Dementia and Alzheimer’s Disease: Laboratory Testing for Early Detection 

Brain health reflects a person’s ability to think, learn, and remember. These factors are collectively referred to as cognition.¹ Mild cognitive impairment (MCI) may develop with advancing age, often manifesting with intermittent forgetfulness and difficulty performing activities of daily living. In some individuals, MCI will progress to dementia and while most persons with MCI can perform the activities of daily life, those with advanced dementia cannot.^2,3 Though dementia mostly affects older adults, it can also affect middle-aged persons.⁴ Alzheimer’s disease is the most common cause of dementia.

This article will discuss MCI and dementia, with a focus on Alzheimer’s disease and laboratory testing to assist diagnosis. Also discussed is the importance of early diagnosis, prevention, and management. Finally, we discuss controversies related to screening for MCI, dementia, and Alzheimer’s disease.

Mild cognitive impairment 

Cognition generally peaks when we are 20 to 30 years old and then declines gradually. The rate of decline depends on many factors, including lifestyle, genetic predisposition, and health conditions such as heart disease and diabetes.⁵ Normal cognitive decline (eg, “senior moments”; see Sidebar) must be distinguished from MCI and onset of dementia, which are not normal consequences of aging.^2,6,7 MCI can be difficult to diagnose, and signs may be missed during a wellness examination. However, a number of objective methods can help test for cognitive impairment (eg, Montreal Cognitive Assessment; Memory and Executive Screening).^8,9

Dementia

The term “dementia” describes symptoms associated with a decline in memory or other thinking skills severe enough to reduce a person’s ability to perform everyday activities.² Older age is the most important risk factor.²

Alzheimer’s disease accounts for 60% to 80% of dementia cases,^2,7 and vascular dementia (multiple infarcts or other causes of altered blood flow to the brain) for about 10%; less common types of dementia include Lewy body and frontotemporal dementia.² Creutzfeldt-Jakob, Parkinson, and Huntington diseases, as well as AIDS, can also cause dementia.⁵ While some causes of dementia are treatable (eg, vitamin B12 deficiency),⁵ most are not. However, disease progression can be slowed in some cases.⁵

Alzheimer’s disease

In 2021, over 6 million Americans were estimated to have Alzheimer’s disease¹⁰; this number is projected to increase to 14 million by 2060.^2,7 In addition to age, other medical conditions and behaviors can also increase risk (see Sidebar).^7,11

Symptoms of Alzheimer’s disease usually begin after age 60. However, Alzheimer’s dementia presents as a clinical spectrum and, depending on an individual’s disease progression status, diagnosis can be challenging. Progression from preclinical Alzheimer’s disease to MCI and then dementia can take from 10 to 25 years.¹¹ Importantly, Alzheimer’s disease and dementia are not associated with the normal aging process.^6,7

Alzheimer’s disease can be categorized as inherited or sporadic.^12-14 The onset age of dominantly inherited Alzheimer’s disease is about 40 years earlier than that of sporadic late-onset Alzheimer’s disease.¹² Mutations in APP, PSEN1, and PSEN2 (which encode amyloid precursor, presenilin 1, and presenilin 2 proteins) account for almost all cases of dominantly inherited Alzheimer’s disease.¹²

Pathogenesis

The pathogenesis of Alzheimer’s disease has been attributed to neuronal degeneration caused by β-amyloid (Aβ)-containing extracellular plaques and tau-containing neurofibrillary tangles.^12-14 The pathogenesis can be understood by comparing and contrasting processes in healthy individuals and those with Alzheimer’s disease.

In healthy individuals

• Aβ peptides (Aβ40, Aβ42) are produced as the result of cleavage of amyloid precursor protein (APP) and are cleared from the cerebrospinal fluid (CSF).^12-14
• Tau, a microtubule-associated protein that includes 6 isoforms, regulates the assembly and maintenance of the structural stability of microtubules.^12-14

In individuals with Alzheimer’s disease

• An increased rate of cleavage of APP results in overproduction of Aβ40 and Aβ42.^12-14
• Aβ42 aggregates into insoluble plaques in the brain, and increasing plaques decrease the clearance of Aβ42 (Aβ40 clearance remains unchanged).^12-14
• Tau becomes abnormally hyperphosphorylated, which ultimately causes the microtubules to disassemble and free tau molecules to aggregate into paired helical filaments resulting in neurofibrillary tangles.^12-14
• Once the level of Aβ peptides reaches a critical point, a rapid spread of tau aggregates throughout the brain may follow.^12-14

In addition to Aβ peptides and tau, apolipoprotein E (ApoE) can play a role in Alzheimer’s disease pathogenesis. Three isoforms of this important lipid transport protein exist in humans, including ApoE2, ApoE3, and ApoE4.¹³ Individuals with APOE4 alleles exhibit an increased risk of Alzheimer’s disease as a result of early accumulation of Aβ42—the risk is higher for people homozygous in APOE4 alleles.¹³ The mechanism is not completely clear, but carriers of ApoE4, with a frequency of about 14%, may have an impaired ability to degrade and clear Aβ peptides from the brain; they may also have a higher propensity to develop Aβ aggregation than those with other phenotypes.¹⁴ In contrast to those with APOE4 alleles, persons homozygous for APOE2 may have a decreased risk of developing Alzheimer’s disease.^13,14

Diagnosis

The gold-standard method for diagnosis of Alzheimer’s disease is post-mortem examination of the brain for amyloid plaques.^12,15 The most well-established methods for diagnosis of Alzheimer’s disease in living persons are positron emission tomography (PET) of the brain and examination of CSF for Aβ (Aβ40, Aβ42) and tau (phosphorylated tau and total tau protein concentration) biomarkers.^12,13,15

CSF levels of Aβ42/40 and tau are widely accepted markers of Alzheimer’s disease. A lower level Aβ42 in CSF generally correlates with a higher presence of Aβ plaques in the brain,¹⁶ and a lower Aβ42/40 CSF ratio is suggestive of an increased risk of Alzheimer’s disease.^12,13,15 On the other hand, increased CSF phosphorylated tau (p-tau181) is associated with an increased risk of Alzheimer’s disease.^12,13,15,16 However, levels of these markers may not always be directly correlated with symptoms or the presence of amyloid plaques.^12,13,15

Similarly, imaging studies (PET, MRI) are useful for identifying neurodegenerative changes and amyloid plaques/neurofibrillary tangles, but findings do not necessarily correlate with clinical symptoms.^12,13,15,16

The degree of correlation between both CSF biomarkers and imaging with symptoms depends on the place of an individual in the Alzheimer’s disease spectrum during the long period of disease progression.^12,17 Several reported models take into account biomarker, imaging, and clinical data to predict the likelihood of Alzheimer’s disease.^12,17

The National Institute of Aging (NIA)^18,19 and the International Working Group (IWG-2)²⁰ combine CSF biomarker (Aβ42/40, p-tau181) and imaging data with the presence and degree of cognitive impairment in the Alzheimer’s disease spectrum in their diagnostic criteria.^12,16 According to the NIA and IWG-2, cognitive testing should include administration of at least 1 standardized and validated instrument for detection of cognitive impairment or dementia (eg, Montreal cognitive assessment test).¹⁸

The amyloid/tau/neurodegeneration (ATN) framework has also been proposed as a method to define the biological state of Alzheimer’s disease and identify individuals more likely to develop Alzheimer’s disease and who may be candidates for early intervention.²⁰

Currently, CSF biomarkers are used in the diagnosis of Alzheimer’s disease in living individuals, but a sensitive and specific blood-based biomarker approach would represent a more accessible, affordable, and less invasive option. The development of blood-based markers is an area of active research—a plasma assay that uses an Aβ42/Aβ40 ratio that correlates with Aβ-PET status was recently approved in the United States and the European Union.¹² In addition, Quest Diagnostics offers a clinically validated blood-based biomarker test that employs the Aβ42/Aβ40 ratio (see Sidebar, How the laboratory can help).

Prevention, management, and screening and early assessment

Prevention

No pharmacological or non-pharmacological approaches are available to prevent cognitive impairment and dementia due to Alzheimer’s disease.¹² However, multidimensional interventions that include exercise, cognitive stimulation, lifestyle changes (eg, diet or vitamin D supplementation; persons with low vitamin D levels seem to have earlier disease onset than those with normal levels), and focused attention on modifiable behaviors may delay the onset of overt dementia.¹²

Management

Management of dementia, including Alzheimer’s dementia, depends on the degree of cognitive impairment. Early in the course of the disease, care is typically provided by family members and includes the development of daily routines and compassion and patience.^12,21-24 The Alzheimer’s Association in the United States provides support and training for caregivers of persons with dementia.¹⁰

While some drugs are available to relieve symptoms of dementia,¹⁸ only one drug has been approved for the treatment of Alzheimer’s disease.²⁵ Aducanumab is a human monoclonal antibody that binds to aggregated amyloid-β to reduce the number of amyloid plaques and potentially slow Alzheimer’s disease progression. It was approved by the US Food and Drug Administration in 2021 and is the first disease-modifying therapy for Alzheimer’s disease.²⁵ However, the ability of aducanumab to slow disease progression is controversial.^25,26

Screening

Screening for objective evidence of cognitive impairment in the absence of cognitive complaints is not recommended, and the United States Preventive Services Task Force has stated there are insufficient data on improved patient outcomes to recommend the utility of cognitive screening.^12,27 However, some organizations do recommend screening individuals 70 years of age or older. Arguments in favor of screening include (1) MCI can be slowed by medications and lifestyle changes, (2) MCI may be due to a treatable cause, and (3) testing is more accurate than previously reported.¹

On the other hand, it is generally agreed that individuals with signs of MCI should be tested, using objective measures, to determine the presence and degree of impairment.²⁷ Early assessment of dementia provides benefits that can potentially improve disease management. These include²⁷

• Allowing prompt initiation of treatment in patients with reversible causes of dementia
• Facilitating participation in clinical trials for currently untreatable causes of dementia
• Increasing the chances of treatment effectiveness through early intervention
• Allowing early initiation of long-term care planning
• Facilitating improved management of co-morbid conditions

A senior moment or dementia?

Certain signs distinguish onset of dementia from “senior moments,” a normal consequence of aging.^2,6,7

Signs of a senior moment

• Not able to quickly remember things like a name or phone number
• Occasionally forget an appointment but remember it afterwards
• Sometimes misplace keys or other items
• Forget what you were going to get when you went into a room
• Lists and other memory aids needed to keep you on track
• Not worried about memory loss

Signs of dementia

• Often forget names, phone numbers, PIN, etc
• Often forget appointments and not remember them afterwards
• Often misplace keys or other items or forget what an item is used for
• Tend to forget recent things but remember things from the past
• Unable to learn new things
• Hard to manage daily affairs like balancing a checkbook or paying bills
• Worried about memory loss or have no awareness of it
• Family and friends notice memory lapses or other symptoms

Major risk factors

Symptoms of Alzheimer’s disease usually begin after age 60; however, neurodegeneration can begin 10 or more years before the onset of symptoms.^12-15

Major risk factors for dementia include

• Age: The strongest known risk factor for dementia is increasing age, with most cases affecting those 65 years of age and older.^7,11
• Sex: Females have an approximately 1.5-fold greater relative risk than males.¹¹
• Family history: Those who have parents or siblings with dementia are more likely to develop dementia themselves.^7,11
• Race/ethnicity: African American and Hispanic individuals are at 1.5–2-fold increased relative risk compared with White individuals (due to a combination of genetic, health disparity, and socioeconomic factors).^7,11
• Poor overall health: High blood pressure and high cholesterol, if not treated properly, increase the risk of dementia.^7,11
• Lifestyle: Smoking increases the risk of dementia.^7,11
• Traumatic brain injury: Head injuries can increase the risk of dementia, especially if they are severe or occur repeatedly.^7,11

How the laboratory can help

Quest Diagnostics provides a comprehensive portfolio of tests to assess cognitive function and diagnose various types of dementia, including Alzheimer’s disease as well as reversible causes of dementia. Quest also provides genetic testing to assess for gene variants that increase the risk of dementia and Alzheimer’s disease.

For information about blood-based testing, view the following resources:

• Webinar: Biomarker Testing in Alzheimer’s Disease
• Webinar: The Emerging Role of Blood-based Biomarkers in Alzheimer's Disease
• Test Summary: QUEST AD-DetectTM, Beta Amyloid 42/40 Ratio, Plasma

For information about testing in CSF and ApoE phenotypes (APOE genotypes), view the following resources:

• Blog article: What is the APOE Gene and How is it Related to Alzheimer’s Disease?
• Test Summary: Beta-Amyloid 42/40 Ratio and Apolipoprotein E (ApoE) Isoform Panel, CSF

A new report from Quest reveals physician and US adult perspectives on the current and future landscape of dementia and Alzheimer's disease (AD) evaluation, testing, treatment, and care. Visit QuestfortheCure.com to download the report

References

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2. What is dementia? Centers for Disease Control and Prevention. Reviewed April 5, 2019. Accessed April 12, 2022. https://www.cdc.gov/aging/dementia/index.html

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4. Alzheimer’s disease. Centers for Disease Control and Prevention. Reviewed January 5, 2022. Accessed April 10, 2022. https://www.cdc.gov/nchs/fastats/alzheimers.htm

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10. Alzheimer’s Association. 2022 Alzheimer’s disease facts and figures. Alzheimers Dement. 2022:18. Accessed April 13, 2022. https://www.alz.org/media/Documents/alzheimers-facts-and-figures.pdf   

11. Atri A. The Alzheimer's disease clinical spectrum: diagnosis and management. Med Clin North Am. 2019;103(2):263-293. doi:10.1016/j.mcna.2018.10.009

12. Knopman DS, Amieva H, Petersen RC, et al. Alzheimer disease. Nat Rev Dis Primers. 2021;7(1):33. doi:10.1038/s41572-021-00269-y

13. Husain MA, Laurent B, Plourde M. APOE and Alzheimer's disease: from lipid transport to physiopathology and therapeutics. Front Neurosci. 2021;15:630502. doi:10.3389/fnins.2021.630502

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15. Scheltens P, De Strooper B, Kivipelto M, et al. Alzheimer's disease. Lancet. 2021;397(10284):1577-1590. doi:10.1016/S0140-6736(20)32205-4

16. Rabbito A, Dulewicz M, Kulczyńska-Przybik A, et al. Biochemical markers in Alzheimer's disease. Int J Mol Sci. 2020;21(6):1989. doi:10.3390/ijms21061989

17. Teunissen CE, Verberk IMW, Thijssen EH, et al. Blood-based biomarkers for Alzheimer's disease: towards clinical implementation. Lancet Neurol. 2022;21(1):66-77. doi:10.1016/S1474-4422(21)00361-6

18. 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. doi:10.1016/j.jalz.2011.03.003

19. McKhann GM, Knopman DS, Chertkow H, et al. The diagnosis of dementia 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):263-269. doi:10.1016/j.jalz.2011.03.005

20. 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. doi:10.1016/S1474-4422(21)00066-1

21. Calvin CM, de Boer C, Raymont V, et al. Prediction of Alzheimer's disease biomarker status defined by the 'ATN framework' among cognitively healthy individuals: results from the EPAD longitudinal cohort study. Alzheimers Res Ther. 2020;12(1):143. doi:10.1186/s13195-020-00711-5

22. Tisher A, Salardini A. A comprehensive update on treatment of dementia. Semin Neurol. 2019;39(2):167-178. doi:10.1055/s-0039-1683408

23. Arvanitakis Z, Shah RC, Bennett DA. Diagnosis and management of dementia: review. JAMA. 2019;322(16):1589-1599. doi:10.1001/jama.2019.4782

24. Livingston G, Huntley J, Sommerlad A, et al. Dementia prevention, intervention, and care: 2020 report of the Lancet Commission. Lancet. 2020;396(10248):413-446. doi:10.1016/S0140-6736(20)30367-6

25. Yang P, Sun F. Aducanumab: the first targeted Alzheimer's therapy. Drug Discov Ther. 2021;15(3):166-168. doi:10.5582/ddt.2021.01061

26. Tampi RR, Forester BP, Agronin M. Aducanumab: evidence from clinical trial data and controversies. Drugs Context. 2021;10:2021-7-3. doi:10.7573/dic.2021-7-3

27. US Preventive Services Task Force. Screening for cognitive impairment in older adults: US Preventive Services Task Force Recommendation Statement. JAMA. 2020;323(8):757-763. doi:10.1001/jama.2020.0435

Models used for illustrative purposes.

Published date: June 2022