What medication should be started for an elderly patient with a history of hypertension (HTN), presenting with symptoms of forgetfulness, misplacing items, and social withdrawal, with a low Mini-Mental Exam result and cortical atrophy on MRI, suggestive of Alzheimer's disease?

Cholinesterase Inhibitor Therapy for Alzheimer's Disease

Start a cholinesterase inhibitor, specifically donepezil 5 mg once daily at bedtime, as the appropriate first-line pharmacological treatment for this patient presenting with clinical features consistent with Alzheimer's disease (progressive memory loss, cortical atrophy on MRI, and low Mini-Mental State Examination score). 1, 2

Rationale for Cholinesterase Inhibitor Selection

The clinical presentation—recent memory impairment with preserved remote memory, misplacing items, social withdrawal, low MMSE score, and cortical atrophy on MRI—is characteristic of Alzheimer's disease rather than vascular dementia or primary depression. 1

Cholinesterase inhibitors improve cognition and global function in patients with mild to moderate Alzheimer's disease, with donepezil demonstrating high-certainty evidence for efficacy. 1, 3

• Donepezil produces statistically significant improvements in cognitive scores (ADAS-cog) and global clinical function (CIBIC-plus) compared to placebo, with beneficial effects observed from week 3 of treatment. 4
• The drug works by compensating for reduced cholinergic neurotransmission, a primary pathophysiological feature of Alzheimer's disease. 5

Specific Dosing Protocol

Begin with donepezil 5 mg once daily in the evening, just prior to retiring. 2

• The dose can be taken with or without food. 2
• After 4 to 6 weeks on the 5 mg dose, increase to 10 mg once daily if the medication is well tolerated. 2, 3
• The 10 mg dose provides additional cognitive and functional benefits over the 5 mg dose, with a mean drug-placebo difference of 3.1 ADAS-cog points versus 2.5 points for the 5 mg dose. 4
• For moderate to severe disease progression, the dose can be further increased to 23 mg daily after at least 3 months on the 10 mg dose. 2, 6

Why Not Antipsychotics or Antidepressants

Antipsychotics should not be used for cognitive symptoms or depression in dementia due to increased mortality risk. 7, 8

While this patient has social withdrawal, the primary presentation is cognitive decline with cortical atrophy, not a primary depressive disorder. 7

• If depression is suspected as a comorbid condition after initiating cholinesterase inhibitor therapy, SSRIs (citalopram, escitalopram, or sertraline) can be added as they have favorable side effect profiles in older adults with dementia. 7
• However, the American Heart Association suggests reserving SSRIs only for moderate to severe depression to balance treatment benefits against risks of increased cognitive decline. 8
• The primary therapeutic target should be the underlying Alzheimer's disease pathology, not isolated neuropsychiatric symptoms. 7

Safety Considerations in This Elderly Patient

Monitor blood pressure carefully, as this patient has hypertension. 1

• Continue BP-lowering medications as recommended for patients over 70 years, provided treatment is well tolerated. 1
• Donepezil is generally well tolerated with no clinically significant changes in vital signs or hepatotoxicity. 4

The most common adverse events are cholinergic in nature: 3, 4

• Nausea, diarrhea, and insomnia occur more frequently with the 10 mg dose than with 5 mg. 4
• These events are typically mild, transient, and can be minimized by the gradual 4-6 week dose escalation schedule. 3
• The incidence of serious adverse events with donepezil (4-10%) is comparable to placebo (5-9%). 3

Critical Medication Review

Avoid strongly anticholinergic medications that would counteract the cholinesterase inhibitor and worsen cognition. 1

• Discontinue or substitute medications such as diphenhydramine, cyclobenzaprine, or oxybutynin if the patient is taking them. 1
• These anticholinergic medications are associated with decline in cognition, functional status, and activities of daily living scores in older patients. 1

Expected Treatment Duration and Monitoring

Improvements in cognition and global function are maintained for approximately 21 to 81 weeks with donepezil 10 mg daily. 3

• Successful treatment should be continued for at least 6 months after significant improvement is noted. 7
• Discontinuation should only be considered if clinically meaningful worsening of dementia has occurred over the past 6 months, no benefit was observed, the patient develops severe or end-stage dementia, or intolerable side effects develop. 8