A critical appraisal of blood-based biomarkers for Alzheimer's disease.

Biomarkers that predict the clinical onset of Alzheimer's disease (AD) enable the identification of individuals in the early, preclinical stages of the disease. Detecting AD at this point may allow for more effective therapeutic interventions and optimized enrollment for clinical trials of novel drugs. The current biological diagnosis of AD is based on the AT(N) classification system with the measurement of brain deposition of amyloid-ß (Aß) ("A"), tau pathology ("T"), and neurodegeneration ("N"). Diagnostic cut-offs for Aß1-42, the Aß1-42/Aß1-40 ratio, tau and hyperphosphorylated-tau concentrations in cerebrospinal fluid have been defined and may support AD clinical diagnosis. Blood-based biomarkers of the AT(N) categories have been described in the AD continuum. Cross-sectional and longitudinal studies have shown that the combination of blood biomarkers tracking neuroaxonal injury (neurofilament light chain) and neuroinflammatory pathways (glial fibrillary acidic protein) enhance sensitivity and specificity of AD clinical diagnosis and improve the prediction of AD onset. However, no international accepted cut-offs have been identified for these blood biomarkers. A kit for blood Aß1-42/Aß1-40 is commercially available in the U.S.; however, it does not provide a diagnosis, but simply estimates the risk of developing AD. Although blood-based AD biomarkers have a great potential in the diagnostic work-up of AD, they are not ready for the routine clinical use.

Neurophysiological Alterations of the Visual Pathway in Posterior Cortical Atrophy: Systematic Review and a Case Series.

Background: The clinical features of posterior cortical atrophy (PCA), a rare condition often caused by Alzheimer's disease, have been recently defined, while little is known about its neurophysiological correlates. Objective: To describe neurophysiological alterations of the visual pathway as assessed using visual field test (VF), visual evoked potentials (VEP), and electroretinogram (ERG) in PCA patients. Methods: Studies reporting VF, VEPs, and ERG in PCA patients were selected according PRISMA method. Of the 323 articles that emerged from the literature, 17 included the outcomes of interest. To these data, we added those derived from a patient cohort enrolled at our clinic. Results: The literature review included 140 patients, half of them (50%) presented with homonymous hemianopia or quadrantanopia. VEPs were available in 4 patients (2 normal findings, 1 decreased amplitude, and 1 increased latency) and ERG in 3 patients (substantially normal findings). Our case series included 6 patients, presenting with homonymous lateral hemianopia in 50% and contralateral cortical atrophy. VEPs showed normal amplitude in 66-83% according to the stimulation check, and increased latency in 67% in absence of myelin damage on MRI. Latency was increased in both eyes in 50% and only on one side in the other 50%. Such alterations were observed in patients with more severe and symmetric atrophy. ERG showed normal findings. Conclusions: Neurophysiological investigations of the visual pathway in PCA are almost absent in literature. Alterations involve both amplitude and latency and can be also monocular. A multiple-point involvement of the optical pathway can be hypothesized.

Monitoring synaptic pathology in Alzheimer's disease through fluid and PET imaging biomarkers: a comprehensive review and future perspectives.

Alzheimer's disease (AD) is currently constrained by limited clinical treatment options. The initial pathophysiological event, which can be traced back to decades before the clinical symptoms become apparent, involves the excessive accumulation of amyloid-beta (Aß), a peptide comprised of 40-42 amino acids, in extraneuronal plaques within the brain. Biochemical and histological studies have shown that overaccumulation of Aß instigates an aberrant escalation in the phosphorylation and secretion of tau, a microtubule-binding axonal protein. The accumulation of hyperphosphorylated tau into intraneuronal neurofibrillary tangles is in turn correlated with microglial dysfunction and reactive astrocytosis, culminating in synaptic dysfunction and neurodegeneration. As neurodegeneration progresses, it gives rise to mild clinical symptoms of AD, which may eventually evolve into overt dementia. Synaptic loss in AD may develop even before tau alteration and in response to possible elevations in soluble oligomeric forms of Aß associated with early AD. These findings largely rely on post-mortem autopsy examinations, which typically involve a limited number of patients. Over the past decade, a range of fluid biomarkers such as neurogranin, α-synuclein, visinin-like protein 1 (VILIP-1), neuronal pentraxin 2, and ß-synuclein, along with positron emission tomography (PET) markers like synaptic vesicle glycoprotein 2A, have been developed. These advancements have facilitated the exploration of how synaptic markers in AD patients correlate with cognitive impairment. However, fluid biomarkers indicating synaptic loss have only been validated in cerebrospinal fluid (CSF), not in plasma, with the exception of VILIP-1. The most promising PET radiotracer, [11C]UCB-J, currently faces significant challenges hindering its widespread clinical use, primarily due to the necessity of a cyclotron. As such, additional research geared toward the exploration of synaptic pathology biomarkers is crucial. This will not only enable their extensive clinical application, but also refine the optimization process of AD pharmacological trials.

Plasma ATN(I) classification and precision pharmacology in Alzheimer's disease.

Evaluating potential therapies for Alzheimer's disease (AD) depends on use of biomarkers for appropriate subject selection and monitoring disease progression. Biomarkers that predict onset of clinical symptoms are particularly important for AD because they enable intervention before irreversible neurodegeneration occurs. The amyloid-ß-tau-neurodegeneration (ATN) classification system is currently used as a biological staging model for AD and is based on three classes of biomarkers evaluating amyloid-ß (Aß), tau pathology and neurodegeneration or neuronal injury. Promising blood-based biomarkers for each of these categories have been identified (Aß42/Aß40 ratio, phosphorylated tau, neurofilament light chain), and this matrix is now being expanded toward an ATN(I) system, where "I" represents a neuroinflammatory biomarker. The plasma ATN(I) system, together with APOE genotyping, offers a basis for individualized evaluation and a move away from the classic "one size fits all" approach toward a biomarker-driven individualisation of therapy for patients with AD.

Investigational treatments for neurodegenerative diseases caused by inheritance of gene mutations: lessons from recent clinical trials.

We reviewed recent major clinical trials with investigational drugs for the treatment of subjects with neurodegenerative diseases caused by inheritance of gene mutations or associated with genetic risk factors. Specifically, we discussed randomized clinical trials in subjects with Alzheimer's disease, Huntington's disease and amyotrophic lateral sclerosis bearing pathogenic gene mutations, and glucocerebrosidase-associated Parkinson's disease. Learning potential lessons to improve future therapeutic approaches is the aim of this review. Two long-term, controlled trials on three anti-ß-amyloid monoclonal antibodies (solanezumab, gantenerumab and crenezumab) in subjects carrying Alzheimer's disease-linked mutated genes encoding for amyloid precursor protein or presenilin 1 or presenilin 2 failed to show cognitive or functional benefits. A major trial on tominersen, an antisense oligonucleotide designed to reduce the production of the huntingtin protein in subjects with Huntington's disease, was prematurely interrupted because the drug failed to show higher efficacy than placebo and, at highest doses, led to worsened outcomes. A 28-week trial of tofersen, an antisense oligonucleotide for superoxide dismutase 1 in patients with amyotrophic lateral sclerosis with superoxide dismutase 1 gene mutations failed to show significant beneficial effects but the 1-year open label extension of this study indicated better clinical and functional outcomes in the group with early tofersen therapy. A trial of venglustat, a potent and brain-penetrant glucosylceramide synthase inhibitor, in Parkinson's disease subjects with heterozygous glucocerebrosidase gene mutations revealed worsened clinical and cognitive performance of patients on the enzyme inhibitor compared to placebo. We concluded that clinical trials in neurodegenerative diseases with a genetic basis should test monoclonal antibodies, antisense oligonucleotides or gene editing directed against the mutated enzyme or the mutated substrate without dramatically affecting physiological wild-type variants.

Role of monomeric amyloid-ß in cognitive performance in Alzheimer's disease: Insights from clinical trials with secretase inhibitors and monoclonal antibodies.

According to the ß-amyloid (Aß) hypothesis of Alzheimer's disease (AD), brain Aß accumulation is the primary cascade event leading to cognitive deficit and dementia. Numerous anti-Aß drugs either inhibiting production or aggregation of Aß or stimulating its clearance have failed to show clinical benefit in large scale AD trials, with ß- and γ-secretase inhibitors consistently worsening cognitive and clinical decline. In June 2021, the FDA approved aducanumab, an anti-Aß monoclonal antibody for early AD based on its ability to reduce brain amyloid plaques, while two other amyloid-clearing antibodies (lecanemab and donanemab) have recently produced encouraging cognitive and clinical results. We reviewed AD trials using PubMed, meeting abstracts and ClinicalTrials.gov and evaluated the effects of such drugs on cerebrospinal fluid (CSF) Aß levels, correlating them with cognitive effects. We found that ß-secretase and γ-secretase inhibitors produce detrimental cognitive effects by significantly reducing CSF Aß levels. We speculate that monoclonal antibodies targeting Aß protofibrils, fibrils or plaques may improve cognitive performance in early AD by increasing soluble Aß levels through Aß aggregate disassembly and/or stabilization of existing Aß monomers.These findings suggest that the real culprit in AD may be decreased levels of soluble monomeric Aß due to sequestration into brain Aß aggregates and plaques.

Heart rate variability and cognitive performance in adults with cardiovascular risk.

Background: Heart rate variability (HRV), a measure of autonomic function, has been associated with both cardiovascular disease and cognitive dysfunction. In turn, cardiovascular risk has been linked to an increased risk of dementia onset. However, whether autonomic dysfunction may represent an early marker of cognitive decline in individuals with high cardiovascular risk is still an open issue. Methods: We performed a complete 24-hour HRV analysis in 50 middle-aged and elderly subjects with cardiovascular risk as assessed with the European Society of Cardiology Systematic Coronary Risk Evaluation (ESC SCORE). Cognitive performance was evaluated by Montreal Cognitive Assessment (MoCA), Free and Cued Selective Reminding Test (FCSRT) and Stroop Color and Word Test. Stepwise regression was used to identify significant associations between 24-hour ambulatory ECGs parameters and cognitive performances. Results: There were 30 women and 20 men with mean age of 64.9 years (range 51-77) and the mean ESC SCORE was 6%. Four subjects were diagnosed with mild cognitive impairment. Associations were found between measures of HRV and measures of cognition. Ultra-low frequency (ULF) band power of HRV significantly correlated with MoCA (r = 0.424, p = 0.003), also after adjustment for demographics and education. A significant association was also found between the ESC SCORE and ULF band power (r = -0.470, p = 0.0009). Conclusions: Ultra-low frequency band power of HRV is associated with cognitive performance of middle-aged and elderly subjects with cardiovascular risk. This finding may indicate that autonomic nervous system dysregulation plays a role in developing cardiovascular risk and cognitive decline.