The Scale of the Problem with Persistent Unmet Needs

Dementia is an acquired loss of cognition in multiple cognitive domains sufficiently severe to affect social or occupational functions. Dementia currently affects 47 million individuals globally and is expected to increase to 131 million by the year 2050. According to epidemiologic studies, the prevalence of dementia is approximately 15% in older adults above the age of 68 and attributed by Alzheimer¡¦s disease (AD) with over 5 million individuals currently affected by AD and projected to increase by up to 13.8 million by the year 2050¹. It is also the 6^th leading cause of death and 5^th leading cause of morbidity among older adults above the age of 65¹. So, what is AD? It is a neurodegenerative disorder that affects the older adults and is characterised by a progressive decline in cognition. AD is the most predominant form of dementia and is categorised by the World Health Organisation (WHO) as a disease of public health priority².

The slow and progressive memory loss seen in AD, followed by cognitive impairment is related to aberrant accumulation of toxic protein fragments, known as the amyloid-beta (Aβ) and microtube-associated Tau protein². In addition, there are two forms of AD, early-onset (affecting those aged between 30-65 years) and late-onset (affecting those above the age of 65). Furthermore, the aetiology of AD can be divided into familial or sporadic cases². With the recent medical advances, the global life expectancy has increased in parallel with the aging population. However, the burden of AD has also increased steadily and will continue to rise, putting more strain on the healthcare systems, globally³. Current therapeutics for AD may help to improve cognitive symptoms in some patients but they do not treat the underlying causes of dementia or slow the rate of the disease progression⁴. Furthermore, the success rate for the development of disease-modifying drugs for dementia remains dismal, until recently.

The True Face of Alzheimer's Disease

AD is a neurodegenerative disorder that typically begins in the entorhinal cortex within the hippocampus⁵. The risk factors for AD includes trisomy 21 (for early-onset AD), increasing age, traumatic head injuries, depression, cardiovascular and cerebrovascular diseases. In addition, smokers and those with a family history of dementia are also at an increased risk of developing AD⁵. But why smoking? Well smoking is a well-known risk factor for dementia and accounts for the third highest population-attributable percentage of dementia cases (5.2%). A Korean cohort study by Jeong et al., (2023) with 789,532 participants investigated the relationship between smoking intensity and lowering the risk of dementia⁶. The study found smoking cessation was associated with reduced risk of dementia compared with the sustained smoking (Figure 1)⁶. Furthermore, an increased risk of dementia was found in patients who reduced or increased cigarette smoked per day compared to those who sustained a consistent rate of consumption. The study concluded that smoking cessation instead of smoking reduction should be emphasised in reducing the disease burden of dementia⁶.

Figure 1.  Smoking cessation, but reduction, was associated with a lower risk of all dementia, including Alzheimer¡¦s disease, and vascular dementia. * Statistical significance⁶.

Aside from smoking cessation, are there any preventative strategies for AD? Very recently, Yu et al., (2020) performed a systematic review and meta-analysis on the current evidence on AD prevention. A total of 44,676 reports were identified with 243 observational prospective studies (OPSs) and 153 randomised controlled trials (RCTs) which were included in the study. Twenty-one suggestions were proposed based on the consolidated evidence with class I suggestions targeted 19 factors (10 with level A strong evidence and 9 with Level B weaker evidence [Figure 2])⁷. Notably, AD often affects the cognitive function, which declines as the disease progresses⁸. Overtime patients develop progressive deficits in cognitive, emotional, and physical functions, which causes significant functional disability and loss of independence. As the disease progresses, there are additional signs of neuropsychiatric symptoms such as periods of confusion, disorientation, mood change, aggression/agitation, and eventually delusion and hallucination during terminal stages of the disease⁹.

Figure 2.  Distribution of modifiable factors with Class I recommendation throughout the course of life. Class I suggestions (benefit >> risk due to intervention) risk factors include 10 factors with Level A evidence (cognitive activity, hyperhomocysteinaemia, increased BMI in late life, depression, stress, diabetes, head trauma, hypertension in midlife, orthostatic hypotension and education) and 9 factors (obesity in midlife, weight loss in late life, physical exercise, smoking, sleep, CVD, frailty, atrial fibrillation and vitamin C) with Level B evidence. The x-axis represents the mean age of the total sample (solid circle) with a range of mean age (short horizontal life) for observational prospective studies included. The y-axis represents the summary relative risk (RR)⁷. AD= Alzheimer¡¦s disease; OH= orthostatic hypotension; CVD= cerebrovascular disease; IMT= intima-media thickness⁷.

An Early Sign of a Promising Future in AD Treatment

Individuals who experience functional impairments or activity limitations in cognitive domains often require support of others to carry out their activity of daily living (ADL)¹⁰. Moreover, most of the support for individuals with cognitive impairment living in the community is provided by family, friends, and neighbours, who are called informal caregivers¹⁰. Therefore, the burden upon them is significant and notably, all the currently approved treatments for AD are symptomatic agents that aim to improve cognitive and behavioural symptoms without altering the underlying course of the disease¹¹. Recent studies have suggested that amyloid removal may slow the progression of the disease, therefore, emerging treatment include anti-amyloid antibody (aducanumab), which has received the accelerated approval from the Food and Drug Administration (FDA) has shown to be a valuable arsenal in combating AD¹². Other promising agents include lecanemab, which is a humanised monoclonal antibody that binds with a higher affinity to soluble amyloid-beta (Aβ) protofibrils. In a recent multicentered, double-blind, phase 3 trial involving a total of 1,795 participants between the ages of 50-90 years with early AD (mild cognitive impairment or mild dementia due to AD) with evidence of amyloid on positron emission tomography (PET) or by cerebrospinal fluid testing were randomly assigned to receive intravenous lecanemab (10 mg per kilograms of body weight every 2 weeks) or placebo¹². The primary endpoint was the change from baseline at 18 months in the score on the Clinical Dementia Rating-Sum of Boxes (CDR-SB; range, 0-18, with higher score indicative of greater impairment). Key secondary endpoints were the change in amyloid burden on PET, the score on the 14-item cognitive subscale of the AD Assessment Scale (ADAS-cog14; range, 0-90; higher score indicative of greater impairment), the AD Composition Score (ADCOMS; range, 0-1.97; higher score indicative of greater impairment), and the score on the AD Cooperative Study Activities of Daily Living Scale for Mild Cognitive Impairment (ADCS-MCI-ADL; range from 0-53, with lower scores indicative of greater impairment)¹².

The results obtained from the study showed lecanemab reduced the markers of amyloid in early AD and resulted in moderately less decline on measures of cognition and function compared to placebo at 18 months (difference, -59.1 centiloids; 95% confidence interval [CI], -62.6 to -55.60; p<0.001) (Figure 3)¹². However, some of the reported side-effects with lecanemab included oedema or effusion seen on the imaging modalities in 12.6% of cohorts¹². Moreover, few cases reported serious adverse effects which included microhaemorrhage and rarely macrohaemorrhage in patients receiving lecanemab with concomitant anticoagulation¹³. Even though lecanemab¡¦s therapeutic effects are undeniably better than the previous AD treatment, the therapeutic effects of lecanemab is not prevalent in all AD patients since 60-75% of AD patients often carries a defective gene for apoliprotein E4 (APOE4). APOE4 has shown to enhance the development and progression of AD¹⁴. Unfortunately, lecanemab does not slow the cognitive decline in APOE4 carriers; instead it enhanced the decline in individuals with two APOE4 genes mutations¹⁴. Regardless of the questions raised, the true therapeutic benefits of lecanemab is yet to be explored further in real-world studies as these treatment options may pave a way for the new disease-modifying agents in the future. Despite the persist unmet needs in AD and other forms of dementia, the future of dementia may not look as bleak as it was in the past.

Figure 3.  Results from the trial shows the change in amyloid burden from baseline on PET as measured in centriloids (with either florbetaben, florbetapir, or flutemetamol tracers) in a trial sub-study. PET= positron-emission tomography¹².

References

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