ACT EARLY, ACT NOW: A Practical Guide to Early Identification of Alzheimer’s Disease

Alzheimer’s disease (AD) is a progressive and serious neurodegenerative disease that causes a considerable burden on patients, families, and the health care system.1 AD is the most common cause of dementia, accounting for 60% to 80% of dementia cases in the United States (Figure 1).2

The term dementia encompasses a group of symptoms that include difficulties with memory, language, problem-solving, and other thinking skills. Other less common types of dementia include but are limited to vascular dementia, dementia with Lewy bodies and frontotemporal dementia.2 A full clinical work-up is necessary to differentiate AD from other forms of dementia and to form a definitive diagnosis, as biological changes associated with various dementias can be similar.3,4

The pathology of AD is characterized by a gathering of abnormal proteins and protein fragments in the brain that contributes to the damage and death of neurons.These brain changes can be thought of according to the amyloid, tau, and neurodegeneration (ATN) framework. 3,5,6 The protein fragment amyloid β (A) gathers outside of neurons, forming toxic protofibrils and plaques that interfere with synapses and that damage neurons. 3 An abnormal form of the protein tau (T) gathers inside of neurons, forming tangles that block the transport of nutrients and essential molecules. 3,6 The accumulation of amyloid β starts a cascade of events, leading to neurodegeneration (N) and neuronal injury. 5

Research results show that amyloid β and tau start accumulating years to decades before clinical symptoms emerge. 7-10 AD exists on a continuum of 5 stages: preclinical AD, mild cognitive impairment (MCI) due to AD, mild AD dementia, moderate AD dementia, and severe AD dementia, at which point physical health is affected, verbal communication is diminished, and care partner assistance becomes necessary. 1,11,12 Patients in the preclinical stage are asymptomatic; however, during this time, there is evidence of AD pathology including the rise of amyloid β and tau. By the time mild cognitive symptoms appear in the stage of MCI due to AD, there is already considerable damage due to toxic proteins (Figure 2). 1,11,13

Therefore, it is crucial to detect AD at the first signs of cognitive problems and to implement early interventions during the MCI and mild dementia stages of AD. 1,13

Mild Cognitive Impairment due to Alzheimer’s Disease

MCI is the earliest stage in which symptoms of AD can be detected.1 Mild cognitive symptoms appear, but they may not interfere with functional abilities that enable participation in activities of daily living and hobbies, and they may be confused as normal signs of aging. 1,14 Cognitive symptoms at this stage may include subtle problems with memory, language, and thinking.1 Behavioral symptoms may include subclinical changes related to depression, anxiety, irritability, and aggression.15 One-third of people with MCI experience progression to dementia within 5 years, which highlights the importance of early disease detection and treatment initiation.2

There is currently an opportunity to improve rates of MCI due to AD diagnosis, as only half of individuals in the US aged 65 and older with MCI are diagnosed.1,2,16 Primary care providers (PCPs), who have regular touchpoints with patients through annual wellness visits, play an important frontline role in detecting AD in its early stages.1 More than half (55%) of Americans report that they would discuss MCI symptoms with their PCP before others, including their spouse (42%) or a specialist (29%). Additionally, 62% of providers share that they receive questions at least weekly from their patients about symptoms that are consistent with MCI.1

As part of an effort to improve detection, it is important for PCPs to be aware of the symptoms of MCI and the high prevalence of the condition among older patients.1 In the United States, 5 million to 7 million adults 65 years and older may have MCI due to AD. 2 MCI occurs in as many as 1 in 15 people aged 60 to 64 years and continues to increase in prevalence among older age groups, occurring in 1 of 4 people aged 80 to 84 years (Figure 3).17

When considering the frequency of MCI among older adults, it may be appropriate to implement cognitive screening for this patient population at the annual wellness visit. In 2021, only 2.4% of traditional Medicare beneficiaries with a diagnosis of AD (or a related disorder) may have received a formal cognitive assessment service during an annual wellness visit, so there is opportunity for increased use.18

Relying on informal observation alone during an annual visit may not be sufficient, but specific questions regarding changes in memory, language, and the ability to complete routine tasks may help guide the decision to administer a cognitive test.2 There is not a gold standard test to detect cognitive impairment, but a validated and sensitive test for MCI could be a trigger for further patient evaluation.16 Valuable observations and information regarding cognitive and functional changes in a patient may also come from office staff, family members, and care partners. 2 This early screening may lead to a specialist referral and initiation of treatment with an anti-amyloid agent; this class of treatments targets the underlying biology (or pathology) of the MCI or mild dementia stages of AD.19,20,21 Anti-amyloid therapies have demonstrated slowing AD of progression when given early in the disease course.20,21

Act Early, Act NOW

The mnemonic Act Early, Act NOW can offer PCPs a detailed, step-by-step framework for achieving early MCI identification and treatment to slow disease progression. First, a PCP should Note and assess MCI, which involves understanding the signs of MCI, evaluating for MCI, and ruling out other causes of symptoms with the use of routine laboratory assessments. Next, a clinician should Obtain a cognitive work-up using a validated and sensitive cognitive test to help stage a patient’s disease progression and potentially screening for AD pathology with a new blood biomarker (BBM) test. Finally, a clinician should Weigh the results and refer the patient to a specialist if results from the assessment indicate AD pathology. The following sections will review these 3 steps in greater detail.

Note and Assess MCI

The first step in the Act NOW plan is to note and assess MCI. People with MCI show changes in cognition from their personal norms and have abnormal results on an MCI-sensitive test.16[Cordell,2013 / slide 20] Through direct observation and discussion with patients and care partners, PCPs should make note of any of the following symptoms of early cognitive decline that may warrant further testing:2

  • forgetting recently learned information;
  • having more frequent poor judgement and decision-making;
  • losing track of dates or missing appointments;
  • having more difficulty holding a conversation;
  • losing items and being less able to backtrack or locate them;
  • repeating questions;
  • forgetting names, places, or common items;
  • having more difficulty following instructions;
  • showing changes in mood; and
  • exhibiting increased apathy.

If a patient or a close contact voices concern about memory or impaired cognition, PCPs should assess for MCI and not assume the concerns are related to normal aging.17

Correctly identifying signs of MCI is an important first step; however, it is not enough. MCI can be caused by several underlying conditions that need to be ruled out as part of an AD work-up. A physical examination and the patient’s medical history could identify alternative causes of MCI such as sleep issues, depression, certain medications, specific comorbidities, and drug or alcohol abuse. Routine laboratory assessments could detect a cobalamin deficiency or thyroid disease, both of which can be causes of MCI. MRI or CT imaging could uncover evidence of masses or lesions, stroke, severe head trauma, cerebrovascular disease, subdural hematoma, or normal pressure hydrocephalus, all of which could be associated with MCI.22-24

Obtain a Cognitive Workup

The next step in the Act NOW plan is to obtain a cognitive workup. Many neurocognitive tests are available to aid in the diagnosis of dementia, but not every test has the sensitivity to detect MCI. A few commonly used tests sensitive to MCI and mild AD dementia are the Montreal Cognitive Assessment (MoCA), Mini- Cog, AD8, and Saint Louis University Mental Status (SLUMS) examination (Figure 4). 16,25-28

The MoCA is a test based on tools commonly used in cognitive screening with the raw score adjusted for education. It consists of 30 questions covering 8 domains with scores ranging from 0 to 30. Any score greater than 26 is classified as normal. The test lasts about 10 minutes; it is designed to be administered to patients by qualified PCPs.25

The Mini-Cog is a test that is easy to administer to non-English speakers. It is less biased by low education and literacy than are other tools. The scores range from 0 to 5, with a score of 0 to 2 indicating a higher likelihood of cognitive impairment and of 3 to 5 indicating a lower likelihood of dementia. The test lasts about 2 to 4 minutes; it is designed to be administered to patients by qualified PCPs.16,26

The AD8 is a test administered by phone or in person that rates change in cognition and function based on a score range of 0 to 8, with 0 or 1 indicating no impairment and of 2 to 8 indicating impairment. The test lasts about 3 minutes. It is designed to be administered to care partners by qualified PCPs. 27

The SLUMS examination minimizes educational bias. This test has scoring similar to that of the mild neurocognitive disorder examination; it includes some additional tasks and involves scores ranging from 0 to 30. A score of 27 to 30 represents a normal score, whereas any score of less than 27 represents increasing levels of dementia. The test lasts about 7 minutes; it is designed to be administered to patients by qualified PCPs. 28

Recent advancements in biomarker detection are starting to enable the use of blood tests to aid in clinical diagnosis and provide previously inaccessible insights.29,30 Amyloid β pathology may be measured via BBM tests in symptomatic individuals and may aid in the collection of evidence to triage a patient to a specialist. Available assays measure the amyloid β 42/40 ratio.30 Some tests also measure p-tau217 protein in plasma with high accuracy and correlation to amyloid PET positivity for AD pathology. 29-31

The results of BBM tests are not intended as stand-alone diagnostic criteria; they should be integrated with patient history, brain imaging, routine laboratory tests, and other findings as appropriate.29,31 Additional tests may be done when appropriate to verify diagnosis; these include, but are not limited to, amyloid PET imaging or a lumbar puncture to collect cerebral spinal fluid (CSF) to confirm brain amyloid pathology.2,4,29

Weigh Results and Refer

The last step in the Act NOW plan is to weigh results and refer.At this stage, a patient can be determined to be a good candidate for anti-amyloid therapy or for participation in a clinical trial if they meet the following 3 criteria. First, they must have evidence of MCI or mild dementia. Anti-amyloid therapies may help slow disease progression for patients who are in the MCI to mild dementia stages of AD. Second, results of routine laboratory tests and MRI or CT must rule out reversible causes of dementia (eg, cobalamin or thyroid hormone deficiency). Third, there must be evidence of AD pathology. Results of BBM testing can help provide evidence that a patient may have AD pathology; this may warrant confirmatory testing via CSF or PET testing.

Additionally, other characteristics that may make a patient a good candidate for anti-amyloid therapy or a clinical trial include having a supportive family member or care partner, having motivation to seek treatment for their memory issues, and having interest in and availability for an intravenous treatment option.

Hypothetical patient case report

This section reviews a patient for whom the Act Early, Act NOW steps were employed to identify MCI early and prompt referral to a neurologist to verify the diagnosis and consider appropriate treatment options.

David is a 66-year-old lawyer with a part-time law practice. He has been struggling with remembering names; he described the experience as 5- to 10-second pauses in recall. Marie, his wife, has noticed that he occasionally confuses appointment times and fails to remember whether he shut the garage door a few moments earlier. Marie noticed the subtle changes and brought him to their PCP to discuss her concerns.

Note and assess MCI: The PCP interviews David and Marie about what they have noticed while performing an initial physical and neurologic examination. Keeping in mind David’s high level of education, the PCP notes a few red flags that might suggest MCI over normal aging; these included the cognitive changes from his baseline that David and Marie recognized. The PCP asks about David’s quality of sleep and screens for depression, noting a low suspicion for obstructive sleep apnea or depression/mood disorder. The PCP reviews David’s comorbidities and medications to make sure that there is nothing that could cause cognitive issues (eg, use of simvastatin for dyslipidemia or diclofenac for joint pain). The PCP orders laboratory tests and a brain MRI to rule out other potential causes of cognitive decline. David’s laboratory results for cobalamin, methylmalonic acid, thyroid-stimulating hormone, and the comprehensive metabolic panel are unremarkable. His brain MRI shows minimal age-appropriate atrophy and no white matter changes. The PCP determines a low likelihood of any reversible or irreversible causes of MCI and decides to proceed with a full work-up to evaluate David for early AD. Additionally, this would need to be confirmed via CSF or PET for amyloid confirmation.

Obtain a cognitive workup: David’s PCP performs a MoCA, because it is familiar to the PCP and sensitive to MCI; further, the raw score can be adjusted to the patient’s education level.1 David’s MoCA score was 23/30, which is consistent with MCI. Next, his PCP orders a BBM test to look for evidence of AD pathology. His results come back positive, suggesting a high likelihood of the presence of brain amyloid pathology that is consistent with AD.

Weigh results and refer: David’s PCP weighs the results of his examinations and tests. He has evidence of MCI according to a validated and sensitive cognitive test. His examinations, laboratory test results, and MRI have ruled out reversible causes of cognitive impairment. He has evidence of AD pathology according to results of a BBM test. His results are consistent with MCI due to AD. His PCP decides to refer him to a neurologist to verify the diagnosis; this may involve additional tests such as PET imaging or CSF testing. In the referral notes, the PCP indicates that David may be a candidate for anti-amyloid therapy or a clinical trial to slow his disease progression, because he is early in the disease course, is motivated to seek treatment, and has a supportive care partner who could help him navigate the treatment journey.

Conclusions

AD is a common form of dementia accounting for between 60 and 80% of all dementia cases.17 Early screening for and identification of the early MCI stage can support referral to a specialist and initiation of anti-amyloid therapy, which, in turn, may slow AD progression.19-21 Annual wellness examinations provide PCPs with the opportunity to implement screenings for MCI in older patients.18 The Act Early, Act NOW framework offers a clear, step-by-step process that guides PCPs through the initial assessment, cognitive workup, and referral processes to support early identification and treatment of MCI and ultimately help to improve outcomes associated with the AD. 20,21

References

1. 2022 Alzheimer’s disease facts and figures. Alzheimer’s Association. Alzheimers Dement. 2022;18(4):700-789.

2. 2023 Alzheimer’s disease facts and figures. Alzheimer’s Association.Alzheimers Dement. 2023;19(4):1598-1695.

3. 2020 Alzheimer’s disease facts and figures. Alzheimer’s Association. Alzheimers Dement. Published online March 10, 2020.

4. Dubois B, Villain N, Frisoni GB, et al. Clinical diagnosis of Alzheimer’s disease: recommendations of the International Working Group. Lancet Neurol. 2021;20(6):484-496.

5. Goure WF, Krafft GA, Jerecic J, Hefti F. Targeting the proper amyloid-beta neuronal toxins: a path forward for Alzheimer’s disease immunotherapeutics. Alzheimers Res Ther. 2014;6(4):42.

6. Weglinski C, Jeans A. Amyloid-β in Alzheimer’s disease—front and centre after all? Neuronal Signal. 2023;7(1):NS20220086.

7. Beason-Held LL, Goh JO, An Y, et al. Changes in brain function occur years before the onset of cognitive impairment. J Neurosci. 2013;33(46):18008-18014.

8. Pettigrew C, Soldan A, Wang J, et al; the BIOCAARD Research Team. Longitudinal CSF Alzheimer’s disease biomarker changes from middle age to late adulthood. Alzheimers Dement (Amst). 2022;14(1):e12374.

9. Insel PS, Donohue MC, Berron D, Hansson O, Mattsson-Carlgren N. Time between milestone events in the Alzheimer’s disease amyloid cascade. Neuroimage. 2021;227:117676.

10. Jagust WJ, Landau SM; Alzheimer’s Disease Neuroimaging Initiative. Temporal dynamics of β-amyloid accumulation in aging and Alzheimer’s disease. Neurology. 2021;96(9):e1347-e1357.

11. Albert MS, DeKosky ST, Dickson D, et al. The diagnosis of mild cognitive impairment due to Alzheimer’s disease: recommendations from the National Institute on Aging-Alzheimer’s Association workgroups on diagnostic guidelines for Alzheimer’s disease. Alzheimers Dement. 2011;7(3):270-279.

12. Sperling RA, Aisen PS, Beckett LA, et al. Toward defining the preclinical stages of Alzheimer’s disease: recommendations from the National Institute on Aging-Alzheimer’s Association workgroups on diagnostic guidelines for Alzheimer’s disease. Alzheimers Dement. 2011;7(3):280-292.

13. Jack CR Jr, Knopman DS, Jagust WJ, et al. Tracking pathophysiological processes in Alzheimer’s disease: an updated hypothetical model of dynamic biomarkers. Lancet Neurol. 2013;12(2):207-216.

14. Cohen S, Cummings J, Knox S, Potashman M, Harrison J. Clinical trial endpoints and their clinical meaningfulness in early stages of Alzheimer's disease. J Prev Alzheimers Dis. 2022;9(3):507-522. doi:10.14283/jpad.2022.41

15. Caselli RJ, Langlais GT, Dueck AC, et al. Personality changes during the transition from cognitive health to mild cognitive impairment. J Am Geriatr Soc. 2018;66(4):671-678.

16. Cordell CB, Borson S, Boustani M, et al. Alzheimer’s Association recommendations for operationalizing the detection of cognitive impairment during the Medicare annual wellness visit in a primary care setting. Alzheimers Dement. 2013;9(2):141-150.

17. Petersen RC, Lopez O, Armstrong MJ, et al. Practice guideline update summary: mild cognitive impairment: report of the Guideline Development, Dissemination, and Implementation Subcommittee of the American Academy of Neurology. Neurology. 2018;90(3):126-135.

18. Medicare cognitive assessments: utilization tripled between 2018 and 2022,but challengesremain. Accessible version. US Government Accountability Office. December 11, 2023. Accessed February 20, 2024. https://www.gao.gov/assets/870/864588.pdf

19. Cummings J. New approaches to symptomatic treatments for Alzheimer’s disease. Mol Neurodegener. 2021;16(1):2.

20. Sims JR, Zimmer JA, Evans CD, et al. Donanemab in early symptomatic Alzheimer disease: the TRAILBLAZER-ALZ 2 randomized clinical trial. JAMA. 2023;330(6):512-527.

21. van Dyck CH, Swanson CJ, Aisen P, et al. Lecanemab in early Alzheimer’s disease. N Engl J Med. 2023;388(1):9-21.

22. Budson AE, Solomon PR. Memory Loss, Alzheimer’s Disease, and Dementia: A Practical Guide for Clinicians. 3rd ed. Elsevier; 2022:4-37.

23. Medical tests for diagnosing Alzheimer's. Alzheimer's Association. Accessed September 29, 2023. https://www.alz.org/alzheimers-dementia/diagnosis/medical_tests https://www.alz.org/alzheimers-dementia/diagnosis/medical_tests

24. Larson E. Evaluation of cognitive impairment and dementia. UpToDate. Updated November 2, 2022. Accessed February 7, 2024. https://www.uptodate.com/contents/evaluation-of-cognitive-impairment-and-dementia/

25. Nasreddine ZS, Phillips NA, Bédirian V, et al. The Montreal Cognitive Assessment, MoCA: a brief screening tool for mild cognitive impairment. J Am Geriatr Soc. 2005;53(4):695-699.

26. Mini-Cog©. Scoring the Mini-Cog©. Quick screening for early dementia detection. Accessed February 19, 2024. https://mini-cog.com/scoring-the-minicog

27. Galvin JE, Roe CM, Powlishta KK, et al. The AD8: a brief informant interview to detect dementia. Neurology. 2005;65(4):559-564.

28. Tariq SH, Tumosa N, Chibnall JT, Perry MH 3rd, Morley JE. Comparison of the Saint Louis University mental status examination and the mini-mental state examination for detecting dementia and mild neurocognitive disorder—a pilot study. Am J Geriatr Psychiatry. 2006;14(11):900-910.

29. Angioni D, Delrieu J, Hansson O, et al. Blood biomarkers from research use to clinical practice: what must be done? A report from the EU/US CTAD Task Force. J Prev Alzheimers Dis. 2022;9(4):569-579.

30. Hansson O, Edelmayer RM, Boxer AL, et al. The Alzheimer’s Association appropriate use recommendations for blood biomarkers in Alzheimer’s disease. Alzheimers Dement. 2022;18(12):2669-2686.

31. Porsteinsson AP, Isaacson RS, Knox S, Sabbagh MN, Rubino I. Diagnosis of early Alzheimer’s disease: clinical practice in 2021. J Prev Alzheimers Dis. 2021;8(3):371-386.

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