Journal of Alzheimer's Disease - Volume 93, issue 2

Authors: Stark, Jessica | Hiersche, Kelly J. | Yu, Ju-Chi | Hasselbach, Alexander N. | Abdi, Hervé | Hayes, Scott M.

Article Type: Research Article

Abstract: Background: Prior work has shown that certain modifiable health, Alzheimer’s disease (AD) biomarker, and demographic variables are associated with cognitive performance. However, less is known about the relative importance of these different domains of variables in predicting longitudinal change in cognition. Objective: Identify novel relationships between modifiable physical and health variables, AD biomarkers, and slope of cognitive change over two years in a cohort of older adults with mild cognitive impairment (MCI). Methods: Metrics of cardiometabolic risk, stress, inflammation, neurotrophic/growth factors, and AD pathology were assessed in 123 older adults with MCI at baseline from the …Alzheimer’s Disease Neuroimaging Initiative (mean age = 73.9; SD  = 7.6; mean education = 16.0; SD  = 3.0). Partial least squares regression (PLSR)—a multivariate method which creates components that best predict an outcome—was used to identify whether these physiological variables were important in predicting slope of change in episodic memory or executive function over two years. Results: At two-year follow-up, the two PLSR models predicted, respectively, 20.0% and 19.6% of the variance in change in episodic memory and executive function. Baseline levels of AD biomarkers were important in predicting change in both episodic memory and executive function. Baseline education and neurotrophic/growth factors were important in predicting change in episodic memory, whereas cardiometabolic variables such as blood pressure and cholesterol were important in predicting change in executive function. Conclusion: These data-driven analyses highlight the impact of AD biomarkers on cognitive change and further clarify potential domain specific relationships with predictors of cognitive change. Show more

Keywords: Episodic memory, executive function, healthy aging, inflammation, metabolic syndrome, neuronal plasticity, neuroprotection, neuropsychology

DOI: 10.3233/JAD-221084

Citation: Journal of Alzheimer's Disease, vol. 93, no. 2, pp. 633-651, 2023

Authors: Brook, Emily S. | D’Alonzo, Zachary J. | Lam, Virginie | Chan, Dick C. | Dhaliwal, Satvinder S. | Watts, Geraldb F. | Mamo, John C.L. | Takechi, Ryusuke

Article Type: Research Article

Abstract: Background: Obesity is linked to a higher incidence of Alzheimer’s disease (AD). Studies show that plasma amyloid-β (Aβ) dyshomeostasis, particularly low 42/40 ratio indicates a heightened risk for developing AD. However, the relationship between body mass index (BMI) and circulating plasma Aβ has not been extensively studied. Objective: We hypothesized that people with a high BMI have altered plasma Aβ homeostasis compared with people with a lower BMI. We also tested whether reducing BMI by calorie-restriction could normalize plasma concentrations of Aβ. Methods: Plasma concentrations of Aβ40 , Aβ42 , and Aβ42/40 ratio were measured …in 106 participants with BMIs classified as lean, overweight, or obese. From this cohort, twelve participants with overweight or obese BMIs entered a 12-week calorie-restriction weight loss program. We then tested whether decreasing BMI affected plasma Aβ concentrations. Results: Plasma Aβ42/40 ratio was 17.54% lower in participants with an obese BMI compared to lean participants (p  < 0.0001), and 11.76% lower compared to participants with an overweight BMI (p  < 0.0001). The weight loss regimen decreased BMI by an average of 4.02% (p  = 0.0005) and was associated with a 6.5% decrease in plasma Aβ40 (p  = 0.0425). However, weight loss showed negligible correlations with plasma Aβ40 , Aβ42 , and Aβ42/40 ratio. Conclusion: Obesity is associated with aberrant plasma Aβ homeostasis which may be associated with an increased risk for AD. Weight loss appears to lower Aβ40 , but large-scale longitudinal studies in addition to molecular studies are required to elucidate the underlying mechanisms of how obesity and weight loss influence plasma Aβ homeostasis. Show more

Keywords: Alzheimer’s disease, amyloid-β, body mass index, obesity, weight loss

DOI: 10.3233/JAD-220529

Citation: Journal of Alzheimer's Disease, vol. 93, no. 2, pp. 653-664, 2023

Authors: Otoki, Yurika | Yu, Di | Shen, Qing | Sahlas, Demetrios J. | Ramirez, Joel | Gao, Fuqiang | Masellis, Mario | Swartz, Richard H. | Chan, Pak Cheung | Pettersen, Jacqueline A. | Kato, Shunji | Nakagawa, Kiyotaka | Black, Sandra E. | Swardfager, Walter | Taha, Ameer Y.

Article Type: Research Article

Abstract: Background: Circulating phospholipid species have been shown to predict Alzheimer’s disease (AD) prognosis but the link between phospholipid disturbances and subcortical small vessel cerebrovascular disease (CeVD) common in AD patients is not known. Objective: Mass-spectrometry lipidomics was applied to quantify serum diacyl, alkenyl (ether), alkyl, and lyso phospholipid species in individuals with extensive CeVD (n  = 29), AD with minimal CeVD (n  = 16), and AD with extensive CeVD (n  = 14), and compared them to age-matched controls (n  = 27). Memory was assessed using the California Verbal Learning Test. 3.0T MRI was used to assess hippocampal volume, atrophy, and white matter …hyperintensity (WMH) volumes as manifestations of CeVD. Results: AD was associated with significantly higher concentrations of choline plasmalogen 18:0_18:1 and alkyl-phosphocholine 18:1. CeVD was associated with significantly lower lysophospholipids containing 16:0. Phospholipids containing arachidonic acid (AA) were associated with poorer memory in controls, whereas docosahexaenoic acid (DHA)-containing phospholipids were associated with better memory in individuals with AD+CeVD. In controls, DHA-containing phospholipids were associated with more atrophy, and phospholipids containing linoleic acid and AA were associated with less atrophy. Lysophospholipids containing 16:0, 18:0, and 18:1 were correlated with less atrophy in controls, and of these, alkyl-phosphocholine 18:1 was correlated with smaller WMH volumes. Conversely, 16:0_18:1 choline plasmalogen was correlated with greater WMH volumes in controls. Conclusion: This study demonstrates discernable differences in circulating phospholipids in individuals with AD and CeVD, as well as new associations between phospholipid species with memory and brain structure that were specific to contexts of commonly comorbid vascular and neurodegenerative pathologies. Show more

Keywords: Alkylphospholipids, Alzheimer’s disease, lysophospholipid, plasmalogens, small vessel disease, vascular cognitive impairment, white matter hyperintensity

DOI: 10.3233/JAD-220795

Citation: Journal of Alzheimer's Disease, vol. 93, no. 2, pp. 665-682, 2023

Authors: Williams, Elizabeth | Mutlu-Smith, Menekşe | Alex, Ashli | Chin, Xi Wei | Spires-Jones, Tara | Wang, Szu-Han

Article Type: Research Article

Abstract: Background: Prior experience in early life has been shown to improve performance in aging and mice with Alzheimer’s disease (AD) pathology. However, whether cognitive training at a later life stage would benefit subsequent cognition and reduce pathology in AD mice needs to be better understood. Objective: This study aimed to verify if behavioral training in mid-adulthood would improve subsequent cognition and reduce AD pathology and astrogliosis. Methods: Mixed-sex APP/PS1 and wildtype littermate mice received a battery of behavioral training, composed of spontaneous alternation in the Y-maze, novel object recognition and location tasks, and spatial training in …the water maze, or handling only at 7 months of age. The impact of AD genotype and prior training on subsequent learning and memory of aforementioned tasks were assessed at 9 months. Results: APP/PS1 mice made more errors than wildtype littermates in the radial-arm water maze (RAWM) task. Prior training prevented this impairment in APP/PS1 mice. Prior training also contributed to better efficiency in finding the escape platform in both APP/PS1 mice and wildtype littermates. Short-term and long-term memory of this RAWM task, of a reversal task, and of a transfer task were comparable among APP/PS1 and wildtype mice, with or without prior training. Amyloid pathology and astrogliosis in the hippocampus were also comparable between the APP/PS1 groups. Conclusion: These data suggest that cognitive training in mid-adulthood improves subsequent accuracy in AD mice and efficiency in all mice in the spatial task. Cognitive training in mid-adulthood provides no clear benefit on memory or on amyloid pathology in midlife. Show more

Keywords: Aging, Alzheimer’s disease, amyloid-β, astrocytes, cognitive reserve, dementia, hippocampus

DOI: 10.3233/JAD-221185

Citation: Journal of Alzheimer's Disease, vol. 93, no. 2, pp. 683-704, 2023

Authors: Singh, Manisha | Jindal, Divya | Kumar, Rupesh | Pancham, Pranav | Haider, Shazia | Gupta, Vivek | Mani, Shalini | R, Rachana | Tiwari, Raj Kumar | Chanda, Silpi

Article Type: Research Article

Abstract: Background: Alzheimer’s disease (AD) is the most common type of neurodegenerative dementia affecting people in their later years of life. The AD prevalence rate has significantly increased due to a lack of early detection technology and low therapeutic efficacy. Despite recent scientific advances, some aspects of AD pathological targets still require special attention. Certain traditionally consumed phytocompounds have been used for thousands of years to treat such pathologies. The standard extract of Gingko biloba (EGB761) is a combination of 13 macro phyto-compounds and various other micro phytocompounds that have shown greater therapeutic potential against the pathology of AD. …Objective: Strong physiological evidence of cognitive health preservation has been observed in elderly people who keep an active lifestyle. According to some theories, consuming certain medicinal extracts helps build cognitive reserve. We outline the research employing EGB761 as a dual target for AD. Methods: This study investigates various inhibitory targets against AD using computational approaches such as molecular docking, network pharmacology, ADMET (full form), and bioactivity prediction of the selected compounds. Results: After interaction studies were done for all the phytoconstituents of EGB761, it was concluded that all four of the phytocompounds (kaempferol, isorhamnetin, quercetin, and ginkgotoxin) showed the maximum inhibitory activity against acetylcholinesterase (AChE) and GSK3β. Conclusion: The highly active phytocompounds of EGB761, especially quercetin, kaempferol, and isorhamnetin, have better activity against AChE and GSK3β than its reported synthetic drug, according to molecular docking and network pharmacology research. These compounds may act on multiple targets in the protein network of AD. The AChE theory was primarily responsible for EGB761’s therapeutic efficacy in treating AD. Show more

Keywords: Acetylcholinesterase inhibitors, amyloid-β, compound target network, neurodegenerative disorders, neurofibrillary tangles, phytocompounds

DOI: 10.3233/JAD-221222

Citation: Journal of Alzheimer's Disease, vol. 93, no. 2, pp. 705-726, 2023

Authors: Williams, Victoria J. | Koscik, Rebecca | Sicinski, Kamil | Johnson, Sterling C. | Herd, Pamela | Asthana, Sanjay

Article Type: Research Article

Abstract: Background: Prior research suggests a link between menopausal hormone therapy (MHT) use, memory function, and diabetes risk. The menopausal transition is a modifiable period to enhance long-term health and cognitive outcomes, although studies have been limited by short follow-up periods precluding a solid understanding of the lasting effects of MHT use on cognition. Objective: We examined the effects of midlife MHT use on subsequent diabetes incidence and late life memory performance in a large, same-aged, population-based cohort. We hypothesized that the beneficial effects of MHT use on late life cognition would be partially mediated by reduced diabetes risk. …Methods: 1,792 women from the Wisconsin Longitudinal Study (WLS) were included in analysis. We employed hierarchical linear regression, Cox regression, and causal mediation models to test the associations between MHT history, diabetes incidence, and late life cognitive performance. Results: 1,088/1,792 women (60.7%) reported a history of midlife MHT use and 220/1,792 (12.3%) reported a history of diabetes. MHT use history was associated with better late life immediate recall (but not delayed recall), as well as a reduced risk of diabetes with protracted time to onset. Causal mediation models suggest that the beneficial effect of midlife MHT use on late life immediate recall were at least partially mediated by diabetes risk. Conclusion: Our data support a beneficial effect of MHT use on late life immediate recall (learning) that was partially mediated by protection against diabetes risk, supporting MHT use in midlife as protective against late life cognitive decline and adverse health outcomes. Show more

Keywords: Adult onset diabetes mellitus, Alzheimer’s disease, estrogen, immediate memory, mediation, menopause

DOI: 10.3233/JAD-221240

Citation: Journal of Alzheimer's Disease, vol. 93, no. 2, pp. 727-741, 2023

Authors: Hattori, Yorito | Saito, Satoshi | Nakaoku, Yuriko | Ogata, Soshiro | Hattori, Masashi | Nakatsuji, Mio | Nishimura, Kunihiro | Ihara, Masafumi

Article Type: Research Article

Abstract: Background: The development of numerous disease-modifying drugs for age-related dementia has been attempted based on the amyloid-β (Aβ) hypothesis without much success. Taxifolin (TAX), a natural bioactive flavonoid, shows pleiotropic neuroprotective effects with inhibition of Aβ aggregation, production, and glycation, antiinflammatory effects, and amelioration of the waste clearance system. We hypothesized that TAX intake is associated with the suppression of cognitive deterioration. Objective: To investigate associations between TAX intake and cognitive changes. Methods: We retrospectively identified patients who orally took TAX 300 mg/day and regularly underwent Alzheimer’s Disease Assessment Scale-Cognitive Subscale 13 (ADAS-Cog) and Montreal Cognitive Assessment …(MoCA) and compared the temporal changes in ADAS-Cog and MoCA between the non-treatment (pre-TAX) period (180±100 days) and following treatment (on-TAX) period (180±100 days) from June 2020 to November 2021. Since some additional patients underwent the Mini-Mental State Examination (MMSE) instead of the MoCA at the beginning of the pre-TAX period, the same comparison was performed using the MoCA total score converted from MMSE as a sensitivity analysis. Results: Sixteen patients were identified. TAX intake was associated with significantly higher interval changes in the MoCA subscale scores of visuospatial/executive function (p  = 0.016), verbal fluency (p  = 0.02), and the total score (p  = 0.034), but not with ADAS-Cog (total score, p  = 0.27). In the sensitivity analysis, 29 patients were included. TAX intake was associated with a significantly higher interval change in the total MoCA score (p  = 0.004) but not with ADAS-Cog (p  = 0.41). Conclusion: Our findings provide a basis for TAX as a novel strategy for maintaining brain health during aging. A prospective cohort study is required to confirm these findings. Show more

Keywords: Alzheimer’s disease, amyloid-β, antidementia agent, cognitive aging, mild cognitive impairment, taxifolin

DOI: 10.3233/JAD-221293

Citation: Journal of Alzheimer's Disease, vol. 93, no. 2, pp. 743-754, 2023

Authors: Soo, See Ann | Kumar, Dilip | Leow, Yi Jin | Koh, Chen Ling | Saffari, Seyed Ehsan | Kandiah, Nagaendran

Article Type: Research Article

Abstract: Background: A delay in the detection of mild cognitive impairment (MCI) in the community delays the opportunity for early intervention. Accurate tools to detect MCI in the community are lacking. The Visual Cognitive Assessment Test (VCAT) is a visual based cognitive test useful for multilingual populations without the need for translation. Objective: Here, we evaluate the usefulness of VCAT in detecting MCI in a community population in Singapore. Methods: We recruited 301 participants from the community who completed a detailed neuropsychological assessment and 170 of them completed a 3T magnetic resonance imaging (MRI) brain scan. We …performed a receiver operating characteristics analysis to test the diagnostic performance of VCAT compared to Montreal Cognitive Assessment (MoCA) in distinguishing MCI from cognitively normal (CN) by measuring area under the curve (AUC). To test for the association of VCAT with structural MRI, we performed a Pearson’s correlation analysis for VCAT and MRI variables. Results: We recruited 39 CN and 262 MCI participants from Dementia Research Centre (Singapore). Mean age of the cohort was 63.64, SD = 9.38, mean education years was 13.59, SD = 3.70 and majority were women (55.8%). VCAT was effective in detecting MCI from CN with an AUC of 0.794 (95% CI 0.723–0.865) which was slightly higher than MoCA 0.699 (95% CI 0.621–0.777). Among subjects with MCI, VCAT was associated with medial temporal lobe atrophy (ρ = –0.265, p  = 0.001). Conclusions: The VCAT is useful in detecting MCI in the community in Singapore and may be an effective measure of neurodegeneration. Show more

Keywords: Alzheimer’s disease, assessment, cognition, community, medial temporal lobe atrophy, mild cognitive impairment

DOI: 10.3233/JAD-221301

Citation: Journal of Alzheimer's Disease, vol. 93, no. 2, pp. 755-763, 2023

Authors: Chen, Charles D. | Ponisio, Maria Rosana | Lang, Jordan A. | Flores, Shaney | Schindler, Suzanne E. | Fagan, Anne M. | Morris, John C. | Benzinger, Tammie L.S.

Article Type: Research Article

Abstract: Background: 18 F-flortaucipir PET received FDA approval to visualize aggregated neurofibrillary tangles (NFTs) in brains of adult patients with cognitive impairment being evaluated for Alzheimer’s disease (AD). However, manufacturer’s guidelines for visual interpretation of 18 F-flortaucipir PET differ from how 18 F-flortaucipir PET has been measured in research settings using standardized uptake value ratios (SUVRs). How visual interpretation relates to 18 F-flortaucipir PET SUVR, cerebrospinal fluid (CSF) biomarkers, or longitudinal clinical assessment is not well understood. Objective: We compare various diagnostic methods in participants enrolled in longitudinal observational studies of aging and memory (n  = 189, 23 were cognitively …impaired). Methods: Participants had tau PET, Aβ PET, MRI, and clinical and cognitive evaluation within 18 months (n  = 189); the majority (n  = 144) also underwent lumbar puncture. Two radiologists followed manufacturer’s guidelines for 18 F-flortaucipir PET visual interpretation. Results: Visual interpretation had high agreement with SUVR (98.4%)and moderate agreement with CSF p-tau181 (86.1%). Two participants demonstrated 18 F-flortaucipir uptake from meningiomas. Visual interpretation could not predict follow-up clinical assessment in 9.52% of cases. Conclusion: Visual interpretation was highly consistent with SUVR (discordant participants had hemorrhagic infarcts or occipital-predominant AD NFT deposition) and moderately consistent with CSF p-tau181 (discordant participants had AD pathophysiology not detectable on tau PET). However, close association between AD NFT deposition and clinical onset in group-level studies does not necessarily hold at the individual level, with discrepancies arising from atypical AD, vascular dementia, or frontotemporal dementia. A better understanding of relationships across imaging, CSF biomarkers, and clinical assessment is needed to provide appropriate diagnoses for these individuals. Show more

Keywords: Alzheimer’s disease, cerebrospinal fluid, positron emission tomography, tauopathies

DOI: 10.3233/JAD-230032

Citation: Journal of Alzheimer's Disease, vol. 93, no. 2, pp. 765-777, 2023

Authors: Hickey, Martha | Hueg, Trine K. | Priskorn, Lærke | Uldbjerg, Cecilie S. | Beck, Astrid L. | Anstey, Kaarin J. | Lim, Youn-Hee | Bräuner, Elvira V.

Article Type: Research Article

Abstract: Background: Depression and dementia confer substantial global health burdens, particularly in women. Understanding the association between depression and dementia may inform new targets for prevention and/or early intervention. Objective: To investigate the association between depression in mid- and later-life and dementia (all-cause, Alzheimer’s disease (AD) or vascular dementia (VaD)) in women. Methods: A prospective study design. Nurses were followed from age 60 years or entry into the cohort, whichever came last, until date of dementia, death, emigration, or end of follow-up, whichever came first. Cox regression models with age as the underlying timeline were used to …estimate the associations between time-varying depression and incident dementia. Results: The study included 25,651 female Danish nurses (≥45 years) participating in the Danish Nurse Cohort. During an average of 23 years of follow-up, 1,232 (4.8%) nurses developed dementia and 8,086 (31.5%) were identified with at least two episodes of treated depression. In adjusted analyses, nurses with depression were at a statistically significant 5.23-fold higher risk of all-cause dementia (aHR 5.23:95% CI, 4.64–5.91) compared to those with no history of depression. The differential effects of depression were greater for VaD (aHR 7.96:95% CI, 5.26–12.0) than AD (aHR 4.64:95% CI, 3.97–5.42). Later life depression (>60 years) (aHR 5.85:95% CI, 5.17–6.64) and recurrent depression (aHR 3.51:95% CI, 2.67–4.61) elevated dementia risk. Severe depression tripled the risk of all cause dementia (aHR 3.14:95% CI, 2.62–3.76). Conclusion: Both later life and severe depression substantially increase dementia risk in women, particularly VaD. Show more

Keywords: Alzheimer’s disease, dementia, depression, prospective cohort study, women

DOI: 10.3233/JAD-230091

Citation: Journal of Alzheimer's Disease, vol. 93, no. 2, pp. 779-789, 2023