Journal of Alzheimer's Disease - Volume 92, issue 1

Authors: Moebius, Hans J. | Church, Kevin J.

Article Type: Review Article

Abstract: An estimated 6.5 million Americans aged 65 years or older have Alzheimer’s disease (AD), which will grow to 13.8 million Americans by 2060. Despite the growing burden of dementia, no fundamental change in drug development for AD has been seen in > 20 years. Currently approved drugs for AD produce only modest symptomatic improvements in cognition with small effect sizes. A growing mismatch exists between the urgent need to develop effective drugs for symptomatic AD and the largely failed search for disease modification. The failure rate of clinical trials in AD is high overall, and in particular for disease-modifying therapies. Research efforts …in AD have focused predominantly on amyloid-β and tau pathologies, but limiting clinical research to these “classical hallmarks” of the disease does not address the most urgent patient, caregiver, or societal needs. Rather, clinical research should consider the complex pathophysiology of AD. Innovative approaches are needed that provide outside-the-box thinking, and re-imagine trial design, interventions, and outcomes as well as progress in proteomics and fluid biomarker analytics for both diagnostics and disease monitoring. A new approach offering a highly specific, yet multi-pronged intervention that exerts positive modulation on the HGF/MET neurotrophic system is currently being tested in mid-to-late-stage clinical trials in mild to moderate AD. Findings from such trials may provide data to support novel approaches for development of innovative drugs for treating AD at various disease stages, including among patients already symptomatic, and may offer benefits for other neurodegenerative diseases. Show more

Keywords: Alzheimer’s disease, hepatocyte growth factor, HGF/MET, neurodegeneration, neurotrophic, pathogenesis, synaptogenesis

DOI: 10.3233/JAD-220871

Citation: Journal of Alzheimer's Disease, vol. 92, no. 1, pp. 1-12, 2023

Authors: Samudra, Niyatee | Ranasinghe, Kamalini | Kirsch, Heidi | Rankin, Katherine | Miller, Bruce

Article Type: Review Article

Abstract: Cortical network hyperexcitability related to synaptic dysfunction in Alzheimer’s disease (AD) is a potential target for therapeutic intervention. In recent years, there has been increased interest in the prevalence of silent seizures and interictal epileptiform discharges (IEDs, or seizure tendency), with both entities collectively termed “subclinical epileptiform activity” (SEA), on neurophysiologic studies in AD patients. SEA has been demonstrated to be common in AD, with prevalence estimates ranging between 22-54%. Converging lines of basic and clinical evidence imply that modifying a hyperexcitable state results in an improvement in cognition. In particular, though these results require further confirmation, post-hoc findings from …a recent phase II clinical trial suggest a therapeutic effect with levetiracetam administration in patients with AD and IEDs. Here, we review key unanswered questions as well as potential clinical trial avenues. Specifically, we discuss postulated mechanisms and treatment of hyperexcitability in patients with AD, which are of interest in designing future disease-modifying therapies. Criteria to prompt screening and optimal screening methodology for hyperexcitability have yet to be defined, as does timing and personalization of therapeutic intervention. Show more

Keywords: Alzheimer’s disease, amyloid-β, epilepsy, hyperexcitability, interictal epileptiform discharge, seizure, tau

DOI: 10.3233/JAD-220983

Citation: Journal of Alzheimer's Disease, vol. 92, no. 1, pp. 13-27, 2023

Authors: Huang, Zhen

Article Type: Review Article

Abstract: Amyloid-β protein precursor (AβPP) gives rise to amyloid-β (Aβ), a peptide at the center of Alzheimer’s disease (AD). AβPP, however, is also an ancient molecule dating back in evolution to some of the earliest forms of metazoans. This suggests a possible ancestral function that may have been obscured by those that evolve later. Based on literature from the functions of Aβ/AβPP in nervous system development, plasticity, and disease, to those of anti-microbial peptides (AMPs) in bacterial competition as well as mechanisms of cell competition uncovered first by Drosophila genetics, I propose that Aβ/AβPP may be part of an ancient mechanism …employed in cell competition, which is subsequently co-opted during evolution for the regulation of activity-dependent neural circuit development and plasticity. This hypothesis is supported by foremost the high similarities of Aβ to AMPs, both of which possess unique, opposite (i.e., trophic versus toxic) activities as monomers and oligomers. A large body of data further suggests that the different Aβ oligomeric isoforms may serve as the protective and punishment signals long predicted to mediate activity-dependent axonal/synaptic competition in the developing nervous system and that the imbalance in their opposite regulation of innate immune and glial cells in the brain may ultimately underpin AD pathogenesis. This hypothesis can not only explain the diverse roles observed of Aβ and AβPP family molecules, but also provide a conceptual framework that can unify current hypotheses on AD. Furthermore, it may explain major clinical observations not accounted for and identify approaches for overcoming shortfalls in AD animal modeling. Show more

Keywords: Alzheimer’s disease, amyloid-β, anti-microbial peptide, axon competition, homeostatic plasticity, inflammatory cytokine, innate immunity, microglia, neuroinflammation, tau phosphorylation

DOI: 10.3233/JAD-221042

Citation: Journal of Alzheimer's Disease, vol. 92, no. 1, pp. 29-57, 2023

Authors: Sagaro, Getu Gamo | Traini, Enea | Amenta, Francesco

Article Type: Systematic Review

Abstract: Background: Choline alphoscerate (alpha glyceryl phosphorylcholine, α-GPC) is a choline-containing phospholipid used as a medicine or nutraceutical to improve cognitive function impairment occurring in neurological conditions including adult-onset dementia disorders. Despite its 1985 marketing authorization, there are still discrepancies between countries regarding its approval as a prescription medicine and discussions about its effectiveness. Objective: This study aimed to evaluate the efficacy of the α-GPC compound for treating cognitive impairment in patients with adult-onset neurological disorders. Methods: Relevant studies were identified by searching PubMed, Web of Science, and Embase. Studies that evaluated the effects of α-GPC alone …or in combination with other compounds on adult-onset cognitive impairment reporting cognition, function, and behavior were considered. We assessed the risk of bias of selected studies using the Cochrane risk of bias tool. Results: A total of 1,326 studies and 300 full-text articles were screened. We included seven randomized controlled trials (RCTs) and one prospective cohort study that met our eligibility criteria. We found significant effects of α-GPC in combination with donepezil on cognition [4 RCTs, mean difference (MD):1.72, 95% confidence interval (CI): 0.20 to 3.25], functional outcomes [3 RCTs, MD:0.79, 95% CI: 0.34 to 1.23], and behavioral outcomes [4 RCTs; MD: –7.61, 95% CI: –10.31 to –4.91]. We also observed that patients who received α-GPC had significantly better cognition than those who received either placebo or other medications [MD: 3.50, 95% CI: 0.36 to 6.63]. Conclusion: α-GPC alone or in combination with donepezil improved cognition, behavior, and functional outcomes among patients with neurological conditions associated with cerebrovascular injury. Show more

Keywords: Alzheimer’s disease, choline alphoscerate, cognitive function, dementia, donepezil

DOI: 10.3233/JAD-221189

Citation: Journal of Alzheimer's Disease, vol. 92, no. 1, pp. 59-70, 2023

Authors: Chithiramohan, Tamara | Threlfall, Grace | Abdelaziz, Hanin | Ellahi, Amira | Subramaniam, Hari | Beishon, Lucy | Mukaetova-Ladinska, Elizabeta B.

Article Type: Research Article

Abstract: Background: The incidence of dementia in Black and Asian populations in the UK is set to rise. There is concern surrounding differences in services provided for different ethnic groups. Objective: This study aimed to examine ethnic variations in survival, services accessed, and medication use across White, Black, and Asian groups in routine memory clinic setting. Methods: We retrospectively examined referrals to a memory service between 2013 and 2021. A random sample of 104 White, 99 Asian, and 74 Black patients were analyzed for differences in support services, voluntary services, medication use, and survival rate. …Results: There were statistically significant differences in survival of the Asian compared to the White group (Hazard ratio (HR = 2.17,95% confidence interval (CI) 1.23–3.85, p  = 0.008)) following adjustment for age, gender, diagnosis, cognitive impairment, severity, access to support and voluntary services, and use of cholinesterase inhibitors, N-methyl-D-aspartate antagonists, and antipsychotics. The Asian group showed a statistically significantly reduction in access to support services compared to the White group (HR = 0.05, 95% CI 0.01–0.37, p  = 0.003). In contrast, the survival rate was similar between the White and Black dementia patients. Conclusion: We found significantly reduced survival and reduced access to support services in Asian compared to White patients with dementia. Further research is needed to investigate the generalizability of our results, and determine the cause, and consequent remedies of these associations in ethnic minority groups. Show more

Keywords: Dementia, ethnicity, Leicester, memory, support, survival

DOI: 10.3233/JAD-220925

Citation: Journal of Alzheimer's Disease, vol. 92, no. 1, pp. 71-79, 2023

Authors: Wan, Ke | Yin, Wenwen | Tang, Yating | Zhu, Wenhao | Wang, Zhiqiang | Zhou, Xia | Zhang, Wei | Zhang, Cun | Yu, Xianfeng | Zhao, Wenming | Li, Chenchen | Zhu, Xiaoqun | Sun, Zhongwu

Article Type: Research Article

Abstract: Background: The primary manifestations of Alzheimer’s disease (AD) include cognitive decline and brain gray matter volume (GMV) atrophy. Recent studies have found that plasma phosphorylated-tau (p-tau) concentrations perform better in diagnosing, differentiating, and monitoring the progression of AD. However, the correlation between plasma p-tau, GMV, and cognition remains unclear. Objective: To investigate whether GMV plays a mediating role in the association between plasma p-tau concentrations and cognition. Methods: In total, 99 participants (47 patients with AD and 52 cognitively unimpaired [CU] individuals) were included. All participants underwent neuropsychological assessments, laboratory examinations, and magnetic resonance imaging scans. …Plasma p-tau217 and p-tau181 concentrations were measured using an enzyme-linked immunosorbent assay kit. Voxel-based morphometry was performed to assess participants’ brain GMV. Partial correlation and mediation analyses were conducted in AD group. Results: Plasma p-tau concentrations were significantly higher in the AD group than in the CU group. Patients with AD had significant brain GMV atrophy in the right hippocampus, bilateral middle temporal gyrus, and right inferior temporal gyrus. In the AD group, there were significant correlations between plasma p-tau217 concentrations, GMV, and Mini-Mental State Examination (MMSE) scores. Brain GMV of the right hippocampus mediated the association between plasma p-tau217 concentrations and MMSE scores. A significant correlation between plasma p-tau181 and MMSE scores was not identified. Conclusion: The findings indicate that p-tau217 is a promising biomarker for central processes affecting brain GMV and cognitive function. This may provide potential targets for future intervention and treatment of tau-targeting therapies in the early stages of AD. Show more

Keywords: Alzheimer’s disease, cognitive function, gray matter volume, plasma biomarkers, phosphorylated tau

DOI: 10.3233/JAD-221100

Citation: Journal of Alzheimer's Disease, vol. 92, no. 1, pp. 81-93, 2023

Authors: Winston, Charisse N. | Langford, Oliver | Levin, Natalie | Raman, Rema | Yarasheski, Kevin | West, Tim | Abdel-Latif, Sara | Donohue, Michael | Nakamura, Akinori | Toba, Kenji | Masters, Colin L. | Doecke, James | Sperling, Reisa A. | Aisen, Paul S. | Rissman, Robert A.

Article Type: Research Article

Abstract: Background: Participant eligibility for the A4 Study was determined by amyloid PET imaging. Given the disadvantages of amyloid PET imaging in accessibility and cost, blood-based biomarkers may serve as a sufficient biomarker and more cost-effective screening tool for patient enrollment into preclinical AD trials. Objective: To determine if a blood-based screening test can adequately identify amyloid burden in participants screened into a preclinical AD trial. Methods: In this cross-sectional study, 224 participants from the A4 Study received an amyloid PET scan (18 Florbetapir) within 90 days of blood sample collection. Blood samples from all study participants …were processed within 2 h after phlebotomy. Plasma amyloid measures were quantified by Shimazdu and C2 N Diagnostics using mass spectrometry-based platforms. A corresponding subset of blood samples (n  = 100) was processed within 24 h after phlebotomy and analyzed by C2 N. Results: Plasma Aβ42 /Aβ40 demonstrated the highest association for Aβ accumulation in the brain with an AUC 0.76 (95%CI = 0.69, 0.82) at C2 N and 0.80 (95%CI = 0.75, 0.86) at Shimadzu. Blood samples processed to plasma within 2 h after phlebotomy provided a better prediction of amyloid PET status than blood samples processed within 24 h (AUC 0.80 versus 0.64; p  < 0.001). Age, sex, and APOE ɛ4 carrier status did not the diagnostic performance of plasma Aβ42 /Aβ40 to predict amyloid PET positivity in A4 Study participants. Conclusion: Plasma Aβ42 /Aβ40 may serve as a potential biomarker for predicting elevated amyloid in the brain. Utilizing blood testing over PET imaging may improve screening efficiency into clinical trials. Show more

Keywords: A4, Alzheimer’s disease, amyloid-β, biomarkers, clinical trial, mass spectrometry, PET

DOI: 10.3233/JAD-221118

Citation: Journal of Alzheimer's Disease, vol. 92, no. 1, pp. 95-107, 2023

Authors: Correro II, Anthony N. | Gauthreaux, Kathryn | Perales-Puchalt, Jaime | Chen, Yen-Chi | Chan, Kwun C.G. | Kukull, Walter A. | Flatt, Jason D.

Article Type: Research Article

Abstract: Background: Lesbian and gay older adults have health disparities that are risk factors for Alzheimer’s disease, yet little is known about the neurocognitive aging of sexual minority groups. Objective: To explore cross-sectional and longitudinal dementia outcomes for adults in same-sex relationships (SSR) and those in mixed-sex relationships (MSR). Methods: This prospective observational study utilized data from the National Alzheimer’s Coordinating Center Uniform Data Set (NACC UDS) collected from contributing Alzheimer’s Disease Research Centers. Participants were adults aged 55+ years at baseline with at least two visits in NACC UDS (from September 2005 to March 2021) who …had a spouse, partner, or companion as a co-participant. Outcome measures included CDR® Dementia Staging Instrument, NACC UDS neuropsychological testing, and the Functional Activities Questionnaire. Multivariable linear mixed-effects models accounted for center clustering and repeated measures by individual. Results: Both MSR and SSR groups experienced cognitive decline regardless of baseline diagnosis. In general, MSR and SSR groups did not differ statistically on cross-sectional or longitudinal estimates of functioning, dementia severity, or neuropsychological testing, with two primary exceptions. People in SSR with mild cognitive impairment showed less functional impairment at baseline (FAQ M  = 2.61, SD = 3.18 vs. M  = 3.97, SD = 4.53, respectively; p  < 0.01). The SSR group with dementia had less steep decline in attention/working memory (β estimates = –0.10 versus –0.18; p  < 0.01). Conclusion: Participants in SSR did not show cognitive health disparities consistent with a minority stress model. Additional research into protective factors is warranted. Show more

Keywords: Cognitive aging, cognitive dysfunction, dementia, sexual minorities

DOI: 10.3233/JAD-220309

Citation: Journal of Alzheimer's Disease, vol. 92, no. 1, pp. 109-128, 2023

Authors: Salem, Haitham | Suchting, Robert | Gonzales, Mitzi M. | Seshadri, Sudha | Teixeira, Antonio L.

Article Type: Research Article

Abstract: Background: Apathy is among the neuropsychiatric symptoms frequently observed in people with cognitive impairment. It has been postulated to be a potential predictor of conversion from mild cognitive impairment (MCI) to Alzheimer’s disease (AD). Objective: To detect conversion rates from MCI to AD, and to determine the effect of apathy on the progression to AD in patients with MCI enrolled in the Texas Alzheimer’s Research and Care Consortium (TARCC) cohort. Methods: Apathy was determined by a positive response to the respective item in the Neuropsychiatric Inventory –Questionnaire (NPI-Q) completed by family members or caregivers. The final …dataset included 2,897 observations from 1,092 individuals with MCI at the baseline. Kaplan-Meier survival curves were estimated to provide indices of the probability of conversion to AD over time across all individuals as well as between those with and without apathy. Cox proportional hazards regression measured the hazard associated with apathy and several other predictors of interest. Results: Over a period of 8.21 years, 17.3% of individuals had conversion from MCI to AD (n  = 190 of 1,092 total individuals) across observations. The median time-to-conversion across all participants was 6.41 years. Comparing individuals with apathy (n  = 158) versus without apathy (n  = 934), 36.1% and 14.2% had conversion to AD, respectively. The median time-to-conversion was 3.79 years for individuals with apathy and 6.83 years for individuals without apathy. Cox proportional hazards regression found significant effects of several predictors, including apathy, on time-to-conversion. Age and cognitive performance were found to moderate the relationship between apathy and time-to-conversion. Conclusions: Apathy is associated with progression from MCI to AD, suggesting that it might improve risk prediction and aid targeted intervention delivery. Show more

Keywords: Alzheimer’s disease, apathy, mild cognitive impairment, neuropsychiatric symptoms

DOI: 10.3233/JAD-220826

Citation: Journal of Alzheimer's Disease, vol. 92, no. 1, pp. 129-139, 2023

Authors: Devos, Hannes | Gustafson, Kathleen M. | Liao, Ke | Ahmadnezhad, Pedram | Kuhlmann, Emily | Estes, Bradley J. | Martin, Laura E. | Mahnken, Jonathan D. | Brooks, William M. | Burns, Jeffrey M.

Article Type: Research Article

Abstract: Background: Cognitive reserve may protect against cognitive decline. Objective: This cross-sectional study investigated the association between cognitive reserve and physiological measures of cognitive workload in older adults with cognitive impairment. Methods: 29 older adults with cognitive impairment (age: 75±6, 11 (38%) women, MoCA: 20±7) and 19 with normal cognition (age: 74±6; 11 (58%) women; MoCA: 28±2) completed a working memory test of increasing task demand (0-, 1-, 2-back). Cognitive workload was indexed using amplitude and latency of the P3 event-related potential (ERP) at electrode sites Fz, Cz, and Pz, and changes in pupillary size, converted to …an index of cognitive activity (ICA). The Cognitive Reserve Index questionnaire (CRIq) evaluated Education, Work Activity, and Leisure Time as a proxy of cognitive reserve. Linear mixed models evaluated the main effects of cognitive status, CRIq, and the interaction effect of CRIq by cognitive status on ERP and ICA. Results: The interaction effect of CRIq total score by cognitive status on P3 ERP and ICA was not significant. However, higher CRIq total scores were associated with lower ICA (p  = 0.03). The interaction effects of CRIq subscores showed that Work Activity affected P3 amplitude (p  = 0.03) and ICA (p  = 0.03) differently between older adults with and without cognitive impairments. Similarly, Education affected ICA (p  = 0.02) differently between the two groups. No associations were observed between CRIq and P3 latency. Conclusion: Specific components of cognitive reserve affect cognitive workload and neural efficiency differently in older adults with and without cognitive impairments. Show more

Keywords: Aging, cognitive dysfunction, cognitive reserve, electroencephalography, evoked potentials, memory, pupil, short-term

DOI: 10.3233/JAD-220890

Citation: Journal of Alzheimer's Disease, vol. 92, no. 1, pp. 141-151, 2023