A Review of the Current Status of Disease-Modifying Therapies and Prevention of Alzheimer’s Disease

Introduction

Cognitive function, or the ability to process thought, gradually declines with age [1,2]. Dementia is a syndrome that includes cognitive impairment that occurs at an earlier age than expected and is either preceded by or accompanied by changes in personality and mood, motivation, behavior, and emotional control [2]. An important diagnostic feature of dementia is that these changes are not associated with impaired consciousness [2]. Dementia can be secondary to diseases that destroy nerve cells over time and damage the brain, including Lewy body dementia, vascular dementia, and frontotemporal dementia [1,2]. Secondary dementia may also develop after a stroke, with chronic excessive alcohol use, nutritional deficiencies (including vitamin B1, B12, and folate deficiency), chronic traumatic encephalopathy (due to repeated brain trauma), or associated with infections, including severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and human immunodeficiency virus (HIV) [2,3].

The World Health Organization (WHO) Global Dementia Observatory (GDO) is a monitoring and accountability mechanism for a global action plan for national and public responses to dementia, 2017–25 [4]. The GDO collates data on 35 key dementia indicators from WHO member states to identify and support the needs of those with dementia, their families, and their carers in each country [4]. In 2019, global data from the GDO identified that 55.2 million people were living with dementia, which was the 7th leading cause of death, with 65% of dementia-related deaths in women, disability-adjusted life years (DALYs) more than doubled between 2000 and 2019 and the total global cost of dementia to society was estimated at US$ 1.3 trillion [4].

In 2019, the Dementia Forecasting Collaborators analyzed data from the Global Burden of Disease Study 2019 and forecasted the prevalence in 2050 [5]. Based on analysis of the projected trends in population growth and aging, the number of people with dementia was forecast to increase from 57·4 million cases in 2019 to 152·8 million cases in 2050 worldwide, with a continued female-to-male ratio of 1·67 [5]. This study highlighted the global geographical heterogeneity in the projected increases, with increased cases in high-income Asia Pacific and Western European countries being less than in North Africa, the Middle East, and eastern sub-Saharan Africa [5]. Currently, the WHO estimates that each year, there are nearly 10 million new cases of dementia worldwide and that Alzheimer’s disease is the most common form of dementia in 60–70% of cases [2]. This article aims to review the current status of disease-modifying therapies and prevention of Alzheimer’s disease.

Epidemiology of Alzheimer’s Disease

Alzheimer’s disease is a progressive neurodegenerative condition associated with characteristic pathological changes in areas of the human brain responsible for cognition [6]. Alzheimer’s disease is characterized by an abnormal accumulation of extracellular amyloid β, which forms senile plaques and intracellular neurofibrillary tangles [7]. Although the global prevalence of dementia continues to increase, the incidence in some Western countries may have begun to decrease because of improved vascular care and brain health [8,9]. Alzheimer’s disease, the most common cause of dementia, has been defined pathologically by the combined presence of amyloid and tau protein; this view may be too simplistic [8,9]. Age-related factors, protective factors, and disease-promoting factors may interact with the core mechanisms that drive Alzheimer’s disease [8,9].

Diagnostic Biomarkers

Amyloid β42 and tau proteins are core diagnostic biomarkers that can be quantified in the cerebrospinal fluid (CSF) [8,9]. Magnetic resonance imaging (MRI) and fluorodeoxyglucose positron emission tomography (FDG-PET) are established diagnostic imaging techniques [8,9]. However, novel candidate biomarkers include amyloid β oligomers, synaptic markers, amyloid PET imaging, and tau PET imaging [8,9]. Although these novel diagnostic biomarkers and imaging methods still require validation and there are cost concerns, they could have a role in establishing the definitive diagnosis and be used to select patients for inclusion in clinical trials [8,9]. Recently, clinical research has begun to focus on preclinical Alzheimer’s disease, which is defined as biomarker evidence of the pathological changes in Alzheimer’s disease in cognitively healthy individuals [8,9]. Early studies now indicate that interventions that target several lifestyle factors in cognitively healthy elderly patients and lowering amyloid in pre-dementia Alzheimer’s disease show moderately positive results [8,9]. Therefore, the future approach to controlling Alzheimer’s disease could include specific anti-Alzheimer’s therapy combined with lifestyle interventions that target brain health and prevent cognitive decline.

Tests for Dementia in Alzheimer’s Disease

Alzheimer’s disease can be a complex clinical condition that includes cognitive, personality, and behavioral changes, but most patients will be evaluated for disease severity based on cognitive testing [6]. The severity of dementia is categorized using the Mini-Mental State Examination (MMSE), the Montreal Cognitive Assessment (MoCA), or the Clinical Dementia Rating (CDR) scores [10]. In Alzheimer’s disease, mild dementia has the following scores: MMSE 19–26; MoCA 12–16; CDR 1 [10]. In Alzheimer’s disease, moderate dementia has the following scores: MSE 10–18; MoCA 4–11; CDR 2 [10]. In Alzheimer’s disease, severe dementia has the following scores: MMSE <10; MoCA <4; CDR 3 [10].

The 2024 Alzheimer’s Association Report

The 2024 report from the Alzheimer’s Association in the US has estimated that 6.9 million older adults in the US are currently living with Alzheimer’s disease and that a further 200,000 people <65 years have younger-onset Alzheimer’s disease [11]. This report supports the results from recent predictive modeling studies that the number of people >65 years with Alzheimer’s disease will double by 2050, with a projected 11.2 million cases by 2040 and 12.7 million cases by 2050 [11]. However, this report has also presented concerning mortality data from death certificate records that Alzheimer’s disease-related mortality between 2001 and 2021 increased by 141% [11]. In comparison, deaths from heart disease, the main disease-associated cause of mortality in the US, decreased 2.1% between 2001 and 2021 [11].

The 2024 report from the Alzheimer’s Association has identified that the cost of healthcare and long-term care for people with Alzheimer’s disease continues to rise [11]. The projected total healthcare costs in 2024 are $360 billion, which is a $15 billion increase compared with 2023 [11]. However, this finding does not include the care given by family and friends, which has been valued at an extra $350 billion [11]. The authors of the report have also estimated more than one million additional care workers will be needed before 2031 to provide adequate patient diagnosis and management [11]. Therefore, without developments in prevention, management, and treatment, the Alzheimer’s Association estimates that healthcare costs for Alzheimer’s disease alone in the US will reach $1 trillion by 2050 [2,4,5,11].

Disease-Modifying Therapies

The main approaches to treatment for patients with Alzheimer’s disease have aimed to improve the symptoms of cognitive and behavioral changes [12]. Alzheimer’s disease has distinct neurodegenerative and pathological brain characteristics [8,9]. The most common form, late-onset Alzheimer’s disease, is characterized by extracellular amyloid deposits [13]. Intracellular neurofibrillary tangles develop up to 20 years before the onset of symptoms [13]. Treatments for Alzheimer’s disease modify the symptoms, but there is no cure. Patients with Alzheimer’s disease have reduced cerebral levels of choline acetyltransferase, reduced acetylcholine synthesis, and impaired cortical cholinergic function [14]. The most common disease-modifying agents include cholinesterase inhibitors, often as a first-line treatment in newly-diagnosed patients [14]. Patients with mild to moderate dementia with an MMSE score of 10–26 may have modest clinical benefit and may be prescribed donepezil, galantamine, or rivastigmine [14]. Cholinesterase inhibitors increase cholinergic transmission by inhibiting cholinesterase at the synaptic level [14]. However, there is no evidence that cholinesterase inhibitors are neuroprotective or halt the progression of Alzheimer’s disease [14]. Glutamate is the main excitatory amino acid neurotransmitter in neurons of the cerebral cortex and hippocampus, and the N-methyl-D-aspartate (NMDA) receptor is activated by glutamate [15]. Memetanine is an NMDA receptor antagonist that may have a neuroprotective role in dementia [15].

The role of antioxidants, including vitamin E (alpha-tocopherol) and the monoamine oxidase inhibitor, selegiline, have been evaluated in randomized trials in patients with Alzheimer’s disease with no clear evidence of any beneficial effects [16,17]. The Alzheimer Disease Cooperative Study (ADCS) trial compared vitamin E, selegiline, and combined vitamin E and selegiline with a placebo [17]. The primary outcomes evaluated were the time to a combined endpoint of death, institutionalization, loss of the ability to perform activities of daily living (ADLs), or progression to severe dementia using the CDR scale [17]. Cognitive tests were similar between the groups [17]. Results from a meta-analysis of 12 clinical trials identified eight studies that showed some beneficial effects of selegiline on cognitive function, behavior, and mood [18]. There is no evidence that estrogen replacement therapy is effective in the treatment or prevention of Alzheimer’s disease. The results from large randomized clinical trials have shown that the use of hormone replacement therapy (HRT) with estrogen plus progestin, or estrogen alone, in women aged >65 years and who are free from dementia may increase the risk of developing dementia in later life [19].

There are ongoing studies to evaluate the role of anti-inflammatory drugs in the prevention and treatment of Alzheimer’s disease, as pathophysiologic studies have shown that amyloid induces an inflammatory reaction that involves activation of microglial and release of inflammatory cytokines [20]. There is no evidence from clinical trials that the use of ginkgo biloba, supplementation with B vitamins, or omega-3 fatty acids have a role in preventing or treating dementia in Alzheimer’s disease.

Targeted Disease-Modifying Therapies – Lessons Learned from Aducanumab

Recent drug developments in Alzheimer’s disease aim to identify disease-modifying therapies to delay or slow the clinical course of this disease in a more targeted way [21]. There was a gap of more than two decades before new drug approvals for disease-modifying treatments for Alzheimer’s disease [21,22]. In the past ten years, more than 50% of the Alzheimer’s disease drug pipeline has included immunotherapies or oral small molecules, with the main disease-modifying drug targets being amyloid β and tau protein [22]. In the past four years, the drug pipeline has included disease-modifying immunotherapies and oral small-molecule drugs [21,22]. The potential targets for disease-modifying therapies in Alzheimer’s disease include treatments that clear amyloid β, the prevention of neurofibrillary tangles by the tau protein, prevention of cell oxidation, and treatments that control or improve neuronal metabolism in patients with Alzheimer’s disease [22]. The most promising disease-modifying drug targets have been amyloid β and tau [21,22].

In June 2021, aducanumab, a humanized recombinant monoclonal antibody to amyloid β was the first disease-modifying therapy that received accelerated approval by the US Food and Drug Administration (FDA) to treat Alzheimer’s disease and mild cognitive impairment [23,24]. Aducanumab is a humanized recombinant monoclonal antibody to amyloid β [25]. In 2016, aducanumab was initially shown to enter the brain and bind to parenchymal amyloid β in a preclinical study that used a transgenic mouse model of Alzheimer’s disease and reduced soluble and insoluble brain amyloid β in a dose-dependent manner [25]. After one year of monthly intravenous infusion in a dose-escalation trial that included 165 patients with mild Alzheimer’s disease, aducanumab reduced brain amyloid β levels in a dose-dependent and time-dependent manner (NCT01677572) [25]. Aducanumab reduced clinical decline when measured using the Mini-Mental State Examination (MMSE) scores and the Clinical Dementia Rating scale [25]. Importantly, at 12-month follow-up, positron emission tomography (PET) imaging showed that almost 50% of the patients diagnosed with mild Alzheimer’s disease no longer had cerebral amyloid [25].

Accelerated regulatory approval of aducanumab was based on the results of two phase 3 clinical trials, EMERGE (NCT02484547) and ENGAGE (NCT02477800), with subsequent critical reviews of the efficacy and safety findings [23,26]. The EMERGE and ENGAGE trials ceased early and underwent post hoc analysis of further trial data [25,27]. The EMERGE trial included 1,638 patients, but high-dose aducanumab showed no apparent improvement in cognitive function, even though brain amyloid β levels were reduced on PET imaging [27]. The ENGAGE trial included 1,647 patients, but there was no significant difference in outcome when the treatment and placebo groups were compared [28,29]. Importantly, in 40% of patients treated with high-dose aducanumab, a major reported side effect was amyloid-related imaging abnormalities (ARIA), which included edema (ARIA-E) or micro-hemorrhage (ARIA-H) [28,29]. Although most patients with ARIA are asymptomatic, ARIA can be associated with confusion, headache, and visual disturbance [28,29]. In patients treated with high-dose aducanumab, brain magnetic resonance imaging (MRI) showed fluid-attenuated inversion recovery (FLAIR) hyperintensity, which could be associated with micro-hemorrhages [24,28].

There have been several concerns and limitations of the real-world use of aducanumab. The approval of aducanumab was controversial, as the FDA scientific advisory panel had previously recommended against approval [30,31]. Also, the surrogate endpoint of supporting clinical trials of reducing plaques of amyloid β has not been established to result in clinical benefit [31,32]. Currently, aducanumab has been used primarily in research settings [32]. There are limitations on the availability and cost of screening and identifying early changes of Alzheimer’s disease using MRI or PET scanning, the cost and availability of this therapeutic monoclonal antibody, the requirements for patient follow-up, the known acute and potentially severe side effects that include ARIA, and the unknown long-term side effects [33]. These limitations may explain why, in the US, healthcare insurers refused coverage and clinicians did not prescribe it [33]. Therefore, in February 2024, the US drug company Biogen ceased production and a post-marketing clinical trial and has now transferred the rights to the Swiss firm Neuroimmune, who originally developed this therapeutic monoclonal antibody [33].

Future Personalized Approaches to Treatment

In 2011, the National Institute on Aging and Alzheimer’s Association (NIAAA) developed recommended diagnostic criteria for preclinical, mild cognitive impairment, and the stages of dementia in Alzheimer’s disease based on underlying pathologic processes or in vivo by biomarkers, including β amyloid deposition, pathologic tau, and neurodegeneration (ATN) [13]. The ATN classification system aims to provide a more precise approach to clinical trials and identify specific pathways that can be individually targeted as the disease progresses and in a more personalized way [13].

Other potential targets for disease-modifying therapies for Alzheimer’s disease exist [34]. The Common Alzheimer’s and Related Dementias Research Ontology (CADRO), which provides a classification framework for drug targets and mechanisms of disease-modifying therapies, continues to identify early-stage and late-stage targets for clinical drug development in Alzheimer’s disease [34]. Because of the number of failed phase 3 trials of patients with symptomatic Alzheimer’s disease, CADRO recommends that trials of disease-modifying treatments should be conducted much earlier [34]. In 2018, the FDA published a draft drug development guidance for early Alzheimer’s disease that supports the stages leading to early Alzheimer’s disease [13].

By January 2023, Cummings and colleagues identified 187 clinical trials in progress to assess 141 new treatments for Alzheimer’s disease, including 55 phase 3 trials, 99 phase 2 trials, and 33 phase 1 trials [22]. They identified that 79% of treatments for Alzheimer’s disease in clinical trials were disease-modifying therapies, and 28% of candidate therapies were repurposed agents [22]. Importantly, populating the ongoing phase 1, 2, and 3 clinical trials required 57,465 study participants [22]. Although treatments are available for some symptoms of this disease, there is no cure, and Alzheimer’s disease inevitably progresses [7,8]. The first approval by the US Food and Drug Administration (FDA) of a potentially disease-modifying has highlighted the importance of accurate diagnosis in patients with cognitive impairment and dementia [7,8]

Modifiable Risk Factors and Prevention of Cognitive Decline

In the past decade, studies have begun to identify networks of higher-order brain regions that are particularly vulnerable to age-related changes, Alzheimer’s disease, and other conditions associated with behavioral and cognitive impairment, including Parkinson’s disease and schizophrenia [35]. However, although the most vulnerable brain networks have been identified, the genetic influences that result in impairment in these brain networks and cognitive function and modifiable external factors that accelerate or increase the severity of cognitive impairment have awaited large-scale, long-term studies [36].

The UK Biobank is a large prospective study that includes clinical, demographic, phenotypic, and genotypic data on 500,000 participants aged 40–69 years when initially recruited in 2006–2010 [37]. Input and follow-up continue, and data are available via open access [37]. In March 2024, Manuello and colleagues reported the findings from a study of approximately 40,000 participants from the UK Biobank [36]. This study identified significant genome-wide associations between changes in the vulnerable higher-order brain regions and seven genetic clusters associated with schizophrenia, Alzheimer’s disease, and Parkinson’s disease [36]. The most significant modifiable risk factors affecting this vulnerable brain network were diabetes mellitus, exposure to nitrogen dioxide (a proxy for air pollution), and the frequency of alcohol intake [36]. These recent findings support previous epidemiological studies that have identified potentially modifiable risk factors that may lead to the prevention of dementia and Alzheimer’s disease [38].

In 2020, the Lancet Commission published a report on dementia prevention, intervention, and care with recommendations on improvements in education, health care, nutrition, and lifestyle modifications [38]. This report was evidence-based and supported by systematic review and meta-analysis of the literature [38]. This evidence-based guideline identified 12 potentially modifiable risk factors for dementia: lack of education and awareness of dementia; hypertension; hearing impairment; obesity; smoking; depression; physical inactivity; social isolation; diabetes; excessive alcohol consumption; traumatic brain injury; and air pollution [38]. The Lancet Commission identified that these 12 modifiable risk factors account for up to 40% of cases of dementia worldwide [38]. The Lancet Commission highlighted that lifestyle modifications based on these modifiable risk factors could benefit all age groups [38]. However, public health policy should begin by prioritizing childhood education and implementing initiatives in primary care to prevent cognitive decline [38].

Predictive Studies for Alzheimer’s Disease and Dementia

Although there has been recent interest in disease-modifying therapies and interventions for Alzheimer’s disease, these therapies have yet to show practical, real-world application [22]. Because dementia in Alzheimer’s disease has a long and varied prodromal period, reduction of known risk factors is most likely to be effective at the population level [38].

A further UK Biobank study, reported this year, aimed to identify the clinical evolution or trajectories of multiple types of clinical and health determinants up to 15 years before the diagnosis of dementia [39]. Each patient diagnosed with dementia was matched with ten healthy controls, and logistic regression analysis was conducted on 400 clinical and health predictors [39]. Evolutional trajectories of the clinical and health predictors were quantified statistically at consecutive timeframes preceding the initial diagnosis of dementia [39]. The findings showed that during a median follow-up of 13.7 years until July 2022, 7,620 subjects in the UK Biobank were diagnosed with dementia [39]. The clinical associations at 15 years preceding the diagnosis included a decline in hand grip strength, a decline in lung function (measured by peak expiratory flow), a decline in renal function (determined by cystatin C levels), and a history of coronary heart disease, stroke, diabetes, and mental illness [39]. The results of cognitive function testing showed a decline more than a decade before the diagnosis [39]. In this study, reduced physical activity, sleep duration, and weight loss only showed significant associations within five years of diagnosis [39]. Serum markers of renal, endocrine, and lipid function showed changes immediately before diagnosis but were not significant diagnostic biomarkers [39]. Long-term prospective biobank studies, such as this, provide a comprehensive clinical and demographic temporal diagnostic landscape that could predict and precede incident dementia [39]. These data could be used to improve patient selection for future clinical trials for preventive and early disease-modifying treatment for Alzheimer’s disease and dementia.

Risk Factors and Early Initiatives to Reduce Dementia

Although age is the leading risk factor for dementia, it is not an inevitable consequence of aging, nor does it exclusively affect older people [40]. Young-onset dementia accounts for approximately 10% of cases and is defined as the onset of symptoms before the age of 65 years [41]. Dementia has physical and psychological effects on the affected patient and has social and economic impacts on carers, family members, and society [40,42]. Also, awareness and understanding of dementia still result in delayed diagnosis and lack of care [42].

Epidemiological studies have shown that the risk of cognitive decline can be reduced by increasing physical activity, maintaining a healthy weight, not smoking, avoiding excess alcohol intake, and controlling blood pressure, blood sugar, and cholesterol levels [40,43]. More recent long-term epidemiological studies have identified low levels of education, a history of depression, social isolation, lack of cognitive stimulation, and air pollution as significantly increasing the risk of dementia [36]. The APOE gene encodes the protein apolipoprotein E [44]. Carriers of the APOE E4 allele are at increased risk of age-related cognitive decline and Alzheimer’s disease [44]. Currently, the E4 allele of the APOE gene is the most significant genetic risk factor for mid-life and late-onset Alzheimer’s disease [44]. Although the underlying neural mechanisms are unclear, genotype differences in medial temporal lobe functional activity and structure at mid-age differ by genotype and memory encoding [44]. Therefore, modification of identifiable risk factors, combined with testing for disease-susceptibility genes, including variants of the APOE gene, could be the most effective approach to reduce the incidence of Alzheimer’s disease [44].

In May 2017, the World Health Assembly endorsed the Global Action Plan on the Public Health Response to Dementia 2017–2025 [45,46]. The action plan was prepared for national, regional, and international policy-makers and the WHO, with the aims of addressing dementia as a public health priority, increasing awareness, reducing the risk of dementia, and improving the diagnosis and treatment through information provision, research, and innovation [45,46]. In 2019, the WHO published new guidelines on reducing the risk of cognitive decline and dementia based on the current information [40]. The WHO recommended a public health approach, as many risk factors for dementia are shared with other major non-communicable diseases [40]. These guidelines introduced the possibility that key risk reduction recommendations may be integrated into programs for improved diet, tobacco cessation, and reduction of risk for cardiovascular disease [40].

Future Challenges

The symptomatic management of Alzheimer’s disease has relied mainly on the use of cholinesterase inhibitors [6]. The urgent need for disease-modifying drugs, which has recently driven preclinical studies and drug development, has resulted in the identification of many new potential therapeutic targets [6]. At the beginning of 2024, more than 170 clinical trials are exploring disease-modifying therapies, cognitive enhancement, and reduction of neuro-psychiatric complications of Alzheimer’s disease [6]. The path to developing safe and effective therapies has not been full of challenges, as several advanced-stage clinical trials have been terminated due to a lack of efficacy or an increased incidence of adverse events [6].

There have been several high-profile failures before recent clinical trials of anti-amyloid drugs have provided the evidence for regulatory approvals of the first disease-modifying therapies for Alzheimer’s disease by the US FDA. Recently, Bradshaw and Georges have outlined Alzheimer Europe’s position on anti-amyloid therapies for Alzheimer’s disease, including with member associations and the European Working Group of People with Dementia [47]. An important aim for future drug development and clinical trials is to determine whether sufficient evidence exists to approve disease-modifying drugs for patients with Alzheimer’s disease and mild cognitive impairment or mild dementia [47]. The European position is that in addition to drug efficacy, safety, and cost, regulatory agencies, industry, healthcare systems, and governments should ensure that all patients have timely and equitable access to innovative treatments [47]. There is also a call for continued investment in research on treatments for more advanced Alzheimer’s disease and developments in care and support to help people live well with dementia at all stages of Alzheimer’s disease [47].

Conclusions

The global burden of Alzheimer’s disease on patients, families and carers, healthcare providers, and society continues to increase. Disease-modifying therapies have limited benefits for a disease with no treatment or cure. Recent developments in therapeutic monoclonal antibody therapies have failed to be of practical use. Therefore, the hope for a reduction in Alzheimer’s disease rests on the identification of individual and population risk factors and disease prevention. Modification of identifiable risk factors, combined with testing for disease-susceptibility genes, could be the most effective approach to reduce the incidence of Alzheimer’s disease.