Who is Really a Candidate for New Drugs to Treat Alzheimer Disease?

It’s time to cut through the noise on coverage decisions and restricted access to new drugs for Alzheimer disease (AD)—lecanemab (Leqembi) and aducanumab (Aduhelm)—and move the discussion to what is really top-of-mind for health care providers and payers: “Who is the right dementia candidate for the drug? What other less costly and less invasive options are available to manage mild cognitive impairment (MCI) and remove the vast subjectivity of AD dementia?”

Given the high variability in the progression from MCI to dementia, with >50% of patients who do not progress to dementiaor even AD in 10 years,¹ the quandary remains not only for patients and families, but also prescribers and payers who are weighing the benefits, cost burdens, and health risks associated with these therapies.²

Moreover, a recent population study suggested that 40% of dementia cases could be avoided by addressing known modifiable risk factors, including obesity, hypertension, diabetes, depression, smoking, physical inactivity, hearing loss, loneliness, heart disease, and stroke.³

Deciding on the appropriate intervention for specific individuals weighs heavily on all stakeholders. Addressing a sequence of unmet medical needs is critical to these considerations:

A Diagnostic Pathway to Treatment

Less than 3 weeks after Medicare said no to providing wider coverage of lecanemab, the Veteran’s Administration gave the drug a thumbs up, announcing that it would cover the cost for veterans in the early stages of AD—but how do you accurately diagnose it?

Anti-amyloid treatments such as lecanemab work by attaching to and removing amyloid-beta, a protein that accumulates into plaques, from the brain. These novel treatments will be costly, burdensome, and are criticized for their marginal risk:benefit ratio.⁴ Such issues increase the need for better AD diagnostic tools for the community generalist and neurologist, as well as support payer coverage decisions.⁵

Alzheimer Disease Therapeutics Launched

June 2021: The FDA approved aducanumab (Aduhelm), the first amyloid beta-directed antibody for treating AD.⁶ Aducanumab is a monthly infusion and is associated with a 24% slowing of progression of AD symptoms and is associated with amyloid related imaging abnormalities (ARIA), which affected up to 40% of patients studied.⁷

Pharmaceutical manufacturer Biogen initially priced aducanumab at $56k per year, then reduced the list price to $28k. Due to concerns over clinical results, as well as the risk-benefit profile, CMS declined to cover aducanumab outside of clinical trials.⁸ Furthermore, CMS stipulated that the patients have (1) either MCI due to AD or AD dementia, and (2) evidence of amyloid consistent with AD.

January 2023: The FDA granted accelerated approval for lecanemab (Leqembi); the second amyloid beta-directed antibody indicated for the treatment of AD. In clinical trials of patients with MCI due to AD or AD dementia, lecanemab demonstrated a 27% slowing in progression of cognitive decline over an 18-month period.⁹

It is a bi-weekly, infusion therapy and Eisai, the maker of lecanemab, has priced the therapy at $26,500 per year.¹⁰ Due to the risk of ARIA, patients will be required to have 4 MRI scans during the first 6 months of treatment to evaluate potential ARIA with edema or with hemorrhaging. Consistent with its previous guidance, CMS has declined to cover lecanemab outside of a clinical trial.¹¹

As these and other drugs gain coverage, decision-makers will need to more accurately diagnose AD, especially in the community setting. The current pathway, which is broadly defined as the route that patients take from first presenting with symptoms to receiving an accurate diagnosis, is woefully inadequate, with major challenges that include:

Is it AD or Dementia?

The National Institute on Aging (NIA)advisesthat AD disrupts this communication among neurons, resulting in loss of function and cell death. The brain typically shrinks to some degree in healthy aging but, surprisingly, does not lose neurons in large numbers. In AD, however, damage is widespread, as many neurons stop functioning, lose connections with other neurons, and die.

AD disrupts processes vital to neurons and their networks, including communication, metabolism, and repair. Many molecular and cellular changes take place in the brain of a person with AD. These changes can be observed in brain tissue under the microscope after death and include amyloid plaques, neurofibrillary tangles, and chronic inflammation.¹⁴

Amyloid beta can increase synaptic dysfunction and accelerate formation of neurofibrillary tangles that eventually cause synaptic failure and neuronal death. While amyloid plaque and tangles are hallmarks of disease at death, cognitive decline during life is caused by damage to the synaptic connections between neurons.¹⁵

The NIA defines dementiaas the loss of cognitive functioning—thinking, remembering, and reasoning—to such an extent that it interferes with daily life and activities.¹⁶ Some people with dementia cannot control their emotions, and their personalities may change, but this may not necessarily be AD. According to the CDC, dementia can be caused by many conditions, some of which are reversible, whereas others are not.¹⁷

Reversible causes of dementia include adverse effects of medication, increased pressure in the brain, vitamin deficiency such as B12, depression, and thyroid hormone imbalance, all of which can be identified and treated.

Irreversible causes of dementia include not just AD, but also Lewy body, vascular, and front-temporal dementia, for example.¹⁸ To further complicate the diagnostic picture, up to 83% of patients with dementia may have multiple causes of the condition occurring simultaneously with AD, commonly known as mixed dementia.¹⁹

As a result of this complexity, clinicians are dissatisfied with the current diagnosis pathway, with many citing a high degree of subjectivity in the diagnosis and the absence of a definitive test to identify AD and distinguish it from other forms of dementia.²⁰

Role of New Tools, Benefits of Early Intervention

Recently available to PCPs and community neurologists, an autopsy-validated skin test has shown >95% sensitivity and specificity to directly identify AD in people recently diagnosed with dementia, even in those with mixed dementia. This signals a new era for increased physician diagnosing and prescribing confidence and better outcomes for patients. Moreover, this type of test supports physician recommendations for people living with SCD or MCI to address lifestyle changes that slow disease progression.

The CDC has identified factors such as hypertension, diabetes, depression, hearing loss, obesity, cigarette smoking, and a lack of physical activities as modifiable risk factors for AD and related dementias.²¹ As noted previously, more effectively addressing these modifiable risk factors may prevent 40% of dementia cases.

Even modest lifestyle changes can be impactful. Data recently presented at the Clinical Trials in Alzheimer’s Disease conference suggested that mild physical activity could stabilize cognition over a 12-month period in people with MCI.22Additionally, data were also presented suggesting that addressing modifiable risk factors through telephone counseling could also slow cognitive decline.²³

Promising Research Underway

Many of the prevention and treatment studies in progress for AD and related dementias do not involve drug candidates that interfere with disease pathways. Instead, these NIH-funded studies are exploring lifestyle and behavioral interventions.²⁴

These interventions include cognitive training, a healthy diet and exercise, as well as combinations of these strategies with pharmacological treatments. While these promising advancements may lead to more cost effective and less burdensome options for patients with MCI or AD dementia, the first step remains access to more accurate diagnostics in the generalist setting.

3. Rolandi et al. Alzheimer's Research & Therapy (2020) 12:94. https://alzres.biomedcentral.com/articles/10.1186/s13195-020-00661-y. accessed March 17,2023

11. https://www.cms.gov/newsroom/press-releases/cms-statement-response-alzheimers-associations-request-reconsider-final-national-coverage

12. Hansson, O; The Alzheimer’s Association appropriate use recommendations for blood biomarkers in Alzheimer’s disease,Alzheimer’s Dement. 2022;1–18.

13. Petrazzuoli F, et al. Brief Cognitive Tests Used in Primary Care Cannot Accurately Differentiate Mild Cognitive Impairment from Subjective Cognitive Decline. J Alzheimers Dis. 2020;75(4):1191-1201. doi: 10.3233/JAD-191191. PMID: 32417771; PMCID: PMC7369041. https://pubmed.ncbi.nlm.nih.gov/32417771/. accessed 3.18.2023.

15. Gómez-Isla, T., Frosch, M.P. Lesions without symptoms: understanding resilience to Alzheimer disease neuropathological changes. Nat Rev Neurol 18, 323–332 (2022). https://doi.org/10.1038/s41582-022-00642-9

18. Biundo R, Weis L, Fiorenzato E, Pistonesi F, Cagnin A, Bertoldo A, Anglani M, Cecchin D, Antonini A. The contribution of beta-amyloid to dementia in Lewy body diseases: a 1-year follow-up study. Brain Commun. 2021 Aug 19;3(3):fcab180. doi: 10.1093/braincomms/fcab180. PMID: 34458730; PMCID: PMC8390473. https://pubmed.ncbi.nlm.nih.gov/34458730/.accessed 3.18.2023.

20. Datar, et al Clinical Utility of a Novel Test to Diagnose Alzheimer’s Disease in Patients with Suspected Dementia, Annals of Cytology & Pathology, December 2022

22. Alzheimer’s Association; Topline Results of EXERT: Can Exercise Slow Cognitive Decline in MCI?:December 20, 2022; https://doi.org/10.1002/alz.069700. accessed 3.17.2023.