Medical Perspectives | Others

July 30, 2021

Camille Frances M. Hanginan, M.D.

The World Health Organization estimates that at least 50 million people are currently living with dementia, with this number seen to triple in 30 years. In 2015, the global societal cost of dementia was reported to be USD800 billion, far greater than the annual cost of hypertension which is estimated to be USD370 billion.1, 2


Even more alarming than the economic burden brought by dementia are the physical, psychological, and emotional impacts on the patient and their families. Alzheimer Disease (AD) is the most common cause of dementia, and is characterized by progressive memory loss, language impairment, apraxia, visuospatial deficits, and eventually loss of judgment and reasoning.3


A Deeper Understanding of Alzheimer Disease


The lesions most commonly associated with this type of dementia are neurofibrillary tangles composed of tau protein and neuritic plaques containing beta-amyloid. As these lesions accumulate in the brain, neuron-to-neuron communication and nutrient transport are disrupted.


The disruption leads to cell death and ultimately brain atrophy that begins in the medial temporal lobes, progressing to the parietal, temporal, and finally, the lateral frontal cortex. In addition to these lesions, a decrease in the levels of acetylcholine, enzyme choline acetyltransferase, nicotinic adrenergic receptors, serotonin, and norepinephrine is also seen.3


Three stages of AD have been developed by experts, namely, (1) preclinical or asymptomatic stage, (2) mild cognitive impairment (MCI) due to AD, and (3) dementia caused by AD.4 In the earliest stage, there is no evidence of cognitive impairment but biomarkers in the blood and CSF can be identified. These are β-amyloid1-42 (Aβ1-42), total tau protein (T-tau), and hyperphosphorylated tau (P-tau181P).5 In this stage, amyloid imaging is possible with positron-emission tomography (PET).3


A person is said to have MCI when there is memory loss that is noticeable and when they fall 1.5 standard deviations lower in standard memory tests. Cognitive function is preserved and activities of daily living are unaffected at this stage.4, 6 Over 30% of individuals with MCI can progress to AD in 5 years.7


In the last stage of AD, activities of daily living such as driving, shopping, housekeeping, etc. are significantly affected. Visuospatial problems are manifested by difficulty reading and determining color, and judging distance. Eventually patients will have loss of judgment and behavioral problems. In end-stage AD, death can be caused by malnutrition, infection, pulmonary emboli, or aspiration.3


Developments on Early Detection


In recent years, there has been an increasing focus on early detection of AD in order to shift attention to timely intervention and effective healthcare planning. This can potentially lead to a relatively improved quality of life of patients and caregivers. A diagnosis of AD is often clinical. Physicians utilize medical and family history, neurologic exam, and cognitive exams to come up with a diagnosis.8


In the United States, the Alzheimer’s Association has launched an algorithm (Medicare Annual Wellness Visit Algorithm for Assessment of Cognition) for the detection of cognitive impairment in the primary care setting. Patient history, clinician observations, and caregiver concerns are all considered.


Questions that explore worsening confusion and forgetfulness within the past 12 months and difficulties in daily activities within the past week are asked during initial clinic visit. Several patient assessment and informant tools were approved to identify those who needed further dementia evaluation.9


The Alzheimer’s Association has also developed the four-year Imaging Dementia—Evidence for Amyloid Scanning (IDEAS) Study to look into the role of amyloid PET imaging and whether it can affect treatment decisions and health outcomes.


Initial results of the IDEAS study showed that PET imaging led to changes in medical management in more than 60% of participants who had MCI. Furthermore, PET scans reduced the need for additional neuropsychological testing and cerebrospinal fluid (CSF) testing.10


What is promising in the field of research on the diagnosis of AD is the development of a blood test that can potentially replace PET imaging and CSF amyloid analysis. A study by Nakamura et. al. demonstrated this possibility by detecting plasma amyloid markers through immunoprecipitation coupled with mass spectrometry.11


What Smartphones Can Offer


Pharmaceutical company Elli Lilly and Co. teamed up with Apple Inc. in 2017 to launch a feasibility study aimed to differentiate individuals with MCI and early AD from healthy controls using and iPhone and digital applications. Data collected from 113 participants included differences in accomplishment of psychomotor tasks, number of messages received daily, and compliance with daily one-question surveys they were assigned to.


The researchers found that symptomatic individuals demonstrated slower typing, received fewer messages, relied more on helper apps, and poorer survey compliance. This study exhibits the potential role of smartphones in recognizing early cognitive changes, contributing to the strength of diagnosis, and testing the efficacy of treatment.12


What We Must Not Forget


Although technology now plays a key role in the diagnosis of Alzheimer Disease, a thorough history and physical examination must never be replaced as an initial tool. Elderly patients who present with worsening memory should not be immediately dismissed as a case of benign forgetfulness attributed to aging. Moreover, family and friends must be consulted early on as they can provide the more essential details that can easily be missed. A high index of suspicion, especially in one with a positive family history, must be entertained before it is too late.




  1. World Health Organization et al. 2017. Global action plan on the public health response to dementia 2017–2025. (2017).
  2. Gaziano TA, Bitton A, Anand S, Weinstein MC. International Society of Hypertension. The global cost of nonoptimal blood pressure. J Hypertens. 2009; 27; 1472-1477
  3. Jameson, J L, Dennis L. Kasper, Anthony S. Fauci, Stephen L. Hauser, Dan L. Longo, Joseph Loscalzo, and Tinsley R. Harrison. Harrison's Principles of Internal Medicine. 2018.
  4. Sperling RA, Aisen PS, Beckett LA, Bennett DA, Craft S, Fagan AM, 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):280-92.
  5. Bjerke M, Engelborghs S.J Cerebrospinal Fluid Biomarkers for Early and Differential Alzheimer's Disease Diagnosis. Alzheimers Dis. 2018; 62(3):1199-1209.
  6. Petersen RC, Smith GE, Waring SC, Ivnik RJ, Tangalos EG, Kokmen E. Mild cognitive impairment: clinical characterization and outcome. Arch Neurol. 1999;56:303–308.
  7. Ward A, Tardiff S, Dye C, Arrighi HM. Rate of conversion from prodromal Alzheimer’s disease to Alzheimer’s dementia: A systematic review of the literature. Dement Geriatr Cogn Disord Extra 2013;3:320-32. 20.
  8. 2019 Alzheimer's disease facts and figures. Alzheimer's & Dementia: The Journal of the Alzheimer's Association, Volume 15, Issue 3, 321 – 387
  9. Cordell CB, Borson S, Boustani M, Chodosh J, Reuben D, Verghese J, 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 Mar;9(2):141-50. 
  10. Gil D Rabinovici, MD, et al. Impact of Amyloid PET on Patient Management: Early Results from the IDEAS Study. (Funder(s): U.S. Center for Medicare and Medicaid Services, Alzheimer’s Association, Eli Lilly, GE Healthcare, Piramal)
  11. High performance plasma amyloid-β biomarkers for Alzheimer's disease. Nature. 2018 Feb 8;554(7691):249-254.
  12. Chen R, Jankovic F, et al. Developing Measures of Cognitive Impairment in the Real World from Consumer-Grade Multimodal Sensor Streams

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