Inequalities in the Prevention and Treatment of Alzheimer Disease

Abstract

Incidence of Alzheimer disease (AD) is going to rise in the next years and to become a health and social emergency. The prevention and the therapeutic management of AD still present unmet needs worldwide. The recent approval of monoclonal antibodies against amyloid β (anti-Aβ mAbs) for AD has increased the level of uncertainty regarding on how such drugs should be administered, to whom, and for how long. Concerns about cost-effectiveness ratios of anti-Aβ mAbs and the need for actual strategies of risk prevention have further dug barriers of inequalities between the national health care systems. Planning research to address questions on the real feasibility of the correct therapeutic management, improving international cooperation on surveillance of risk factors, implementing pathways for timely diagnosis, and effective medical and social support for patients with AD worldwide would be extremely valuable to fight against this upcoming pandemic.

Life Expectancy and Incidence of Dementia

One of the pathologies whose prevalence will increase in the near future is dementia.¹ The increase in life expectancy worldwide will result in an aging general population and, therefore, a greater prevalence of the age-related diseases, including dementia.¹ Several risk factors have been identified as modifiers of both the number of years of life lost² and of the number of years lived with dementia.³ Environmental risk factors include the use of dirty and not sanitized water, air pollution, malnutrition, and second-hand tobacco smoke. Personal risk factors encompass elevated systolic blood pressure, glucose intolerance, high body mass index, high low-density lipoprotein cholesterol level, kidney disease, sexually transmitted diseases, alcohol abuse, head injury, and occupational risks.^2,4-6 Because effective management of these risk factors cannot be insured equally in all countries of the world because of disparities in both national economies and health systems, maintaining health and preventing dementia become grounds for inequality.⁷

Future Variations in Demographics and Risk Factors of AD

Health policies targeting disease prevention and therapeutics are commonly established based on the results of previous epidemiologic studies. The world is facing changes whose speeds closely resemble a growing exponential curve rather than a straight line with a constant slope. The bulk of dementia-related risk factors may change accordingly, and we may fight against unknown or unpredictable risk factors in the future.

Comparing populations from different generations is not a straightforward task, and the individuals who will be age 50 years in 2040 cannot be readily compared with those who were age 50 years in 1990. Genetic and epigenetic factors will change the prevalence and phenomenology of diseases in an incomparable way. Changes in pollution levels, average ambient temperature,⁸ frequency of tumors, and the introduction of new drugs with significant potential, such as immune checkpoint inhibitors, could introduce novel and unforeseen risk factors of dementia.

Social withdrawal is a well-established risk factor of dementia, and its increase would greatly weaken efforts to reduce the incidence of cognitive dysfunction.⁹ We are experiencing an enormous shift from face-to-face contact to remote interactions through communication technologies established either for work purposes or social interactions. As a result, the excessive use of social media minimizes and simplifies interactions to a virtual and discontinuous level, thus worsening social withdrawal.

Difficulties in Implementing Sustainable and Realistic Strategies in the Adoption of New Anti-Aβ mAbs Drugs for AD

AD has been recently characterized by the appearance of drugs promising for modifying the disease history (disease-modifying drugs [DMDs]). Aducanumab, donanemab, and lecanemab are monoclonal antibodies (mAbs) capable of binding to and scavenging the protein amyloidβ (Aβ) which triggers neurodegeneration in AD.¹⁰

General results from trials exploring the effects of lecanemab and aducanumab revealed small significance and raised concerns on its clinical relevance in clinical practice.^11-13 At least some of these disappointing results were possibly related to the inclusion of patients who were already in the clinical phase of AD, either mild cognitive impairment or mild dementia. These might be too advanced stages of AD for anti-Aβ mAbs to be effective because cognitive deficits appear many years after the onset of the amyloidogenic and neurodegenerative cascade in the brain.

Possibly, starting DMDs in the very early prodromal stage of AD on the guidance of either blood or brain imaging biomarkers which are currently under study might enhance in the future the clinical effect of anti-Aβ mAbs at a higher level than that observed in previous clinical trials.

However, given the extension of life expectancy and the well-established evidence of Aβ accumulation in the aging brain,¹⁴ it is reasonable to assume that an increasing number of aged individuals will carry Aβ in the next future. Therefore, the question arises: At what serum concentration and when should biomarkers truly be considered as predictive of pathology? Can biomarkers cutoffs be ever considered significant at the same levels in future populations?

Complexity and Costs of AD-Related Strategies

The current AD-associated costs vary greatly across nations worldwide.¹⁵ Expenditure items include the costs derived from diagnostic activities for patients, increased utilization of pharmacologic therapies to address various comorbidities, costs incurred for symptomatic or rehabilitative AD therapies, diminished productivity of both patients and caregivers, greater frailty, and the need for assistance in carrying out daily activities (Figure 1).¹⁶ In Europe, costs can vary from approximately 8,000 euros/year in the Eastern Europe to more than 70,000 euros/year in the British Isles.¹⁶ In low- and medium-income countries (LMICs) the annual costs for severe forms of dementia span from as little as 5357,09 US dollars/year in India up to 25.510 US dollars/year in the richer China.¹⁷

Figure 1. Expenditure Items Responsible for Future Inequalities in the Prevention and Treatment of Alzheimer Disease.

The availability of anti-Aβ mAbs has made the direct cost scenario for treating AD even more complex. As LMICs will endure the greatest explosion of dementia cases in the coming decades, the resulting costs will increase exponentially in these countries. Costs for anti-Aβ mAbs will exacerbate the hefty total costs of managing patients with dementia,¹⁸ making it virtually impossible to supply them to all eligible patients and increasing current inequalities between high-income countries (HICs) and LMICs.

The cost of lecanemab supply would rise to $120 billion if all patients with AD were elected to receive treatment in the United States.¹² Beyond being scarcely sustainable even for a rich nation like the United States, such an expense would unequivocally lead to the abandonment of existing effective symptomatic therapies and the restriction of lecanemab prescription to only a small percentage of patients, who are probably the richest and able to pay for larger insurance costs. These consequences could exacerbate inequalities in the management and treatment of AD, even in a rich country like the United States.

Perspectives for Sustainable Prevention and Treatment of AD

In the real world, where the necessity to make health policy decisions based on the optimal cost/benefit ratio will continue to rise, it will become increasingly important to modulate preventive and therapeutic medicine choices based on precision medicine studies.¹⁹

Epidemiologic studies will have to identify, with the utmost precision, the risk factors profile at either the individual or the population levels worldwide. Numbers of people with dementia are expected to rise under a deeper slope in LMICs with respect to HICs because of population growth and greater diffusion of specific risk factors in the first.²⁰ Thus, having built a fingerprint of the risk factors insistent on its own territory, each geopolitical unit (at a national or, possibly, continental level) will have to institute suitable health policy actions aimed at the removal or at the reduction of all risk factors of dementia acting on its own population. To facilitate the achievement of these goals, even by the most economically disadvantaged nations, international economic funds need to be established, from which the aforementioned nations can avail resources. Overall, several risk factors of dementia, such as pollution, contaminated food, and infectious diseases, have the potential to “cross” geopolitical borders, and rebounds on health can be felt even at 1,000 of kms apart. The large-scale implementation of health economic policies depends on a collective multinational awareness and costly interventions which, unfortunately, have not always implemented in a shared way up to date.²¹ Therefore, strategic and drastic interventions beyond the borders of the single country should be adopted in the future (Figure 2).⁷

Figure 2. Key Recommendations for Governments and National Health Systems to Improve Sustainability and Reduce Inequalities in Alzheimer Disease Prevention and Treatment.

Studies of precision medicine should identify a panel of low-cost biomarkers useful for identifying AD in the prodromal phase. This would allow the start and maintenance of the optimal treatment schedule according with an individual tailored approach and the best cost/benefit ratio.²²

The allocation of economic resources devoted to AD management and therapeutics will undoubtedly face difficult choices. Future studies will need to clarify the true long-term magnitude of protective effect of anti-Aβ mAbs by an individual and a social point of view. If this proves to be more important than ongoing therapies, the latter should be put aside to concentrate all economic efforts on anti-Aβ mAbs. Lacking this evidence, a reasonable decision from health policies could be to continue granting existing symptomatic drugs, such as donepezil, to patients with AD without investing in expensive anti-Aβ mAbs.

Conclusions

The forthcoming AD pandemic has raised several issues regarding affordability, suitability, safety, and effectiveness of prevention and therapeutic strategies. Setting up the most effective and inclusive preventive protocols worldwide appears to be critical. Studies have to clarify whether adoption of anti-Aβ mAbs therapeutic strategies would have clear-cut positive long-term effects on preventing the clinical onset of AD. Comparison of the cost/benefit ratio of these DMDs with respect to ongoing therapies is also of fundamental importance.

The sustainability of preventive and therapeutic strategies against AD will increasingly need to shift from relying solely on general concepts and approaches, as has been the case until now, toward a medical approach that is based on the principles of evidence, specificity, and precision.

Appendix. Authors

Name	Location	Contribution
Maurizio Giorelli, MD, PhD, MMSc	Operative Unit of Neurology, Barletta, ASL BT, Italy	Drafting/revision of the manuscript for content, including medical writing for content; major role in the acquisition of data; study concept or design; analysis or interpretation of data

Study Funding

The author reports no targeted funding.

Disclosure

The author reports no relevant disclosures. Full disclosure form information provided by the author is available with the full text of this article at Neurology.org/cp.