Article Archive
November/December 2023

Alzheimer’s Disease: Accurate Diagnosis Ensures Appropriate Prescribing and Treatment for Alzheimer’s
By Frank Amato
Today’s Geriatric Medicine
Vol. 16 No. 6 P. 8

The introduction of new drugs to treat Alzheimer’s disease (AD), coupled with growing public awareness of dementia and its potential precursor—mild cognitive impairment (MCI)—challenges geriatricians to address this question that is top-of-mind for a growing number of families: “How do I know if my loved one has dementia or AD?”

Geriatricians understand age is the biggest risk factor for developing dementia. The Alzheimer’s Society estimates that in the United States there are more than six million people living with AD. By 2050, this number is projected to rise to almost 13 million.1

Physician practices serving older patients also recognize the importance of getting an accurate dementia diagnosis, especially with the pressure to prescribe expensive new therapies and ensure they are safely administered to the right patients. This is particularly significant since the current diagnostic pathway to accurately diagnose AD is woefully inadequate. Taking it a step further and implementing an objective, definitive diagnostic would immensely help clinicians manage this burgeoning disease state.

People who visit a geriatrician with vague symptoms often do not meet the criteria to be referred for tests, resulting in long delays to a definitive diagnosis and appropriate treatment. In fact, the Alzheimer’s Association reports that in the community setting, 50% to 70% of symptomatic patients are incorrectly diagnosed with AD and that number is reduced to 25% to 30% even in specialized memory clinics. The association faults the inconsistency of routine cognitive screening and the lack of easily accessible, accurate, and time- and cost-effective diagnostic tools.2

This diagnostic dilemma is even worse in early stages of the disease, affecting patients without dementia who have either subjective cognitive decline (SCD) or MCI.3 Unfortunately, cognitive tests now available for primary care settings are inadequate to differentiate SCD and MCI.4 In fact, very few patients with MCI are eligible for treatment with FDA-approved Leqembi, which is associated with serious safety issues. In the absence of cognitive criteria being met, the pool of potential patients would double in size. The Mayo Clinic Study of Aging applied the entry criteria for the drug to its database of 237 MCI and concluded the following5:

• applying the entry criteria: 8%, or 19 of 237, would qualify for treatment with Leqembi;
• removing cognitive criteria: 17.4%, or 41 of 237, would qualify for treatment; and
• applying the study exclusion criteria: 5.1%, or 12 of 237, would qualify for treatment.

Causes of Dementia: Reversible Health Conditions
Dementialike symptoms could be caused by other reversible health conditions, emphasizing the need for an accurate diagnosis that leads to proper treatment. People with dementia typically experience the following6:

• difficulty with one or more types of mental function, like learning, memory, language, and judgment;

• problems that differ from the person’s usual abilities;

• problems that make it difficult for them to manage everyday life responsibilities like work or family; and

• problems that aren’t caused by another mental disorder, such as depression.

Geriatricians are tasked to determine who is the right candidate for the drug and what other options are available to manage MCI and AD dementia for those who are not candidates. Performing cognitive testing can improve the identification of patients at risk and reduce the burden on patients, providers, and the health care system.

In geriatric medical practices nationwide, physicians are following CMS current requirements to perform cognitive testing as part of the annual wellness visits for Medicare recipients. Cognitive assessments and care plans are covered under CPT code 99483 and reimbursed when provided in an office setting.7 The annual wellness visit specifically requires “detection of any cognitive impairment,” defined as “assessment of an individual’s cognitive function by direct observation, with due consideration of information obtained by way of patient report, concerns raised by family members, friends, caretakers, or others.”8

Importance of Early Intervention
As with many progressive diseases, people experiencing cognitive deficits benefit from early intervention, a key for long-term success in people living with SCD or MCI. As a caveat, there is high variability in progression from MCI to dementia, with more than 50% of patients not progressing to dementia, let alone AD, in 10 years.9

The CDC has identified factors such as hypertension, diabetes, depression, hearing loss, obesity, cigarette smoking, and a lack of physical activities as modifiable risk factors for AD and related dementias.10 Geriatric physicians are uniquely positioned to point out meaningful opportunities for people to make lifestyle changes that slow disease progression. As an example, hearing aids are documented to reduce the rate of cognitive decline in older adults at high risk of dementia by almost 50% over a three-year period. Treating hearing loss may be a simple way to lower the risk of dementia in vulnerable populations.11

A recent population-based study suggested that excluding genetic risk factors that are not preventable, about 40% of dementia cases in the present population could be attributable to preventable comorbid diseases, which are also associated with increased mortality.12 Even modest lifestyle changes can be impactful, with data recently presented at the Clinical Trials in Alzheimer’s Disease conference suggesting that mild physical activity could stabilize cognition over a 12-month period in people with MCI.13

Diagnostic Pathways
Researchers are continuing to study and develop biomarkers to improve diagnosis, keeping in mind the prevalence of misdiagnosis with AD due to the inaccuracies in current diagnostic tests as well as the cost of certain testing.

Brain Imaging
Several types of brain scans, including CT, MRI, and PET, may help doctors diagnose AD or a related dementia. These tests are very expensive and may not be available in every community. Furthermore, the available evidence supporting the clinical utility and cost-effectiveness of amyloid PET imaging in routine clinical practice remains unclear and inconclusive.14 While studies suggest its role in identifying amyloid plaques in the brain, there’s a lack of robust evidence demonstrating its impact on patient outcomes or treatment decision-making, and it may lead to misdiagnosis.15

For example, various studies have shown that between 20% to 40% of middle-aged and older individuals are amyloid positive without apparent signs of dementia.16 In individuals 80 years of age or older, 60% presented at autopsy with AD neuropathology but no cognitive impairment during life.17

Cerebrospinal Fluid Biomarkers
In clinical practice, cerebrospinal fluid (CSF) biomarkers may be used to help diagnose AD or other types of dementia.18 For older adults, the risks of a CSF culture include discomfort or pain during the procedure; bleeding into the spinal cord, particularly in people who take blood thinners or have a low platelet count (thrombocytopenia); headache as a result of CSF leakage; infection; and nerve damage.19

Doctors perform a lumbar puncture, also called a spinal tap, to get CSF.20 The most widely used CSF biomarkers for AD measure beta-amyloid 42 (the major component of amyloid plaques in the brain), tau, and phospho-tau (major components of tau tangles in the brain, which are another hallmark of AD).

Blood Tests
Proteins that originate in the brain may be measured with sensitive blood tests. These blood biomarkers have historically been less accurate than CSF biomarkers for identifying AD and related dementias. Many blood biomarkers assess amyloid positivity, validated against amyloid findings from PET scans.21 While amyloid positivity is a hallmark of AD at death, blood tests assessing it do not identify AD itself.

As noted previously, patients with normal cognition may have levels of amyloid plaque consistent with AD based on a PET scan. Given that MCI and dementia can be caused by a variety of risk factors, some of which are modifiable, assessing amyloid positivity before ruling out other causes may lead to excessive diagnostic workups and potential exposure to inappropriate treatments.

Skin Test
The link between the brain and skin is documented: looking at morphological changes that take place in the skin has shown to be a useful tool in the diagnosis of AD. A more objective and highly accurate diagnostic skin test is now available to geriatricians.22 The introduction of DISCERN, an autopsy validated skin test has shown more than 95% sensitivity and specificity to identify AD in people recently diagnosed with dementia, even in those with mixed dementia.23

DISCERN has received reimbursement PLA (CPT) codes (206U and 207U) and can be reimbursed by Medicare. The test is based on a 3 mm skin punch biopsy that’s minimally invasive and can easily be administered in the geriatric physician office setting, with the skin sample then processed in an approved laboratory. This test is the only autopsy-validated test (at 98%) to identify AD and meets the National Institutes of Health Gold Standard for confirming diagnostic accuracy, with patients followed for as long as eight years prior to death. The test comprises three assays that assess the factors directly related to the formation of synaptic connections in the brain impacting loss of memory and cognition in people living with AD. The assays are also related to the formation of amyloid plaques and tau in neurofibrillary tangles, hallmarks of AD at autopsy.

Improved Outlook
Scientific advancements are helping geriatricians make early diagnoses, which might lead to more effective treatment and better outcomes. Genetic testing can also help to predict who might develop AD, and experts are looking into suitable ways to use these techniques.24

For older patients with MCI and in the absence of drug treatment, geriatric specialists are helping people to better manage the condition and avoid disease progression by recommending lifestyle changes that include the following25:

• following a daily routine;
• learning a new skill;
• spending time with friends and family;
• getting enough sleep;
• limiting alcohol consumption; and
• seeking help for health conditions such as high blood pressure or depression.

Looking ahead, both physicians and older patients remain hopeful that more people will receive an accurate diagnosis and appropriate treatment.

— Frank Amato is CEO and president of SYNAPS Dx, an Alzheimer’s disease diagnostic company. After more than two decades in the pharmaceutical and biotech industry, he became president, CEO, and director of electroCore, a NASDAQ-traded bioelectronic medicine company focused on treating neurological conditions. Prior to electroCore, Amato was vice president of the Specialty Commercial Operations at Merck.


1. Alzheimer's Association 2023 Alzheimer’s disease facts and figures report: at a glance statistics. Alzheimer's Association website. Accessed August 21, 2023

2. 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.

3. How is Alzheimer's disease diagnosed? National Institute on Aging website. Published December 8, 2022. Accessed March 27, 2023.

4. Petrazzuoli, F, Vestberg S, Midlöv P, Thulesius H, Stomrud E, Palmqvist S. Brief cognitive tests used in primary care cannot accurately differentiate mild cognitive impairment from subjective cognitive decline. J Alzheimers Dis. 2020;75(4):1191-1201.

5. Roberts RO, Geda YE, Knopman DS, et al. The Mayo Clinic Study of Aging: design and sampling, participation, baseline measures and sample characteristics. Neuroepidemiology. 2008;30(1):58-69.

6. How is dementia diagnosed? A geriatric doctor explains. Dailycaring website. Accessed August 21, 2023.

7. Cognitive assessment & care plan services. Centers for Medicare & Medicaid Services website. Published February 1, 2023. Accessed August 17, 2023.

8. Centers for Medicare and Medicaid Services. 42 CFR § 410.15: Annual wellness visits providing personalized prevention plan services: conditions for limitations on coverage [Internet]. Baltimore, MD: CMS; 2011.

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10. Centers for Disease Control and Prevention. MMWR Weekly Report. 2022;71(20).

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16. Katzman R, Terry R, DeTeresa R, et al. Clinical, pathological, and neurochemical changes in dementia: a subgroup with preserved mental status and numerous neocortical plaques. Ann Neurol. 1988;23(2):138-144.

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18. What is dementia? Symptoms, types, and diagnosis. National Institute on Aging website. Published December 8, 2022. Accessed August 17, 2023.

19. Donohue M. Cerebrospinal fluid culture. Healthline website. Accessed August 17, 2023.

20. Cerebrospinal fluid (CSF) collection. Medline Plus website. Published April 29, 2023. Published December 17, 2016. Accessed August 17, 2023.

21. Hu Y, Kirmess KM, Meyer MR, et al. Assessment of a plasma amyloid probability score to estimate amyloid positron emission tomography findings among adults with cognitive impairment. JAMA Netw Open. 2022;5(4):e228392.

22. Datar M, Mark N, Samson C, Howell S, Huie F, Goss TF. Clinical utility of a novel test to diagnose Alzheimer’s disease in patients with suspected dementia. Ann Clin Cytol Pathol. 2022;8(1):1143.

23. Chirila FV, Xu G, Fontaine D, et al. Morphometric imaging biomarker identifies Alzheimer's disease even among mixed dementia patients. Sci Rep. 2022;12(1):17675.

24. Rentería ME, Mitchell BL, de Lara AM. Genetic testing for Alzheimer's disease: trends, challenges and ethical considerations. Curr Opin Psychiatry. 2020;33(2):136-140.

25. Forgetfulness, and aging: what's normal and what's not? National Institute of Aging Memory website. Published October 21, 2020. Accessed August 17, 2023.