BRAIN Α-TOCOPHEROL CONCENTRATION IS INVERSELY ASSOCIATED WITH NEUROFIBRILLARY TANGLE COUNTS IN BRAIN REGIONS AFFECTED IN EARLIER BRAAK STAGES: A CROSS-SECTIONAL FINDING IN THE OLDEST OLD

Objectives: Higher vitamin E status has been associated with lower risk of Alzheimer’s disease (AD). However, evidence of the association of vitamin E concentration in neural tissue with AD pathologies is limited. Design: The cross-sectional relationship between the human brain concentrations of α- and γ-tocopherol and the severity of AD pathologies – neurofibrillary tangle (NFT) and neuritic plaque (NP) – was investigated. Setting & Participants: Brains from 43 centenarians (≥ 98 years at death) enrolled in the Phase III of the Georgia Centenarian Study were collected at autopsy. Measurements: Brain α- and γ-tocopherol concentrations (previously reported) were averaged from frontal, temporal, and occipital cortices. NP and NFT counts (previously reported) were assessed in frontal, temporal, parietal, entorhinal cortices, amygdala, hippocampus, and subiculum. NFT topological progression was assessed using Braak staging. Multiple linear regression was performed to assess the relationship between tocopherol concentrations and NP or NFT counts, with and without adjustment for covariates. Results: Brain α-tocopherol concentrations were inversely associated with NFT but not NP counts in amygdala (β = -2.67, 95% CI [-4.57, -0.79]), entorhinal cortex (β = -2.01, 95% CI [-3.72, -0.30]), hippocampus (β = -2.23, 95% CI [-3.82, -0.64]), and subiculum (β = -2.52, 95% CI [-4.42, -0.62]) where NFT present earlier in its topological progression, but not in neocortices. Subjects with Braak III-IV had lower α-tocopherol (median = 69,622 pmol/g, IQR = 54,389-72,155 pmol/g) than those with Braak I-II (median = 72,108 pmol/g, IQR = 64,056-82,430 pmol/g), but the difference was of borderline significance (p = 0.063). γ-Tocopherol concentrations were not associated with either NFT or NP counts in any brain regions assessed. Conclusions: Higher brain α-tocopherol level is specifically associated with lower NFT counts in brain structures affected in earlier Braak stages. Our findings emphasize the possible importance of α-tocopherol intervention timing in tauopathy progression and warrant future clinical trials

Distribution and inter-regional relationship of amyloid-beta plaque deposition in a 5xFAD mouse model of Alzheimer’s disease

Alzheimer’s disease (AD) is the most common form of dementia. Although previous studies have selectively investigated the localization of amyloid-beta (Aβ) deposition in certain brain regions, a comprehensive characterization of the rostro-caudal distribution of Aβ plaques in the brain and their inter-regional correlation remain unexplored. Our results demonstrated remarkable working and spatial memory deficits in 9-month-old 5xFAD mice compared to wildtype mice. High Aβ plaque load was detected in the somatosensory cortex, piriform cortex, thalamus, and dorsal/ventral hippocampus; moderate levels of Aβ plaques were observed in the motor cortex, orbital cortex, visual cortex, and retrosplenial dysgranular cortex; and low levels of Aβ plaques were located in the amygdala, and the cerebellum; but no Aβ plaques were found in the hypothalamus, raphe nuclei, vestibular nucleus, and cuneate nucleus. Interestingly, the deposition of Aβ plaques was positively associated with brain inter-regions including the prefrontal cortex, somatosensory cortex, medial amygdala, thalamus, and the hippocampus. In conclusion, this study provides a comprehensive morphological profile of Aβ deposition in the brain and its inter-regional correlation. This suggests an association between Aβ plaque deposition and specific brain regions in AD pathogenesis

New insights into the genetic etiology of Alzheimer's disease and related dementias

Characterization of the genetic landscape of Alzheimer's disease (AD) and related dementias (ADD) provides a unique opportunity for a better understanding of the associated pathophysiological processes. We performed a two-stage genome-wide association study totaling 111,326 clinically diagnosed/'proxy' AD cases and 677,663 controls. We found 75 risk loci, of which 42 were new at the time of analysis. Pathway enrichment analyses confirmed the involvement of amyloid/tau pathways and highlighted microglia implication. Gene prioritization in the new loci identified 31 genes that were suggestive of new genetically associated processes, including the tumor necrosis factor alpha pathway through the linear ubiquitin chain assembly complex. We also built a new genetic risk score associated with the risk of future AD/dementia or progression from mild cognitive impairment to AD/dementia. The improvement in prediction led to a 1.6- to 1.9-fold increase in AD risk from the lowest to the highest decile, in addition to effects of age and the APOE ε4 allele

APOE ϵ4, rated life experiences, and affect among centenarians

Additional authors include M. Gearing, W. R. Markesbery, J. S. Tenover, W. L. Rodgers, D. B. Hausman, & C. Rott who are involved with the Georgia Centenarian Study.Objectives: The purpose of this study was to assess the relationship between apolipoprotein E (APOE), life events and engagement, and subjective well-being (as measured by positive and negative affect) among centenarians. Based on the life stress paradigm, we predicted that higher levels of stress would allow APOE to influence positive and negative affect. Method: 196 centenarians and near-centenarians (98 years and older) of the Georgia Centenarian Study participated in this research. The APOE, positive and negative affect, the number of recent (last 2 years) and lifelong (more than 20 years prior to testing) events, as well as a number of life engagement tasks were assessed. Results: Results suggested that centenarians carrying the APOE ϵ4 allele rated lower in positive affect, the number of lifelong events, and in engaged lifestyle, when compared to centenarians without the APOE ϵ4 allele (t = 3.43, p < .01; t = 3.19, p < .01; and t = 2.33, p < .05, respectively). Blockwise multiple regressions indicated that the APOE ϵ4 predicted positive but not negative affect after controlling for demographics. Gene–environment interactions were obtained for the APOE ϵ4 and lifelong events, suggesting that carriers of the APOE ϵ4 allele had higher scores of negative affect after having experienced more events, whereas noncarriers had reduced negative affect levels after having experienced more events. Conclusion: APOE ϵ4 is directly related to positive affect and is related to negative affect in interaction with life events

A brief comparative look at experimental memory editing techniques for cognitive dysfunction

Neuroscience has long sought to develop methods that can “edit” or even “erase” memories, with the aim to provide treatments for memory-related neurological and psychiatric diseases such as anxiety and addiction. Current efforts are heavily focused on modifying cognitive behavioral therapy protocols or pharmacological treatments, but the efficacy and safety of these methods have been called into question by several studies. Advances in modern technology and the rapid emergence of techniques that can directly stimulate/alter neuronal activity, such as neuromodulation, have great potential in achieving the goal of memory modification for treating dementia such as Alzheimer’s disease. However, more research and validation studies are required before these memory editing technologies can be applied clinically. In this mini-review, we compare and highlight the advantages and disadvantages of cognitive behavioral therapy, pharmacological methods, and neuromodulation techniques. We believe that neuromodulation techniques will play a key role in overcoming the challenges of translating memory-manipulating techniques to clinical applications

Functional roles of neuronal nitric oxide synthase in neurodegenerative diseases and mood disorders

Nitric oxide synthase (NOS) is well known for its involvement in the regulation of the nervous, cardiovascular, and immune systems. Neuronal NOS (nNOS) is the most characterized NOS among all the isoforms. It accounts for most of the production of nitric oxide (NO) in the nervous system required for synaptic transmission and neuroplasticity. Previous studies have described the localization of nNOS in specific brain regions of interest. There is substantial evidence in the literature suggesting that nNOS signaling has significant involvement in several disease pathologies. However, the association between brain nNOS expression profiles and disease remains largely unknown. In this review, we attempt to delineate the contribution of nNOS signaling in memory and mood disorders in order to achieve a better understanding of nNOS in disease modulation