July 15, 2024

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How to Conduct Preventive Treatments for Alzheimer’s Disease?

How to Conduct Preventive Treatments for Alzheimer’s Disease?

How to Conduct Preventive Treatments for Alzheimer’s Disease?

Alzheimer’s disease (AD) is a heterogeneous neurodegenerative disease and the most common cause of dementia in the elderly.

AD’s global incidence is steadily rising, and with an aging population, it’s projected that the number of adults with dementia worldwide will more than double by 2050, with no effective cure currently available.


In ongoing clinical trials for AD, identifying and proving definitive treatments for AD remains challenging.

Potential targets are numerous and uncertain, including Aβ (plaques, peripheral amyloid fibrils/oligomers, monomers, and Aβ modifications), tau (tangles, oligomers, aggregates, phosphorylation, acetylation), inflammation (microglia, activated astrocytes, complement), neurodegenerative changes (protein homeostasis, vascular transport mechanisms, cytokines), apolipoprotein E, and neurovascular units.


One major issue with current AD trials is that participants are often too far along in their disease course, or the chosen targets are incorrect for the disease stage.

Even if current trials succeed, they may only slow disease progression by 25% to 40%, leaving millions of patients and families to suffer the gradual loss of cognitive abilities and daily functioning. Therefore, early intervention is crucial, ideally before severe cognitive impairment occurs.


How to Conduct Preventive Treatments for Alzheimer's Disease?



Progress in the field of AD research is rapidly improving our ability to intervene early. Recent discoveries include quantitative biomarkers that identify pre-symptomatic stages of AD and measure the extent of disease changes, along with simple and fast blood-based biomarker screening to identify high-risk individuals. This allows us to implement interventions before evidence of disease or injury becomes apparent, or to treat asymptomatic individuals with subclinical presentations.


Preventive Treatment Based on Aβ

The amyloid hypothesis suggests that the formation of amyloid plaque from the aggregation of Aβ peptides produced through the cleavage of amyloid precursor protein (APP) is at the core of AD pathology. Increased levels or ratios of Aβ42 induce the formation of Aβ amyloid fibrils, which develop into amyloid plaques, causing local plaque-associated neurotoxicity and subsequent changes in tau pathology. Oligomers and fibrils are considered the most toxic forms, potentially leading to over-phosphorylation of tau, disruption of proteasomes and mitochondrial function, calcium dyshomeostasis, synaptic failure, astrocyte activation, neuronal cell death, neurodegeneration, and cognitive impairment. Aβ accumulation is the first pathogenic event leading to subsequent downstream changes and is a critical target for AD prevention.

The concept of preventive Aβ-based therapies received support from the latest results of the DIAN-TU clinical trial. In this trial, gantenerumab (a monoclonal antibody targeting Aβ aggregation) significantly reduced brain amyloid deposition, with a strong impact on downstream biomarkers. Participants receiving gantenerumab treatment showed a significant reduction in CSF total tau and p-tau compared to placebo, and a slowing of the increase in CSF NfL. In asymptomatic individuals, gantenerumab seemed to have a greater impact on plaque reduction, tau pathology, and downstream biomarkers associated with neuronal damage compared to symptomatic groups. These findings suggest that removing amyloid plaques at the right time might be a feasible strategy for preventing or slowing AD’s biological progression.

The table below summarizes ongoing and planned Aβ prevention therapy trials currently in clinical testing.

How to Conduct Preventive Treatments for Alzheimer's Disease?





Preventive Treatment Based on Tau

Neurofibrillary tangles (NFTs) with high phosphorylation, intracellular insoluble tau are pathological markers of AD. Tau pathology is much more closely related to clinical status and dementia than amyloid plaque, atrophy, or glucose metabolism disorders in the brain. Tau aggregation is associated with the onset and progression of cognitive symptoms, as well as focal neurological symptoms like memory, visual-spatial function, and language. Normal tau serves as a regulator of axon remodeling, is actively regulated, and produced as an extracellular form related to the number of amyloid plaques. Importantly, tau changes begin after amyloid plaque pathology, meaning there’s a window of opportunity to intervene before symptoms and tau tangle aggregation.


How to Conduct Preventive Treatments for Alzheimer's Disease?


With the latest understanding of tau pathology, various novel tau therapies have entered early clinical trial phases. These new drugs include antibodies targeting different epitopes and forms of tau, genetic therapies against tau (antisense oligonucleotides, small interfering RNA, and adenoviral vectors), as well as small molecules to inhibit or reverse aggregation. Currently, more than 20 tau-targeted treatments are in early-phase I-II clinical trials, with most of them focusing on soluble or insoluble tau proteins with different amino acid sequences.

How to Conduct Preventive Treatments for Alzheimer's Disease?




Treatment Targeting Inflammation and Microglial Cells

Neuroinflammation is now recognized as a prominent feature of the neurodegenerative process leading to symptomatic AD. The activation of microglial cells and astrocytes plays a major role in the onset and worsening of central nervous system inflammation in AD pathology. While classical neuropathological lesions in AD include neuroinflammatory plaques composed of Aβ and NFTs characterized by tau hyperphosphorylation, many studies describe the presence of activated glial cells near these plaques. The spatial relationship between Aβ and reactive glial cells suggests that aggregated Aβ activates microglial cells, triggering an inflammatory response in the early stages of the disease. These chronic inflammatory responses may lead to acute neuronal membrane damage, neurotoxicity, and later-stage neurodegeneration.

Various strategies are currently being developed to modulate the immune cell function in neuroinflammation. Many studies explore the use of non-steroidal anti-inflammatory drugs, although clinical trials of these compounds in AD treatment have largely been disappointing. Other promising candidates for regulating inflammatory response include proteins involved in microglial cell function and inflammation, such as TREM2, APOE, CD33, CR1, ABCA7, and SHIP1. Recent findings have identified TREM2 variants as genetic risk factors for late-onset AD (LOAD), and TREM2 appears to play a critical role in microglial recruitment, phagocytosis, and Aβ clearance. Several reports suggest that TREM2 deficiency leads to reduced microglial activation, subsequently reducing plaque-associated microglia, increasing local Aβ toxicity, and amyloid-induced neurodegeneration.


Treatment Targeting Apolipoprotein E

APOE4 is the most common genetic risk factor for AD, with multiple studies indicating a close relationship between APOE-4 and AD pathology. APOE-4 carriers are more likely to develop AD several years earlier than other APOE subtypes, and the effect is dose-dependent. These findings suggest that APOE-4 may exert toxic effects in the brain, and targeting APOE-4 expression may slow or prevent AD’s progression.

Current APOE-targeted treatments for AD include: (1) regulating APOE levels, (2) modifying the properties or structure of ApoE, (3) reprogramming APOE function through gene editing, and (4) indirect therapeutic methods via APOE receptor modification, maintaining vascular system integrity, and inflammation regulation.


Combination Therapy in Preventive Treatments

The use of combination therapy has proven successful in complex diseases such as cancer, autoimmune diseases, and infectious diseases, which may increase the likelihood of success in AD treatment development. This is based on two assumptions: (1) mechanism-based AD treatments will

be most beneficial when initiated in the pre-symptomatic stage before substantial damage to synapses and neurons occurs, and (2) once the cascade of AD pathology begins, combined treatments targeting multiple aspects of AD pathology may be more effective than single therapies against a single pathological factor.

Aβ remains the most important target for AD treatment, and combination Aβ-based therapies might involve addressing different nodes in the aggregation pathway of Aβ-42, such as monoclonal antibodies targeting Aβ-42 and β-secretase inhibitors. Another approach to combination therapy is targeting two (or more) pathogenic pathways. Anti-tau drugs are currently in clinical trials, so combining anti-Aβ and anti-tau therapies is a consideration. Other potential combinations with different mechanisms of action might include treatments for neuroinflammation, apolipoprotein E, mitochondrial modifications, free radicals, autophagy, or drugs to improve or maintain the integrity of the blood-brain barrier.

Despite the complexity of AD’s biology, which suggests that combination therapy may be more effective than single therapy, most AD trials have only assessed single therapies based on a single mechanism. Therefore, new and more innovative research designs, including the implementation of combination trials, are needed.


In Summary

AD is a multifactorial heterogeneous neurodegenerative disease that significantly impacts human health, and there are currently no curative treatments. Approved drugs can only slow disease progression.

Therefore, early intervention for AD is crucial, and AD prevention trials have the potential to achieve the treatment goal of delaying or preventing AD dementia.


In recent years, significant progress has been made in the application of imaging and genomics tools, helping to identify potential genetic risks with precision molecular pathways.

Detection techniques for pathological physiological processes have also advanced significantly.

These advances have led to the inclusion of personalized and targeted therapies in various clinical trials for AD, including anti-amyloid research in asymptomatic AD, AD prevention programs, and dominant genetic AD network trials.

The focus of these studies is patients with recognized AD risk factors, as well as neuroimaging and biomarkers to aid in detecting AD onset.

In the future, personalized and precision medicine may offer new treatment options for AD patients.




How to Conduct Preventive Treatments for Alzheimer’s Disease?


1.The informed road map to prevention of Alzheimer Disease: A call to arms. Mol Neurodegener.2021 Jul 21;16(1):49.

(source:internet, reference only)

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