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Screening and Diagnosing Early AD
Expert Guidance on Screening and Diagnosing Early AD

Released: September 19, 2023

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Key Takeaways
  • Identification of mild cognitive impairment (MCI) and Alzheimer’s disease (AD) can be done by a range of healthcare professionals, and education for all regarding rapid screening and assessments is imperative.
  • Amyloid beta (Aβ) testing is essential to confirm AD pathology for people with MCI and early-stage AD who are interested in targeted therapy.
  • Studies reveal improvement in cognition and function with use of Aβ monoclonal antibody therapy, as well as reduction of Aβ, tau, neurodegeneration, and neuroinflammation.

Why is identification of mild cognitive impairment (MCI) and Alzheimer’s disease (AD) so important? Prevalence! For people in their early 70s, risk for MCI and AD are 10% and 5%, respectively. This more than doubles in less than 1 decade—The early 80s welcome an MCI and AD prevalence of 25% and 13%, respectively. For people in their mid-80s and later, 1 in 4 has MCI and 1 in 3 has AD.

AD and MCI Risk Factors
Risk factors for AD are modifiable and nonmodifiable in nature. Some nonmodifiable risks include being a woman, Black, Latino/a, having the apolipoprotein E-ε4 allele, or having a family history of AD. Modifiable risk factors include diabetes, hypertension, elevated lipids, obesity, low physical activity, cerebral vascular accident or injury, hypoperfusion, tobacco use, severe head trauma, traumatic brain injury, depression, hearing impairment, and lower cognitive reserve.

MCI does not typically affect instrumental activities of daily living (ADLs). On the contrary, mood is affected in 35% to 85% of individuals with MCI, with common neuropsychiatric symptoms including apathy, depression, irritability, anxiety, agitation, or sleep disorders. The most common type of MCI is amnestic, which affects memory to a greater extent than its counterpart, nonamnestic MCI. In nonamnestic MCI, impairment in a nonmemory domain, such as executive function or language, dominates.

Detecting AD and Dementia
When evaluating for MCI or AD, a full psychiatric history is necessary to rule out other causes of cognitive, mood, or behavioral changes. Are there new or previous behaviors that are suggestive of AD? Is the patient experiencing delusions (eg, home intrusion, abandonment, paranoia)? In my practice, I often see patients with AD having visual hallucinations, misidentifications, and providing descriptions of family members’ activities who are currently deceased or whose age is incorrectly described by decades.

Loss of instrumental ADLs co-occurs with AD progression, even in the early stages of disease. By contrast, basic ADLs (eg, bathing, dressing, toileting) begin to decline in the moderate AD stage. A thorough patient history can help you identify such deficits. When taking the history, it is helpful to ask patients retrospective questions to estimate their timeline of disease progression and better understand their functional history (ie, “When was the last time you were able to drive long distances, entertain, or manage finances?”).

Further, a complete medication review of any over-the-counter sleep aids, memory supplements, and herbs is important. Healthcare professionals (HCPs) should also inquire about any current or past use of cannabis, alcohol, illegal drugs, narcotics, cholinesterase inhibitors, or memantine. If a patient answers yes to the latter 2, HCPs should assess the dosing range used, effectiveness, adverse effects, and reason for stopping (if discontinued). If these agents were discontinued, HCPs should determine if ADLs, cognition, or behaviors worsened in the absence of the medication.

After learning patients’ medication history, HCPs need to inquire if (and when) any cerebrovascular incidents, anoxic episodes, and anesthesia precipitation has occurred. In addition, patients’ homes and lifestyles should be examined to uncover any potential environmental or occupational toxins, as well as tick exposure.

Screening and Diagnostic Tools
Available instruments to assist in behavioral assessment include the Neuropsychiatric Inventory or Cohen-Mansfield Agitation Inventory. Although HCPs may not feel they have the time to perform screening for dementia, there are rapid options available: The clock drawing test is simple and quick, and the Mini-Cog takes only 3 minutes. Its results are as predictive of cognitive impairment as the mini-mental state examination (MMSE).

HCPs in primary care (eg, physicians, nurse practitioners, physician associates) are the most accessible for patients in need of MCI and AD rapid screening, as well as completion of initial dementia workup. Regarding sensitivity of cognitive tests, objective cognitive tests like the Montreal Cognitive Assessment and the Saint Louis University Mental Status Examination are superior to the MMSE for MCI detection across diagnoses. The MMSE is not as sensitive when it comes to detecting MCI, but it has been used for decades to detect and stage dementia. Of note, some of these tools are copyrighted.

Evidence-based data now guide HCPs on how to order initial diagnostic testing for AD and dementia using a tiered approach. The full tier 1 cognitive laboratory and diagnostic panel includes thyroid-stimulating hormone, B12, homocysteine, complete blood count with differential, comprehensive metabolic panel (magnesium and liver function tests), erythrocyte sedimentation rate, and C-reactive protein. Tier 1 neuroimaging comprises brain MRI scan (without contrast) or noncontrast head CT scan if MRI is not an option. Patient-specific symptoms and diagnoses are used to guide selection of any necessary tests from the tier 2 menu (in addition to the entire tier 1 panel), such as antinuclear antibody, lipids, A1C, lyme, lead, folate, ammonia, rapid plasma regain, HIV, chest x-ray, methylmalonic acid, prothrombin time, partial thromboplastin time, and serum protein electrophoresis. A sleep study for obstructive sleep apnea and rapid eye movement sleep behavior disorders falls within tier 2 diagnostics if symptoms indicate they are needed.

Tier 3 and 4 diagnostic testing is typically limited to memory specialists who order biomarkers like amyloid beta (Aβ) and tau in cerebrospinal fluid, PET, and fludeoxyglucose (FDG)-PET, among others. Cerebrospinal fluid results revealing decreased Aβ and/or increased tau and phosphorylated tau are indicative of AD. PET scan results may reveal Aβ plaques and fibrillar tau. FDG-PET may uncover neuronal and synaptic deficits.

The following patient profiles would likely benefit from referral to a memory specialist: (1) Those with early-onset dementia (starting earlier than 65 years of age), (2) those with rapidly progressing dementia, (3) those with any atypical dementia presentation, and (4) those with MCI or mild AD who are interested in and appropriate candidates for Aβ monoclonal antibody targeting treatments.

Disease-Modifying Therapies for AD Treatment
Aβ plaque formation begins very slowly, with no neurodegeneration or cognitive impairment seen for years as it accumulates in the brain. Now, monoclonal antibodies like aducanumab and lecanemab are available to target this plaque buildup in the asymptomatic stage by significantly reducing plaque burden, neurofibrillary tangles, and their resulting vascular damage and neurodegeneration. By reducing or removing Aβ plaques, appropriate use of Aβ monoclonal antibodies results in a significantly decreased rate of cognitive and functional decline, making them disease-modifying therapies.

Aducanumab was granted accelerated approval by the FDA in 2021 based on 2 trials (EMERGE and ENGAGE), which enrolled people with MCI or early AD and compared high-dose and low-dose groups with placebo. EMERGE showed a 22% reduction in the Clinical Dementia Rating-Sum of Boxes score among the high-dose group. This group also saw benefits with secondary endpoints of cognition and function vs placebo. ENGAGE failed to meet either primary or secondary endpoints, with the high-dose group performing worse than placebo. Both trials were subsequently halted based on futility analysis.

Lecanemab was granted traditional approval by the FDA in 2023 based on the CLARITY trial that evaluated a 10 mg/kg of body weight biweekly dose. The primary endpoint was met, favoring lecanemab vs placebo. Similar results followed among secondary endpoints, ultimately leading to markers of Aβ, tau, neurodegeneration, and neuroinflammation being reduced to a greater extent with lecanemab vs placebo.

Both agents have prescribing protocols requiring confirmation of the presence of Aβ plaques before initiation. Brain MRIs are required within 1 year of treatment initiation and at regular intervals throughout treatment.

Your Thoughts?
We have agents available to target AD in its early stages. However, if HCPs are not identifying early AD and MCI, these agents are of little help to patients. Do you feel confident in your ability to detect and diagnose MCI or early-stage AD? Answer the polling question and let us know in the comments.

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