Current Alzheimer Research - Volume 19, Issue 4, 2022

It has been hypothesized that the shift in gut microbiota composition, known as gut microbe dysbiosis, may be correlated with the onset of Alzheimer's disease (AD), which is the most common cause of dementia characterized by a gradual deterioration in cognitive function associated with the development of amyloid-beta (Aβ) plaques. The gut microbiota dysbiosis induces the release of significant amounts of amyloids, lipopolysaccharides, and neurotoxins, which might play a role in modulating signaling pathways and immune activation, leading to the production of proinflammatory cytokines related to the pathogenesis of AD. The dysbiosis of gut microbe is associated with various diseases such as type 2 diabetes, obesity, hypertension, and some neuropsychiatric disorders like depression, anxiety, and stress. It is conceivable that these diseases trigger the onset of AD. Thus, modifying the gut microbiota composition with probiotic and prebiotic supplementation can reduce depression and anxiety symptoms, lower stress reactivity, and improve memory. This narrative review aimed to examine the possible role of gut microbe dysbiosis in AD's pathogenesis.

Behavioral and psychotic manifestations, including aggression, delusions, and hallucinations, are frequent comorbidities in patients with debilitating nervous illnesses such as Alzheimer’s disease (AD), Amyotrophic Lateral Sclerosis, Multiple Sclerosis, and Parkinson’s disease. ADrelated psychosis may be linked to a poor disease prognosis, highlighting that early detection and management are mandatory. The manifestations are variable and may be very heterogeneous, imposing a real diagnostic issue. Some assessment tools such as BEHAVE-AD, CERAD-BRSD, and the Psycho-Sensory Hallucinations Scale have been designed to facilitate the diagnosis. The mechanisms behind neurodegeneration-related psychosis are complex and are not fully understood, imposing a burden on researchers to find appropriate management modalities. Familial history and some genetic disturbances may have a determinant role in these delusions and hallucinations in cases with AD. The loss of neuronal cells, atrophy in some regions of the central nervous, and synaptic dysfunction may also contribute to these comorbidities. Furthermore, inflammatory disturbances triggered by pro-inflammatory agents such as interleukins and tumor necrosis factors are stratified among the potential risk factors for the onset of numerous psychotic symptoms in Alzheimer’s patients. Little is known about the possible management tools; therefore, it is urgent to conduct well-designed trials to investigate pharmacological and non-pharmacological interventions that can improve the care process of these patients. This review summarizes the current findings regarding the AD-related psychosis symptoms, pathological features, assessment, and management.

Background: Alzheimer’s disease (AD) is the most common form of neurodegenerative disorder. The association of BIN1, CLU, and IDE genetic polymorphisms with AD risk have been evaluated overtimes that produced conflicting outcomes. Objective: We performed this meta-analysis to investigate the contribution of BIN1 (rs744373 and rs7561528), CLU (rs11136000 and rs9331888), and IDE (rs1887922) polymorphisms to AD risk. Methods: From a systemic literature search up to July 15, 2021, we included 25 studies with rs744373, 16 studies with rs7561528, 37 studies with rs11136000, 16 studies with rs9331888, and 4 studies with rs1887922. To analyze the correlation, we constructed seven genetic models that used odds ratio and 95% confidence intervals. We used RevMan 5.4 for meta-analysis. Results: Our study suggests that BIN1 rs744373 is associated with a significantly increased risk of AD in five genetic models (OR>1). Again, CLU rs11136000 showed reduced association in all genetic models (OR<1). CLU rs9331888 revealed an increased association in two models (OR>1). The IDE rs1887922 showed significantly increased risk in four models (OR>1). From subgroup analysis, a significantly increased risk of AD was observed in Caucasians and Asians for BIN1 rs744373. Again, BIN1 rs7561528 showed a significantly enhanced risk of AD only in Caucasians. CLU rs11136000 showed significantly reduced risk in Caucasians but rs9331888 showed increased risk in the same ethnicity. Conclusion: Our meta-analysis confirms the association of BIN1 rs744373, CLU rs9331888, and IDE rs1887922 polymorphisms with an increased risk of AD, especially in Caucasians. Again, CLU rs11136000 is associated with reduced AD risk in the overall population and Caucasians.

Background: Alzheimer’s disease (AD) is initiated by aberrant accumulation of amyloid beta (Aβ) protein in the brain parenchyma. The microenvironment surrounding amyloid plaques is characterized by the swelling of presynaptic terminals (dystrophic neurites) associated with lysosomal dysfunction, microtubule disruption, and impaired axonal transport. Aβ-induced plasma membrane damage and calcium influx could be potential mechanisms underlying dystrophic neurite formation. Objective: We tested whether promoting membrane integrity by brain administration of a safe FDA approved surfactant molecule poloxamer-188 (P188) could attenuate AD pathology in vivo. Methods: Three-month-old 5XFAD male mice were administered several concentrations of P188 in the brain for 42 days with mini-osmotic pumps. After 42 days, mice were euthanized and assessed for amyloid pathology, dystrophic neurites, pathogenic microglia activation, tau phosphorylation, and lysosomal / vesicular trafficking markers in the brain. Results: P188 was lethal at the highest concentration of 10mM. Lower concentrations of P188 (1.2, 12, and 120μM) were well tolerated. P188 increased brain Aβ burden, potentially through activation of the γ-secretase pathway. Dystrophic neurite pathology was exacerbated in P188 treated mice as indicated by increased LAMP1 accumulation around Aβ deposits. Pathogenic microglial activation was increased by P188. Total tau levels were decreased by P188. Lysosomal enzyme cathepsin D and calciumdependent vesicular trafficking regulator synaptotagmin-7 (SYT7) were dysregulated upon P188 administration. Conclusion: P188 brain delivery exacerbated amyloid pathology, dystrophic neurites, and pathogenic microglial activation in 5XFAD mice. These effects correlated with lysosomal dysfunction and dysregulation of plasma membrane vesicular trafficking. P188 is not a promising therapeutic strategy against AD pathogenesis.

Background: Alzheimer’s disease can present atypically as a progressive dysexecutive syndrome (dAD), an entity that preferentially affects younger individuals and is frequently misdiagnosed, highlighting the imperative for additional research. Objective: The objective of this study is to characterize the clinical, antemortem neuroimaging, and postmortem neuropathologic features of two cases of young-onset dAD who displayed evidence of Lewy body disease (LBD) co-pathology at autopsy. Methods: Clinical histories, antemortem MRI and PET imaging, and postmortem neuropathologic data were reviewed for each patient. Case Presentation: Canonical features of dAD were observed in both cases, including progressive and predominant impairment in tasks related to working memory and cognitive flexibility, a lack of major behavioral/personality changes, and evidence of abnormal amyloid and tau deposition by antemortem amyloid and tau PET and postmortem neuropathology. Relative sparing of hippocampal involvement was observed in both individuals, in keeping with many cases of clinically atypical AD. One of the patients developed subtle parkinsonian signs as well as paranoia and irritability in the years prior to passing. In both cases, transitional (brainstem and limbic) LBD co-pathology was observed at autopsy. Results and Discussion: Although LBD co-pathology is not uncommon in AD overall, the presence of LBD pathology in these young-onset cases of dAD (including a case with apparent symptomatic correlate) warrants further investigation for broader frequency and underlying pathophysiology. Conclusion: A better understanding of which specific young-onset AD phenotypes are associated with LBD co-pathology would have important implications for counseling, treatment, clinical trial enrollment, and knowledge on disease mechanisms.