Journal of Alzheimer's Disease - Volume 74, issue 3

Authors: Stozicka, Zuzana | Korenova, Miroslava | Uhrinova, Ivana | Cubinkova, Veronika | Cente, Martin | Kovacech, Branislav | Babindakova, Nikoleta | Matyasova, Katarina | Vargova, Greta | Novak, Michal | Novak, Petr | Zilka, Norbert | Jadhav, Santosh

Article Type: Research Article

Abstract: Alzheimer’s disease (AD) is the most frequent neurodegenerative disorder, affecting over 44 million people worldwide. There are no effective pharmaco-therapeutic options for prevention and treatment of AD. Non-pharmacological approaches may help patients suffering from AD to significantly ameliorate disease progression. In this study, we exposed a transgenic rat model (tg) of human tauopathy to enriched environment for 3 months. Behavioral testing at 6 months of age revealed improvement in functional deficits of tg rats reared under enriched conditions, while sedentary tg rats remained severely impaired. Interestingly, enriched environment did not reduce tau pathology. Analysis of neurotrophic factors revealed an increase …of nerve growth factor (NGF) levels in the hippocampus of both enriched groups (tg and non-tg rats), reflecting a known effect of enriched environment on the hippocampal formation. On the contrary, NGF levels decreased markedly in the brainstem of enriched groups. The non-pharmacological treatment also reduced levels of tissue inhibitor of metalloproteinase 1 in the brainstem of transgenic rats. Expression analysis of inflammatory pathways revealed upregulation of microglial markers, such as MHC class II and Cd74, whereas levels of pro-inflammatory cytokines remained unaffected by enriched environment. Our results demonstrate that exposure to enriched environment can rescue functional impairment in tau transgenic rats without reducing tau pathology. We speculate that non-pharmacological treatment modulates the immune response to pathological tau protein inclusions, and thus reduces the damage caused by neuroinflammation. Show more

Keywords: Enriched environment, nerve growth factor, neuroinflammation, non-pharmacological intervention, tauopathy

DOI: 10.3233/JAD-191112

Citation: Journal of Alzheimer's Disease, vol. 74, no. 3, pp. 951-964, 2020

Authors: Kresge, Hailey A. | Liu, Dandan | Gupta, Deepak K. | Moore, Elizabeth E. | Osborn, Katie E. | Acosta, Lealani Mae Y. | Bell, Susan P. | Pechman, Kimberly R. | Gifford, Katherine A. | Mendes, Lisa A. | Wang, Thomas J. | Blennow, Kaj | Zetterberg, Henrik | Hohman, Timothy J. | Jefferson, Angela L.

Article Type: Research Article

Abstract: Background: Subclinical cardiac dysfunction is associated with decreased cerebral blood flow, placing the aging brain at risk for Alzheimer’s disease (AD) pathology and neurodegeneration. Objective: This study investigates the association between subclinical cardiac dysfunction, measured by left ventricular ejection fraction (LVEF), and cerebrospinal fluid (CSF) biomarkers of AD and neurodegeneration. Methods: Vanderbilt Memory & Aging Project participants free of dementia, stroke, and heart failure (n  = 152, 72±6 years, 68% male) underwent echocardiogram to quantify LVEF and lumbar puncture to measure CSF levels of amyloid-β42 (Aβ42 ), phosphorylated tau (p-tau), and total tau (t-tau). Linear regressions …related LVEF to CSF biomarkers, adjusting for age, sex, race/ethnicity, education, Framingham Stroke Risk Profile, cognitive diagnosis, and apolipoprotein E ɛ 4 status. Secondary models tested an LVEF x cognitive diagnosis interaction and then stratified by diagnosis (normal cognition (NC), mild cognitive impairment (MCI)). Results: Higher LVEF related to decreased CSF Aβ42 levels (β= –6.50, p  = 0.04) reflecting greater cerebral amyloid accumulation, but this counterintuitive result was attenuated after excluding participants with cardiovascular disease and atrial fibrillation (p  = 0.07). We observed an interaction between LVEF and cognitive diagnosis on CSF t-tau (p  = 0.004) and p-tau levels (p  = 0.002), whereas lower LVEF was associated with increased CSF t-tau (β= –9.74, p  = 0.01) and p-tau in the NC (β= –1.41, p  = 0.003) but not MCI participants (p -values>0.13). Conclusions: Among cognitively normal older adults, subclinically lower LVEF relates to greater molecular evidence of tau phosphorylation and neurodegeneration. Modest age-related changes in cardiovascular function may have implications for pathophysiological changes in the brain later in life. Show more

Keywords: Aging, Alzheimer’s disease, atrophy, cerebrospinal fluid proteins, echocardiography, tau proteins

DOI: 10.3233/JAD-190813

Citation: Journal of Alzheimer's Disease, vol. 74, no. 3, pp. 965-974, 2020

Authors: Tomaszewski, Natalie | He, Xulei | Solomon, Victoria | Lee, Mitchell | Mack, Wendy J. | Quinn, Joseph F. | Braskie, Meredith N. | Yassine, Hussein N.

Article Type: Research Article

Abstract: Background: Docosahexaenoic acid (DHA), eicosapentaenoic acid (EPA), and arachidonic acid (AA) play key roles in several metabolic processes relevant to Alzheimer’s disease (AD) pathogenesis and neuroinflammation. Carrying the APOE ɛ 4 allele (APOE4 ) accelerates omega-3 polyunsaturated fatty acid (PUFA) oxidation. In a pre-planned subgroup analysis of the Alzheimer’s Disease Cooperative Study-sponsored DHA clinical trial, APOE4 carriers with mild probable AD had no improvements in cognitive outcomes compared to placebo, while APOE 4 non-carriers showed a benefit from DHA supplementation. Objective: We sought to clarify the effect of APOE ɛ 4/ɛ 4 on both …the ratio of plasma DHA and EPA to AA, and on hippocampal volumes after DHA supplementation. Methods: Plasma fatty acids and APOE genotype were obtained in 275 participants randomized to 18 months of DHA supplementation or placebo. A subset of these participants completed brain MRI imaging (n  = 86) and lumbar punctures (n  = 53). Results: After the intervention, DHA-treated APOE ɛ 3/ɛ 3 and APOE ɛ 2/ɛ 3 carriers demonstrated significantly greater increase in plasma DHA/AA compared to ɛ 4/ɛ 4 carriers. APOE ɛ 2/ɛ 3 had a greater increase in plasma EPA/AA and less decline in left and right hippocampal volumes compared to compared to ɛ 4/ɛ 4 carriers. The change in plasma and cerebrospinal fluid DHA/AA was strongly correlated. Greater baseline and increase in plasma EPA/AA was associated with a lower decrease in the right hippocampal volume, but only in APOE 4 non-carriers. Conclusion: The lower increase in plasma DHA/AA and EPA/AA in APOE ɛ 4/ɛ 4 carriers after DHA supplementation reduces brain delivery and affects the efficacy of DHA supplementation. Show more

Keywords: Arachidonic acid, Alzheimer’s disease, apolipoprotein E, docosahexaenoic acid, eicosapentaenoic acid

DOI: 10.3233/JAD-191017

Citation: Journal of Alzheimer's Disease, vol. 74, no. 3, pp. 975-990, 2020

Authors: Zhang, Haihua | Wang, Tao | Han, Zhifa | Wang, Longcai | Zhang, Yan | Wang, Lijun | Liu, Guiyou

Article Type: Research Article

Abstract: Until now, observational studies, randomized controlled trials (RCTs), and Mendelian randomization (MR) studies have explored the impact of vitamin D on Alzheimer’s disease (AD), and reported inconsistent findings. In MR studies, the sensitivity analysis by removing GC rs2282679 variant highlighted no association of 25OHD levels with AD risk, which indicates that vitamin D-binding protein (DBP) encoded by GC may have distinct effects on AD risk. Here, we aim to clarify this assumption. We selected the GC rs2282679 variant associated with DBP levels (p  = 3.30E-76) as the instrumental variable, and extracted the summary statistics of rs2282679 variant in multiple …AD GWAS datasets from IGAP, Complex Trait Genetics (CTG) lab, and UK Biobank. We then performed a MR study to investigate the causal association between DBP levels and AD. In IGAP, MR analysis showed that the genetically DBP levels (per 1 standard deviation (SD) increase 50 mg/L) were significantly associated with reduced AD risk (OR = 0.63, 95% CI: 0.45-0.89, p  = 0.009). Importantly, the estimates from two sensitivity analyses were consistent with the main estimate in terms of direction and magnitude. Meanwhile, we found no causal association between DBP levels and other four AD phenotypes in CTG lab and UK Biobank. In summary, we highlight the role of DBP levels in AD risk, and provide strong support evidence that DBP may be the therapeutic agent for the treatment of AD. Meanwhile, our findings clarify the assumption that DBP may drive the observed relationship between 25OHD levels and AD. Show more

Keywords: Alzheimer’s disease, genome-wide association study, Mendelian randomization, vitamin D, vitamin D-binding protein

DOI: 10.3233/JAD-191051

Citation: Journal of Alzheimer's Disease, vol. 74, no. 3, pp. 991-998, 2020

Authors: Richardson, Kathryn | Wharton, Stephen B. | Grossi, Carlota M. | Matthews, Fiona E. | Fox, Chris | Maidment, Ian | Loke, Yoon K. | Steel, Nicholas | Arthur, Antony | Myint, Phyo Kyaw | Boustani, Malaz | Campbell, Noll | Robinson, Louise | Brayne, Carol | Savva, George M.

Article Type: Research Article

Abstract: Background: Benzodiazepines and anticholinergic drugs have been implicated in causing cognitive decline and potentially increasing dementia risk. However, evidence for an association with neuropathology is limited. Objective: To estimate the correlation between neuropathology at death and prior use of benzodiazepines and anticholinergic drugs. Methods: We categorized 298 brain donors from the population-based Medical Research Council Cognitive Function and Ageing Study, according to their history of benzodiazepine (including Z-drugs) or anticholinergic medication (drugs scoring 3 on the Anticholinergic Cognitive Burden scale) use. We used logistic regression to compare dichotomized neuropathological features for those with and without history …of benzodiazepine and anticholinergic drug use before dementia, adjusted for confounders. Results: Forty-nine (16%) and 51 (17%) participants reported benzodiazepine and anticholinergic drug use. Alzheimer’s disease neuropathologic change was similar whether or not exposed to either drug, for example 46% and 57% had intermediate/high levels among those with and without anticholinergic drug use. Although not significant after multiple testing adjustments, we estimated an odds ratio (OR) of 0.40 (95% confidence interval [95% CI] 0.18–0.87) for anticholinergic use and cortical atrophy. For benzodiazepine use, we estimated ORs of 4.63 (1.11–19.24) and 3.30 (1.02–10.68) for neuronal loss in the nucleus basalis and substantial nigra. There was evidence of neuronal loss in the nucleus basalis with anticholinergic drug use, but the association reduced when adjusted for confounders. Conclusions: We found no evidence that benzodiazepine or anticholinergic drug use is associated with typical pathological features of Alzheimer’s disease; however, we cannot rule out effects owing to small numbers. Show more

Keywords: Alzheimer’s disease, basal nucleus of Meynert, benzodiazepines, cholinergic antagonists, neurofibrillary tangles, neuritic plaques, neuropathology

DOI: 10.3233/JAD-191199

Citation: Journal of Alzheimer's Disease, vol. 74, no. 3, pp. 999-1009, 2020

Article Type: Correction

DOI: 10.3233/JAD-209008

Citation: Journal of Alzheimer's Disease, vol. 74, no. 3, pp. 1011-1011, 2020