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

Authors: Mao, Chenhui | You, Hui | Hou, Bo | Chu, Shanshan | Jin, Wei | Huang, Xinying | Shang, Li | Feng, Feng | Peng, Bin | Gao, Jing

Article Type: Research Article

Abstract: Background: Arterial spin labeling (ASL) is helpful in early diagnosis and differential diagnosis of Alzheimer’s disease (AD), with advantages including no exposure to radioactivity, no injection of a contrast agent, more accessible, and relatively less expensive. Objective: To establish the perfusion pattern of different dementia in Chinese population and evaluate the effectiveness of ASL in differentiating AD from cognitive unimpaired (CU), mild cognitive impairment (MCI), and frontotemporal dementia (FTD). Methods: Four groups of participants were enrolled, including AD, FTD, MCI, and CU based on clinical diagnosis from PUMCH dementia cohort. ASL image was collected using 3D …spiral fast spin echo–based pseudo-continuous ASL pulse sequence with background suppression and a high resolution T1-weighted scan covering the whole brain. Data processing was performed using Dr. Brain Platform to get cerebral blood flow (ml/100g/min) in every region of interest cortices. Results: Participants included 66 AD, 26 FTD, 21 MCI, and 21 CU. Statistically, widespread hypoperfusion neocortices, most significantly in temporal-parietal-occipital cortices, but not hippocampus and subcortical nucleus were found in AD. Hypoperfusion in parietal lobe was most significantly associated with cognitive decline in AD. Hypoperfusion in parietal lobe was found in MCI and extended to adjacent temporal, occipital and posterior cingulate cortices in AD. Significant reduced perfusion in frontal and temporal cortices, including subcortical nucleus and anterior cingulate cortex were found in FTD. Hypoperfusion regions were relatively symmetrical in AD and left predominant especially in FTD. Conclusion: Specific patterns of ASL hypoperfusion were helpful in differentiating AD from CU, MCI, and FTD. Show more

Keywords: Alzheimer’s disease, arterial spin labeling, frontotemporal dementia, hypoperfusion, mild cognitive impairment

DOI: 10.3233/JAD-221023

Citation: Journal of Alzheimer's Disease, vol. 93, no. 2, pp. 509-519, 2023

Authors: Imai, Ayu | Matsuoka, Teruyuki | Narumoto, Jin

Article Type: Research Article

Abstract: Background: Mild behavioral impairment (MBI) has attracted attention as a possible precursor symptom of dementia, but its neural basis has not been fully investigated. Objective: We aimed to investigate the relationship between MBI and surface area, cortical thickness, and volume in the temporal and parietal lobes, which are strongly associated with dementia and emotional disorders. Methods: This retrospective study evaluated 123 participants: 90 with mild cognitive impairment (MCI), 13 with subjective cognitive decline (SCD), and 20 cognitively healthy (CH). Using analysis of covariance (ANCOVA) with sex, age, and MMSE score as covariates, cortical thickness, surface area, …and volume in 10 regions were compared between groups with and without MBI. Groups with MBI emotional dysregulation were also compared with groups without MBI. Results: ANCOVA revealed significantly smaller cortical thickness in the MBI group’s right parahippocampal (p  = 0.01) and supramarginal gyri (p  = 0.002). After multiple comparison correction, only the right supramarginal gyrus was significantly smaller (p  = 0.02). When considering only MBI emotional dysregulation, the right parahippocampal and supramarginal gyrus’ cortical thicknesses were significantly smaller in this MBI group (p  = 0.03, 0.01). However, multiple comparison correction identified no significant differences (p  = 0.14, 0.11). Conclusion: Overall MBI and the emotional dysregulation domains were associated with reduced cortical thickness in the right parahippocampal and supramarginal gyri. Since neurodegeneration in the medial temporal and parietal lobe precedes early Alzheimer’s disease (AD), MBI, particularly emotion dysregulation, may predict early AD below the diagnostic threshold. Show more

Keywords: Alzheimer’s disease, cortical thickness, emotional dysregulation, mild behavioral impairment, mild cognitive impairment, neural basis, surface area

DOI: 10.3233/JAD-220948

Citation: Journal of Alzheimer's Disease, vol. 93, no. 2, pp. 521-532, 2023

Authors: Sible, Isabel J. | Nation, Daniel A.

Article Type: Research Article

Abstract: Background: Blood pressure variability (BPV) is associated with cognitive decline and Alzheimer’s disease (AD), but relationships with AD risk gene apolipoprotein (APOE ) ɛ4 remain understudied. Objective: Examined the longitudinal relationship between BPV and cognitive change in APOE ɛ4 carriers and APOE ɛ3 homozygotes. Methods: 1,194 Alzheimer’s Disease Neuroimaging Initiative participants (554 APOE ɛ4 carriers) underwent 3-4 blood pressure measurements between study baseline and 12-month follow-up. Visit-to-visit BPV was calculated as variability independent of mean over these 12 months. Participants subsequently underwent ≥1 neuropsychological exam at 12-month follow-up or later (up to 156 …months later). Composite scores for the domains of memory, language, executive function, and visuospatial abilities were determined. Linear mixed models examined the 3-way interaction of BPV×APOE ɛ4 carrier status x time predicting change in composite scores. Results: Higher systolic BPV predicted greater decline in memory (+1 SD increase of BPV: β = –0.001, p  < 0.001) and language (β = –0.002, p  < 0.0001) among APOE ɛ4 carriers, but not APOE ɛ3 homozygotes (memory: +1 SD increase of BPV: β = 0.0001, p  = 0.57; language: β = 0.0001, p  = 0.72). Systolic BPV was not significantly associated with change in executive function or visuospatial abilities in APOE ɛ4 carriers (p s = 0.08–0.16) or APOE ɛ3 homozygotes (p s = 0.48–0.12). Conclusion: Cognitive decline associated with high BPV may be specifically accelerated among APOE ɛ4 carriers. Show more

Keywords: Alzheimer’s disease, APOE, blood pressure, cognitive dysfunction, neuropsychology

DOI: 10.3233/JAD-221103

Citation: Journal of Alzheimer's Disease, vol. 93, no. 2, pp. 533-543, 2023

Authors: Zhang, Junyao | Zhang, Tong | Wang, Yinuo | Yao, Liangfang | Yao, Junyan

Article Type: Research Article

Abstract: Background: Our previous studies indicated that anesthesia and surgery could aggravate cognitive impairment of 5XFAD transgenic (Tg) mice, and this aggravation was associated with tau hyperphosphorylation. We previously identified that GNA13 (the gene encoding Gα13) was a hub gene with tau hyperphosphorylation. Objective: This study aims to further investigate the mechanism that whether the Gα13-mediated signaling pathway acts as an instigator to regulate cofilin activation and autophagy impairment in this process. Methods: 5XFAD Tg mice and their littermate (LM) mice were randomly allocated into four groups: LM Control group, LM Anesthesia/Surgery group, AD Control group, and …AD Anesthesia/Surgery group. For mice in the Anesthesia/Surgery groups, abdominal surgery was performed under 1.4% isoflurane anesthesia followed by sustaining anesthetic inhalation for up to 2 h. Results: Compared with the AD Control group, protein levels of Gα13, ROCK2, LPAR5, and p-tau/tau46 ratio were increased, while p-cofilin/cofilin protein expression ratio was decreased in the AD Anesthesia/Surgery group. However, the differences in these protein levels were not significant among LM groups. Conclusion: This study demonstrated that anesthesia and surgery might exacerbate p-tau accumulation in 5XFAD Tg mice but not in LM mice. And this might be closely related to cofilin activation via Gα13-mediated signaling cascade. Show more

Keywords: Alzheimer’s disease, anesthesia, autophagy, cofilin, cognitive dysfunction, Gα13, surgery, tau

DOI: 10.3233/JAD-221039

Citation: Journal of Alzheimer's Disease, vol. 93, no. 2, pp. 545-560, 2023

Authors: Biswas, Roshni | Kawas, Claudia | Montine, Thomas J. | Bukhari, Syed A. | Jiang, Luohua | Corrada, Maria M.

Article Type: Research Article

Abstract: Background: Some oldest-old individuals can maintain superior cognition despite advanced age. Little is known about the neuropathological changes in the brains of oldest-old superior cognitive performers. Objective: Our objective was to examine the associations between Alzheimer’s disease (AD) and non-AD neuropathologic features in relation to superior cognitive performance in oldest-old individuals. Methods: We analyzed brain autopsy data from 102 participants with normal cognition from The 90+ Study . Superior global cognitive performers (SGCP) were defined as having Mini-Mental State Examination (MMSE) score ≥28 in the last visit 12 to 2 months before death. To examine the …associations between individual and multiple comorbid neuropathologic features with SGCP status we used multiple logistic regression models adjusting for age, sex, and education. Results: Alzheimer’s disease neuropathological change (ADNC) and low levels of vascular pathologic change were not associated with superior cognition. In contrast, participants with limbic (OR = 8.37; 95% CI: 1.48–47.44) and neocortical (OR = 10.80;95% CI: 1.03–113.82) Lewy body disease (LBD), or with hippocampal sclerosis (HS) (OR = 5.28; 95% CI: 1.10–25.47) were more likely to be non-SGCP. High total burden of multiple comorbid neuropathologic features was associated with a lower likelihood of being SGCP. Conclusion: Oldest-old superior cognitive performers were resilient to ADNC and low levels of vascular pathologic change and were resistant to non-AD neurodegenerative changes and multiple comorbid neuropathologic features. Understanding the factors underlying the ability of superior cognitive performers to resist these changes might provide useful insights on maintenance of superior cognition despite advanced age. Show more

Keywords: Alzheimer’s disease, cognitive aging, neurodegenerative disease, oldest-old, successful aging, vascular

DOI: 10.3233/JAD-221062

Citation: Journal of Alzheimer's Disease, vol. 93, no. 2, pp. 561-575, 2023

Authors: McIntyre, Clayton C. | Gaitán, Julian M. | Edmunds, Kyle J. | Lose, Sarah R. | Bendlin, Barbara B. | Sager, Mark | Asthana, Sanjay | Johnson, Sterling C. | Okonkwo, Ozioma C.

Article Type: Research Article

Abstract: Background: Cardiorespiratory fitness (CRF) supports cognition, though it is unclear what mechanisms underly this relationship. Insulin resistance adversely affects cognition but can be reduced with habitual exercise. Objective: We investigated whether insulin resistance statistically mediates the relationship between CRF and cognition. Methods: In our observational study, we included n  = 1,131 cognitively unimpaired, nondiabetic older adults from a cohort characterized by elevated Alzheimer’s disease (AD) risk. We estimated CRF (eCRF) using a validated equation that takes age, sex, body mass index, resting heart rate, and habitual physical activity as inputs. The Homeostatic Model Assessment for Insulin Resistance …(HOMA-IR) quantified insulin resistance. Standardized cognitive factor scores for cognitive speed/flexibility, working memory, verbal learning/memory, and immediate memory were calculated from a battery of neuropsychological tests. Linear regression models and bootstrapped estimates of indirect effects were used to determine whether HOMA-IR mediated significant relationships between eCRF and cognition. Results: eCRF was positively associated with cognitive speed/flexibility (p  = 0.034). When controlling for HOMA-IR, eCRF was no longer associated with cognitive speed/flexibility (p  = 0.383). HOMA-IR had a significant indirect effect on the eCRF-cognition relationship (B  = 0.025, CI = [0.003,0.051]). eCRF was not associated with working memory (p  = 0.236), immediate memory (p  = 0.345), or verbal learning/memory (p  = 0.650). Conclusion: Among older adults at risk for AD, peripheral insulin resistance mediates the relationship between CRF and cognitive speed. Show more

Keywords: Alzheimer’s disease, cognition, cognitive decline, insulin, physical fitness

DOI: 10.3233/JAD-221249

Citation: Journal of Alzheimer's Disease, vol. 93, no. 2, pp. 577-584, 2023

Authors: Zhao, Zixiao | Wang, Jie | Wang, Ying | Liu, Xia | He, Kun | Guo, Qihao | Xie, Fang | Huang, Qi | Li, Zijing

Article Type: Research Article

Abstract: Background: Subjective cognitive decline (SCD) is a self-perceived decline in cognitive ability, which exhibits no objective impairment but increased risk of conversion to mild cognitive impairment and Alzheimer’s disease (AD). Objective: To investigate how influencing factors (risk gene, age, sex, and education) affect amyloid-β (Aβ) deposition and gray matter (GM) atrophy in SCD population. Methods: 281 SCD subjects were included in this study, who underwent clinical evaluation, cognitive ability assessment, apolipoprotein E (APOE ) genotyping, 18 F-Florbetapir positron emission computed tomography, and magnetic resonance imaging screening. Two-sample t tests and analysis of variance were performed …based on voxel-wise outcome. Results: In 281 SCD subjects with an average age of 63.86, 194 subjects (69.04%) were females, and 56 subjects carried APOE ɛ4 genes. Statistical results revealed APOE ɛ4 gene, age, and sex influenced Aβ deposition in different brain regions; moreover, only the interaction exhibited between age and APOE ɛ4 genes. The GM atrophy of hippocampal, amygdala, precentral, and occipital lobes occurred in the group age over 60. The GM volume of the hippocampal, frontal, and occipital lobe in females was less than males. Education had an effect only on cognitive function. Conclusion: In SCD, APOE ɛ4 gene, age, and sex significantly influenced Aβ deposition and APOE ɛ4 gene can interact with age in impacting Aβ deposition. Both age and sex can affect GM atrophy. The results suggested that female SCD with APOE ɛ4 genes and aged more than 60 years old might exhibit advanced AD biomarkers. Show more

Keywords: Alzheimer’s disease, amyloid-β, atrophy, deposition, gray matter, subjective cognitive decline

DOI: 10.3233/JAD-221251

Citation: Journal of Alzheimer's Disease, vol. 93, no. 2, pp. 585-594, 2023

Authors: Zhang, Li-Ya | Wang, Duo-Zi | Wang, Jian | Guo, Lei | Li, Bing-Hu | Wang, Jian-Hong

Article Type: Research Article

Abstract: Background: A potential role of the antimicrobial peptide LL-37, which is upregulated after infection, in the pathogenesis of Alzheimer’s disease (AD) was identified. However, the clinical relevance of LL-37 in AD is not clear yet. Objective: This study aims to investigate the association of circulating LL-37 with longitudinal cognitive decline and neurodegeneration among older adults with memory complaints. Methods: This cohort study recruited 357 older adults with memory complaints. Participants were followed-up for two years and the cognitive functions were assessed using the Mini-Mental State Examination (MMSE). Serum LL-37, pTau181, and tTau levels were determined at …baseline. Associations of baseline LL-37 with longitudinal cognitive decline and change of neurodegenerative biomarkers were analyzed. Results: No difference was found in the slope of longitudinal cognitive decline during follow-up between the low and high LL-37 group, adjusting for age, sex, education, body mass index, APOE ɛ4 carrier status, comorbidities, and baseline MMSE scores (difference in slope: 0.226, 95% CI: –0.169 to 0.621). Higher LL-37 levels were associated with longitudinal cognitive decline, as indicated by a decrease of MMSE scores of 3 points or above during follow-up (OR = 2.11, 95% CI: 1.32 to 3.38). The high LL-37 group had larger slopes of the increase in neurofilament light (difference in slope: 3.759, 95% CI: 2.367 to 5.152) and pTau181 (difference in slope: 0.325, 95% CI: 0.151 to 0.499) than the low LL-37 group. Conclusion: These findings support an association of the antimicrobial peptide LL-37 with AD from a clinical perspective. Show more

Keywords: Alzheimer’s disease, Amyloid-β, antimicrobial peptide LL-37, cognitive decline, infection, neurodegeneration, neurofilament light, tau

DOI: 10.3233/JAD-230007

Citation: Journal of Alzheimer's Disease, vol. 93, no. 2, pp. 595-603, 2023

Authors: Tian, Jing | Stucky, Chase Samuel | Wang, Tienju | Muma, Nancy A. | Johnson, Michael | Du, Heng

Article Type: Research Article

Abstract: Background: Deprivation of extracellular serotonin has been linked to cognitive decline and neuropsychiatric disturbances in Alzheimer’s disease (AD). However, despite degeneration of serotonin-producing neurons, whether serotonin release is affected in AD-sensitive brain regions is unknown. Objective: This study investigated the impact of mitochondrial dysfunction in decreased hippocampal serotonin release in AD amyloidosis mouse model 5xFAD mice. Methods: Electrochemical assays were applied to examine hippocampal serotonin release. We also employed multidisciplinary techniques to determine the role of oligomeric amyloid-β (Aβ) in hippocampal mitochondrial deficits and serotonin release deficiency. Results: 5xFAD mice exhibited serotonin release decrease …and relatively moderate downregulation of serotonergic fiber density as well as serotonin content in the hippocampal region. Further experiments showed an inhibitory effect of oligomeric amyloid-β (Aβ) on hippocampal serotonin release without affecting the density of serotonergic fibers. Pharmaceutical uncoupling of mitochondrial oxidative phosphorylation (OXPHOS) disrupted hippocampal serotonin release in an ex vivo setting. This echoes the mitochondrial defects in serotonergic fibers in 5xFAD mice and oligomeric Aβ-challenged primary serotonergic neuron cultures and implicates a link between mitochondrial dysfunction and serotonin transmission defects in AD-relevant pathological settings. Conclusion: The most parsimonious interpretation of our findings is that mitochondrial dysfunction is a phenotypic change of serotonergic neurons, which potentially plays a role in the development of serotonergic failure in AD-related conditions. Show more

Keywords: Alzheimer’s disease, amyloid-β, hippocampus, mitochondria, serotonin

DOI: 10.3233/JAD-230072

Citation: Journal of Alzheimer's Disease, vol. 93, no. 2, pp. 605-619, 2023

Authors: Aguilar-Barberà, Miquel | Soler-Girabau, Paquita | Tabuenca-Martín, Ana Isabel | Prieto-del Val, Laura

Article Type: Research Article

Abstract: Background: Behavioral and psychological symptoms of dementia (BPSD) manifest in the early stages of the disease and impair patients’ and caregivers’ quality of life. Objective: To assess the effectiveness of the nutritional supplement Fortasyn Connect on BPSD for 12 months in people with mild cognitive impairment (MCI) and dementia in clinical practice. Methods: Retrospective, national, single-center study of 236 patients (158 MCI and 78 dementia; 55.1% of AD etiology). BPSD were assessed with the Neuropsychiatric Inventory (NPI) at month 3, 6, and 12. Cognition (Mini-Mental State Examination, MMSE), depression (Geriatric Depression Scale, GDS), and everyday functioning …(Blessed Dementia Scale, BLS-D; Rapid Disability Rating Scale 2, RDRS2) were also evaluated. Results: Total NPI score, caregiver impact, and symptoms of depression, anxiety, apathy, and irritability improved after 3, 6, and 12 months from Fortasyn Connect initiation (p  < 0.001). NPI decreases were more pronounced when baseline NPI score was higher than > 20 points (p  < 0.001). The benefit was independent of gender, age, diagnosis, etiology, or concomitant treatment (p  < 0.0001), although larger decreases in NPI total score were observed in MCI patients (p  < 0.0001). After 12 months, GDS scores decreased (p  = 0.042), and MMSE, BLS-D, and RDRS 2 scores remained stable. Conclusion: Fortasyn Connect improved BPSD over at least a year in patients with MCI and dementia. Depression, anxiety, apathy, and irritability were the symptoms that improved the most. The benefit was independent of patients’ characteristics and treatment but was greater if prescribed early and when baseline NPI scores were higher. Show more

Keywords: Alzheimer’s disease, anxiety, apathy, dementia, depression, mild cognitive impartment, neuropsychiatric symptoms

DOI: 10.3233/JAD-221122

Citation: Journal of Alzheimer's Disease, vol. 93, no. 2, pp. 621-631, 2023

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

Authors: Xiao, Yaqiong | Liao, Liangjun | Huang, Kaiyu | Yao, Shun | Gao, Lei

Article Type: Research Article

Abstract: Background: Hippocampal atrophy is a significant brain marker of pathology in Alzheimer’s disease (AD). The hippocampal parenchymal fraction (HPF) was recently developed to better assess the hippocampal volumetric integrity, and it has been shown to be a sensitive measure of hippocampal atrophy in AD. Objective: To investigate the clinical relevance of hippocampal volumetric integrity as measured by the HPF and the coupling between the HPF and brain atrophy during AD progression. Methods: We included data from 143 cognitively normal (CN), 101 mild cognitive impairment (MCI), and 125 AD participants. We examined group differences in the HPF, …associations between HPF and cognitive ability, and coupling between the HPF and cortical grey matter volume in the CN, MCI, and AD groups. Results: We observed progressive decreases in HPF from CN to MCI and from MCI to AD, and increases in the asymmetry of HPF, with the lowest asymmetry index (AI) in the CN group and the highest AI in the AD group. There was a significant association between HPF and cognitive ability across participants. The coupling between HPF and cortical regions was observed in bilateral hippocampus, parahippocampal gyrus, temporal, frontal, and occipital regions, thalamus, and amygdala in CN, MCI, and AD groups, with a greater involvement of temporal, occipital, frontal, and subcortical regions in MCI and AD patients, especially in AD patients. Conclusion: This study provides novel evidence for the neuroanatomical basis of cognitive decline and brain atrophy during AD progression, which may have important clinical implications for the prognosis of AD. Show more

Keywords: Alzheimer’s disease, brain atrophy, cognitive decline, cortical grey matter volume, hippocampal parenchymal fraction, hippocampus

DOI: 10.3233/JAD-230124

Citation: Journal of Alzheimer's Disease, vol. 93, no. 2, pp. 791-801, 2023

Authors: Castellani, Rudolph J. | Shanes, Elisheva D. | McCord, Matthew | Reish, Nicholas J. | Flanagan, Margaret E. | Mesulam, M-Marsel | Jamshidi, Pouya

Article Type: Research Article

Abstract: Host responses to anti-amyloid-β (Aβ) antibody therapy are evident in neuroimaging changes and clinical symptoms in a subset of clinical trial subjects receiving such therapy. The pathological basis for the imaging changes and clinical symptoms is not known, nor is the precise mechanism of Aβ clearing. We report the autopsy findings in a 65-year-old woman who received three open label infusions of the experimental anti-Aβ drug lecanemab over about one month. Four days after the last infusion, she was treated with tissue plasminogen activator for acute stroke symptoms and died several days later with multifocal hemorrhage. Neuropathological examination demonstrated …histiocytic vasculitis involving blood vessels with cerebral amyloid angiopathy. Fragmentation and phagocytosis of vascular Aβ were present throughout the cerebral cortex. Phagocytosis of parenchymal Aβ plaques was noted. Changes suggestive of Aβ and phosphorylated tau “clearing” were also noted. The findings overall suggest that anti-Aβ treatment stimulated a host response to Aβ, i.e., target engagement. The findings also provide evidence that amyloid-related imaging abnormalities might be indicative of an Aβ phagocytic syndrome within cerebral vasculature and parenchymal brain tissue in some cases. Show more

Keywords: Alzheimer’s disease, amyloid-β , amyloid-related imaging abnormalities, Apolipoprotein E, cerebral amyloid angiopathy, hemorrhage, lecanemab, phosphorylated tau, vasculitis

DOI: 10.3233/JAD-221305

Citation: Journal of Alzheimer's Disease, vol. 93, no. 2, pp. 803-813, 2023

Authors: Fletcher, Evan

Article Type: Article Commentary

Abstract: Current research trends emphasize complex models of cognitive outcomes, with multiple, interacting predictors, including factors amenable to interventions toward sustaining healthy cognitive aging. Such models often require advanced analysis techniques. The article by Stark et al., ‘Partial least squares regression analysis of Alzheimer’s disease biomarkers, modifiable health variables, and cognitive change in older adults with mild cognitive impairment’, uses partial least squares regression to examine the associations to memory and executive change of 29 biomarker and demographic variables. This commentary discusses the significance of their results and methods within the context of current research foci.

Keywords: Alzheimer’s disease, biomarkers, cognitive change, partial least squares analysis

DOI: 10.3233/JAD-230304

Citation: Journal of Alzheimer's Disease, vol. 93, no. 2, pp. 815-819, 2023