Alzheimer's Disease

Alzheimer's disease (AD) is a neurodegenerative disorder characterised by cognitive decline, memory loss, and behavioural changes.

Blood Diagnostics

Early and accurate diagnosis is crucial for effective management and treatment. Traditional diagnostic methods, such as amyloid-PET scans and cerebrospinal fluid (CSF) tests, are invasive, expensive, and not universally available. Blood-based diagnostics offer a less invasive, more accessible, and potentially cost-effective alternative.

Blood biomarkers are molecular indicators that reflect the presence, progression, or response to treatment of AD. These biomarkers can be classified into several categories based on their diagnostic and prognostic utility:

• Diagnostic Biomarkers: These biomarkers, such as specific protein levels indicative of amyloid or tau pathology, are used to detect or confirm the presence of AD.
• Monitoring Biomarkers: These biomarkers are measured repeatedly to assess disease progression or response to treatment.
• Predictive Biomarkers: These biomarkers identify individuals more likely to respond positively to specific therapies or experience adverse effects.
• Prognostic Biomarkers: These biomarkers indicate the likelihood of disease progression or clinical events in individuals already diagnosed with AD.
• Susceptibility/Risk Biomarkers: These biomarkers, such as the APOE ε4 allele, indicate the potential for developing AD in individuals without clinically apparent disease.

Recent studies have compared the accuracy and cost-effectiveness of blood biomarkers with traditional diagnostic methods. One study found that blood biomarkers, specifically the Ab42/Ab40 ratio, demonstrated lower accuracy (71.72%) compared to amyloid-PET (82.60%) and CSF biomarkers (81.46%). However, blood biomarkers were significantly less expensive ($130.00) than amyloid-PET ($3,935.37) and CSF tests ($468.28), making them a cost-effective alternative.

Another study compared the accuracy of six commercial blood tests in detecting signs of AD, particularly the presence of amyloid plaques and tau tangles in the brain. The analysis showed that some tests, such as those measuring phosphorylated tau 217 (p-tau217), were accurate enough to replace spinal taps and brain scans in many patients with cognitive impairment.

To improve the specificity and diagnostic power of blood biomarkers, researchers recommend:

• Combining Multiple Biomarkers: Using an ATN framework (amyloid, tau, neurodegeneration) or genetic panel testing can enhance diagnostic accuracy.
• Focusing on Specificity: Future research should prioritise developing blood biomarkers with higher accuracy and specificity, rather than solely advancing detection methodologies.
• Role as a Screening Tool: Given their current limitations, blood biomarkers may initially serve as a valuable screening tool to identify individuals who would benefit from more established diagnostic tests.

Senolytics

Senolytics — drugs that selectively eliminate senescent cells — remove senescent cells from AD iNs.

Senescent cells — dormant cells that promote tissue damage with aging — are elevated in the post-mortem brains of Alzheimer’s disease (AD) patients.

An induced neuron (iN) model from AD patients recapitulates post-mortem tissue, including elevated senescent cells.

Herdy and colleagues took post-mortem brains from 30 AD patients and 99 age-matched cognitively normal (NC) individuals and measured CDKN2A mRNA. The CDKN2A gene is considered to be the most specific marker of senescent cells. In AD brains, CDKN2A mRNA levels were increased in a region called the prefrontal cortex, which has an abundance of neurons.

To determine if the CDKN2A gene was being activated in neurons specifically, prefrontal cortex tissue from another set of AD and NC individuals was examined. The CDKN2A gene codes for p16, a protein that can be measured with fluorescent staining. By showing that p16 fluorescence overlapped with fluorescent NeuN, a neuron-specific protein, the researchers demonstrated that senescent neurons were increased in AD brains.

Since it is difficult to test drugs on post-mortem tissue, Herdy and colleagues tested the D + Q senolytic combo on induced neurons (iNs). To generate iNs, skin biopsies were collected from AD patients and non-demented individuals. Then, cells called fibroblasts from the skin samples were converted into neurons using a previously established process. A 3-fold increase in senescent neurons was found in AD iN cultures compared to iN cultures from non-demented individuals, suggesting that iNs can model neuronal senescence.

Clearing senescent cells from the brain of AD mouse models has previously been shown to alleviate cognitive impairment. The pharmacological elimination of senescent cells using D + Q has had similar results. Herdy and colleagues showed that D + Q could lower senescent neuron abundance in AD iN cultures to levels comparable to iN cultures from non-demented individuals. Together with previous findings in animal models, these results suggest that D + Q could alleviate cognitive impairment in AD patients.

Senescent cells can be beneficial for wound healing and preventing the spread of cancerous cells. However, if senescent cells are not cleared and allowed to accumulate, as with aging, they can cause damage to surrounding cells by secreting molecules collectively known as the senescence-associated secretory phenotype (SASP). The results of Herdy and colleagues provide evidence suggesting that these SASP factors are increased AD neurons, leading to increased brain inflammation.

Aging is the single highest risk factor for AD, so targeting the underlying source of aging — including senescent cells — may prove to be a viable treatment option. As such, in an upcoming clinical trial (NCTO4063124) called Senolytic Therapy to Modulate the Progression of Alzheimer’s Disease (SToMP-AD), Mayo Clinic scientists will give five early-stage AD patients 100 mg of dasatinib and 1000 mg of quercetin every two weeks for twelve weeks.

The outcome measures of the STomP-AD study will include senescence markers measured from the spinal fluid of the participants, cognitive function tests, and physical function tests like gait speed and grip strength. The brain will also be imaged via MRI to assess neurodegeneration. With the hope of D + Q leading to improvements in these outcome measures, a phase II clinical trial is already in the works. Therefore, it may not be too long until we use senolytics as a treatment option for AD.

Lifestyle Intervention

Lifestyle intervention and cognition are directly linked, particularly in the context of brain health. Lifestyle medicine addresses several key pillars that are fundamental to maintaining and improving cognitive function throughout life. These include managing stress, ensuring adequate sleep, engaging in physical activity, maintaining a healthy diet, and fostering positive social connections.

Regular exercise is well-documented to improve mood, reduce stress, and enhance cognitive functions such as memory, attention, and executive function. A well-rounded approach to physical activity can contribute to a healthier brain.

Exercise positively impacts metabolic rates, vascular health, psychological well-being, and neuronal connections. High-intensity aerobic exercise for longer durations is considered beneficial, with studies showing a 45% lower risk of AD and a 40% lower risk of cognitive impairment with regular physical activity.

Lifelong cognitive engagement, social interaction, and intellectual stimulation contribute to cognitive reserve, the brain's capacity to resist neuropathological damage. This is considered a critical factor in risk reduction.

Regular exercise is recognized as a primary strategy for promoting longevity, positively affecting both healthspan and lifespan. It is crucial for the prevention, treatment, and management of chronic diseases.

In summary, lifestyle intervention and cognition are deeply interconnected, with lifestyle choices playing a significant role in maintaining and enhancing cognitive function throughout life. By adopting healthy behaviours and making informed choices, individuals can promote cognitive health and overall well-being.