What is the appropriate workup and treatment for an older patient suspected of having Alzheimer's disease with symptoms of cognitive impairment?

Alzheimer's Disease Workup

The workup for suspected Alzheimer's disease requires a structured three-step diagnostic approach: (1) assess cognitive functional status using validated instruments, (2) characterize the cognitive-behavioral syndrome, and (3) determine the underlying etiology through systematic laboratory testing, structural neuroimaging, and consideration of AD biomarkers when diagnostic uncertainty persists. 1, 2

Step 1: Initial Assessment with Informant History

• Always obtain collateral history from a reliable informant (family member or close friend), as patients with Alzheimer's disease typically lack insight into their cognitive changes 2, 3
• Use validated structured questionnaires such as the AD8 or Alzheimer's Questionnaire to document changes in cognition, function, and behavior over time 2
• Document the time course of symptoms—insidious onset over months to years (not sudden) with clear-cut worsening by report or observation 1

Step 2: Objective Cognitive Testing

• Administer the Montreal Cognitive Assessment (MoCA) rather than the Mini-Mental State Examination (MMSE), as the MoCA is superior for detecting mild cognitive impairment and early dementia due to its comprehensive assessment of executive functions and visuospatial abilities 2
• The patient's performance should not be interpreted in isolation but integrated with overall risk profile, history, and other examination findings 1
• Consider referral to neuropsychology if validated brief cognitive tests are insufficiently informative, particularly in individuals with extremes of age, education, intelligence, or complex demographic considerations 1

Step 3: Functional Assessment

• Carefully probe instrumental activities of daily living (IADLs) with the informant to detect intra-individual decline 2
• Use structured instruments such as the Pfeffer Functional Activities Questionnaire (FAQ) or Disability Assessment for Dementia (DAD) 2, 4
• The diagnosis of dementia requires that cognitive deficits are sufficiently severe to affect social or occupational function 3

Step 4: Tier 1 Laboratory Testing (Mandatory in All Patients)

Obtain a comprehensive "cognitive lab panel" in all patients to identify reversible or contributing causes: 1, 2

• Complete blood count (CBC) with differential
• Complete metabolic panel (Chem-20) with renal and hepatic panels, electrolytes, glucose, calcium, magnesium, and phosphate
• Thyroid-stimulating hormone (TSH)
• Vitamin B12 level
• Homocysteine level
• C-reactive protein (CRP) and erythrocyte sedimentation rate (ESR)

These tests aid in recognition and treatment of common comorbid conditions that rarely cause but often contribute to cognitive symptoms 1

Step 5: Structural Neuroimaging (Mandatory)

• Obtain brain MRI as the preferred modality; if MRI is contraindicated or unavailable, obtain CT 1, 2
• MRI is superior to CT for detecting vascular lesions, regional atrophy patterns, white matter hyperintensities, and patterns suggesting alternative diagnoses 2
• Structural imaging helps exclude non-AD/ADRD conditions and provides evidence of regional brain atrophy consistent with neurodegenerative disease 1
• Absence of atrophy does not exclude underlying AD pathological changes 1

Step 6: Medication Review

• Systematically review all medications, as certain drugs (particularly anticholinergics) can contribute to cognitive impairment 2, 4
• Assess for excessive alcohol use and screen for obstructive sleep apnea 1

Step 7: AD Biomarker Testing (When Diagnostic Uncertainty Exists)

Consider AD biomarkers only after completing the above evaluation if clinical diagnostic uncertainty persists: 2

• Cerebrospinal fluid (CSF) analysis via lumbar puncture has 85-90% sensitivity and 80-84% specificity for AD neuropathologic changes 2
• Amyloid PET imaging has 89-98% sensitivity and 88-100% specificity against autopsy 2
• Blood-based biomarkers (plasma p-tau) are emerging but should currently only be used in symptomatic patients at specialist clinics, with results confirmed by CSF or PET whenever possible 1

Step 8: Diagnostic Formulation

Integrate all findings to determine: 2

1. Cognitive functional status: Normal cognition, subjective cognitive decline, mild cognitive impairment (MCI), or dementia
2. Syndromic diagnosis: Amnestic presentation (most common), or non-amnestic presentations (language, visuospatial, or executive dysfunction) 1
3. Etiologic diagnosis: Recognize that most individuals older than age 80 with cognitive impairment harbor more than one type of brain pathological change (mixed etiology dementia) 2

Step 9: Behavioral and Psychological Assessment (If Present)

• Use the Neuropsychiatric Inventory-Questionnaire (NPI-Q) to systematically document presence, severity, and caregiver distress across 12 neuropsychiatric domains 4
• Screen for depression using validated tools such as the Patient Health Questionnaire-9 (PHQ-9), Geriatric Depression Scale (GDS), or Cornell Scale for Depression in Dementia (CSDD) 4

Common Pitfalls to Avoid

• Do not assume "normal aging" or ascribe cognitive symptoms to aging without appropriate evaluation 1, 4
• Do not rely solely on patient self-report without informant corroboration 2, 4
• Do not skip structural neuroimaging—it is mandatory, not optional 1, 2
• Do not order AD biomarkers as first-line tests; they should only be used when diagnostic uncertainty persists after completing the standard workup 1, 2
• Do not overlook potentially reversible contributors such as medication effects, thyroid dysfunction, vitamin B12 deficiency, or depression 1, 2

Longitudinal Monitoring Strategy

• Track disease progression using serial cognitive assessments with the same validated instruments at each visit 2
• Use a multi-dimensional approach assessing cognitive function, functional autonomy, behavioral symptoms, and caregiver burden 2, 4
• Serial assessments help optimize diagnostic accuracy, document trajectory of decline, and distinguish progressive neurodegenerative disease from static conditions 2