What is the appropriate diagnostic workup for Alzheimer’s dementia?

Diagnostic Workup for Alzheimer's Dementia

The diagnostic workup for Alzheimer's dementia requires establishing cognitive decline through corroborated history, objective cognitive testing, functional assessment, exclusion of reversible causes via laboratory testing and neuroimaging, and documentation of neuropsychiatric symptoms—all integrated to determine whether dementia criteria are met and whether the pattern is consistent with Alzheimer's disease. 1, 2

Step 1: Establish Cognitive Decline Through Corroborated History

Obtaining reliable informant information about changes in cognition, function, and behavior is the single most important diagnostic step and carries critical prognostic significance. 1 Do not rely solely on patient self-report, as lack of insight leads to missed diagnoses. 1

• Use structured informant-based tools: AD-8, IQCODE (Informant Questionnaire on Cognitive Decline in the Elderly), ECog (Everyday Cognition), or Alzheimer's Questionnaire to systematically document cognitive changes. 3, 1, 2
• Document baseline functioning and compare with current functioning to establish intra-individual decline over months to years with insidious onset. 3, 4
• The diagnosis requires clear-cut history of cognitive worsening, not just a single abnormal test result. 4

Step 2: Objective Cognitive Assessment

Use the Montreal Cognitive Assessment (MoCA) when mild cognitive impairment or early dementia is suspected, as it is more sensitive than MMSE for detecting mild impairment. 1 For moderate dementia screening, the Mini-Mental State Examination (MMSE) remains acceptable with high sensitivity and specificity. 1

• Add the Clock Drawing Test as a supplementary assessment to either MoCA or MMSE. 1
• Cognitive impairment must involve at minimum two of five domains: memory (learning and recall of recently learned information), executive function, visuospatial abilities, language, and personality/behavior. 4
• For amnestic presentation (most common), document impaired learning and recall of recently learned information as the predominant deficit, plus evidence of dysfunction in at least one other cognitive domain. 2, 4
• Scores on cognitive tests for MCI patients are typically 1 to 1.5 standard deviations below the mean for age and education-matched peers. 3
• If assessment is inconclusive (symptoms present but normal examination findings), neuropsychological testing can help determine whether dementia is present and establish the extent and severity of cognitive impairment objectively. 3, 1, 5

Step 3: Functional Assessment

The key distinction between MCI and dementia rests on whether cognitive changes significantly interfere with daily functioning. 1 Dementia is diagnosed when cognitive symptoms interfere with ability to function at work or usual activities and represent a decline from previous functioning. 1

• Use structured functional scales: Pfeffer Functional Activities Questionnaire (FAQ), Disability Assessment for Dementia (DAD), Lawton Instrumental Activities of Daily Living Scale, or ECog to objectively assess functional autonomy. 3, 1, 2
• Document specific changes in instrumental activities of daily living: medication management, financial management (paying bills), transportation abilities, household management, meal preparation, shopping abilities, and use of technology. 3, 2
• Assess basic self-care activities: bathing, dressing, toileting. 3
• MCI patients commonly have mild problems performing complex functional tasks they previously performed, taking more time and making more errors, but generally maintain independence with minimal aids. 3

Step 4: Neuropsychiatric Symptom Documentation

Use the Neuropsychiatric Inventory-Questionnaire (NPI-Q) or Mild Behavioural Impairment Checklist (MBI-C) to systematically document behavioral and psychological symptoms. 3, 1, 2

• Screen for depression using PHQ-2/PHQ-9 and anxiety using GAD-7 as part of the baseline evaluation. 1
• Document agitation, depression, apathy, delusions, hallucinations, sleep disturbances, and their severity. 2
• Psychiatric symptoms occur in more than half of AD patients before cognitive impairment becomes apparent, making differentiation from primary psychiatric disorders challenging. 4

Step 5: Laboratory Testing for Reversible Causes

Complete a systematic medication review to identify agents with anticholinergic or other cognitive-impairing properties in all patients. 1

• Thyroid function tests (TSH, free T4). 1
• Vitamin B12 and folate levels. 1
• HIV testing if risk factors are present. 1
• Assess for sleep disorders, particularly obstructive sleep apnea, as untreated sleep apnea can generate subjective memory worries. 1
• Evaluate sensory deficits (hearing loss, vision loss) and pain/mobility problems that may affect function. 1

Step 6: Structural Neuroimaging

Anatomical neuroimaging with MRI is recommended in most situations, especially with onset of cognitive symptoms within the past 2 years, unexpected decline in cognition/function, recent significant head trauma, unexplained neurological manifestations, or significant vascular risk factors. 1

• MRI is preferred over CT, especially for detecting vascular lesions, focal atrophy, infarcts, and tumors. 1, 5
• Brain neuroimaging may demonstrate structural changes that may not be identified on physical examination. 5

Step 7: Diagnostic Formulation

Probable AD dementia requires: (1) dementia criteria met, (2) insidious onset over months to years, (3) clear cognitive worsening, (4) prominent deficits in memory OR non-amnestic domains (language, visuospatial, executive), and (5) exclusion of other conditions. 4

Mandatory exclusions: Do not diagnose probable AD dementia if substantial cerebrovascular disease, core features of dementia with Lewy bodies, prominent features of behavioral variant frontotemporal dementia, or another concurrent active neurological disease or medical comorbidity are present. 4

• Integrate information about risk profile, history of symptoms, and examination findings to determine whether cognitive-behavioral syndrome is present. 1
• Specify presentation type: Amnestic (most common) versus non-amnestic (language variant, visuospatial variant, or executive variant). 2, 4
• Document disease stage: Mild, moderate, or severe dementia based on cognitive scores, functional impairment severity, and behavioral symptoms. 2

Step 8: Advanced Biomarker Testing (When Indicated)

Routine ordering of amyloid PET or cerebrospinal fluid biomarker studies in cognitively normal individuals is not recommended. 1 However, biomarker testing may be appropriate in specific circumstances:

• Obtain amyloid PET scan when diagnostic uncertainty persists after structural imaging with or without FDG-PET and/or CSF testing, according to appropriate use criteria. 4
• Consider CSF analysis for Aβ42 and tau/p-tau when diagnostic uncertainty remains, early-onset dementia (age <65 years) is suspected, or very high diagnostic confidence is needed for treatment decisions. 3, 4
• CSF AD biomarkers (reduced Aβ1-42, elevated tau and p-tau) are recommended as a supplement to clinical evaluation, particularly in uncertain and atypical cases, to identify or exclude AD as the cause of dementia. 3
• Genetic testing should be considered in patients with established cognitive-behavioral syndrome and likely autosomal dominant family history, with genetic counselor involvement throughout. 4

Common Pitfalls to Avoid

• Do not overlook medical conditions that can influence biomarker interpretation. 1
• Do not rely on cognitive test cutoff scores alone—interpret the full profile in context of demographics, education, language, and culture. 4
• Failing to use standardized, validated instruments reduces diagnostic accuracy and makes longitudinal tracking unreliable. 1
• Mixed pathology is extremely common in adults over age 80, and atypical presentations should raise suspicion for mixed etiology dementia. 4
• Anxiety, depression, fatigue, sleep disturbances, attention-deficit symptoms, and medication side effects are the most frequent reversible causes of subjective cognitive concerns. 1

Follow-Up and Monitoring

Schedule follow-up visits every 6-12 months to track disease progression using a multi-dimensional approach that assesses cognition (MMSE/MoCA), functional autonomy (FAQ/DAD), behavioral symptoms (NPI-Q), and caregiver burden. 1, 2

• Patients with prominent behavioral symptoms should be reassessed more frequently (every 3-6 months). 1, 2
• Serial assessments help distinguish static conditions from progressive neurodegenerative disease. 1
• Document caregiver stress, safety concerns (driving, home safety, wandering risk), and support needs. 2