Journal of Alzheimer's Disease - Volume 92, issue 3

Authors: Yin, Wenwen | Wan, Ke | Zhu, Wenhao | Zhou, Xia | Tang, Yating | Zheng, Wenhui | Cao, Jing | Song, Yu | Zhao, Han | Zhu, Xiaoqun | Sun, Zhongwu

Article Type: Research Article

Abstract: Background: β-site amyloid precursor protein cleaving enzyme 1 (BACE1) is a key enzyme in the formation of amyloid-β (Aβ) protein. Increasing evidence suggests that BACE1 concentration is a potential biomarker for Alzheimer’s disease (AD). Objective: To evaluate the correlations between plasma BACE1 concentration, cognition, and hippocampal volume at different stages of the AD continuum. Methods: Plasma BACE1 concentrations were measured in 32 patients with probable dementia due to AD (ADD), 48 patients with mild cognitive impairment (MCI) due to AD, and 40 cognitively unimpaired (CU) individuals. Memory function was evaluated using the auditory verbal learning test …(AVLT), and voxel-based morphometry was used to analyze bilateral hippocampal volumes. Correlation and mediation analyses were performed to investigate the associations between plasma BACE1 concentration, cognition, and hippocampal atrophy. Results: The MCI and ADD groups exhibited elevated BACE1 concentrations compared with the CU group after adjusting for age, sex, and apolipoprotein E (APOE ) genotype. Increased BACE1 concentration was found in AD continuum patients who were APOE ɛ4 carriers (p  < 0.05). BACE1 concentration was negatively associated with the scores of the subitems of the AVLT and hippocampal volume (p  < 0.05, false discovery rate correction) in the MCI group. Moreover, bilateral hippocampal volume mediated the relationship between BACE1 concentration and recognition in the MCI group. Conclusion: BACE1 expression increased in the AD continuum, and bilateral hippocampal volume mediated the effect of BACE1 concentration on memory function in patients with MCI. Research has indicated that the plasma BACE1 concentration might be a biomarker at the early stage of AD. Show more

Keywords: Alzheimer’s disease, β-secretase, BACE1, hippocampus, mild cognitive impairment

DOI: 10.3233/JAD-221174

Citation: Journal of Alzheimer's Disease, vol. 92, no. 3, pp. 1001-1013, 2023

Authors: Selwood, Amanda E. | Catts, Vibeke S. | Numbers, Katya | Lee, Teresa | Thalamuthu, Anbupalam | Wright, Margaret J. | Sachdev, Perminder S.

Article Type: Research Article

Abstract: Background: Subjective cognitive complaints (SCCs) may be a precursor to mild cognitive impairment (MCI) and dementia. Objective: This study aimed to examine the heritability of SCCs, correlations between SCCs and memory ability, and the influence of personality and mood on these relationships. Methods: Participants were 306 twin pairs. The heritability of SCCs and the genetic correlations between SCCs and memory performance, personality, and mood scores were determined using structural equation modelling. Results: SCCs were low to moderately heritable. Memory performance, personality and mood were genetically, environmentally, and phenotypically correlated with SCCs in bivariate analysis. …However, in multivariate analysis, only mood and memory performance had significant correlations with SCCs. Mood appeared to be related to SCCs by an environmental correlation, whereas memory performance was related to SCCs by a genetic correlation. The link between personality and SCCs was mediated by mood. SCCs had a significant amount of both genetic and environmental variances not explained by memory performance, personality, or mood. Conclusion: Our results suggest that SCCs are influenced both by a person’s mood and their memory performance, and that these determinants are not mutually exclusive. While SCCs had genetic overlap with memory performance and environmental association with mood, much of the genetic and environmental components that comprised SCCs were specific to SCCs, though these specific factors are yet to be determined. Show more

Keywords: Affect, Alzheimer’s disease, cognitive aging, depression, human genetics, memory disorders, neuroticism, personality, twin study

DOI: 10.3233/JAD-221008

Citation: Journal of Alzheimer's Disease, vol. 92, no. 3, pp. 1015-1026, 2023

Authors: Johnson, Chelsea N. | McCoin, Colin S. | Kueck, Paul J. | Hawley, Amelia G. | John, Casey S. | Thyfault, John P. | Swerdlow, Russell H. | Geiger, Paige C. | Morris, Jill K.

Article Type: Research Article

Abstract: Background: Individuals with mild cognitive impairment (MCI) have reduced lipid-stimulated mitochondrial respiration in skeletal muscle. A major risk factor for Alzheimer’s disease (AD), the apolipoprotein E4 (APOE4 ) allele, is implicated in lipid metabolism and is associated with metabolic and oxidative stress that can result from dysfunctional mitochondria. Heat shock protein 72 (Hsp72) is protective against these stressors and is elevated in the AD brain. Objective: Our goal was to characterize skeletal muscle ApoE and Hsp72 protein expression in APOE4 carriers in relationship to cognitive status, muscle mitochondrial respiration and AD biomarkers. Methods: We analyzed …previously collected skeletal muscle tissue from 24 APOE4 carriers (60y+) who were cognitively healthy (CH, n  = 9) or MCI (n  = 15). We measured ApoE and Hsp72 protein levels in muscle and phosphorylated tau181 (pTau181) levels in plasma, and leveraged previously collected data on APOE genotype, mitochondrial respiration during lipid oxidation, and VO2 max. Results: Muscle ApoE (p  = 0.013) and plasma pTau181 levels (p  < 0.001) were higher in MCI APOE4 carriers. Muscle ApoE positively correlated with plasma pTau181 in all APOE4 carriers (R2  = 0.338, p  = 0.003). Hsp72 expression negatively correlated with ADP (R2  = 0.775, p  = <0.001) and succinate-stimulated respiration (R2  = 0.405, p  = 0.003) in skeletal muscle of MCI APOE4 carriers. Plasma pTau181 negatively tracked with VO2 max in all APOE4 carriers (R2  = 0.389, p  = 0.003). Analyses were controlled for age. Conclusion: This work supports a relationship between cellular stress in skeletal muscle and cognitive status in APOE4 carriers. Show more

Keywords: Alzheimer’s disease, APOE4 , Hsp72, mitochondria, skeletal muscle, stress

DOI: 10.3233/JAD-221192

Citation: Journal of Alzheimer's Disease, vol. 92, no. 3, pp. 1027-1035, 2023

Authors: Walker, Jamie M. | Gonzales, Mitzi M. | Goette, William | Farrell, Kurt | White III, Charles L. | Crary, John F. | Richardson, Timothy E.

Article Type: Research Article

Abstract: Background: Alzheimer’s disease neuropathologic change (ADNC) is defined by the progression of both hyperphosphorylated-tau (p-tau) and amyloid-β (Aβ) and is the most common underlying cause of dementia worldwide. Primary age-related tauopathy (PART), an Aβ-negative tauopathy largely confined to the medial temporal lobe, is increasingly being recognized as an entity separate from ADNC with diverging clinical, genetic, neuroanatomic, and radiologic profiles. Objective: The specific clinical correlates of PART are largely unknown; we aimed to identify cognitive and neuropsychological differences between PART, ADNC, and subjects with no tauopathy (NT). Methods: We compared 2,884 subjects with autopsy-confirmed intermediate-high stage …ADNC to 208 subjects with definite PART (Braak stage I–IV, Thal phase 0, CERAD NP score “absent”) and 178 NT subjects from the National Alzheimer’s Coordinating Center dataset. Results: PART subjects were older than either ADNC or NT patients. The ADNC cohort had more frequent neuropathological comorbidities as well as APOE ɛ4 alleles than the PART or NT cohort, and less frequent APOE ɛ2 alleles than either group. Clinically, ADNC patients performed significantly worse than NT or PART subjects across cognitive measures, but PART subjects had selective deficits in measures of processing speed, executive function, and visuospatial function, although additional cognitive measures were further impaired in the presence of neuropathologic comorbidities. In isolated cases of PART with Braak stage III-IV, there are additional deficits in measures of language. Conclusion: Overall, these findings demonstrate underlying cognitive features specifically associated with PART, and reinforce the concept that PART is a distinct entity from ADNC. Show more

Keywords: Alzheimer’s disease, cerebrovascular disease, Clinical Dementia Rating, Lewy body dementia, limbic-predominant age-related TDP-43 encephalopathy neuropathologic change (LATE-NC), Mini-Mental State Examination, primary age-related tauopathy

DOI: 10.3233/JAD-230022

Citation: Journal of Alzheimer's Disease, vol. 92, no. 3, pp. 1037-1049, 2023

Authors: Rao, Stephen M. | Galioto, Rachel | Sokolowski, Megan | Pierce, Madelyn | Penn, Lisa | Sturtevant, Anna | Skugor, Blazenka | Anstead, Brent | Leverenz, James B. | Schindler, David | Blum, David | Alberts, Jay L. | Posk, Lori

Article Type: Research Article

Abstract: Background: The self-administered iPad-based Cleveland Clinic Cognitive Battery (C3B) was designed specifically for the efficient screening of cognitive functioning of older adults in a primary care setting. Objective: 1) Generate regression-based norms from healthy participants to enable demographic corrections to facilitate clinical interpretation; 2) estimate test-retest reliability and practice effects; 3) examine ability to discriminate mild cognitive impairment (MCI) from healthy aging; 4) d etermine validity of screening in a distracting clinical environment; and 5) determine completion rates and patient satisfaction in a primary care setting. Methods: Study 1 (S1 ) recruited a stratified sample …of 428 healthy adults, ages 18–89, to generate regression-based equations. S2 assessed 2-week test-retest reliability and practice effects in 30 healthy elders. S3 recruited 30 MCI patients and 30 demographically-matched healthy controls. In S4, 30 healthy elders self-administered the C3B in a distracting environment and in a quiet private room in counterbalanced order. In a demonstration project, 470 consecutive primary care patients were administered the C3B as part of routine clinical care (S5 ). Results: C3B performance was primarily influenced by age, education, and race (S1 ), had acceptably high test-retest reliability and minimal practice effects (S2 ), discriminated MCI from healthy controls (S3 ), was not negatively impacted by a distracting clinical environment (S4 ), had high completion rates (>92%) and positive ratings from primary care patients (S5 ). Conclusion: The C3B is a computerized cognitive screening tool that is reliable, validated, self-administered, and is conducive to integration into a busy primary care clinical workflow for detecting MCI, early Alzheimer’s disease, and other related dementias. Show more

Keywords: Cognitive Assessment Screening Instrument, mild cognitive impairment, Mini-Cog, neuropsychological testing, primary health care, regression analysis, test-retest reliability

DOI: 10.3233/JAD-220929

Citation: Journal of Alzheimer's Disease, vol. 92, no. 3, pp. 1051-1066, 2023

Authors: Perales-Puchalt, Jaime | Strube, Kelsey | Townley, Ryan | Niedens, Michelle | Arreaza, Hector | Zaudke, Jana | Burns, Jeffrey M.

Article Type: Research Article

Abstract: Background: Dementia has no cure, but interventions can stabilize the progression of cognitive, functional, and behavioral symptoms. Primary care providers (PCPs) are vital for the early detection, and long-term management of these diseases, given their gatekeeping role in the healthcare system. However, PCPs rarely implement evidence-based dementia care due to time limitations and knowledge about diagnosis and treatment. Training PCPs may help address these barriers. Objective: We explored the preferences of PCPs for dementia care training programs. Methods: We conducted qualitative interviews with 23 PCPs recruited nationally via snowball sampling. We conducted remote interviews and organized …the transcripts for qualitative review to identify codes and themes, using thematic analysis methods. Results: PCP preferences varied regarding many aspects of ADRD training. Preferences varied regarding how to best increase PCP participation in training, and what content and materials were needed to help them and the families they serve. We also found differences regarding the duration and timing of training, and the modality of training sessions (remote versus in-person). Conclusion: The recommendations arising from these interviews have the potential to inform the development and refinement of dementia training programs to optimize their implementation and success. Show more

Keywords: Attitude of health personnel, dementia, education, healthcare professionals

DOI: 10.3233/JAD-221014

Citation: Journal of Alzheimer's Disease, vol. 92, no. 3, pp. 1067-1075, 2023

Authors: DeMarshall, Cassandra A. | Viviano, Jeffrey | Emrani, Sheina | Thayasivam, Umashanger | Godsey, George A. | Sarkar, Abhirup | Belinka, Benjamin | Libon, David J. | Nagele, Robert G.

Article Type: Research Article

Abstract: Background: Evidence for the universal presence of IgG autoantibodies in blood and their potential utility for the diagnosis of Alzheimer’s disease (AD) and other neurodegenerative diseases has been extensively demonstrated by our laboratory. The fact that AD-related neuropathological changes in the brain can begin more than a decade before tell-tale symptoms emerge has made it difficult to develop diagnostic tests useful for detecting the earliest stages of AD pathogenesis. Objective: To determine the utility of a panel of autoantibodies for detecting the presence of AD-related pathology along the early AD continuum, including at pre-symptomatic [an average of 4 …years before the transition to mild cognitive impairment (MCI)/AD)], prodromal AD (MCI), and mild-moderate AD stages. Methods: A total of 328 serum samples from multiple cohorts, including ADNI subjects with confirmed pre-symptomatic, prodromal, and mild-moderate AD, were screened using Luminex xMAP® technology to predict the probability of the presence of AD-related pathology. A panel of eight autoantibodies with age as a covariate was evaluated using randomForest and receiver operating characteristic (ROC) curves. Results: Autoantibody biomarkers alone predicted the probability of the presence of AD-related pathology with 81.0% accuracy and an area under the curve (AUC) of 0.84 (95% CI = 0.78–0.91). Inclusion of age as a parameter to the model improved the AUC (0.96; 95% CI = 0.93–0.99) and overall accuracy (93.0%). Conclusion: Blood-based autoantibodies can be used as an accurate, non-invasive, inexpensive, and widely accessible diagnostic screener for detecting AD-related pathology at pre-symptomatic and prodromal AD stages that could aid clinicians in diagnosing AD. Show more

Keywords: Alzheimer’s disease, antibody, autoantibodies, biomarkers, blood-based biomarkers, diagnostics, early diagnosis, mild cognitive impairment

DOI: 10.3233/JAD-221091

Citation: Journal of Alzheimer's Disease, vol. 92, no. 3, pp. 1077-1091, 2023

Authors: Tarawneh, Hadeel Y. | Jayakody, Dona M.P. | Verma, Shipra | Doré, Vincent | Xia, Ying | Mulders, Wilhelmina H.A.M. | Martins, Ralph N. | Sohrabi, Hamid R.

Article Type: Research Article

Abstract: Background: Auditory event-related potentials (AERPs) have been suggested as possible biomarkers for the early diagnosis of Alzheimer’s disease (AD). However, no study has investigated AERP measures in individuals with subjective memory complaints (SMCs), who have been suggested to be at a pre-clinical stage of AD. Objective: This study investigated whether AERPs in older adults with SMC can be used to objectively identify those at high risk of developing AD. Methods: AERPs were measured in older adults. Presence of SMC was determined using the Memory Assessment Clinics Questionnaire (MAC-Q). Hearing thresholds using pure-tone audiometry, neuropsychological data, levels …of amyloid-β burden and Apolipoprotein E (APOE) ɛ genotype were also obtained A classic two-tone discrimination (oddball) paradigm was used to elicit AERPs (i.e., P50, N100, P200, N200, and P300). Results: Sixty-two individuals (14 male, mean age 71.9±5.2 years) participated in this study, of which, 43 (11 male, mean age 72.4±5.5 years) were SMC and 19 (3 male, mean age 70.8±4.3 years) were non-SMC (controls). P50 latency was weakly but significantly correlated with MAC-Q scores. In addition, P50 latencies were significantly longer in Aβ+ individuals compared to Aβ– individuals. Conclusion: Results suggest that P50 latencies may be a useful tool to identify individuals at higher risk (i.e., participants with high Aβ burden) of developing measurable cognitive decline. Further longitudinal and cross-sectional studies in a larger cohort on SMC individuals are warranted to determine if AERP measures could be of significance for the detection of pre-clinical AD. Show more

Keywords: Alzheimer’s disease, amyloid-β, APOE ɛ4, auditory event-related potentials, cognitive decline, pure-tone audiometry

DOI: 10.3233/JAD-221119

Citation: Journal of Alzheimer's Disease, vol. 92, no. 3, pp. 1093-1109, 2023