

Citation: Journal of Alzheimer's Disease, vol. 94, no. 1, pp. 303-311, 2023

Authors: Meduri, Geri | Guillemeau, Kevin | Daguinot, Corentin | Dounane, Omar | Genet, Melanie | Ferrara, Luigi | Chambraud, Beatrice | Baulieu, Etienne Emile | Giustiniani, Julien

Article Type: Research Article

Abstract: Background: Pathological tau proteins constitute neurofibrillary tangles that accumulate in tauopathies including Alzheimer’s disease (AD), progressive supranuclear palsy (PSP), and familial frontotemporal lobar degeneration (FTLD-Tau). We previously showed that the FKBP52 immunophilin interacts functionally with tau and strongly decreases in AD brain neurons in correlation with tau deposition. We also reported that FKBP52 co-localizes with autophagy-lysosomal markers and an early pathological tau isoform in AD neurons, suggesting its involvement in autophagic tau clearance. Objective: Our objective was to evaluate if differences in neuronal FKBP52 expression levels and subcellular localization might be detected in AD, PSP, familial …FTLD-Tau, and in the hTau-P301 S mouse model compared to controls. Methods: Cell by cell immunohistofluorescence analyses and quantification of FKBP52 were performed on postmortem brain samples of some human tauopathies and on hTau-P301 S mice spinal cords. Results: We describe a similar FKBP52 decrease and its localization with early pathological tau forms in the neuronal autophagy-lysosomal pathway in various tauopathies and hTau-P301 S mice. We find that FKBP52 decreases early during the pathologic process as it occurs in rare neurons with tau deposits in the marginally affected frontal cortex region of AD Braak IV brains and in the spinal cord of symptomless 1-month-old hTau-P301 S mice. Conclusion: As FKBP52 plays a significant role in cellular signaling and conceivably in tau clearance, our data support the idea that the prevention of FKBP52 decrease or the restoration of its normal expression at early pathologic stages might represent a new potential therapeutic approach in tauopathies including AD, familial FTLD-Tau, and PSP. Show more

Keywords: Alzheimer’s disease, caspase-cleaved tau, FK506-binding protein, FKBP52, FTLD-Tau, lysosome, progressive supranuclear palsy, tau protein, tauopathy

DOI: 10.3233/JAD-230127

Citation: Journal of Alzheimer's Disease, vol. 94, no. 1, pp. 313-331, 2023

Authors: Di, Jing | Nelson, Ruth S. | Jicha, Gregory A. | Moga, Daniela C. | Barber, Justin M. | Cykowski, Matthew D. | Fardo, David W. | Abner, Erin L. | Nelson, Peter T.

Article Type: Research Article

Abstract: Background: Dementia and urinary incontinence (UI) are etiologically complex clinical syndromes. Dementia and UI often occur in the same individuals, but underlying factors connecting them are incompletely understood. Objective: Query data from a community-based autopsy series to assess pathologies that underlie UI. Methods: Included research subjects came to autopsy from the University of Kentucky Alzheimer’s Disease Research Center longitudinal cohort. A total of 368 research volunteers met inclusion criteria for this cross-sectional study. The average age at death was 85.3 years and the average number of annual clinic visits was 5.2 visits. Statistical …models were run to evaluate which pathologies were associated with UI. Data included pathologies scored according to conventional stage-based systems, and these studies were complemented by quantitative digital neuropathology. Results: Dementia was diagnosed at the final clinical visit in 208 (56.7% of the sample) and UI was documented in 156 (42.7%). UI was associated with depression and dementia (both p  < 0.001). More women than men had a history of UI (p  < 0.04), and women with UI had had more biological children than those without UI (p  < 0.005). Participants with limbic predominant age-related TDP-43 encephalopathy neuropathologic changes (LATE-NC) were more likely to have UI than those without LATE-NC (p  < 0.001). The presence of LATE-NC (Stage > 1) was associated with UI with or without severe Alzheimer’s disease neuropathologic changes and/or Lewy body pathology. Conclusion: In this community-based autopsy cohort, multiple factors were associated with UI, but the neuropathologic change most robustly associated with UI was LATE-NC. Show more

Keywords: ADNC, ARTAG, clinical dementia rating, obstetric, oldest-old, ScanScope, sex, synuclein, urology

DOI: 10.3233/JAD-230425

Citation: Journal of Alzheimer's Disease, vol. 94, no. 1, pp. 333-346, 2023

Authors: Martin, Tim | Kero, Katherine | Požar, Rok | Giordani, Bruno | Kavcic, Voyko

Article Type: Research Article

Abstract: Background: Identification of older individuals with increased risk for cognitive decline can contribute not only to personal benefits (e.g., early treatment, evaluation of treatment), but could also benefit clinical trials (e.g., patient selection). We propose that baseline resting-state electroencephalography (rsEEG) could provide markers for early identification of cognitive decline. Objective: To determine whether rsEEG theta/beta ratio (TBR) differed between mild cognitively impaired (MCI) and healthy older adults. Methods: We analyzed rsEEG from a sample of 99 (ages 60–90) consensus-diagnosed, community-dwelling older African Americans (58 cognitively typical and 41 MCI). Eyes closed rsEEGs were acquired before and …after participants engaged in a visual motion direction discrimination task. rsEEG TBR was calculated for four midline locations and assessed for differences as a function of MCI status. Hemispheric asymmetry of TBR was also analyzed at equidistant lateral electrode sites. Results: Results showed that MCI participants had a higher TBR than controls (p  = 0.04), and that TBR significantly differed across vertex location (p  < 0.001) with the highest TBR at parietal site. MCI and cognitively normal controls also differed in hemispheric asymmetries, such that MCI show higher TBR at frontal sites, with TBR greater over right frontal electrodes in the MCI group (p  = 0.003) and no asymmetries found in the cognitively normal group. Lastly, we found a significant task aftereffect (post-task compared to pre-task measures) with higher TBR at posterior locations (Oz p  = 0.002, Pz p  = 0.057). Conclusion: TBR and TBR asymmetries differ between MCI and cognitively normal older adults and may reflect neurodegenerative processes underlying MCI symptoms. Show more

Keywords: Alzheimer’s disease, hemispheric asymmetry, mild cognitive impairment, older Black Americans, resting-state electroencephalography, theta/beta ratio

DOI: 10.3233/JAD-220981

Citation: Journal of Alzheimer's Disease, vol. 94, no. 1, pp. 347-357, 2023

Authors: Karima, Saeed | Aghamollaii, Vajiheh | Mahmoodi Baram, Somayeh | Balenci, Laurent | Lanctôt, Krista L. | Kiss, Alex | Tafakhori, Abbas | Mahdavi, Meisam | Rajaei, Shima | Shateri, Somayeh | Yarhoseini, Amir | Mokhtari, Farzad | Fotouhi, Akbar | Riazi, Ali

Article Type: Research Article

Abstract: Background: Recent therapeutic approaches for Alzheimer’s disease (AD) have had limited success. Considering the association of neuroinflammation with AD symptoms as demonstrated in multiple studies, assessment of the clinical efficacy of molecules that reduce systemic or brain inflammation is warranted. Objective: This clinical trial assessed whether boswellic acids can improve cognitive and neuropsychiatric symptoms while reducing inflammation in AD patients. Methods: A double-blind, placebo-controlled, study was conducted on 85 AD patients randomized to boswellic acids (K-Vie™ as the main ingredient in Memowell™) or placebo for 6 months. Clinical Dementia Rating–Sum of Boxes (CDR-SOB) …and Mini-Mental State Examination (MMSE) scores were compared to baseline and between groups and constituted the co-primary clinical efficacy endpoints. Secondary outcomes included neuropsychiatric assessment (Neuropsychiatric Inventory-Questionnaire, NPI-Q) and assessment of AD and inflammation biomarkers. Results: Patients on K-Vie™ showed a 3.1- and 1.6-unit improvement in MMSE and CDR-SOB scores, respectively, when compared to patients on placebo. NPI-Q analysis revealed significant improvement in the K-Vie™ but not in the placebo group. Only mild gastrointestinal side effects were reported in a few patients. Patients on K-Vie™ showed improvement in plasma AD biomarkers and reduction of key inflammatory cytokines including IL-6 and TNF. Conclusion: Our results support the positive cognitive effects of boswellic acids by reducing the systemic inflammation. Show more

Keywords: Alzheimer’s disease, boswellic acids, central nervous system, cognition, inflammation

DOI: 10.3233/JAD-221026

Citation: Journal of Alzheimer's Disease, vol. 94, no. 1, pp. 359-370, 2023

Authors: Findley, Caleigh A. | McFadden, Samuel A. | Cox, MaKayla F. | Sime, Lindsey N. | Peck, Mackenzie R. | Quinn, Kathleen | Bartke, Andrzej | Hascup, Kevin N. | Hascup, Erin R.

Article Type: Research Article

Abstract: Background: Prior research supports a strong link between Alzheimer’s disease (AD) and metabolic dysfunction that involves a multi-directional interaction between glucose, glutamatergic homeostasis, and amyloid pathology. Elevated soluble amyloid-β (Aβ) is an early biomarker for AD-associated cognitive decline that contributes to concurrent glutamatergic and metabolic dyshomeostasis in humans and male transgenic AD mice. Yet, it remains unclear how primary time-sensitive targeting of hippocampal glutamatergic activity may impact glucose regulation in an amyloidogenic mouse model. Previous studies have illustrated increased glucose uptake and metabolism using a neuroprotective glutamate modulator (riluzole), supporting the link between glucose and glutamatergic homeostasis. Objective: …We hypothesized that targeting early glutamatergic hyperexcitation through riluzole treatment could aid in attenuating co-occurring metabolic and amyloidogenic pathologies with the intent of ameliorating cognitive decline. Methods: We conducted an early intervention study in male and female transgenic (AβPP/PS1) and knock-in (APPNL - F/NL - F ) AD mice to assess the on- and off-treatment effects of prodromal glutamatergic modulation (2–6 months of age) on glucose homeostasis and spatial cognition through riluzole treatment. Results: Results indicated a sex- and genotype-specific effect on glucose homeostasis and spatial cognition with riluzole intervention that evolved with disease progression and time since treatment. Conclusion: These findings support the interconnected nature of glucose and glutamatergic homeostasis with amyloid pathology and petition for further investigation into the targeting of this relationship to improve cognitive performance. Show more

Keywords: Alzheimer’s disease, amyloid, hippocampus, insulin, learning, memory, metabolism

DOI: 10.3233/JAD-221245

Citation: Journal of Alzheimer's Disease, vol. 94, no. 1, pp. 371-392, 2023

Authors: Li, Dan | Yu, Yue-Yi | Hu, Nan | Zhang, Min | Sun, Fang-Ling | Liu, Li | Fan, Li-Mei | Ruan, Shi-Shuang | Wang, Fen | Rosa-Neto, Pedro

Article Type: Research Article

Abstract: Background: The Boston Naming Test (BNT) is the most widely used measure to assess anomia. However, it has been criticized for failing to differentiate the underlying cognitive process of anomia. Objective: We validated the color-picture version of BNT (CP-BNT) in a sample with diverse neurodegenerative dementia diseases (NDDs). We also verified the differential ability of the composite indices of CP-BNT across NDDs groups. Methods: The present study included Alzheimer’s disease (n  = 132), semantic variant primary progressive aphasia (svPPA, n  = 53), non-svPPA (n  = 33), posterior cortical atrophy (PCA, n  = 35), and normal controls (n  = 110). We evaluated …psychometric properties of CP-BNT for the spontaneous naming (SN), the percentage of correct responses on semantic cuing and word recognition cuing (% SC, % WR). Receiver operating characteristic analysis was used to examine the discriminatory power of SN alone and the composite indices (SN, % SC, and % WR). Results: The CP-BNT had sufficient internal consistency, good convergent, divergent validity, and criterion validity. Different indices of CP-BNT demonstrated distinct cognitive underpinnings. Category fluency was the strongest predictor of SN (β= 0.46, p  < 0.001). Auditory comprehension tests highly associated with % WR (Sentence comprehension: β= 0.22, p  = 0.001; Word comprehension: β= 0.20, p  = 0.001), whereas a lower visuospatial score predicted % SC (β= –0.2, p  = 0.001). Composite indices had better predictability than the SN alone when differentiating between NDDs, especially for PCA versus non-svPPA (area under the curve increased from 63.9% to 81.2%). Conclusion: The CP-BNT is a highly linguistically relevant test with sufficient reliability and validity. Composite indices could provide more differential information beyond SN and should be used in clinical practice. Show more

Keywords: Alzheimer’s disease, anomia, language tests, neurodegenerative disease, primary progressive aphasia

DOI: 10.3233/JAD-221227

Citation: Journal of Alzheimer's Disease, vol. 94, no. 1, pp. 393-404, 2023

Authors: Akuffo, Kwadwo Owusu | Wooten, Billy R. | Ofori-Asare, Wendy | Osei Duah Junior, Isaiah | Kumah, David Ben | Awuni, Moses | Obiri-Yeboah, Stephannie Rhoda | Horthman, Stacy Ewurama | Addo, Emmanuel Kofi | Acquah, Eldrick Adu | Boateng, Bridget Senya | Johnson, Elizabeth J.

Article Type: Research Article

Abstract: Background: Macular pigment optical density (MPOD) remains an indispensable biomarker to measure fruit and vegetable intake, with a biologically plausible correlation to vision and cognition. However, evidence in the sub-Saharan regions, including Ghana, is lacking. Objective: This study explored dietary carotenoid intake on MPOD and its influence on cognitive and visual function in a healthy Ghanaian sample. Methods: The MPOD of 301 healthy subjects (aged 21.1±1.9 years) was evaluated using the customized Macular DensitometerTM . A battery of cognitive tests and standard vision assessments were employed to assess cognition and visual function, respectively. Dietary lutein and …zeaxanthin (L and Z) were estimated based on a twenty-four-hour repeated dietary recall. Results: The mean MPOD at 0.5° and 1.0° eccentricities were 0.37±0.16 and 0.34±0.15 optical density units, respectively. Dietary intake of L (4.06±10.54 mg/day) was considerably higher than Z (0.33±2.25 mg/day), with cumulative L+Z estimated at 4.39±11.58 mg/day. MPOD was not significantly influenced by demographic, dietary, and visual measures (p ≥0.05). However, after statistical adjustment, we found a small but statistically significant positive relationship between F-A-S phonemic verbal fluency (Unstandardized co-efficient (β) = 0.002, p  = 0.016) and the never consumed alcohol category (β= 0.062, p  = 0.02) with MPOD. Conclusion: The findings in this population showed significant positive relationships between measures of cognition and no alcohol intake, with MPOD. These findings necessitate dietary education to augment carotenoid intake and limit alcohol intake for better cognitive functioning. Show more

Keywords: Alzheimer’s disease, cognition, heterochromatic flicker photometry, lutein, macular pigment optical density, vision, zeaxanthin

DOI: 10.3233/JAD-230233

Citation: Journal of Alzheimer's Disease, vol. 94, no. 1, pp. 405-413, 2023