A 55-year-old Hispanic woman presents with concerns about mood swings and memory issues. She has never smoked but drinks two to three glasses of wine per week. She says her family urged her to get evaluated because they are tired of her suddenly getting angry over nothing. Her adult daughter, who accompanies her to the appointment, says that her mother has increasingly had difficulty with word finding, which is often the trigger for an angry outburst. According to the daughter, the patient rarely forgets older events but occasionally forgets recent events, such as seeing her granddaughter last week.
Physical exam reveals the patient is 5 ft 4 in (1.63 m) and 158 lb (71.67 kg) (body mass index, 27.1). She appears tired and frustrated. Additionally, she repeats herself and has trouble finding the words to describe her moods. Relevant medical history includes type 2 diabetes first diagnosed 10 years ago. Blood pressure in 130/85 mm Hg. Current medications include metformin (750 mg twice daily with meals), lisinopril (10 mg/d), and atorvastatin (10 mg/d). Lab tests reveal an A1c of 7.0% and low-density lipoprotein cholesterol level of 90 mg/dL and are otherwise unremarkable. Cranial MRI reveals atrophy in the posterior cingulate cortex.
On the basis of the patient's symptoms, she most likely has early-onset Alzheimer's disease (AD), which is defined as AD occurring in patients younger than 65 years. Presentation usually includes language problems (such as difficulty with word finding) and changes in mood or behavior previously uncharacteristic of the patient. These patients tend to have relatively preserved memory and are more likely to have attention, language, visuospatial, and executive function deficits that affect their family, social, and work lives. Early diagnosis is important because this form of AD has been shown to have a more aggressive course than late-onset AD. Studies suggest that a more rapid rate of decline in cognition.
The patient's current diabetes regimen is not associated with hypoglycemia, and she has relatively good glycemic control, with an A1c value of 7.0%. She has not reported any symptoms of sleep apnea, nor does she have evidence of advanced vascular disease.
The Mini-Cog is a simple screening tool for the detection of cognitive impairment. It asks patients to repeat and remember three words and to draw a complete clock face showing all 12 hours with hands showing a time of 10 past 11 o'clock. The test usually takes about 3-4 minutes. Total scores can range from 0-5, with 1 point for each correctly remembered word and 2 points for a correctly drawn clock (all numbers plus hands in correct position). Scores of 0-2 suggest likelihood of cognitive impairment and need for comprehensive follow up. Scores of 3-5 mean that cognitive impairment is less likely but not definitively ruled out.
Other recommended cognitive assessments include the General Practitioner Assessment of Cognition (GPCOG) and the Memory Impairment Screen. Proper assessment also includes having family members or caregivers complete assessments such as the Informant GPCOG or the AD 8-Question Screen.
Electrocardiography, electroencephalography, and the 6-minute walk test are not the appropriate assessments in this case.
The acetylcholinesterase inhibitors are approved by the US Food and Drug Administration for treatment of AD. The most recent American Academy of Neurology guideline for mild cognitive impairment states that these drugs can be offered after frank discussion with patients about the limited evidence of benefit and potential for side effects. They predominantly impact memory, but they might help patients with early-onset AD and language or executive function deficits as well. Regular monitoring for response is needed for potential treatment-related behavioral changes. In clinical trials, efficacy of these drugs is similar in patients with early-onset AD and those with late-onset AD.
Monoclonal antibodies that target amyloid plaque within the brain to slow cognitive decline are of interest. Lecanemab is administered intravenously every 2 weeks and is approved for mild cognitive impairment related to AD. The monoclonal antibody aducanumab has been discontinued after initial hopes for an effective alternative.
The pathogenesis of early-onset and late-onset AD is complex and multifactorial and presents an ongoing challenge in treatment development. At this time, novel treatments for AD continue to be explored with targets including butyrylcholinesterase, neurotransmitter modulation (serotonin, H3 receptors, phosphodiesterase), anti-inflammatory cyclo-oxygenase-2 and nonsteroidal anti-inflammatory drugs, and monoamine oxidase B. Patients should be informed about and encouraged to enroll in clinical trials where appropriate.
Watch-and-wait might seem reasonable but will allow cognitive impairment to progress. At the very least, the patient should be apprised of the options for pharmacologic therapy so she can make an informed decision.
As it stands, there is no reason to modify this patient's metformin dosage, which is providing the patient with adequate glycemic control. Furthermore, metformin might have some benefit in reducing cognitive impairment in patients with type 2 diabetes and has been associated with a lower risk for AD development in older people with type 2 diabetes.
A recent meta-analysis reported that treatment with a dipeptidyl peptidase 4 (DPP-4) inhibitor improved cognitive impairment while also improving diabetes endpoints. Another meta-analysis with data from 27 studies across the gamut of diabetes medications supported a benefit in decreased dementia risk with sodium-glucose cotransporter 2 inhibitors, glucagon-like peptide 1 receptor agonists, and DPP4 inhibitors and an increased dementia risk with sulfonylureas.
Depending on the type of deficits experienced by patients with early-onset AD, interventions such as speech therapy, behavioral modification, psychoactive medications, or assistive devices (eg, calculators or vision assistance) can help to improve the patient's symptoms and quality of life. Patients with AD might have concerns about remaining in control and processing their diagnosis.
Psychosocial support to manage depression and anxiety helps patients cope with the diagnosis and optimize their potential. Regular exercise is helpful for many reasons, and evidence suggests that it might also help improve cognition in patients with mild cognitive impairment.
On the basis of the patient's current condition, home nursing care and retirement planning are not most appropriate for her.
Further evaluation confirmed that the patient had early-onset AD. After discussion of pharmacologic options, she and her family opted not to start therapy. She began a guided exercise program with three sessions each week and enrolled her husband and herself in nutrition counseling to ensure a healthy diet. At 3-month follow-up, she was pleased with the exercise and nutrition and had lost about 5 lb. She had no decline on the Mini-Cog or MRI evidence of progression, but having had time to process, she wanted to discuss starting treatment with lecanemab.
Editor's Note: Skill Checkups are wholly fictional or fictionalized clinical scenarios intended to provide evidence-based educational takeaways.
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