Journal of Alzheimer's Disease - Volume 80, issue 1

Authors: Loeffler, David A.

Article Type: Review Article

Abstract: There is an extensive literature relating to factors associated with the development of Alzheimer’s disease (AD), but less is known about factors which may contribute to its progression. This review examined the literature with regard to 15 factors which were suggested by PubMed search to be positively associated with the cognitive and/or neuropathological progression of AD. The factors were grouped as potentially modifiable (vascular risk factors, comorbidities, malnutrition, educational level, inflammation, and oxidative stress), non-modifiable (age at clinical onset, family history of dementia, gender, Apolipoprotein E ɛ4, genetic variants, and altered gene regulation), and clinical (baseline cognitive level, neuropsychiatric symptoms, …and extrapyramidal signs). Although conflicting results were found for the majority of factors, a positive association was found in nearly all studies which investigated the relationship of six factors to AD progression: malnutrition, genetic variants, altered gene regulation, baseline cognitive level, neuropsychiatric symptoms, and extrapyramidal signs. Whether these or other factors which have been suggested to be associated with AD progression actually influence the rate of decline of AD patients is unclear. Therapeutic approaches which include addressing of modifiable factors associated with AD progression should be considered. Show more

Keywords: Alzheimer’s disease, baseline cognition, extrapyramidal signs, genetic factors, malnutrition, neuropsychiatric symptoms, progression

DOI: 10.3233/JAD-201182

Citation: Journal of Alzheimer's Disease, vol. 80, no. 1, pp. 1-27, 2021

Authors: Ferini-Strambi, Luigi | Hensley, Michael | Salsone, Maria

Article Type: Review Article

Abstract: Obstructive sleep apnea (OSA) and Alzheimer’s disease (AD) are two common chronic diseases with a well-documented association. Whether the association is causal has been highlighted by recent evidence reporting a neurobiological link between these disorders. This narrative review discusses the brain regions and networks involved in OSA as potential vulnerable areas for the development of AD neuropathology with a particular focus on gender-related implications. Using a neuroimaging perspective supported by neuropathological investigations, we provide a new model of neurodegeneration common to OSA and AD, that we have called OSA-AD neurodegeneration in order to decode the causal links between these two …chronic conditions. Show more

Keywords: Alzheimer’s disease, amygdala, cingulate gyrus, hippocampus, insula, magnetic resonance imaging, obstructive sleep apnea

DOI: 10.3233/JAD-201066

Citation: Journal of Alzheimer's Disease, vol. 80, no. 1, pp. 29-40, 2021

Authors: Dennison, Jessica L. | Ricciardi, Natalie R. | Lohse, Ines | Volmar, Claude-Henry | Wahlestedt, Claes

Article Type: Review Article

Abstract: Female sex is a leading risk factor for developing Alzheimer’s disease (AD). Sexual dimorphism in AD is gaining attention as clinical data show that women are not only more likely to develop AD but also to experience worse pathology and faster cognitive decline. Pre-clinical AD research in animal models often neglects to address sexual dimorphism in evaluation of behavioral or molecular characteristics and outcomes. This can compromise its translation to a clinical setting. The triple-transgenic AD mouse model (3xTg-AD) is a commonly used but unique AD model because it exhibits both amyloid and tau pathology, essential features of the human …AD phenotype. Mounting evidence has revealed important sexually dimorphic characteristics of this animal model that have yet to be reviewed and thus, are often overlooked in studies using the 3xTg-AD model. In this review we conduct a thorough analysis of reports of sexual dimorphism in the 3xTg-AD model including findings of molecular, behavioral, and longevity-related sex differences in original research articles through August 2020. Importantly, we find results to be inconsistent, and that strain source and differing methodologies are major contributors to lack of consensus regarding traits of each sex. We first touch on the nature of sexual dimorphism in clinical AD, followed by a brief summary of sexual dimorphism in other major AD murine models before discussing the 3xTg-AD model in depth. We conclude by offering four suggestions to help unify pre-clinical mouse model AD research inspired by the NIH expectations for considering sex as a biological variable. Show more

Keywords: Alzheimer’s disease, mouse models, sex as a biological variable (SABV), sexual dimorphism, triple transgenic, 3xTg-AD

DOI: 10.3233/JAD-201014

Citation: Journal of Alzheimer's Disease, vol. 80, no. 1, pp. 41-52, 2021

Authors: Chen, Yu-si | Shu, Kai | Kang, Hui-cong

Article Type: Review Article

Abstract: Alzheimer’s disease (AD) is becoming a prevalent disease in the elderly population. Past decades have witnessed the development of drug therapies with varying targets. However, all drugs with a single molecular target fail to reverse or ameliorate AD progression, which ultimately results in cortical and subcortical network dysregulation. Deep brain stimulation (DBS) has been proven effective for the treatment of Parkinson’s disease, essential tremor, and other neurological diseases. As such, DBS has also been gradually acknowledged as a potential therapy for AD. The current review focuses on DBS of the nucleus basalis of Meynert (NBM). As a critical component of …the cerebral cholinergic system and the Papez circuit in the basal ganglia, the NBM plays an indispensable role in the subcortical regulation of memory, attention, and arousal state, which makes the NBM a promising target for modulation of neural network dysfunction and AD treatment. We summarized the intricate projection relations and functionality of the NBM, current approaches for stereotactic localization and evaluation of the NBM, and the therapeutic effects of NBM-DBS both in patients and animal models. Furthermore, the current shortcomings of NBM-DBS, such as variations in cortical blood flow, increased temperature in the target area, and stimulation-related neural damage, were presented. Show more

Keywords: Alzheimer’s disease, deep brain stimulation, functional neurosurgery, neuromodulation, nucleus basalis of Meynert, technical consideration

DOI: 10.3233/JAD-201141

Citation: Journal of Alzheimer's Disease, vol. 80, no. 1, pp. 53-70, 2021

Authors: Chen, Fan | Zhang, Yan | Wang, Longcai | Wang, Tao | Han, Zhifa | Zhang, Haihua | Gao, Shan | Hu, Yang | Liu, Guiyou

Article Type: Short Communication

Abstract: We aimed to evaluate the association of PLCG2 rs72824905 variant with Alzheimer’s disease (AD) and multiple sclerosis (MS) using large-scale genetic association study datasets. We selected 50,024 AD cases and 467,330 controls, and 32,367 MS cases and 36,012 controls. We found moderate heterogeneity of rs72824905 in different studies. We found significant association between rs72824905 G allele and reduced AD risk (OR = 0.66, 95% CI 0.59–0.74, p  = 5.91E-14). Importantly, rs72824905 G allele could also significantly reduce the risk of MS with OR = 0.94, p  = 3.63E-05. Hence, the effects of rs72824905 on AD and MS are consistent.

Keywords: Alzheimer’s disease, genome-wide association study, multiple sclerosis, PLCG2, rs72824905 variant

DOI: 10.3233/JAD-201140

Citation: Journal of Alzheimer's Disease, vol. 80, no. 1, pp. 71-77, 2021

Authors: Zhou, Jing | Walker, Rod L. | Gray, Shelly L. | Marcum, Zachary A. | Barthold, Douglas | Bowen, James D. | McCormick, Wayne | McCurry, Susan M. | Larson, Eric B. | Crane, Paul K.

Article Type: Research Article

Abstract: Background: Higher glucose levels are associated with dementia risk in people with and without diabetes. However, little is known about how this association might vary by hypertension status and antihypertensive treatment. Most studies on modifiable dementia risk factors consider each factor in isolation. Objective: To test the hypothesis that hypertension and antihypertensive treatments may modify associations between glucose levels and dementia. Methods: Analyses of data generated from a research study and clinical care of participants from a prospective cohort of dementia-free older adults, including glucose measures, diabetes and antihypertensive treatments, and blood pressure data. We defined …groups based on blood pressure (hypertensive versus not, ≥140/90 mmHg versus <140/90 mmHg) and antihypertensive treatment intensity (0, 1, or ≥2 classes of antihypertensives). We used Bayesian joint models to jointly model longitudinal exposure and time to event data. Results: A total of 3,056 participants without diabetes treatment and 480 with diabetes treatment were included (mean age at baseline, 75.1 years; mean 7.5 years of follow-up). Higher glucose levels were associated with greater dementia risk among people without and with treated diabetes. Hazard ratios for dementia were similar across all blood pressure/antihypertensive treatment groups (omnibus p  = 0.82 for people without and p  = 0.59 for people with treated diabetes). Conclusion: Hypertension and antihypertensive treatments do not appear to affect the association between glucose and dementia risk in this population-based longitudinal cohort study of community-dwelling older adults. Future studies are needed to examine this question in midlife and by specific antihypertensive treatments. Show more

Keywords: Antihypertensive agents, blood pressure, dementia, diabetes mellitus, glucose, hypertension

DOI: 10.3233/JAD-201138

Citation: Journal of Alzheimer's Disease, vol. 80, no. 1, pp. 79-90, 2021

Authors: Dao, Elizabeth | Tam, Roger | Hsiung, Ging-Yuek R. | ten Brinke, Lisanne | Crockett, Rachel | Barha, Cindy K. | Yoo, Youngjin | Al Keridy, Walid | Doherty, Stephanie H. | Laule, Cornelia | MacKay, Alex L. | Liu-Ambrose, Teresa

Article Type: Research Article

Abstract: Background: Myelin damage is a salient feature in cerebral small vessel disease (cSVD). Of note, myelin damage extends into the normal appearing white matter (NAWM). Currently, the specific role of myelin content in cognition is poorly understood. Objective: The objective of this exploratory study was to investigate the association between NAWM myelin and cognitive function in older adults with cSVD. Methods: This exploratory study included 55 participants with cSVD. NAWM myelin was measured using myelin water imaging and was quantified as myelin water fraction (MWF). Assessment of cognitive function included processing speed (Trail Making Test Part …A), set shifting (Trail Making Test Part B minus A), working memory (Verbal Digit Span Backwards Test), and inhibition (Stroop Test). Multiple linear regression analyses assessed the contribution of NAWM MWF on cognitive outcomes controlling for age, education, and total white matter hyperintensity volume. The overall alpha was set at ≤0.05. Results: After accounting for age, education, and total white matter hyperintensity volume, lower NAWM MWF was significantly associated with slower processing speed (β  = –0.29, p  = 0.037) and poorer working memory (β= 0.30, p  = 0.048). NAWM MWF was not significantly associated with set shifting or inhibitory control (p  > 0.132). Conclusion: Myelin loss in NAWM may play a role in the evolution of impaired processing speed and working memory in people with cSVD. Future studies, with a longitudinal design and larger sample sizes, are needed to fully elucidate the role of myelin as a potential biomarker for cognitive function. Show more

Keywords: Cerebral small vessel disease, myelin, myelin water imaging, executive functions, vascular cognitive impairment, white matter hyperintensities

DOI: 10.3233/JAD-201134

Citation: Journal of Alzheimer's Disease, vol. 80, no. 1, pp. 91-101, 2021

Authors: Smith, Eric. E. | Ismail, Zahinoor

Article Type: Research Article

Abstract: Background: Persons with dementia have higher mortality than the general population. Objective, standardized predictions of mortality risk in persons with dementia could help with planning resources for care close to the end of life. Objective: To systematically review prediction models for risk of death in persons with dementia. Methods: The Medline and PsycInfo databases were searched on November 29, 2020, for prediction models estimating the risk of death in persons with dementia. Study quality was assessed using the Prediction model Risk Of Bias ASsessment Tool. Results: The literature search identified 2,828 studies, of which …18 were included. These studies described 16 different prediction models with c statistics mostly ranging from 0.67 to 0.79. Five models were externally validated, of which four were applicable. There were two models that were both applicable and had reasonably low risk of bias. One model predicted risk of death at six months in persons with advanced dementia residing in a nursing home. The other predicted risk of death at three years in persons seen in primary care practice or a dementia specialty clinic, derived from a nationwide registry in Sweden but not externally validated. Conclusion: Valid, applicable models with low risk of bias were found in two settings: advanced dementia in a nursing home and outpatient practices. The outpatient model requires external validation. Better models are needed for persons with mild to moderate dementia in nursing homes, a common demographic. These models may be useful for educating persons living with dementia and care partners and directing resources for end of life care. Registration: The study protocol is registered on PROSPERO as RD4202018076. Show more

Keywords: Dementia, mortality, prediction

DOI: 10.3233/JAD-201364

Citation: Journal of Alzheimer's Disease, vol. 80, no. 1, pp. 103-111, 2021

Authors: Jorge, Lília | Martins, Ricardo | Canário, Nádia | Xavier, Carolina | Abrunhosa, Antero | Santana, Isabel | Castelo-Branco, Miguel

Article Type: Research Article

Abstract: Background: It has been proposed that amyloid-β (Aβ) plays a causal role in Alzheimer’s disease (AD) by triggering a series of pathologic events—possibly including neuroinflammation—which culminate in progressive brain atrophy. However, the interplay between the two pathological molecular events and how both are associated with neurodegeneration is still unclear. Objective: We aimed to estimate the spatial inter-relationship between neurodegeneration, neuroinflammation and Aβ deposition in a cohort of 20 mild AD patients and 17 healthy controls (HC). Methods: We resorted to magnetic resonance imaging to measure cortical atrophy, using the radiotracer 11 C-PK11195 PET to measure neuroinflammation …levels and 11 C-PiB PET to assess Aβ levels. Between-group comparisons were computed to explore AD-related changes in the three types of markers. To examine the effects of each one of the molecular pathologic mechanisms on neurodegeneration we computed: 1) ANCOVAs with the anatomic data, controlling for radiotracer uptake differences between groups and 2) voxel-based multiple regression analysis between-modalities. In addition, associations in anatomically defined regions of interests were also investigated. Results: We found significant differences between AD and controls in the levels of atrophy, neuroinflammation, and Aβ deposition. Associations between Aβ aggregation and brain atrophy were detected in AD in a widely distributed pattern, whereas associations between microglia activation and structural measures of neurodegeneration were restricted to few anatomically regions. Conclusion: In summary, Aβ deposition, as opposed to neuroinflammation, was more associated with cortical atrophy, suggesting a prominent role of Aβ in neurodegeneration at a mild stage of the AD. Show more

Keywords: Alzheimer’s disease, amyloid-β, magnetic resonance imaging, neuroinflammation, neurodegeneration, positron emission tomography

DOI: 10.3233/JAD-200840

Citation: Journal of Alzheimer's Disease, vol. 80, no. 1, pp. 113-132, 2021

Authors: Plotzker, Alan S. | Henson, Rachel L. | Fagan, Anne M. | Morris, John C. | Day, Gregory S.

Article Type: Research Article

Abstract: Background: Cerebral amyloid angiopathy with related inflammation (CAA-ri) is a rare age-associated disorder characterized by an inflammatory response to amyloid in cerebral blood vessels. CAA-ri is often treated with corticosteroids, but response to treatment is variable. Objective: To assess the relationship between clinical and paraclinical measures and outcomes in patients with CAA-ri treated with high doses of methylprednisolone. Methods: Longitudinal clinical course, and results from serum and cerebrospinal fluid (CSF) testing, electroencephalography, and neuroimaging were reviewed from 11 prospectively-accrued CAA-ri patients diagnosed, treated, and followed at Barnes Jewish Hospital (St. Louis, MO, USA). Magnetic resonance imaging …(MRI) changes were quantified using a scoring system validated in cases of amyloid related imaging abnormality (ARIA-E). Clinical outcomes were assessed as change in modified Rankin Scale (ΔmRS) from baseline to final assessment (median 175 days from treatment with high doses of methylprednisolone; range, 31–513). Results: Worse outcomes following methylprednisolone treatment were associated with requirement for intensive care unit admission (median ΔmRS, 5 versus 1.5; p  = 0.048), CSF pleocytosis (median ΔmRS 4.5 versus 1; p  = 0.04), or lower CSF Aβ40 at presentation (rho = –0.83; p  = 0.02), and diffusion restriction (median ΔmRS 4 versus 1.5; p  = 0.03) or higher late ARIA-E scores (rho = 0.70; p  = 0.02) on MRI, but not preexisting cognitive decline (median ΔmRS 2 versus 2; p  = 0.66). Conclusion: Clinical and paraclinical measures associated with outcomes may inform clinical counseling and treatment decisions in patients with CAA-ri. Baseline cognitive status was not associated with treatment responsiveness. Show more

Keywords: Alzheimer’s disease, amyloid-beta related angiitis, biomarkers, cerebral amyloid angiopathy, inflammation, treatment outcome

DOI: 10.3233/JAD-201299

Citation: Journal of Alzheimer's Disease, vol. 80, no. 1, pp. 133-142, 2021