Alzheimer disease (AD) is the most common cause of dementia,¹ the sixth leading cause of death in the United States, and the fifth among adults aged 65 years or older.² It is estimated that the prevalence of AD in adults aged 65 years or older is approximately 6.5 million in 2022, corresponding to a prevalence rate of 10.7%.³ Importantly, the prevalence in Americans aged 65 or older is expected to increase to 12.7 million by 2050.³ Furthermore, the proportion of deaths related to AD in the United States increased 89% between 2000 and 2014,⁴ and the estimated direct and indirect health-care–related costs for AD are nearly $500 billion annually.⁵ AD is characterized by an irreversible and progressive decline in 2 or more cognitive domains (ie, memory, language, executive and visuospatial function, personality, and behavior) resulting in a decreased ability to perform instrumental and/or basic daily activities.⁶ Therefore, it is critical to screen for, diagnose, and treat AD.

Various etiological mechanisms have been proposed to explain the underlying AD pathology.^7,8 First, there is an abnormal production of amyloid-β that is then deposited extracellularly in diffuse neuritic plaques and can trigger synaptic damage and a neuron loss cascade. The accumulation amyloid-β leads to hyperphosphorylation of τ (p-τ), a microtube assembly protein, which then accumulates in intracellular neurofibrillary tangles.^7,8 These tangles prevent the normal functioning of other cellular proteins, and toxic τ also enhances amyloid-β production.⁷ In addition, the brains of patients with AD have a cholinergic deficit, which plays a role in memory and learning and may explain some of the symptoms associated with AD. Finally, the progressive neuronal loss of AD is related to overexposure to the neurotransmitter glutamate.⁷

Other important etiological mechanisms include vascular disease, diabetes and hyperinsulinemia, and neuron inflammation.⁷ The risk for AD increases with age, one of the main risk factors for the disease. Another important risk factor is being a carrier for the fourth form of the apolipoprotein E gene (APOE-ε4 genotype).⁹ In addition, women older than 80 years are more likely to develop AD and to have a higher τ load than men, despite a similar amyloid burden.¹⁰

The hallmark pathological criteria for diagnosing AD include increased levels of amyloid-β neuritic plaques and p-τ neurofibrillary tangles, and updated diagnostic guidelines for AD were published in 2011.^11-16 Diagnosis of AD involves a series of tests in addition to considering both medical and family histories. A neurological examination, mental cognitive status tests (Mini-Cog, Short Informant Questionnaire on Cognitive Decline in the Elderly, AD8 Dementia Screening Interview, Quick Dementia Rating System), measurement of vitamin B12 levels, and examination of AD biomarkers are recommended.^15,17

AD biomarkers include:^6,9

• Imaging studies including positron emission tomography imaging with amyloid-specific tracers (florbetapir, florbetaben, and flutemetamol) and τ-specific tracers (flortaucipir, THK5317, PBB3, and [18F]MK-6240), and with fluorodeoxyglucose to detect decreased metabolic activity; and magnetic resonance imaging to detect hippocampal volume or medial temporal lobe atrophy.^18,19
• Measurement of amyloid-β 42, p-τ, and total τ levels in the cerebrospinal fluid.
• Various serum tests are in development. PrecivityAD™, which is not approved by the US Food and Drug Administration (FDA), was the first commercially available blood test for patients aged 60 years or older who experienced cognitive impairment.^20,21 The FDA has granted Breakthrough Device Designation for 2 serum tests: pTau-181 and AlzoSure® Predict.^22,23

Finally, there are genetic tests for risk genes, APOE-ε4, and for deterministic genes, the amyloid-β precursor protein, presenilin 1, and presenilin 2. Genetic testing for APOE-ε4 is not recommended outside of a research setting, as having the allele does not mean a person has or will develop AD. In families with a risk of early onset AD, genetic testing for deterministic genes is common. However, it is important to note that the time course for progression in patients with these genes is variable.^13,15  

Currently, no medications cure AD, but some FDA-approved medications may change the progression of the disease or help manage the symptoms.⁷ Aducanumab, an amyloid-β–directed antibody, is the only treatment that targets the pathophysiology of the disease.²⁴ FDA-approved treatments for cognitive symptoms include the NMDA-receptor blocker memantine and cholinesterase inhibitors such as tacrine, donepezil, rivastigmine, and galantamine.⁷ In addition, the combination of memantine and donepezil is also FDA approved for moderate to severe AD.⁷ Suvorexant is approved for treating insomnia in adults and is effective in patients with mild to moderate AD.^25,26 In addition to these treatments, the management of cardiovascular disease risk factors, the adherence to the Mediterranean diet, and regular aerobic exercise are recommended to help reduce the risk of disease progression.⁶

There are also several treatments that may be used off-label to help manage the symptoms of AD, including antidepressants (ie, citalopram, fluoxetine, paroxetine, sertraline, and trazodone), anxiolytics (ie, lorazepam and oxazepam), antipsychotic medications (ie, aripiprazole, clozapine, haloperidol, olanzapine, quetiapine, risperidone, ziprasidone), stimulants (ie, modafinil), and mood stabilizers (ie, carbamazepine and lithium).^27,28 These also include therapies that do not directly affect the nervous system, such as calcium-channel blockers (ie, dihydropyridines and dantrolene), phosphodiesterase inhibitors (ie, sildenafil), insulin and glucagon-like peptide-1 receptor agonists (ie, insulin and liraglutide), nonsteroidal anti-inflammatory drugs (ie, diclofenac), antivirals (ie, acyclovir) antibiotics (ie, minocycline and rifamycin), and antioxidants (ie, melatonin).²⁸

Finally, in addition to FDA-approved treatments, patients may also be eligible for enrollment in clinical trials. Currently, ClinicalTrials.gov lists 717 studies for patients with AD that are not yet recruiting, recruiting, or enrolling by invitation.²⁹ Patients may qualify for participation in ongoing clinical trials depending on their demographics, disease status, and location.

The number of patients with AD will rapidly increase in the next few decades. While currently no treatments cure AD, some medications can be used to slow the progression of the disease and help manage the symptoms. There are also many ongoing clinical trials that may result in newer treatments in the future. Because of the expected rise in cases, it is important that health care professionals are aware of the guidelines for diagnosing and treating patients with AD.

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2. Matthews KA, Xu W, Gaglioti AH, et al. Racial and ethnic estimates of Alzheimer's disease and related dementias in the United States (2015-2060) in adults aged ≥65 years. Alzheimers Dement. 2019;15(1):17-24. doi:10.1016/j.jalz.2018.06.3063

3. 2022 Alzheimer's disease facts and figures. Alzheimers Dement. 2022;18(4):700-789. doi:10.1002/alz.12638

4. 2017 Alzheimer's disease facts and figures. Alzheimers Dement. 2017;13(4):325-373. doi:10.1016/j.jalz.2017.02.001

5. Takizawa C, Thompson PL, van Walsem A, Faure C, Maier WC. Epidemiological and economic burden of Alzheimer's disease: a systematic literature review of data across Europe and the United States of America. J Alzheimers Dis. 2015;43(4):1271-1284. doi:10.3233/JAD-141134

6. Weller J, Budson A. Current understanding of Alzheimer's disease diagnosis and treatment. F1000Res. 2018;7:F1000. doi:10.12688/f1000research.14506.1

7. Briggs R, Kennelly SP, O'Neill D. Drug treatments in Alzheimer's disease. Clin Med (Lond). 2016;16(3):247-253. doi:10.7861/clinmedicine.16-3-247

8. Crous-Bou M, Minguillón C, Gramunt N, Molinuevo JL. Alzheimer's disease prevention: from risk factors to early intervention. Alzheimers Res Ther. 2017;9(1):71. doi:10.1186/s13195-017-0297-z

9. Mantzavinos V, Alexiou A. Biomarkers for Alzheimer's disease diagnosis. Curr Alzheimer Res. 2017;14(11):1149-1154. doi:10.2174/1567205014666170203125942

10. Buckley RF, Mormino EC, Rabin JS, et al. Sex differences in the association of global amyloid and regional tau deposition measured by positron emission tomography in clinically normal older adults. JAMA Neurol. 2019;76(5):542-551. doi:10.1001/jamaneurol.2018.4693

11. Dubois B, Hampel H, Feldman HH, et al. Preclinical Alzheimer's disease: definition, natural history, and diagnostic criteria. Alzheimers Dement. 2016;12(3):292-323. doi:10.1016/j.jalz.2016.02.002

12. De-Paula VJ, Radanovic M, Diniz BS, Forlenza OV. Alzheimer's disease. Subcell Biochem. 2012;65:329-352. doi:10.1007/978-94-007-5416-4_14

13. 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. doi:10.1016/j.jalz.2011.03.008

14. Jack CR Jr, Albert MS, Knopman DS, et al. Introduction to the recommendations from the National Institute on Aging-Alzheimer's Association workgroups on diagnostic guidelines for Alzheimer's disease. Alzheimers Dement. 2011;7(3):257-262. doi:10.1016/j.jalz.2011.03.004

15. 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

16. 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

17. Alzheimer's and related dementia resources for professionals. National Institute on Aging. Reviewed November 5, 2021. Accessed April 27, 2022. https://www.nia.nih.gov/health/alzheimers-dementia-resources-for-professionals

18. Breijyeh Z, Karaman R. Comprehensive review on Alzheimer's disease: causes and treatment. Molecules. 2020;25(24):5789. doi:10.3390/molecules25245789

19. Okamura N, Harada R, Ishiki A, Kikuchi A, Nakamura T, Kudo Y. The development and validation of tau PET tracers: current status and future directions. Clin Transl Imaging. 2018;6(4):305-316. doi:10.1007/s40336-018-0290-y

20. Alzheimer’s Breakthrough: C2N First to Offer a Widely Accessible Blood Test. News release. PrevivityAD. October 29, 2020. Accessed April 26, 2022. https://bit.ly/3OHq943

21. The First Alzheimer’s Blood Test Is Now Commercially Available. News Release. Massachussets General Hospital. December 4, 2020. Accessed April 26, 2022. https://ftdboston.org/2020/12/04/the-first-alzheimers-blood-test-is-now-commercially-available

22. Quanterix’s Alzheimer’s Blood Test Designated a Breakthrough Device. News Release. FDA News. October 15, 2021. Accessed April 26, 2022. https://www.fdanews.com/articles/204866-quanterixs-alzheimers-blood-test-designated-a-breakthrough-device

23. FDA Grants Breakthrough Device Designation to Diadem's AlzoSure® Predict Prognostic Blood Test for the Early Prediction of Alzheimer's Disease. BioSpace. News Release. January 18, 2022. Accessed April 26, 2022. https://www.biospace.com/article/releases/fda-grants-breakthrough-device-designation-to-diadem-s-alzosure-predict-prognostic-blood-test-for-the-early-prediction-of-alzheimer-s-disease/

24. FDA Grants Accelerated Approval for Alzheimer’s Drug. US Food & Drug Association. News Release. June 7, 2021. Accessed April 26, 2022. https://www.fda.gov/news-events/press-announcements/fda-grants-accelerated-approval-alzheimers-drug

25. FDA Approves BELSOMRA® (suvorexant) for the Treatment of Insomnia. Merck. News Release. August 13, 2014. Accessed April 27, 2022. https://www.merck.com/news/fda-approves-belsomra-suvorexant-for-the-treatment-of-insomnia

26. Herring WJ, Ceesay P, Snyder E, et al. Polysomnographic assessment of suvorexant in patients with probable Alzheimer's disease dementia and insomnia: a randomized trial. Alzheimers Dement. 2020;16(3):541-551. doi:10.1002/alz.12035

27. Treatments for behavior. Alzheimer's Association. Accessed April 27, 2022. https://www.alz.org/alzheimers-dementia/treatments/treatments-for-behavior

28. Norins LC. Repurposing licensed drugs for use against Alzheimer's disease. J Alzheimers Dis. 2021;81(3):921-932. doi:10.3233/JAD-210080

29. Recruiting, Not yet recruiting, Enrolling by invitation Studies: Alzheimer Disease. ClinicalTrials.gov. Accessed April 27, 2022. https://bit.ly/3kiZkFz