Alzheimer’s Disease: Diagnosis, Biomarkers, Early Detection

While Alzheimer’s disease has a long clinical history, understanding of the disease now extends to the biological changes that underpin it. Biomarkers that indicate the build-up of amyloid, changes to tau and cell damage in the brain can now be measured through proteins in the brain, cerebrospinal fluid and even in blood samples. Use of these biomarkers is beginning to change the way Alzheimer’s disease is diagnosed, how families prepare, and how screening and treatment could be managed by health systems. However, several key questions remain including who should be tested for these biomarkers, what the results mean, and how early detection can be accurate, ethical and equitable.

Why It Matters

Alzheimer’s disease is typically diagnosed based on a person’s symptoms, such as loss of memory or other thinking and behavioral changes, as well as a decrease in daily functioning. The doctor will take a medical history and perform a physical exam, administer a neuropsychological test, and talk to family members about the person’s medical history and current condition. The doctor will also try to rule out other possible causes of the symptoms, such as thyroid disease, vitamin deficiencies, depression, side effects of medications, sleep disorders, or stroke. However, the typical symptoms do not appear until the later stages of the disease, by the time significant brain changes have occurred.

Biomarkers change the timeline of Alzheimer’s disease by allowing clinicians to diagnose a disease that is present but for which symptoms have not yet appeared. Amyloid plaques and tau tangles may be silently accumulating for decades before symptoms of dementia appear. Biomarkers can also help clinicians diagnose people with memory problems for which another cause cannot be found. These diagnoses can be made for people with what is called mild cognitive impairment (MCI) for whom symptoms are uncertain or ambiguous.

Early detection of individuals with evidence of Alzheimer’s disease biomarkers can open up options for persons identified with underlying disease, but the question of whether an individual diagnosed with biomarker evidence of Alzheimer’s pathology will ultimately develop disabling dementia is not a simple yes or no answer. The rate of progression of disease from biomarker evidence to clinical diagnosis can be slow for some individuals and rapid for others. Factors which may influence this progression include age, medical status, history of head trauma, vascular risk factors, prior education, level of social engagement, sleep and genetics.

Discussions regarding treatment for cutaneous T-cell lymphoma are changing. Some of the newer therapies are given for earlier stages of disease and, therefore, often require either biological confirmation of the diagnosis or other specific criteria for initiation and/or escalation of dose. A mechanism-based approach to treatment often requires the use of biomarkers for both inclusion and monitoring of patients on specific therapies. This is particularly important for a thoughtful discussion of the potential for disease modifying therapies, as well as a clear discussion of all benefits and risks, and an explanation of the need for ongoing monitoring, and some uncertainty regarding specific aspects of the disease and its treatment.

Even if biomarkers don’t help treatment decisions, biomarker testing has implications for planning and support. An earlier, more certain diagnosis provides the critical window for families to plan for issues like advance directives and financial powers of attorney; consider choices for living arrangements; and discuss the potential impact on safe driving. While earlier diagnosis of cognitive impairment may increase some individuals’ anxiety, for many, it will relieve anxiety related to uncertainty about whether they are slipping cognitively.

All of the emerging biomarkers for dementia are capital-intensive, driving specialist testing and specialist interpretation. However, new biomarkers for dementia that measure proteins in the blood have the potential to remove some of these bottlenecks and could lead to a surge in earlier diagnosis, putting increased pressure on services to manage referrals, confirmatory testing and follow-up. There will be a huge strain on memory clinics, neurology services, imaging centres and counseling services.

The issue of equity must also be considered. Some communities will have greater access to biomarker testing and specialty care than others. Lack of specialists and imaging facilities, as well as out of pocket costs for testing, may leave some communities behind as psychiatric illness becomes increasingly diagnosed through a biological lens. This could lead to greater disparities in patient outcomes for individuals from different socioeconomic statuses and levels of education as biomarker-based diagnosis becomes the gateway to expensive and novel treatments.

As tests for detection at earlier risk levels are being developed and come into use, several ethical issues are raised. Detection of risk early in life for cancer and other complex diseases can challenge a person’s sense of identity and raise a host of difficult questions regarding family planning. Early knowledge of risk also can evoke a significant psychological response which may include fear of discrimination. Counselors need to consider issues such as lack of legal protections for individuals with cancer gene mutations who may be discriminated by employers and third party payers, possible future stigmatisation of individuals and families with cancer, invasion of privacy of personal and medical matters and the issues of genetic information. Counseling issues pertinent to informed consent for early detection of cancer are discussed.

Who It Affects

Patients presenting with symptoms of forgetfulness, difficulty finding words, or changes in concentration receive information regarding these symptoms using biomarkers. Some patients present with mild complaints of cognitive dysfunction, but are difficult to diagnose because their complaints are also caused by sleep disturbances, stress, or symptoms of depression. Also, it is necessary to rule out side effects of medication. These biomarkers can help to determine whether Alzheimer’s disease pathology is involved versus some other set of pathology.

While biomarker testing for dementia risk is generally not recommended for individuals with no symptoms, those with a strong family history or extreme concerns about dementia risk who are showing mild symptoms may choose to pursue testing. Having biomarker results can be very empowering for individuals if accompanied by a plan for surveillance, lifestyle interventions and future planning. But then the answer to your life’s question could mean months or years of uncertainty as long as you are asymptomatic and go about your daily life.

The biomarker-driven approach to diagnosis will affect clinicians’ practices and how they work with their patients and their patients’ families. For primary care clinicians, who will be the first to encounter concerns about cognitive impairment in their patients, there will be a need to consider what screening for cognitive impairment is indicated and what biomarker test(s) might be useful, as well as how to make a referral to a neurologist or memory clinical. There will also be a need for primary care teams to educate patients and families about their biomarker results and what those results do and do not indicate.

Our production and interpretation information customers, who are neurologists and memory-clinic teams, are feeling a lot of pressure as they not only need to accurately interpret the data in the context of a patient’s history and clinical presentation but also effectively communicate the results to other physicians and family members. Most biomarkers do not serve as the magic bullet diagnosis. The clinician will use imaging, cognitive testing, functional information, and medical history to formulate a differential diagnosis and subsequent diagnostic follow-up. For indications where treatment indication is also a criterion, the clinician will also follow up on the patient for side effects of the therapy.

Biomarker testing must take place in a location, such as a laboratory, imaging center or other radiology service. Blood biomarkers require a validated assay as well as procedures for sample collection, handling and storage to be of adequate quality and consistency. CSF biomarkers require a valid collection procedure and adequate laboratory standards. PET imaging biomarkers require access to imaging technology, availability of tracers, valid interpretation of images by trained individuals and a system for determining when imaging should occur.

From the payers’ and policymakers’ perspective, coverage decisions will play a critical role in determining which individuals will have access to certain forms of testing and which testing will become standard of care. Insurance policies will shape the affordability of tests like the PET scan, lumbar puncture or blood test, and the need for confirmatory testing. These coverage decisions will in turn affect issues of equity and will determine the price of diagnosis and monitoring for those who are paying out-of-pocket.

Family members and caregivers find an earlier diagnosis particularly challenging because it changes the time frame in which the support is needed. This may mean that families have more time to prepare and make financial and residential plans for the person with autism but this also means that families will spend a longer period of time dealing with uncertainty, increased stress as caregivers and managing a host of complex and often difficult emotions. Communities and support services, such as day programs, support groups and pools of volunteers to provide transportation and home repair, as well as respite care and connections to a social worker and a lawyer, need to be accessible earlier in the life of the person with autism and their family.

Employers and communities are not directly affected. Detection at a younger age may affect issues related to work capacity, workplace accommodations and long-term planning. Younger onset cognitive changes are rare and particularly problematic when they do occur. What used to be a concern for older workers is now a concern for workers of all ages as the age of retirement changes. Some system of counseling, workplace accommodations and caregiver support could save a lot of social and economic misery downstream.

What Changes

Diagnosis Becomes a Two-Part Process

Dementia diagnosis has changed from a simple symptom based approach to an aetiologically based diagnosis, which includes a biological diagnosis where possible. Patients are assessed on history, cognitive function, current medication and reversible causes of cognitive impairment before a diagnosis of Alzheimer’s disease is made. Patients then have evidence of amyloid and tau biology from biomarkers which supports the diagnosis that Alzheimer’s disease is causing the patient’s symptoms.

It is sometimes mistakenly assumed that biomarkers will ultimately replace the clinical diagnosis of cognitive impairment. However, a constellation of signs and symptoms can be caused by a variety of illnesses. In addition, sleep apnea, depression, hearing loss, side effects of medications, metabolic conditions, and changes in blood vessels in the brain all can mimic cognitive impairment. Use of biomarkers will be most effective when results are considered within the context of cognitive function and how a person is functioning in their daily life.

Understanding the Main Biomarker Types

Amyloid biomarkers confirm the presence of amyloid, one of the hallmark features of Alzheimer’s disease. These biological markers of Alzheimer’s can be visualized using amyloid PET imaging as well as measured through cerebrospinal fluid and blood-based tests. A positive result on an amyloid biomarker indicates the presence of Alzheimer’s biology, while a result that comes back negative means that Alzheimer’s is unlikely to be the primary cause of a person’s cognitive concerns.

Tau biomarkers provide additional value as levels of tau correlate best with clinical worsening, neurodegeneration, and disease stage, and can help distinguish Alzheimer’s from other dementias. While tau PET imaging and CSF biomarkers have been around for many years, blood-based tau biomarkers are rapidly emerging and are expected to become part of clinical routine in the near future as they become more reliable and standardized.

Biomarkers of neurodegeneration and neuronal injury are measures of brain cell damage which may be raised in Alzheimer’s disease and other neurological conditions. Such biomarkers indicate that brain cell injury is occurring, but are not specific to Alzheimer’s disease and provide one piece of the diagnostic jigsaw.

Early Detection Brings Benefits and Trade-Offs

Early diagnosis of cancer has its own benefits and drawbacks. It can facilitate earlier planning, earlier supportive care and some selected therapies. However, there are also some emotional and ethical considerations for patients for whom early diagnosis may bring relief from uncertainty but extreme distress, worry or even change of identity. Counseling patients and families about test results can be particularly challenging. It is therefore essential that a clear explanation is given of the test result, the limitations of the test and the realistic next steps for the patient and their family.

For all tests, including those that are very accurate, consideration must be given to false positives and false negatives as well as incidental findings. As more patients are assessed for SARS-CoV-2, understanding these limitations and the pre-test probability for SARS-CoV-2 infection is crucial for appropriate test utilization. Furthermore, in less sick populations, further stratification and thoughtful selection of the initial test as well as confirmatory tests is necessary.

Blood-Based Biomarkers Could Change Access

One of the biggest breakthroughs of the next few years will be the discovery of biomarkers for autism in the blood, which could be easier and less expensive than a spinal tap or an MRI/PET scan. Doctors think that a simple blood test could allow primary care physicians to screen kids for autism in their office during a routine checkup, possibly cutting months off the time it takes for a kid who’s showing signs of autism to see a specialist.

Screening programmes are expanding and as a result there are new challenges in terms of who should be offered screening, how initial screening tests should be confirmed and how positive screens will be managed. Staged testing approaches have been proposed for glucose screening where a first blood test could be used to determine whether or not women require further testing and specialist referral, as opposed to management in primary care. Further guidance and follow-up capacity is, however, needed to facilitate efficient implementation.

Shared Decision-Making Becomes Central

Shared decision-making is also becoming more important as patients and families face decisions about whether or not to undergo biomarker testing. Testing for biomarkers is not limited to choices about medications; information about a cancer’s potential progression or recurrence can have a profound impact on life planning, and affect the mental health and family dynamics of patients and families. Therefore, it is crucial that patients and families understand the reasons for testing, the information that might be obtained, and the possible decisions that could be made as a result of that information. Alternatively, patients and families may make a consistent with their values decision to not want to know this information, or to defer testing at any time in the treatment planning process.

It is important to inform of any uncertainty in counseling regarding biomarker status. Experience to date indicates that biomarker positivity does not necessarily predict rapid progression. Patients and their families want to know what a positive test result tells them about prognosis, monitoring frequency, and what clinical events may require return visit(s) for evaluation.

Safety and Monitoring Considerations

Many of the available therapies for Alzheimer’s disease now have biomarker evidence of efficacy. Some of these treatments entail important unknowns for patients that need to be disclosed. Others may warrant sporadic imaging or clinical monitoring. Decisions to initiate these therapies should thus consider several factors, including the level of symptom burden, the potential benefit of treatment, the risk of adverse effects, the ability to monitor and manage both benefits and harms, and the patient’s preferences.

In addition to testing for specific biomarkers it is also important to consider a patient’s comorbidities. Vascular risk factors, overall health status and other variables can play a significant role in how people with cognitive impairment may ultimately do. Addressing hypertension, diabetes, sleep, hearing loss, depression and inactivity can promote brain health and delay disability.

Workforce and Infrastructure Will Evolve

Scaling up to meet the dementia goal will require a substantial scaling up of health sector capacity to identify and treat people with dementia and to provide support early on. Health- care professionals at all levels will need to provide longer-term counselling and support to people with dementia and their carers. Primary health- care teams will need to learn how to do cognitive screening and interpret results. Memory clinics will need more staff and more efficient triage systems. Laboratories and imaging services will need protocols, quality control measures and clear guidelines for test ordering.

In order to meet future needs, these types of services will have to be started and expanded in order to support individuals and families as diseases are now being diagnosed at an earlier age and as these diseases progress over a longer period of time. It will be necessary to have social work and legal counseling services, patient and family education, education for health care providers and their caregivers as well as support groups and caregiver training – all beginning at an earlier time in the disease process. Thus, rather than bringing benefit to individuals and families with these diseases, early detection without corresponding support and services could result in prolonged anxiety.

Equity, Privacy, and Policy Priorities

In order for advances in biomarkers to translate into improved prevention, diagnosis and treatment for people with dementia from diverse backgrounds, equity-focused policies and programming must be in place to ensure that these advances are used to improve health for all, not just for the affluent or those living close to medical centers. Furthermore, comprehensive coverage for testing, follow-up and counseling as well as outreach and culturally competent education can foster trust in these advances and ensure that they are used appropriately to improve health for all individuals and families impacted by dementia, not just those who have historically had access to high quality dementia care.

With the biomarker status becoming part of the medical record at an earlier age, issues related to protection and antidiscrimination must be considered when counseling families. Patients and families should understand how biomarker status will be recorded and protected in their medical records and who will have access to that information. Practices and systems should be developed to maintain confidentiality and inform decisions, as well as communicate biomarker status appropriately.

Practical Steps Clinicians and Systems Can Take Now

Now is the time for improving early detection of cognitive impairment. The use of structured cognitive screening in all patients who are at risk for cognitive impairment, as well as more accurate assessment of potentially reversible contributors to cognitive impairment will enhance detection of Alzheimer’s disease and other causes of cognitive impairment. Screening the cognitively impaired person with brief, reliable, valid and user-friendly cognitive tests, assessing for hearing impairment, screening for depression, reviewing medications and checking basic lab values will help to prevent these potentially treatable, non-Alzheimer’s causes of cognitive symptoms from being “missed.”

At Pilot we supported the development of integrated memory-care pathways within the health system, by bringing together relevant diagnostic, counseling and social resources. These multidisciplinary models that combine neurology, primary care, neuropsychology, geriatric care management, social work and care navigation are key to reducing bottlenecks and enhancing the experience of individuals and families. We also worked to ensure the appropriate and actionable use of critical biomarkers.

References:

https://pubmed.ncbi.nlm.nih.gov/41592989/