Journal of Alzheimer's Disease - Volume 96, issue 1

Authors: Fernandes, Carina Pereira | Montalvo, Gemma | Caligiuri, Michael | Pertsinakis, Michael | Guimarães, Joana

Article Type: Systematic Review

Abstract: Background: Handwriting is a complex process involving fine motor skills, kinesthetic components, and several cognitive domains, often impaired by Alzheimer’s disease (AD). Objective: Provide a systematic review of handwriting changes in AD, highlighting the effects on motor, visuospatial and linguistic features, and to identify new research topics. Methods: A search was conducted on PubMed, Scopus, and Web of Science to identify studies on AD and handwriting. The review followed PRISMA norms and analyzed 91 articles after screening and final selection. Results: Handwriting is impaired at all levels of the motor-cognitive …hierarchy in AD, particularly in text, with higher preservation of signatures. Visuospatial and linguistic features were more affected. Established findings for motor features included higher variability in AD signatures, higher in-air/on-surface time ratio and longer duration in text, longer start time/reaction time, and lower fluency. There were conflicting findings for pressure and velocity in motor features, as well as size, legibility, and pen lifts in general features. For linguistic features, findings were contradictory for error patterns, as well as the association between agraphia and severity of cognitive deficits. Conclusions: Further re-evaluation studies are needed to clarify the divergent results on motor, general, and linguistic features. There is also a lack of research on the influence of AD on signatures and the effect of AD variants on handwriting. Such research would have an impact on clinical management (e.g., for early detection and patient follow-up using handwriting tasks), or forensic examination aimed at signatory identification. Show more

Keywords: Agraphia, Alzheimer’s disease, dementia, forensic examination, kinematics, signature

DOI: 10.3233/JAD-230438

Citation: Journal of Alzheimer's Disease, vol. 96, no. 1, pp. 1-11, 2023

Authors: Lardelli, Michael

Article Type: Research Article

Abstract: Probabilistic and parsimony-based arguments regarding available genetics data are used to propose that Hardy and Higgin’s amyloid cascade hypothesis is valid but is commonly interpreted too narrowly to support, incorrectly, the primacy of the amyloid-β peptide (Aβ) in driving Alzheimer’s disease pathogenesis. Instead, increased activity of the βCTF (C99) fragment of AβPP is the critical pathogenic determinant altered by mutations in the APP gene. This model is consistent with the regulation of APP mRNA translation via its 5’ iron responsive element. Similar arguments support that the pathological effects of familial Alzheimer’s disease mutations in the genes PSEN1 …and PSEN2 are not exerted directly via changes in AβPP cleavage to produce different ratios of Aβ length. Rather, these mutations likely act through effects on presenilin holoprotein conformation and function, and possibly the formation and stability of multimers of presenilin holoprotein and/or of the γ-secretase complex. All fAD mutations in APP , PSEN1 , and PSEN2 likely find unity of pathological mechanism in their actions on endolysosomal acidification and mitochondrial function, with detrimental effects on iron homeostasis and promotion of “pseudo-hypoxia” being of central importance. Aβ production is enhanced and distorted by oxidative stress and accumulates due to decreased lysosomal function. It may act as a disease-associated molecular pattern enhancing oxidative stress-driven neuroinflammation during the cognitive phase of the disease. Show more

Keywords: Alzheimer’s disease, amyloid-β protein precursor, familial Alzheimer’s disease, mutation, presenilins

DOI: 10.3233/JAD-230313

Citation: Journal of Alzheimer's Disease, vol. 96, no. 1, pp. 13-39, 2023

Authors: Rogers, Jack T. | Cahill, Catherine M.

Article Type: Article Commentary

Abstract: Familial Alzheimer’s disease (fAD) mutations in the amyloid-β protein precursor (AβPP) enhance brain AβPP C-Terminal Fragment (CTF) levels to inhibit lysosomal v-ATPase. Consequent disrupted acidification of the endolysosomal pathway may trigger brain iron deficiencies and mitochondrial dysfunction. The iron responsive element (IRE) in the 5’Untranslated-region of AβPP mRNA should be factored into this cycle where reduced bioavailable Fe-II would decrease IRE-dependent AβPP translation and levels of APP-CTFβ in a cycle to adaptively restore iron homeostasis while increases of transferrin-receptors is evident. In healthy younger individuals, Fe-dependent translational modulation of AβPP is part of the neuroprotective function of sAβPPα with …its role in iron transport. Show more

Keywords: Alzheimer’s disease, amyloid-β protein precursor, C-terminal fragments, iron, iron homeostasis, iron responsive element, iron regulatory protein, lysosomes, 5’Untranslated region

DOI: 10.3233/JAD-230953

Citation: Journal of Alzheimer's Disease, vol. 96, no. 1, pp. 41-45, 2023

Authors: Pacheco Pachado, Mayra | Casas, Ana I. | Elbatreek, Mahmoud H. | Nogales, Cristian | Guney, Emre | Espay, Alberto J. | Schmidt, Harald H.H.W.

Article Type: Research Article

Abstract: Alzheimer’s disease (AD) and other forms of dementia are together a leading cause of disability and death in the aging global population, imposing a high personal, societal, and economic burden. They are also among the most prominent examples of failed drug developments. Indeed, after more than 40 AD trials of anti-amyloid interventions, reduction of amyloid-β (Aβ) has never translated into clinically relevant benefits, and in several cases yielded harm. The fundamental problem is the century-old, brain-centric phenotype-based definitions of diseases that ignore causal mechanisms and comorbidities. In this hypothesis article, we discuss how such current outdated nosology of dementia is …a key roadblock to precision medicine and articulate how Network Medicine enables the substitution of clinicopathologic phenotypes with molecular endotypes and propose a new framework to achieve precision and curative medicine for patients with neurodegenerative disorders. Show more

Keywords: Alzheimer’s disease, dementia, endophenotypes, precision medicine, protein-protein interaction network, systems medicine

DOI: 10.3233/JAD-230694

Citation: Journal of Alzheimer's Disease, vol. 96, no. 1, pp. 47-56, 2023

Authors: Zhang, Yan | Xue, Yanli | Wang, Longcai | Han, Zhifa | Wang, Tao | Zhang, Haihua | Liu, Guiyou | Xiao, Xingjun

Article Type: Short Communication

Abstract: The first primary age-related tauopathy (PART) genome-wide association study confirmed significant associations of Alzheimer’s disease (AD) and progressive supranuclear palsy (PSP) genetic variants with PART, and highlighted a novel genetic variant rs56405341. Here, we perform a comprehensive analysis of rs56405341. We found that rs56405341 was significantly associated with C4orf33 mRNA expression, but not JADE1 mRNA expression in multiple brain tissues. C4orf33 was mainly expressed in cerebellar hemisphere and cerebellum, and JADE1 was mainly expressed in thyroid, and coronary artery. Meanwhile, we found significantly downregulated C4orf33 expression both AD and PSP compared with normal controls, respectively.

Keywords: Alzheimer’s disease, gene expression, primary age-related tauopathy, progressive supranuclear palsy, rs56405341, eQTLs analysis

DOI: 10.3233/JAD-230327

Citation: Journal of Alzheimer's Disease, vol. 96, no. 1, pp. 57-64, 2023

Authors: Cavaillès, Clémence | Yaffe, Kristine | Blackwell, Terri | Buysse, Daniel | Stone, Katie | Leng, Yue

Article Type: Short Communication

Abstract: Specific sleep characteristics have been associated with cognitive decline, Alzheimer’s disease, and related dementias; however, studies examining the association between multidimensional sleep (a more comprehensive integration of sleep parameters) and cognitive decline are lacking. Among 2,811 older men without dementia, those with none, 1-2, and 3–5 “poor” self-reported sleep health dimensions had an adjusted 10-year change score of global cognition (3MS) of 2.9, 4.0 and 3.5 points (p-trend = 0.05), and in executive function (Trails B) completion time of 36.7, 42.7, and 46.7 seconds (p-trend < 0.01), respectively. In conclusion, a multidimensional measure of sleep health was associated with greater cognitive decline.

Keywords: Alzheimer’s disease, cognitive decline, elderly, sleep health

DOI: 10.3233/JAD-230737

Citation: Journal of Alzheimer's Disease, vol. 96, no. 1, pp. 65-71, 2023

Authors: Tzeng, I-Shiang

Article Type: Article Commentary

Abstract: Akada et al. conducted a nationwide database study on patients with Alzheimer’s disease, examining risk factors and outcomes over 3 years. A significant association emerged between decreased daily activities and hip fractures. However, the odds ratio was 1.95 (with p  = 0.020) may be inaccurate in men, considering the wide 95% confidence interval (1.12–3.51). Possible influencing factors include an inappropriate outcome variable, sparse-data bias, collinear covariates, and comorbidities. Moreover, exact propensity-score matching would be more efficient than nested matching. Limitations include potential recall bias in measuring daily activities and limited applicability of cause-effect relationships in a national database study.

Keywords: Alzheimer’s disease, collinearly covariates, database, exact propensity-score matching, hip injuries, risk factors

DOI: 10.3233/JAD-230701

Citation: Journal of Alzheimer's Disease, vol. 96, no. 1, pp. 73-75, 2023

Authors: Merlo, Sara | Costa, Lara | Chiechio, Santina | Busceti, Carla Letizia | Ciranna, Lucia | Santangelo, Rosa | Sortino, Maria Angela | Fornai, Francesco | Nicoletti, Ferdinando | Copani, Agata

Article Type: Research Article

Abstract: Background: The effects of Alzheimer’s disease (AD) pathology on the experience of pain are poorly understood. Objective: To understand the pathophysiological mechanisms underlying pain sensory transmission in the transgenic mouse model of AD, CRND8. Methods: We explored AD-related pathology in the spinal cord and dorsal root ganglia of 18-week-old female CRND8 mice. We assessed nociceptive responses to both acute heat stimuli and persistent inflammatory pain in CRND8 mice and non-transgenic (non-Tg) littermates. In addition, we searched for differences in biochemical correlates of inflammatory pain between CRND8 and non-Tg mice. Finally, we investigated the excitability of dorsal …horn noc iceptive neurons in spinal cord slices from CRND8 and non-Tg mice. Results: We demonstrated the presence of intracellular AD-like pathology in the spinal cord and in the dorsal root ganglia nociceptive sensory neurons of CRND8 mice. We found that CRND8 mice had a reduced susceptibility to acute noxious heat stimuli and an increased sensitivity to tonic inflammatory pain. Tonic inflammatory pain correlated with a lack of induction of pro-opiomelanocortin in the spinal cord of CRND8 mice as compared to non-Tg mice. Electrophysiological recording in acute spinal cord slice preparations indicated an increased probability of glutamate release at the membrane of dorsal horn nociceptive neurons in CRND8 mice. Conclusion: This study suggests that an increased thermal tolerance and a facilitation of nociception by peripheral inflammation can coexist in AD. Show more

Keywords: Alzheimer’s disease, dementia, dorsal root ganglia, nociceptive neurons, spinal cord, transgenic AD mice

DOI: 10.3233/JAD-230148

Citation: Journal of Alzheimer's Disease, vol. 96, no. 1, pp. 77-91, 2023

Authors: Liu, Li-Yang | Xing, Yi | Zhang, Zi-Heng | Zhang, Qing-Ge | Dong, Ming | Wang, Haibo | Cai, Longjun | Wang, Xiaoyi | Tang, Yi

Article Type: Research Article

Abstract: Background: Age-related cognitive decline is a chronic, progressive process that requires active clinical management as cognitive status changes. Computerized cognitive training (CCT) provides cognitive exercises targeting specific cognitive domains delivered by computer or tablet. Meanwhile, CCT can be used to regularly monitor the cognitive status of patients, but it is not clear whether CCT can reliably assess cognitive ability or be used to diagnose different stages of cognitive impairment. Objective: To investigate whether CCT can accurately monitor the cognitive status of patients with cognitive impairment as well as distinguish patients with dementia from patients with mild cognitive impairment …(MCI). Method: We included 116 patients (42 dementia and 74 MCI) in final analysis. Cognitive ability was assessed by averaging the patient performance on the CCT to determine the Cognitive Index. The validity of the Cognitive Index was evaluated by its correlation with neuropsychological tests, and internal consistency was measured to assess the reliability. Additionally, we determined the diagnostic ability of the Cognitive Index to detect dementia using receiver operating characteristic (ROC) analysis. Results: The Cognitive Index was highly correlated with the Montreal Cognitive Assessment (r  = 0.812) and the Mini-Mental State Examination (r  = 0.694), indicating good convergent validity, and the Cronbach’s alpha coefficient was 0.936, indicating excellent internal consistency. The area under the ROC curve, sensitivity, and specificity of the Cognitive Index to diagnose dementia were 0.943, 83.3%, and 91.9%, respectively. Conclusions: CCT can be used to assess cognitive status and detect dementia in patients with cognitive impairment. Show more

Keywords: Alzheimer’s disease, cognitive assessment, cognitive monitoring, computerized cognitive training, dementia, mild cognitive impairment

DOI: 10.3233/JAD-230416

Citation: Journal of Alzheimer's Disease, vol. 96, no. 1, pp. 93-101, 2023

Authors: Pase, Matthew P. | Pinheiro, Adlin | Rowsthorn, Ella | Demissie, Serkalem | Hurmez, Saoresho | Aparicio, Hugo J. | Rodriguez-Lara, Frances | Gonzales, Mitzi M. | Beiser, Alexa | DeCarli, Charles | Seshadri, Sudha | Romero, Jose Rafael

Article Type: Research Article

Abstract: Background: Magnetic resonance imaging (MRI) visible perivascular spaces (PVS) are associated with the risk of incident dementia but their association with the early stages of cognitive impairment remains equivocal. Objective: We examined the association between MRI visible PVS and the risk of incident mild cognitive impairment (MCI) in the community-based Framingham Heart Study (FHS). Methods: FHS participants aged at least 50 years free of stroke, cognitive impairment, and dementia at the time of MRI were included. PVS were rated according to severity in the basal ganglia and centrum semiovale (CSO) using established criteria. …Cox regression analyses were used to relate PVS to incident MCI adjusted for demographic and cardiovascular variables. Results: The mean age of the sample (1,314 participants) at MRI was 68 years (SD, 9; 54% women). There were 263 cases of incident MCI over a median 7.4 years follow-up (max, 19.8 years). MCI risk increased with higher PVS severity in the CSO. Relative to persons with the lowest severity rating, persons with the highest severity rating in the CSO had a higher risk of incident MCI (hazard ratio [HR] = 2.55; 95% confidence interval [CI], 1.48–4.37; p  = 0.0007). In secondary analysis, this association seemed stronger in women. Risk of incident MCI was nominally higher for participants with the highest severity grade of PVS in the basal ganglia, though not statistically significant relative to the lowest grade (HR = 2.19; 95% CI, 0.78–6.14; p  = 0.14). Conclusions: PVS burden in the CSO may be a risk marker for early cognitive impairment. Show more

Keywords: Alzheimer’s disease, cerebral small vessel disease, magnetic resonance imaging, mild cognitive impairment, perivascular spaces

DOI: 10.3233/JAD-230445

Citation: Journal of Alzheimer's Disease, vol. 96, no. 1, pp. 103-112, 2023