List of Comments
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PLEASE NOTE: The Public Comments included here are not an endorsement of the views or information by National Alzheimer's Project Act, its Advisory Council members, the Administration or the federal agencies involved in this project.
I am the Industry Director for PET Drugs at MITA. My thanks to the Advisory Council for allowing MITA to comment today.
With the encouraging FDA approval of Aduhelm™, it becomes even more important that the appropriate patients, those who have the amyloid plaque the drug is targeting, get identified to go on to treatment. FDA-approved amyloid and tau imaging PET agents are available today to detect the hallmark pathologies of Alzheimer's disease.
Amyloid PET imaging was used in the most extensive Alzheimer's disease study ever conducted, the IDEAS Study, and resulted in a change in a patient's disease management over 60 percent of the time. In 36% of cases, there was a change in diagnosis as a result of the patient's PET scan results. 77% of patients in the Study had a diagnosis of Alzheimer's Disease before the PET scan, but in over 3,100 patients, the PET scan was negative, meaning no amyloid pathology could be detected in the brain.
But amyloid PET diagnostics are currently non-covered by CMS. We urge CMS to immediately open the non-coverage reconsideration request that was submitted last September to prevent a delay in patient access to the first ever disease modifying treatment.
With regard to Medicare payment, the current inequitable "packaged" payment methodology makes these new, targeted diagnostic radiopharmaceuticals a financial liability to hospitals, particularly acute in some states that limit PET scanning outside of hospital outpatient departments.
A recent GAO report highlighted the enrollment challenges to the New IDEAS Study which examines Alzheimer's in the minority population. The enrollment challenges are a direct result of the CMS packaging policy which results in significant losses in the Medicare outpatient hospitals. As an update to the GAO Report, only about a handful of the hospitals invited to date have accepted the invitation to participate in New IDEAS.
We urge support for rational coverage and payment policies for amyloid PET diagnostics to help ensure the right patients are selected to receive Aduhelm™.
Thank you for allowing me to comment today.
Thank you to this committee and for the opportunity to bring the voice of people living with dementia. I work for Teepa Snow's Positive Approach to Care. We educate and advocate for people living with dementia, their families, and professionals.
As you have heard from Dr. Beresh, we have spent the past weeks fielding calls from families and providers with regard to the information coming out daily on aducanumab. They are confused and desperate, without a proper infrastructure around disease modifying protocols.
We ask this committee to not only continue to support the excellent sub-committee work reported on today, but also to advocate for two public health areas. First, we can all agree that we are talking about dementia here, today, and not just Alzheimers. We ask the committee to demonstrate leadership by using consistent nomenclature--first by changing the name of the committee from Alzheimers to dementia. Second, we ask that the committee advocate for public health services funding to identify best practices around infrastructure for disease modifying protocols. Specifically, we ask for public health funding around: (a) access to diagnosis; (b) infrastructure around dissemination of enrollment, findings, and efficacy of clinical trials; and (c) infrastructure around creation and dissemination of practice guidelines to establish standard of care for disease modifying protocols, including cost-benefit language for providers and families with an emphasis on meaningful clinical outcomes, especially with regard to magnitude of benefit.
Thank you all for your work.
Good afternoon. I live with Mild Cognitive Impairment with early Onset Dementia. I would like to believe that this new drug was my ticket out, but instead I am discouraged by the findings.
This drug has twice been rejected by the FDA and in November, ten of the 11 panel members voted that there was not enough evidence to show that this drug could slow cognitive decline. It has now been passed in its third presentation and since its introduction on June 7, has had to revise and narrow the patient base that it can be used for. There was still no convincing evidence that it slowed down the patients' cognitive decline, but instead it based its approval on the drug's ability to reduce levels of amyloid protein in the brain. It does not treat, nor does it cure, Alzheimers.
The cost is $56,000 per year. This does not include administration of the drug or the ancillary costs such as multiple MRI and PET scans to monitor the effects of the drug on the brain or make a difference in the patient's cognition. Further, this medication has not been tested on a population of patients with co-morbid conditions such as diabetes or heart disease. Now hospital systems such as Cleveland Clinic and Mount Sinai, as well as some insurance companies, are already restricting the use of this drug. There has already been a Congressional investigation started about the approval process, marketing, and pricing of this controversial drug. We all want hope, and need hope, but this is not the panacea.
Cost estimates will break the back of Medicare. People will demand the drug because they know it is there but will be very frustrated when they are told they don't qualify for the medication. If I thought this would help patients with dementia, I would be the first in line. However, after what I have heard and read I just don't think so. But this is just my opinion.
I am with the Association for Frontotemporal Degeneration. Thank you for this opportunity to offer input from the perspective of FTD one of the "related dementias".
AFTD strongly supports adding a sixth goal to the National Alzheimer's Plan. Reducing the burden of risk factors for Alzheimer's disease and the related dementia is a vital and achievable goal. As scientific understanding of modifiable risk factors for dementia grows it is increasingly important that the nation's response, as expressed by the National Alzheimer's Plan, include public health and policy steps to address these risks, and potentially delay onset and reduce the prevalence of ADRD. We greatly appreciate the work of the Risk Reduction sub-committee and the attention you have given to all forms of dementia.
The majority, of the research on modifiable risk factors for dementia has, understandably, focused on Alzheimer's Disease. It seems fair to assume that reducing the ten modifiable factors that the subcommittee identified will benefit those living with FTD. However, with an estimated 60% of FTD cases considered sporadic and without more focused research on non-genetic risk factors for FTD we will only be able to make that assumption. There is a great need for more research on risk factors associated with non-Alzheimer's dementia. AFTD strongly supports the addition of this sixth goal along with the strategies and recommendations made by the Risk Reduction Subcommittee but urge the subcommittee to be more explicit in their recommendations for additional research to determine whether and to what extent modifiable risk factors for dementia effect non-Alzheimer's dementia including FTD, Lewy Body Dementia and mixed dementias.
Good afternoon. Thank you for the opportunity to offer brief remarks to the Advisory Council. The FDA approved ADUHELM under the accelerated approval pathway based on reduction in amyloid plaques, a biomarker that is reasonably likely to predict clinical benefit. ADUHELM has been studied extensively in clinical trials.
ADUHELM is an amyloid beta-directed antibody indicated for the treatment of Alzheimer's disease. Treatment with ADUHELM should be initiated in patients with mild cognitive impairment or mild dementia stage of disease, the population in which treatment was initiated in clinical trials. There are no safety or effectiveness data on initiating treatment at earlier or later stages of the disease than were studied. This indication is approved under accelerated approval based on reduction in amyloid-beta plaques observed in patients treated with ADUHELM. Continued approval for this indication may be contingent upon verification of clinical benefit in confirmatory trial(s).
We are at a historic juncture in the treatment of Alzheimer's disease. I feel honored and humbled to be here to speak not only to the discovery and FDA's accelerated approval of ADUHELM that has brought us to this point, but to what we believe it has the potential to mean in the lives of people with AD, their caregivers, families, friends, and the doctors, nurses and so many others that help care for them, as well as to the scientific community that can build on this and drive further innovation. A diagnosis of mild cognitive impairment due to AD or mild AD before June 7, 2021, was different from being diagnosed today. Today there is something we can offer to appropriate patients; there is a treatment option. We believe we are on a path that diseases like MS have been on before, where the first treatment that was approved sparked further innovation and builds on the scientific understanding we now have. Our focus now must be on working together to support access to care for the right patients and work on future innovative treatments to change the course of the disease.
It is a privilege to be part of this moment where I can tell my family members, friends, and this community that there is a new treatment option that we believe is likely to catalyze a renaissance in future AD medicines. While we launch ADUHELM, we are also continuing to invest in more than 30 clinical development programs. These include several potential additional treatments for Alzheimer's disease and other debilitating neurological conditions such as Parkinson's disease, amyotrophic lateral sclerosis (ALS), and stroke. Today AD is a progressive disease, but as the field continue to innovate, our hope is that one day it will be different. Thank you.
Lilly is excited that meaningful change for people living with Alzheimer's disease is upon us. However, hope from the availability of current and future approved amyloid plaque-reducing therapies can become reality only if patients have timely and equitable access to both diagnostics and therapies.
In addition to informing treatment duration, existing and emerging diagnostics can identify the patients who likely will, and will not, benefit from these therapies. Existing data suggest approximately 40% of clinically diagnosed AD patients are actually negative for amyloid plaque by amyloid PET scan. Amyloid-negative patients are highly unlikely to benefit from amyloid plaque targeted therapies, so patient burden from unhelpful therapies would be minimized and economic resources could be saved if these tools were readily accessible and reimbursed. To minimize unnecessary resource utilization, CMS needs to establish appropriate coverage and payment rates for Alzheimer's diagnostics, including amyloid and tau PET.
Class-based access decisions for therapeutics are pre-mature at this time because amyloid-lowering agents may have different degrees of amyloid plaque reduction, trial entry criteria, dosing approaches, and duration of treatment. CMS coverage policies on Alzheimer's therapeutics should evaluate each product based on its own label, clinical trial design, and results. Limitations placed on the first product should not automatically apply to future products.
Lilly supports post-marketing confirmatory trial commitments for products under accelerated approval. Such commitments should be guided by the FDA rather than CMS.
Establishing sufficient coverage for the patients that is consistent with the studied populations is necessary. Lilly does not support class-based Coverage with Evidence Development (CED) as the only form of coverage for all new beta amyloid-targeted therapies because each new treatment has its own benefit-risk profile, and CED alone would be too limiting to current and future patients.
We urge providers, payers, and policymakers to work together to provide access to Alzheimer's diagnostics and therapies for patients who are most likely to benefit. Let's together ensure we are helping patients rather than hindering progress.
- Rabinovici GD, Gatsonis C, Apgar C, et al., "Association of Amyloid Positron Emission Tomography with Subsequent Change in Clinical Management Among Medicare Beneficiaries with Mild Cognitive Impairment or Dementia," Journal of the American Medical Association 2019; 321(13): 1286-1294.
For those don't know me, I'm Senior Director of Research and Advocacy from the Lewy Body Dementia Association (LBDA). And I lost my father to Lewy body dementia (LBD).
LBDA receives questions about aducanumab from the LBD community because over 50% of those with LBD have co-existing Alzheimer's disease (AD). And this mixed pathology results in worsened outcomes than just Lewy body disease alone.
Our position on aducanumab as it pertains to aducanumab and Lewy body dementias is this: People with LBD can have severe medication side effects that are not common in people with Alzheimer's. As such, clinical trials are needed to determine if aducanumab is safe and effective in people with LBD who also have co-existing Alzheimer's disease.
To be clear, LBDA strongly advocates for the study of aducanumab in individuals with LBD who have coexisting AD. There are extremely important unanswered questions about safety and potential long-term benefits in LBD that must be answered. LBDA supports a network of experts in LBD through its Research Centers of Excellence Program. If there is a decision to conduct a study of aducanumab in LBD, LBDA and its Research Center of Excellence Program is prepared to participate in such a study.
Given that most people with dementia have more than one disease process underlying their symptoms, I want to make a few points about taking a broader look at who may benefit from potential disease modifying treatments.
Autopsy studies show that up to 50% of people with AD have some degree of Lewy body pathology. Without assessing for biomarkers of other diseases like Lewy body disease, Alzheimer's disease clinical trial results may be confounded by mixed pathologies. There is an important role for using emerging biomarkers for Lewy body disease to enrich AD study populations. There are highly sensitive and specific biomarkers now using cerebrospinal fluid and skin biopsies.
Last, and what concerns me most, is that people with LBD and also co-existing AD may NEVER benefit from disease-modifying therapies for AD. We need to take the intentional approach of moving past studying drugs in a single primary disease or syndrome. Robust study designs that accommodate multiple types of dementias are needed.
Thank you very much for the opportunity to address the council.
I am Co-Vice President of the National Task Group on Intellectual Disabilities and Dementia Practices (NTG). I also co-chair the NTG's Training and Education Committee. Thank you for the opportunity to make these public comments. The NTG urges the Assistant Secretary for Planning and Evaluation (ASPE) and the Advisory Council to develop policies that will expand capacity to care for a group of individuals that has received little attention but who face significant challenges as they age and face the risk of developing Alzheimer's or a related dementia, aging individuals with autism spectrum disorder (ASD), a topic that one writer in 2016 described as a "black hole."
In fact, it is such a black hole that I am unable to even tell you how many adults with ASD there are over the age of 65, to say nothing of how many adults with ASD have Alzheimer's or a related dementia. If you embark on a Google search for 'adults with ASD over the age of 65' you will find no data at all. A 2018 report of The Interagency Autism Coordinating Committee (IACC) found that only about 3% ($13.3 M) of funding for autism research supports studies on the lifespan needs of adults with the vast majority of those funds aimed at adolescents transitioning from the secondary education system to higher education and/or employment and vocational/job skills and social skills training for both transitional aged youth and adults.
In 2014 the NTG developed a national model training curriculum on dementia-capable care of adults with intellectual disabilities. To date, over 55 workshops have been held in 25 states across the country with over 3,000 participants. A consistent question at those workshops is, "what can you tell us about dementia in adults with ASD?" The answer, "very little."
What we do know is that the first individuals formally diagnosed with ASD were diagnosed in the 1940's and those individuals are now at the age of risk of developing dementia. It is likely that there are anywhere from tens of thousands to hundreds of thousands of adults with ASD over the age of 65.
We also know that people with ASD have a range of health conditions that place them at special risk of developing dementia, such as an increased risk of developing dementia, such as an increased risk of Parkinson's disease, depression, sedentary lifestyle, social isolation, long term antipsychotic medication use that can raise the risk of diabetes and heart disease, and sleep apnea to name but a few. Additionally, we know that many people with ASD are being supported by aging family members and that when that family support system is lost, they will require alternative placements and support for the remainder of their years.
Finally, we know that the pre-existing sensory processing issues along with verbal communication and behavioral challenges that characterize ASD makes diagnosis of dementia challenging which can lead to inappropriate treatment.
Consistent with Strategy 2.H: Improve Care for Populations Disproportionally Affected by Alzheimer's Disease and Related Dementias, and for Populations Facing Care Challenges contained in the National Plan to Address Alzheimer's Disease we urge you to consider the following issues for inclusion in your deliberations:
- Research on aging with ASD and the specific risk of dementia.
- Development of validated clinical interventions specific to aging adults with ASD and dementia.
- Development of education and training curriculums for health care providers and community service providers who lack understanding of and expertise in the problems of aging with ASD.
- Studies on the efficacy and safety of pharmacological interventions in aging adults with ASD, especially regarding cholinesterase inhibitors and antipsychotics.
Thank you for the opportunity to speak today about the challenges faced by aging adults with ASD who are at risk for or who have developed Alzheimer's disease or a related dementia. The NTG greatly appreciates the effort and actions that the Advisory Council has undertaken to date to raise the visibility of the needs of all aging adults with intellectual disabilities and respectfully asks that you add the challenges facing aging adults with ASD who are at risk of or who have developed a form of dementia to your work plan.
I am concerned about the cost of aducanumab that Medicare, the VA and other healthcare systems have to pay now that it is FDA approved, when it has no clinical benefit. This will leave less money for other services that would clearly help families. Caregiving support, or education how to manage dementia. The medicine gives patients and family false reassurance that they don't have to deal with the disease, such as advanced directives, driving cessation, firearm safety, etc. that have to be dealt with while the patient still has capacity.
May I submit my written comments for the upcoming July 19, 2021 meeting of the Advisory Council on Alzheimer's Research, Care, and Services?
I am a neurologist, retired from clinical practice. I had been a Medicare Medical Director and a Medcac panelist and Vice-Chair. I am currently involved in research on social underpinnings of health and the role of Progressive Era women on social issues. I have consulted, on a one-time basis, on issues of diagnosis of dementias and their management. I do not have an organizational affiliation, and I am not employed or retained by any agency or organization.
Outcomes of personal importance when cognitive difficulties set in.
People experiencing cognitive difficulties rely to varying degrees on others for their daily needs. Some care recipients, however, deny such dependency; some others, even when in need of care, reject it. The patient-caregiver dyad and its input are seldom the primary focus of outcome measures used in trials that evaluate new pharmacological therapies in the dementia field. [Reilly 2020, Harding 2021].
Outcome metrics for treatment of patients with cognitive impairment, especially Alzheimer's Disease, stress investigator and healthcare provider chosen cognitive scales.[Webster 2017, Harding 2021] What is important to patients and their caregivers is not a tardier decline in numerical values, an impalpable imaging alteration or an unrelatable change in plasma biomarker values. They need reliable safe communities to age-in, living environment modifications, scope for cognitive stimulation, dependable transportation, safeguard of their finances and trustworthy care givers.[WHO 2019, Nicholas 2020] Ensuring the integrity and availability of these non-pharmacological resources are as important as pharmacotherapy. Resource allocation should not favor biomedical interventions only.
Outcomes of importance to patients, family and caregivers have centered around their lived experiences. Often, a caregiver already provides help in the management of ongoing multimorbidity for an older dependent member. The intensity of additional care required by the newly emerging pharmacological treatment modalities will stress a caregiver even more. The time and effort expected in monthly follow-up visits for infusions, testing, attention and care for adverse effects are all additive to the already existing caregiving responsibilities. Core outcome measures about what patients and caregivers want should be validated. Some of these are currently under development. If validated, they should be given a weighting that is equivalent to any beneficial changes detected in trials of pharmacological agents that measure cognitive scales and biomarker values. [Webster 2017, Reilly 2020, Watt 2021]
Thus, the key question is whether, or not, we are overlooking outcomes that matter to the caregivers and patients. Are we relegating this metric to a second place? Emerging pharmacotherapies rely excessively, if not exclusively, on narrow trialist preferred short duration outcomes. Resources and energies focused on detecting changes in cognitive metrics, and their presumed surrogates, reward the investigators more than the patients.
Reilly ST, Harding AJE, Morbey H, et al. What is important to people with dementia living at home? A set of core outcome items for use in the evaluation of non-pharmacological community-based health and social care interventions. Age and Ageing. 2020;49(4):664-671. doi:10.1093/ageing/afaa015
Harding A, Reilly S. Dementia trials, outcomes, and outcome measurement instruments for people living with dementia and family carers -- considerations on how to improve the "gold standard." International Psychogeriatrics. 2021;33(4):327-330. doi:10.1017/S1041610220003749
Webster L, Groskreutz D, Grinbergs-Saull A, et al. Core outcome measures for interventions to prevent or slow the progress of dementia for people living with mild to moderate dementia: Systematic review and consensus recommendations. Quinn TJ, ed. PLoS ONE. 2017;12(6):e0179521. doi:10.1371/journal.pone.0179521
World Health Organization. Risk Reduction of Cognitive Decline and Dementia: WHO Guidelines; 2019. Accessed July 9, 2021. https://www.ncbi.nlm.nih.gov/books/NBK542796/
Nicholas LH, Langa KM, Bynum JP, Hsu JW. Financial presentation of Alzheimer disease and related dementias. JAMA internal medicine. 2021;181(2):220-227.
Watt JA, Goodarzi Z, Veroniki AA, et al. Comparative efficacy of interventions for reducing symptoms of depression in people with dementia: systematic review and network meta-analysis. BMJ. 2021;372:n532. doi:10.1136/bmj.n532
An Issues Consensus Statement
Aducanumab and Persons with Down Syndrome: What Do We Do Now?
Summary: This statement raises issues related to Down syndrome and the use of Aduhelm, Biogen's new drug for use with early-stage Alzheimer's disease. Issues noted include a lack of data on applicability of drug with adults with Down syndrome, lack of protocols for its use by practitioners, and unknowns as to efficacy of the drug with presence of high amyloid load from early age. Statement recommends (a) including participants with Down syndrome in ongoing and further clinical trials and research, (b) assuring research-informed appropriate oversight over its usage, (c) developing protocols that guide assessment and decision-making for the use of the drug with this group, (d) screening systematically for early symptoms of AD, (e) determining optimal age for prophylactic use of drug, (f) involving families and caregivers in the prescribing and decision-making process, and (g) providing orientation and education to healthcare providers and ancillary staff involved with use and aftercare.
Globally, people are living longer than ever before, including adults with intellectual disability. Age-associated physical and cognitive decline is commonly a part of the aging process that will eventually have an impact on most people. Some of these changes may be normal but some may herald the onset of dementia stemming from Alzheimer's disease (AD) and other neurodegenerative diseases. As noted by the WHO[i] and in the US National Plan to Address Alzheimer's Disease[ii] many adults with an intellectual disability will face the same concerns about cognitive decline when they age and for the most part experience similar prevalence rates of dementia as the general population.[iii] However, adults with Down syndrome, one of the most common forms of intellectual disability, have an extremely high risk for AD dementia. Therefore, they face a more substantial concern for developing cognitive decline due to the accumulation of beta amyloid protein, often starting while they are in their teens.[iv,v] As noted by the NIH, DS is a noted risk factor for early-onset AD.[vi]
It is estimated that the lifetime risk of AD dementia is >90%[vii] and it is the leading cause of death for older adults with Down syndrome.[viii] Estimates are that there may be some 57,700 adults age 40 and older with Down syndrome[ix,x] and that their average age at death is 55.8.[xi] Many people with Down syndrome are diagnosed with AD dementia in their 50s but it is not uncommon for symptoms to also occur in their late 40s[xii]. AD in most people with Down syndrome can be rapid, leading to progressive cognitive decline, and is often associated with significant behavioral distress, seizures, gait dysfunction, markedly increased care needs, and death within five to seven years from diagnosis.[xiii]
Parents, siblings, spouses, and other caregivers embrace, encourage, advocate, and often begin the fight for services and aid for their family members with Down syndrome beginning at birth. This continues throughout childhood, adolescence, and into young adulthood as family members work to ensure their offspring receive access to equitable care and support in all aspects of their lives -- including education, healthcare, vocational support, social inclusion, and civil rights. The concern that they will have to deal with and worry about early-onset AD is a hugely emotional and difficult prospect -- especially when the previous ensuing years often involved battles to provide a positive and proactive approach to life, the promotion of greater autonomy and inclusion, and support for the most of what societal integration would offer.
The realization that AD may be on the horizon for many adults with Down syndrome may not have been something that families and other caregivers thought about during earlier years when they were advocating for issues noted above. However, recent research in AD biomarkers and therapeutics for the general population and specifically for adults with Down syndrome has increased attention and dedicated focus to determine whether there might be ameliorative measures forthcoming that might help stave off or mitigate the effects of AD in adults with Down syndrome.[xiv,xv] The recent news of the FDA's accelerated approval of Biogen's Aduhelm (aducanumab)[xvi] for the treatment of adults with mild cognitive impairment and dementia stemming from AD has created an avalanche of obvious interest about this product's utility and application for adults with Down syndrome.
But is this exciting news justified and does it provide the options and hope that many families have been expecting? The reality is that this new medication's availability is far from a straightforward solution not for only those adults with AD in the general population, but also for adults with Down syndrome and their families.[xvii]
The conundrum for families, caregivers, and adults with Down syndrome themselves, is this: the clinical trials noting the efficacy of aducanumab were conducted only on neurotypical adults with symptoms of MCI or dementia. Thus, it is unknown to what degree aducanumab may help people with Down syndrome, as they were not included among the trial participants. Questions arise as to whether aducanumab's impact on brain amyloid, associated vascular complications, doses used and its titration, may also be similar in people with Down syndrome. Furthermore, cognitive benefits have yet to be clearly demonstrated with aducanumab and it is still unknown whether the MRI-related changes [including amyloid related imaging abnormalities (ARIA)] and other possible side effects (such as brain swelling and microhemorrhages) would also apply to adults with Down syndrome. To what degree are these factors equally applicable for adults with Down syndrome who are at high risk for early-onset dementia stemming from Alzheimer's disease? Are there additional side effects that we may not be aware of as there are no studies that include people with Down syndrome related to the overexpression of other proteins from chromosome 21?
Research in the last several years is providing new data that are beginning to shed evidence about the pathology and natural history of AD in people with Down syndrome, including biomarker research and potential therapeutics.[xviii,xix] Research demonstrates that beta amyloid (which is present in excess in people with Down syndrome due to the extra copy of the amyloid precursor protein on chromosome 21) begins to accumulate early in life, and steadily builds up over decades long before cognitive decline is notable.[xx] The data also indicate AD biomarkers in people with Down syndrome behave similarly to those with other genetic forms of AD.[xxi] Further, vascular (blood vessel) complications including microhemorrhages (small bleeds) are not uncommon.[xxii] Like most people who are diagnosed with AD, there are variabilities as to the age of onset of mild cognitive impairment (MCI) and dementia, as well as the rate of progression and its trajectory in people with Down syndrome.
A key question is whether the much earlier accumulation of amyloid and degree of vascular changes that we typically see in older adults with Down syndrome respond to aducanumab in a predictable and clear fashion. Also, as amyloid accumulation is seen in 100% of adults with Down syndrome over age 40, to what degree will this affect testing and assessment for AD, as it is known that this build-up is prevalent also in asymptomatic adults with Down syndrome. During the treatment phase, will the individual's underlying cognitive and lifelong intellectual disability have an impact upon his or her ability to tolerate post-infusion testing (including MRIs) and being exposed to invasive biomarker measures. Given significant loss of cognition in some people with DS and AD (that is not regained) after the often-required anesthesia for MRI, will potential gains from using aducanumab be lost by post-anesthesia effects? Also, will follow-up assessments of their cognition and behaviors be clear to those who must care and support them as well as to provide feedback to the healthcare provider treating them? In addition, what will be the prescribed optimal timeline for receiving infusions and how will decisions be made relative to termination of treatment?
Most healthcare providers, including neurologists, are not trained in how to assess and diagnose AD in adults with intellectual disability (including adults with Down syndrome). During the pre-prescription assessment phase, specific challenges may arise in communicating with the patient, parsing memory loss from premorbid intellectual functioning, and mitigating examination intolerance. Most memory centers are bereft of staff skilled in interviewing and assessing persons with pre-existing cognitive limitations and who also may be uninformed as to the best courses of health and social care for adults with Down syndrome.[xxiii,xxiv]
As protocols for the use of aducanumab are implemented, adults with Down syndrome must be provided with equitable care and support once diagnosed with AD. This includes understanding whether prescribing aducanumab is medically indicated and appropriate, as well as ensuring equitable access to the medication once that determination is made (including medication cost supported by insurers and CMS).[xxv]
Leaders in the Down syndrome advocacy community are exercising due caution at this point with respect to recommendations given the paucity of empirical support for applicability of aducanumab for persons with Down syndrome and are (a) calling for the inclusion of participants with Down syndrome in ongoing and further clinical trials and research, (b) asking for research-informed appropriate oversight over its usage, as well as safety data on aducanumab, and (c) calling for protocols to be developed and disseminated guiding the clinical practice of assessment and decision-making include provisions for the use of aducanumab with this group. The NIH-funded Alzheimer's Clinical Trials Consortium - Down Syndrome (ACTC-DS) network is poised to address some of these questions in collaboration with Biogen and various regulatory agencies by running safety studies on persons with Down syndrome. However, given the longitudinal nature of such studies, answers to many of these questions may not be available for several years.
Advance protocols for assessment and use should be agreed upon by expert panels to, at minimum, provide cautioned guidance for practitioners considering prescribing aducanumab in adults with Down syndrome (and other intellectual disabilities). Firstly, a well-defined screening process is needed for determining the stage of AD, as well as a recognized and approved process for the therapeutic use of aducanumab that all healthcare providers could follow to ensure safety and ability to determine efficacy in adults with Down syndrome specifically, and with adults with intellectual disability generally. Secondly, needed also is a commitment to early detection and screening by the nation's disability services provider network and state regulatory authorities to pick up on early symptoms at a stage when the use of aducanumab may be effective. Thirdly, the involvement of the adult with Down syndrome, families, and other caregivers in the decision-making process is imperative and needs to be appreciated while the prescribed medical care is being provided. Lastly, an orientation and education package is necessary to help educate healthcare providers and any ancillary staff involved in the clinical use of this therapeutic.
The strong and cohesive network of Down syndrome advocacy stakeholders and associated professional and healthcare groups are willing and able to work in partnership with governmental agencies and provider associations, as well as with the biopharmaceutical industry to move this forward. We all wish for the new advancements in AD therapeutics to succeed for the millions affected by sporadic AD as well as those thousands who are genetically determined to develop early-onset AD. Dedicated clinical trials for people with Down syndrome or the inclusion of people with Down syndrome in ongoing studies is critical. Building an information base to aid with the assessment of AD dementia in adults with Down syndrome, providing medical management guidelines when therapeutics are prescribed and used, and follow-along guidance not only for recognizing adverse effects, but also for enabling those adults on the medication to function optimally with clinically meaningful benefit.
Thus, we are calling for action.
- Authors listed at end of document.
- WHO. (2012). Dementia: A Public Health Priority. Geneva, Switzerland: World Health Organization and Alzheimer's Disease International.
- ASPE. (2020). National Plan to Address Alzheimer's Disease. Washington: DHHS. https://aspe.hhs.gov/national-plan-address-alzheimers-disease.
- Zigman, W.B., Schupf, N., Devenny, D., Miezejeski, C., Ryan, R., Urv, T.K., Schubert, R., & Silverman, W. Incidence and prevalence of dementia in elderly adults with mental retardation without Down syndrome. American Journal on Mental Retardation, 2004, 109, 126–141. doi:10.1352/0895-8017(2004)109<126:IAPODI>2.0.CO;2.
- Head, E., Lott, I.T., Wilcock, D.M., & Lemere, C.A. (2016). Aging in Down syndrome and the development of Alzheimer's disease neuropathology. Current Alzheimer Research, 13(1), 18-29. doi:10.2174/1567205012666151020114607
- Zammit, M.D., Laymon, C.M., Betthauser, T.J., Cody, K.A., Tudorascu, D.L., Minhas, D.S., Sabbagh, M.N., Johnson, S.C., et al. Amyloid accumulation in Down syndrome measured with amyloid load. Diagnosis, Assessment & Disease Monitoring, 2020, 12(1), e12020. https://doi.org/10.1002/dad2.12020
- National Institute on Aging. (2021). Alzheimer's Disease in People With Down Syndrome. https://www.nia.nih.gov/health/alzheimers-disease-people-down-syndrome
- McCarron, M., McCallion, P., Reilly, E., Dunne, P., Carroll, R., & Mulryan, N. (2017). A prospective 20-year longitudinal follow-up of dementia in persons with Down syndrome. Journal of Intellectual Disability Research, 61(9), 843-852. doi: 10.1111/jir.12390. Epub 2017 Jun 29.
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CONTRIBUTORS (alpha order):
Brian Chicoine. M.D. -- Advocate Medical Group Adult Down Syndrome Center, Park Ridge, IL
Elizabeth Head, Ph.D. -- Department of Pathology & Laboratory Medicine, University of California, Irvine, CA
James Hendrix, Ph.D. -- LuMind IDSC Foundation, Burlington, MA
Matthew P. Janicki, Ph.D. -- University of Illinois at Chicago; National Task Group on Intellectual Disabilities and Dementia Practices, Rockport, ME
Seth M. Keller, M.D. -- National Task Group on Intellectual Disabilities and Dementia Practices; American Academy of Developmental Medicine and Dentistry, Lumberton, NJ
Rick Rader, M.D. -- Orange Grove Center, Chattanooga, TN
Michael Rafii, M.D. -- Alzheimer's Therapeutic Research Institute, Keck School of Medicine of USC, Los Angeles, CA
Kathryn P. Service, RN, MS, FNP-BC -- National Task Group on Intellectual Disabilities and Dementia Practices, Northampton, MA
The following associations, organizations, and entities have endorsed this statement:
AADMD -- American Association of Developmental Medicine and Dentistry
ANCOR -- American Network of Community Options and Resources
DS-MIG -- Down Syndrome -- Medical Interest Group
Global Down Syndrome Foundation
LuMind IDSC -- Down Syndrome Foundation
NDSC -- National Down Syndrome Congress
NACDD -- National Association of Councils on Developmental Disabilities
NTG -- National Task Group on Intellectual Disabilities and Dementia Practices