Current Alzheimer Research - Volume 20, Issue 2, 2023

Beyond the time-honoured targeting of protein misfolding and aggregation, Alzheimer’s disease needs new, innovative therapeutic directions. When exploring alternative druggable mechanisms, multifaceted in vitro and in vivo data demonstrate that immune system dysfunction is a pivotal driver of Alzheimer’s disease progression. In pursuing neuroimmunological targets, a major but often under-discussed consideration regards the issue of whether innate or adaptive immunity (or both) within the neuroimmune network should be the centre of focus when devising immunotherapeutic approaches to Alzheimer’s. This perspective article briefly reviews current data, concluding that while both innate and adaptive immunity contributes to the immunopathology of Alzheimer’s, the proinflammatory microglia and cytokines of innate immunity will provide higher yield targets with a greater likelihood of efficacy. Although it seems paradoxical to focus on a rapid, short-lived aspect of immunity when seeking approaches to a quintessentially chronic brain disease, accumulating evidence affords ample data to support the target-rich cascade of innate immunity for the development of much-needed new diagnostics and therapeutics.

Background: An annual plant, Fenugreek (Trigonellafoenum-graecum L.) has well-known health care benefits in Ayurvedic and Chinese medicine. Its leaves and seeds have alkaloids, amino acids, caumarins, flavonoids, saponins, and other bioactive components. Various pharmacological properties such as antioxidants, hypoglycemic, and hypolipidemic have been attributed to fenugreek. Trigonelline, diosgenin, and 4- hydroxyisoleucine have shown neuroprotection against Alzheimer’s disease, and the extract have also been reported to act as an anti-depressant, anti-anxiety, and also regulate cognitive functions. This review highlights various studies carried out on animals as well as on humans for the protective effect against Alzheimer’s disease. Methods: The data presented in this review is taken from popular search engines, viz, Google Scholar, PubMed, and Scopus. This review highlights the studies and clinical trials performed to show the protective effect of Fenugreek on neurodegenerative diseases with special reference to AD from 2005 to 2023. Results: Fenugreek improves cognitive deficits by Nrf2-mediated antioxidative pathway and provides neuroprotection against amyloid-beta-induced mitochondria dysfunction. It enhances SOD and catalase activities and scavenges reactive oxygen species to protect the cellular organelle from oxidative stress. It normalizes the tubulin protein and improved axonal growth by regulating nerve growth factors. Fenugreek can also influence metabolism. Discussion: Fenugreek significantly improves the pathological symptoms of neurodegenerative disease, especially AD and can be used as a therapeutic agent to control disease conditions as evidenced by the review of the literature.

Background: Neuropsychiatric symptoms (NPS) in patients with Alzheimer’s disease (AD) worsened during the COVID-19 lockdowns, but their progression thereafter is unknown. We present the first longitudinal study tracking them before, during, and after restrictions. Objectives: To describe the effect of the COVID-19 mandatory lockdowns on Cognitive and Neuropsychiatric symptoms in patients with Mild Cognitive Impairment (MCI) and Alzheimer’s Disease (AD). Methods: Cohort of 48 patients with amnestic MCI and 38 with AD in Lima, Peru. They received three rounds of cognitive (RUDAS, CDR, M@T), behavioral (NPI), and functional (ADCS-ADL) assessments. We assessed the change in score means across the time points and for each domain of NPS and tracked the changes in individual patients. Results: RUDAS declined 0.9 (SD 1.0) from baseline to lockdown and 0.7 (SD 1.0) after restrictions. M@T declined 1.0 (SD 1.5) from baseline to lockdown and 1.4 (SD 2.0) after restrictions. CDR worsened in 72 patients (83.72%) from baseline to post-lockdown. NPI worsened by 10 (SD 8.3) from baseline to lockdown but improved by 4.8 (SD 6.4) after restrictions. Proportionally, 81.3% of all patients had worsened NPS during the lockdowns, but only 10.7% saw an increase thereafter. Improvement was statistically significant for specific NPS domains except hallucinations, delusions, and appetite changes. Anxiety, irritability, apathy, and disinhibition returned to baseline levels. Conclusion: Following confinement, cognition continued to decline, but NPS demonstrated either stability or improvement. This highlights the role modifiable risk factors may have on the progression of NPS.

Background: Identifying individuals with mild cognitive impairment (MCI) who are at increased risk of Alzheimer’s Disease (AD) in cognitive screening is important for early diagnosis and prevention of AD. Objective: This study aimed at proposing a screening strategy based on landmark models to provide dynamic predictive probabilities of MCI-to-AD conversion according to longitudinal neurocognitive tests. Methods: Participants were 312 individuals who had MCI at baseline. The longitudinal neurocognitive tests were the Mini-Mental State Examination, Alzheimer Disease Assessment Scale-Cognitive 13 items, Rey Auditory Verbal Learning Test immediate, learning, and forgetting, and Functional Assessment Questionnaire. We constructed three types of landmark models and selected the optimal landmark model to dynamically predict 2-year probabilities of conversion. The dataset was randomly divided into training set and validation set at a ratio of 7:3. Results: The FAQ, RAVLT-immediate, and RAVLT-forgetting were significant longitudinal neurocognitive tests for MCI-to-AD conversion in all three landmark models. We considered Model 3 as the final landmark model (C-index = 0.894, Brier score = 0.040) and selected Model 3c (FAQ and RAVLT-forgetting as neurocognitive tests) as the optimal landmark model (C-index = 0.898, Brier score = 0.027). Conclusion: Our study shows that the optimal landmark model with a combination FAQ and RAVLTforgetting is feasible to identify the risk of MCI-to-AD conversion, which can be implemented in cognitive screening.

Background: Self-imagination refers to a mnemonic strategy of imagining oneself at a scene related to a cue. Objective: We tested the effect of self-imagination on memory recall in Alzheimer’s disease (AD) Methods: Individuals with AD and healthy controls were invited to perform two conditions. In the control (i.e., semantic elaboration) condition, participants were asked to define to which semantic category (e.g., dance) words (e.g., waltz) belong. However, in a self-imagining condition, participants were asked to imagine themselves in a scene related to the stimuli (e.g., dancing waltz). Both conditions were followed by two free memory tests with two different intervals (20 seconds vs. 20 minutes). Results: Analysis showed a beneficial effect of self-imagination for the 20-second but not for the 20- minute recall in AD participants and controls. Conclusion: Clinicians can incorporate our findings when assessing, especially when trying to rehabilitate, episodic memory in AD.

Background: Metformin, the first-line anti-diabetic drug treatment in patients with type 2 diabetes mellitus (T2DM), is suggested to be anti-inflammatory, antioxidative, and improve cognitive function, making it a promising contribution to treating Alzheimer´s disease (AD). However, the effect of metformin on behavioral and psychological symptoms of dementia (BPSD) in patients with AD has not been explored. Objective: To investigate the associations between metformin and BPSD in patients with AD and T2DM and explore possible interaction with other antidiabetic drugs. Methods: This cross-sectional study was based on data from the Swedish BPSD register. A total of 3745 patients with AD and antidiabetic drug treatment were included. Associations and interactions between antidiabetic drugs and BPSD were investigated by binary logistic regression. Results: The use of metformin was associated with lower odds for symptoms of depression (OR 0.77, CI (95%) 0.61-0.96, p = 0.022) and anxiety (OR 0.74, CI (95%) 0.58-0.94, p = 0.015) after adjustment for age, gender, specific diagnosis, and drugs. We could not demonstrate this association with another antidiabetic drug. Interaction effects were limited to an increasing association in eating and appetite disorders using metformin and other antidiabetic drugs (i.e., drugs other than insulin, sulfonylurea, or dipeptidyl peptidase-4 inhibitors). Conclusion: The result of this study suggests that metformin could be beneficial for patients diagnosed with AD, other than for blood glucose control. Although, more knowledge is needed before assigning metformin a role in treating BPSD.

Background: Alzheimer’s disease (AD) and Multiple sclerosis (MS) lead to neurodegenerative processes negatively affecting millions of people worldwide. Their treatment is still difficult and practically incomplete. One of the most commonly used drugs against these neurodegenerative diseases is 4-aminopyridine. However, its use is confined by the high toxicity. Objectives: The aim of this work is to obtain new peptide derivatives of 4-aminopyridine with decreased toxicity compared to 4-aminopyridine. Methods: Synthesis was conducted in solution using a consecutive condensation approach. The new derivatives were characterized by melting points, NMR, and Mass spectra. Important ADME (absorption, distribution, metabolism, and excretion) properties have been studied in silico using ACD/Percepta v.2020.2.0 software. Acute toxicity was determined in mice according to a Standard protocol. All new derivatives were tested in vitro for cytotoxic activity in a panel of human (HEP-G2, BV-173) and murine (NEURO 2A) tumor cell lines via a standard MTT-based colorimetric method. β-secretase inhibitory activity was determined by applying the fluorescent method. Results: New derivatives of 4-aminopyridine containing analogues of the β-secretase inhibitory peptide (Boc-Val-Asn-Leu-Ala-OH) were obtained. The in vivo toxicity of the tested compounds was found to be as high as 1500 mg/kg. Cell toxicity screening against tumor cell lines of different origins showed negligible growth-inhibitory effects of all investigated 4-aminopyridine analogues. Conclusion: Synthesis of new peptide derivatives of 4-aminopyridine is reported. Acute toxicity studies revealed a ca. 150 times lower toxicity of the new compounds as compared to 4-aminopyridine that may be ascribed to their peptide fragment.