Journal of Alzheimer's Disease - Volume 95, issue 2

Authors: Norris, Christopher M.

Article Type: Article Commentary

Abstract: Numerous preclinical and human tissue studies implicate the protein phosphatase calcineurin (CN) as a pathophysiologic mechanism in Alzheimer’s disease (AD) and other neurodegenerative conditions. Using public electronic records of tens of thousands of individuals across the United States, Silva et al. (2023) show that use of the FDA-approved CN inhibitor, tacrolimus (for purposes of immunosuppression) is also associated with reduced prevalence of dementia-related symptoms. Notably, the study controls for age, sex, and race as well as multiple risk factors for AD. The results suggest that tacrolimus, and possibly other immunosuppressants could be repurposed for the treatment of AD-related dementia.

Keywords: Alzheimer’s disease, Ca2+ dysregulation, calcineurin, dementia, immunosuppressant

DOI: 10.3233/JAD-230780

Citation: Journal of Alzheimer's Disease, vol. 95, no. 2, pp. 599-602, 2023

Authors: Yang, Yi | Lv, Jiaxi | Bai, Huimin | Ren, Liang | Yang, Jing | Ding, Yi | Liu, Chengcheng | Chen, Xueping

Article Type: Research Article

Abstract: Background: Characterizing the periodontal status of patients with Alzheimer’s disease (AD), investigating differences in salivary metabolism between patients with and without AD under the same periodontal conditions, and understanding how it is related to oral flora are critical. Objective: We aimed to examine the periodontal condition of patients with AD and to screen salivary metabolic biomarkers from the saliva of individuals with and without AD with matched periodontal conditions. Furthermore, we aimed to explore the possible relationship between salivary metabolic changes and oral flora. Methods: In total, 79 individuals were recruited into the experiment for periodontal …analysis. Especially, 30 saliva samples from the AD group and 30 from healthy controls (HCs) with matched periodontal conditions were selected for metabolomic analysis. The random-forest algorithm was used to detect candidate biomarkers. Among these, 19 AD saliva and 19 HC samples were selected to investigate the microbiological factors influencing the alterations in saliva metabolism in patients with AD. Results: The plaque index and bleeding on probing were considerably higher in the AD group. Further, Cis-3-(1-carboxy-ethyl)-3,5-cyclohexadiene-1,2-diol, dodecanoic acid, genipic acid, and N, N-dimethylthanolamine N-oxide were determined as candidate biomarkers, based on the area under the curve (AUC) value (AUC = 0.95). The results of oral-flora sequencing showed that dysbacteriosis may be a reason for the differences in AD saliva metabolism. Conclusion: Dysregulation of the proportion of specific bacterial flora in saliva plays a vital role in metabolic changes in AD. These results will contribute to further improving the AD saliva biomarker system. Show more

Keywords: Alzheimer’s disease, metabolomics, microbiota, periodontitis, saliva

DOI: 10.3233/JAD-230291

Citation: Journal of Alzheimer's Disease, vol. 95, no. 2, pp. 603-613, 2023

Authors: Wang, Xin | Sundermann, Erin E. | Buckley, Rachel F. | Reas, Emilie T. | McEvoy, Linda K. | Banks, Sarah J.

Article Type: Research Article

Abstract: Background: The association between obesity and Alzheimer’s disease (AD) is complex. Recent studies indicated the relationships between obesity and AD may differ by sex, and women may benefit from being overweight in terms of AD risk. Objective: We investigated whether sex modifies the associations of obesity with tau positron emission tomography (PET), amyloid PET, and cognition in preclinical AD. Methods: We included 387 cognitively-unimpaired amyloid-positive participants (221 women, 166 men, 87.6% non-Hispanic White) with available 18 F-flortaucipir PET, 18 F-florbetapir PET, and completed the Preclinical Alzheimer Cognitive Composite (PACC) tests from the Anti-Amyloid Treatment in Asymptomatic …Alzheimer’s Disease (A4) study. Participants were categorized based on body mass index (BMI: kg/m2 ): normal-weight (BMI: 18.5-25), overweight (BMI: 25-30), and obese (BMI≥30). Results: Significant sex by BMI category interactions on PACC and its components: Mini-Mental State Examination (MMSE) and Reminding Test–Free+Total Recall (FCSRT96) revealed that overweight and obese women outperformed normal-weight women on FCSRT96, while obese men showed poorer MMSE performance than normal-weight men. These interactions were independent of APOE4 . There were no significant interactions of sex by BMI category on tau and amyloid PET. However, sex-stratified analyses observed obesity was associated with less regional tau and mean cortical amyloid in women, not in men. Conclusion: This study found that in preclinical AD, overweight and obesity were associated with better verbal memory in women, whereas obesity was associated with worse global cognition among men. Future studies focusing on the mechanism for this relationship may inform sex-specific interventions for AD prevention. Show more

Keywords: Alzheimer’s disease, cognition, obesity, overweight, sex differences

DOI: 10.3233/JAD-230466

Citation: Journal of Alzheimer's Disease, vol. 95, no. 2, pp. 615-624, 2023

Authors: Huan, Sheng | Liu, Mengling | Liu, Ziqiu | Gao, Jing | Yin, Guoping

Article Type: Research Article

Abstract: Background: The association between dietary or serum cholesterol and cognitive performance in older adults has not been well-established. Objective: This study aimed to investigate the potential association between dietary or serum cholesterol and cognitive performance in the elderly population. Methods: A cross-sectional analysis was conducted using data from the National Health and Nutrition Examination Survey (NHANES) 2011-2012 and 2013-2014. Diet and supplement cholesterol was estimated based on two non-consecutive 24-hour dietary recalls. Cognitive function was assessed using various statistical tests. Poor cognitive performance was defined as scores below the lowest quartile within age groups. Regression models …were adjusted for demographic factors, and subgroup analyses were performed for non-Hispanic White (NHW) and non-Hispanic Black (NHB) individuals. Results: Among 759 participants aged 60 years and above, dietary cholesterol was only associated with dietary saturated fatty acids and serum high-density lipoprotein cholesterol. There was no evidence of an association between dietary cholesterol and cognitive function, except for NHB individuals, where dietary cholesterol showed a positive correlation with cognitive function. In the overall sample and NHW participants, there were consistent positive associations between serum total cholesterol and cognitive performance across statistical tests, while such associations were rare among NHB individuals. Although not statistically significant, NHB individuals had higher dietary/supplementary/total cholesterol intake compared with NHW individuals. Conclusion: Within the normal range, increasing serum cholesterol may be a potential factor to prevent or relieve cognitive dysfunction. However, ethnic differences should be taken into account when considering the association between cholesterol and cognitive performance. Show more

Keywords: Alzheimer’s disease, cholesterol, cognitive function, dietary, NHANES

DOI: 10.3233/JAD-230422

Citation: Journal of Alzheimer's Disease, vol. 95, no. 2, pp. 625-640, 2023

Authors: Kenkpen, Angel K. | Storey, Joshua J. | Olson, Emma R. | Guden, Ty E. | Card, Tate T. | Jensen, Ashley S. | Ahrens, Jordyn L. | Hellmann Whitaker, Rachel A.

Article Type: Research Article

Abstract: Background: Long non-coding RNAs are ubiquitous throughout the human system, yet many of their biological functions remain unknown. LINC00298 RNA, a long intergenic non-coding RNA, has been shown to have preferential expression in the central nervous system where it contributes to neuronal differentiation and development. Furthermore, previous research has indicated that LINC00298 RNA is known to be a genetic risk factor for the development of Alzheimer’s disease. Objective: To biochemically characterize LINC00298 RNA and to elucidate its biological function within hippocampal neuronal cells, thereby providing a greater understanding of its role in Alzheimer’s disease pathogenesis. Methods: …LINC00298 RNA was in vitro transcribed and then subjected to structural analysis using circular dichroism, and UV-Vis spectroscopy. Additionally, affinity column chromatography was used to capture LINC00298 RNA’s protein binding partners from hippocampal neuronal cells, which were then identified using liquid chromatography and mass spectrometry (LC/MS). Results: LINC00298 RNA is comprised of stem-loop secondary structural elements, with a cylindrical tertiary structure that has highly dynamic regions, which result in high positional entropy. LC/MS identified 24 proteins within the interactome of LINC00298 RNA. Conclusion: Through analysis of LINC00298 RNA’s 24 protein binding partners, it was determined that LINC00298 RNA may play significant roles in neuronal development, proliferation, and cellular organization. Furthermore, analysis of LINC00298 RNA’s interactome indicated that LINC00298 RNA is capable of intracellular motility with dual localization in the nucleus and the cytosol. This biochemical characterization of LINC00298 RNA has shed light on its role in Alzheimer’s disease pathogenesis. Show more

Keywords: Alzheimer’s disease, genetic risk factors, long non-coding RNA, transcriptome

DOI: 10.3233/JAD-230057

Citation: Journal of Alzheimer's Disease, vol. 95, no. 2, pp. 641-661, 2023

Authors: Passmore, Susan Racine | Longhurst, Colin | Gerbitz, Abigail | Green-Harris, Gina | Norris, Nia | Edwards, Dorothy Farrar

Article Type: Research Article

Abstract: Background: Although African Americans experience the highest risk of Alzheimer’s disease (AD), they are dramatically underrepresented in preclinical biomarker research. This is especially true for studies involving lumbar puncture as it may involve more perceived risk even for those participants who are otherwise supportive of research. Objective: To understand the unique concerns of African American participants regarding biomarker studies involving lumbar puncture who demonstrate support for AD research. Methods: Study participants were African American adults contacted through an AD research registry. We employed a novel method used to create hypothetical research studies varying on a set …number of factors. The method is designed to collect potential patterns in decision making regarding research participation but differs from experimental vignette design in that the survey is administered with an accompanying qualitive interview to determine the meaning participants ascribe to factors independently and in conjunction with one another. Results: Sixty-one participants each reviewed three randomly selected research scenarios and created their “ideal” study involving lumbar puncture. Scenario variables included: disclosure of research results, racial and ethnic identity of the researcher, recruitment method, and amount of incentive. Conclusion: Findings indicate that transparency in the return of AD research results to be the strongest driver of participation, followed by race of the researcher and amount of incentive. Recruitment method had limited impact on hypothetical decision making. Show more

Keywords: Alzheimer’s disease, Black or African American, ethics, health, health equity

DOI: 10.3233/JAD-230275

Citation: Journal of Alzheimer's Disease, vol. 95, no. 2, pp. 663-675, 2023

Authors: Katisko, Kasper | Krüger, Johanna | Soppela, Helmi | Hartikainen, Päivi | Haapasalo, Annakaisa | Remes, Anne M. | Solje, Eino

Article Type: Research Article

Abstract: Background: Due to the significant presence of neuropsychiatric symptoms in patients with frontotemporal dementia (FTD) spectrum disorders, psychiatric misdiagnoses, diagnostic delay, and use of psychiatric treatments are common prior to the FTD diagnosis. Furthermore, treatment of diagnosed FTD patients mainly relies on off-label psychopharmacological approaches. Currently, limited real-world data are available regarding the actual use of psychopharmacological medications in FTD. Objective: To evaluate psychopharmacological medication use at the time of FTD diagnosis. Methods: Psychopharmacological medication use was evaluated in a Finnish FTD cohort containing 222 FTD patients, including the major clinical disease phenotypes (behavioral, language, and …motor variants) and genetic patients carrying the C9orf72 repeat expansion. A cohort of 214 Alzheimer’s disease (AD) patients was used as a neurodegenerative disease reference group. Results: Active use of psychopharmacological medications at the time of diagnosis was significantly more common in FTD compared to AD, especially in the case of antidepressants (26.1% versus 15.0%, OR = 2.01, p  = 0.008), antipsychotics (23.9% versus 9.3%, OR = 3.15, p  < 0.001), and mood-stabilizers (6.3% versus 1.9%, OR = 2.93, p  = 0.085; not statistically significant), whereas the use of cholinesterase inhibitors or memantine was nearly nonexistent in FTD patients. Female gender and behavioral variant of FTD phenotype alongside with depressive and psychotic symptoms were the most prominent factors associating with the use of these medications among the FTD spectrum patients. Conclusion: Use of off-label psychopharmacological medication and polypharmacy is substantially common at the time of FTD diagnosis. This likely reflects the challenges in using symptom-driven treatment approaches, especially prior to the eventual diagnosis. Show more

Keywords: Alzheimer’s disease, frontotemporal dementia, pharmacology, psychiatry, psychopharmacology, therapeutics

DOI: 10.3233/JAD-230494

Citation: Journal of Alzheimer's Disease, vol. 95, no. 2, pp. 677-685, 2023

Authors: Bruffaerts, Rose | Crosiers, David

Article Type: Article Commentary

Abstract: Although neuropsychiatric symptoms are a hallmark of the behavioral variant of frontotemporal degeneration (FTD), there is limited evidence on the optimal therapeutic management of these symptoms. In this issue, Katisko et al. report real-world multicentric data on the use of psychopharmacological medication in newly diagnosed patients with FTD. Such reports contribute to knowledge sharing between clinicians caring for patients with FTD. Here, we outline how improved collection of clinical data can assure more robust evidence for future therapies in FTD and other rare neurological diseases.

Keywords: Alzheimer’s disease, frontotemporal dementia, pharmacology, psychiatry, psychopharmacology, therapeutics

DOI: 10.3233/JAD-230788

Citation: Journal of Alzheimer's Disease, vol. 95, no. 2, pp. 687-689, 2023

Authors: Yin, Grace S. | van der Heide, Frank | Littlejohns, Thomas J. | Kuźma, Elżbieta | Hayat, Shabina | Brayne, Carol | Foster, Paul J. | Luben, Robert | Khawaja, Anthony P.

Article Type: Research Article

Abstract: Background: Retinal nerve fiber layer (RNFL) thickness may reflect cerebral status. Objective: This study assessed the relationship between RNFL thickness and incident all-cause dementia in the European Prospective Investigation into Cancer in Norfolk (EPIC-Norfolk) Eye Study. Methods: Glaucoma detection with variable corneal compensation (GDx-VCC) and Heidelberg Retinal Tomograph II (HRT II) derived global mean RNFL thickness from dementia-free participants at baseline within the EPIC-Norfolk Eye Study were analyzed. Incident dementia was identified through linkage to electronic medical records. Cox proportional hazard mixed-effects regression models adjusted for key confounders were used to examine the associations between RNFL …thickness and incident dementia in four separate models. Results: 6,239 participants were included with 322 cases of incident dementia and mean age of 67.5-years old, with 49.7% women (median follow-up 13.2-years, interquartile range (11.7 to 14.6 years). Greater RNFL thickness (GDx-VCC) was not significantly associated with a lower risk of incident dementia in the full adjusted model [HR per quartile increase 0.95; 95% CI 0.82–1.10]. Similarly, RNFL thickness assessed with HRT II was also not associated with incident dementia in any model (full adjusted model; HR per quartile increase: 1.06; [95% CI 0.93–1.19]. Gender did not modify any associations under study. Conclusion: GDx-VCC and HRT II derived RNFL thickness are unlikely to be useful predictors of incident dementia. Higher resolution optical imaging technologies may clarify whether there are useful relationships between neuro-retinal morphology and brain measures. Show more

Keywords: Alzheimer’s disease, dementia, retinal ganglion cells, retinal nerve fiber layer, scanning laser polarimetry

DOI: 10.3233/JAD-230073

Citation: Journal of Alzheimer's Disease, vol. 95, no. 2, pp. 691-702, 2023

Authors: Harris, Kristofer | Ling, Yaobin | Bukhbinder, Avram S. | Chen, Luyao | Phelps, Kamal N. | Cruz, Gabriela | Thomas, Jenna | Kim, Yejin | Jiang, Xiaoqian | Schulz, Paul E.

Article Type: Research Article

Abstract: Background: Accumulating evidence suggests that adult vaccinations can reduce the risk of developing Alzheimer’s disease (AD) and Alzheimer’s disease related dementias. Objective: To compare the risk for developing AD between adults with and without prior vaccination against tetanus and diphtheria, with or without pertussis (Tdap/Td); herpes zoster (HZ); or pneumococcus. Methods: A retrospective cohort study was performed using Optum’s de-identified Clinformatics® Data Mart Database. Included patients were free of dementia during a 2-year look-back period and were≥65 years old by the start of the 8-year follow-up period. We compared two similar cohorts identified using propensity score …matching (PSM), one vaccinated and another unvaccinated, with Tdap/Td, HZ, or pneumococcal vaccines. We calculated the relative risk (RR) and absolute risk reduction (ARR) for developing AD. Results: For the Tdap/Td vaccine, 7.2% (n  = 8,370) of vaccinated patients and 10.2% (n  = 11,857) of unvaccinated patients developed AD during follow-up; the RR was 0.70 (95% CI, 0.68–0.72) and ARR was 0.03 (95% CI, 0.02–0.03). For the HZ vaccine, 8.1% (n  = 16,106) of vaccinated patients and 10.7% (n  = 21,417) of unvaccinated patients developed AD during follow-up; the RR was 0.75 (95% CI, 0.73–0.76) and ARR was 0.02 (95% CI, 0.02–0.02). For the pneumococcal vaccine, 7.92% (n  = 20,583) of vaccinated patients and 10.9% (n  = 28,558) of unvaccinated patients developed AD during follow-up; the RR was 0.73 (95% CI, 0.71–0.74) and ARR was 0.02 (95% CI, 0.02–0.03). Conclusion: Several vaccinations, including Tdap/Td, HZ, and pneumococcal, are associated with a reduced risk for developing AD. Show more

Keywords: Alzheimer’s disease, cohort, dementia, diphtheria, epidemiology, herpes zoster, pertussis, pneumococcus, tetanus, vaccine

DOI: 10.3233/JAD-221231

Citation: Journal of Alzheimer's Disease, vol. 95, no. 2, pp. 703-718, 2023

Authors: Kobro-Flatmoen, Asgeir | Hormann, Thea Meier | Gouras, Gunnar

Article Type: Research Article

Abstract: Background: Amyloid-β (Aβ) is a normal product of neuronal activity, including that of the aggregation-prone Aβ42 variant that is thought to cause Alzheimer’s disease (AD). Much knowledge about AD comes from studies of transgenic rodents expressing mutated human amyloid-β protein precursor (AβPP) to increase Aβ production or the Aβ42/40 ratio. Yet, little is known about the normal expression of Aβ42 in rodent brains. Objective: To characterize the brain-wide expression of Aβ42 throughout the life span of outbred Wistar rats, and to relate these findings to brains of human subjects without neurological disease. …Methods: Aβ42 immunolabeling of 12 Wistar rat brains (3–18 months of age) and brain sections from six human subjects aged 20–88 years. Results: In healthy Wistar rats, we find intracellular Aβ42 (iAβ42 ) in neurons throughout the brain at all ages, but levels vary greatly between brain regions. The highest levels are in neurons of entorhinal cortex layer II, alongside hippocampal neurons at the CA1/subiculum border. Concerning entorhinal cortex layer II, we find similarly high levels of iAβ42 in the human subjects. Conclusion: Expression of iAβ42 in healthy Wistar rats predominates in the same structures where iAβ accumulates and Aβ plaques initially form in the much used, Wistar based McGill-R-Thy1-APP rat model for AD. The difference between wild-type Wistar rats and these AD model rats, with respect to Aβ42 , is therefore quantitative rather that qualitative. This, taken together with our human results, indicate that the McGill rat model in fact models the underlying wild-type neuronal population-specific vulnerability to Aβ42 accumulation. Show more

Keywords: Alzheimer’s disease, animal model, disease onset, entorhinal cortex

DOI: 10.3233/JAD-230349

Citation: Journal of Alzheimer's Disease, vol. 95, no. 2, pp. 719-733, 2023

Authors: Panikkar, Daniel | Vivek, Sithara | Crimmins, Eileen | Faul, Jessica | Langa, Kenneth M. | Thyagarajan, Bharat

Article Type: Research Article

Abstract: Background: Sample collection and preanalytical protocols may significantly impact the results of large-scale epidemiological studies incorporating blood-based biomarkers of neuropathology. Objective: To evaluate the stability and assay variability of several blood-based biomarkers of neuropathology for common preanalytical conditions. Methods: We collected serum and plasma samples from 41 participants and evaluated the effect of processing delay of up to 72 h when stored at 4∘C, three freeze-thaw cycles, and a combination of 48-h processing delay when stored at 4∘C and three freeze-thaw cycles on biomarker stability. Using the Simoa assay (Quanterix Inc.), we measured amyloid-β 40 (Aβ40 ), …amyloid-β 42 (Aβ42 ), neurofilament light (NfL), glial fibrillary acidic protein (GFAP), and phosphorylated tau 181 (p-tau-181). Results: We found that Aβ40 and Aβ42 levels significantly decreased after a 24-h processing delay in both plasma and serum samples, and a single freeze-thaw cycle (p  < 0.0001). Nevertheless, serum Aβ42/40 ratio remained stable with a processing delay up to 48 h while plasma Aβ42/40 ratio showed only small but significant increase with a delay up to 72 h. Both plasma and serum GFAP and NfL levels were only modestly affected by processing delay and freeze-thaw cycles. Plasma p-tau-181 levels notably increased with a 24-, 48-, and 72-h processing delay, but remained stable in serum. Intra-individual variation over two weeks was minimal for all biomarkers and their levels were substantially lower in serum when compared with plasma. Conclusion: These results suggest that standardizing preanalytical variables will allow robust measurements of biomarkers of neuropathology in population studies. Show more

Keywords: Alzheimer’s disease, amyloid-β , blood-based biomarkers, pre-analytical variables, Simoa assay, stability

DOI: 10.3233/JAD-230384

Citation: Journal of Alzheimer's Disease, vol. 95, no. 2, pp. 735-748, 2023

Authors: Perry, George

Article Type: Book Review

DOI: 10.3233/JAD-239008

Citation: Journal of Alzheimer's Disease, vol. 95, no. 2, pp. 749-749, 2023

Article Type: Retraction

DOI: 10.3233/JAD-239009

Citation: Journal of Alzheimer's Disease, vol. 95, no. 2, pp. 751-751, 2023