What initial diagnostic tests are recommended for an older adult presenting with progressive memory loss, executive dysfunction, or behavioral changes suggestive of Alzheimer’s disease?

Testing for Alzheimer's Disease

Begin with a structured multi-tiered diagnostic evaluation that includes validated cognitive testing, corroborative informant history, functional assessment, core laboratory testing to exclude reversible causes, and brain MRI—all of which should be completed before considering biomarker testing. 1, 2

Step 1: Obtain Reliable Informant History

This is the single most important diagnostic step with critical prognostic significance. 2

• Use structured validated tools such as the AD8, IQCODE (Informant Questionnaire on Cognitive Decline in the Elderly), ECog (Everyday Cognition), or Alzheimer's Questionnaire to systematically capture changes in cognition, function, and behavior 1, 2
• Document baseline functioning and compare with current abilities over months to years to demonstrate insidious decline 2
• If the informant reports no observable changes despite patient concerns, true dementia is highly unlikely 2

Step 2: Perform Objective Cognitive Testing

Use the Montreal Cognitive Assessment (MoCA) as the preferred tool for suspected mild cognitive impairment or early dementia, as it is more sensitive than the MMSE for detecting mild deficits. 1, 2

• For moderate dementia, the Mini-Mental State Examination (MMSE) remains acceptable with high sensitivity and specificity, using a cut point of 23/24 or 24/25 for most populations 1
• Add the Clock Drawing Test as a supplementary assessment 2
• For rapid office screening when time is limited, use combinations such as Mini-Cog, AD-8, or GPCOG 2
• Interpret the full score profile rather than simply applying cut-off scores, integrating results with the patient's educational background, age, language, and culture 3

Step 3: Assess Functional Status

Apply validated functional scales to objectively measure impact on instrumental activities of daily living (IADLs). 1, 2

• Use the Pfeffer Functional Activities Questionnaire (FAQ), Disability Assessment for Dementia (DAD), Lawton IADL Scale, or ECog 4, 1
• Document specific deficits in medication management, financial handling, transportation, household tasks, meal preparation, shopping, and technology use 2
• The key distinction between mild cognitive impairment and dementia rests on whether cognitive changes significantly interfere with daily functioning 2

Step 4: Core Laboratory Testing ("Cognitive Lab Panel")

Order these tests in all patients to identify potentially reversible contributors, not necessarily reversible causes of dementia itself. 4, 1

• Complete blood count (CBC) 1, 3
• Comprehensive metabolic panel 1, 3
• Thyroid-stimulating hormone (TSH) and free T4 1, 3
• Vitamin B12 and folate levels 1, 2
• Liver function tests 1
• HIV testing if risk factors are present 1
• Consider hemoglobin A1C and lipid panel to assess vascular risk factors 2

Common pitfall: These conditions rarely cause the primary progressive cognitive syndrome but often exacerbate underlying neurodegenerative disease. 4

Step 5: Structural Brain Imaging

Brain MRI without contrast is strongly recommended over CT and should not be postponed while awaiting laboratory results. 1, 2, 3

• MRI is superior for detecting vascular lesions, white matter disease, medial temporal lobe atrophy, tumors, hydrocephalus, and hemorrhages 1
• Use imaging to exclude non-AD conditions, identify regional atrophy patterns, and assess vascular cognitive impairment contributions 3
• CT scan is acceptable only if MRI is unavailable or contraindicated 3

Step 6: Physical and Neurological Examination

Perform a dementia-focused neurological examination to identify atypical presentations. 1, 3

• Assess for focal neurologic abnormalities, gait speed and motor movements, reflexes and Babinski signs, and extrapyramidal signs 1
• Evaluate sensory function (hearing loss, vision loss) as these are potentially reversible dementia risk factors 4, 1
• Assess gait and balance problems, which increase fall risk and may indicate Lewy body disease, vascular dementia, or frontotemporal lobar degeneration 4

Step 7: Screen for Common Contributors and Comorbidities

Systematically evaluate conditions that can exacerbate or mimic dementia. 1, 2

• Screen for depression using PHQ-2/PHQ-9 and anxiety using GAD-7 2
• Assess neuropsychiatric symptoms with NPI-Q (Neuropsychiatric Inventory-Questionnaire) or MBI-C (Mild Behavioural Impairment Checklist) 4, 2
• Evaluate sleep quality and specifically screen for obstructive sleep apnea 2
• Review medications for anticholinergic or cognitively impairing agents 2
• Assess for pain and mobility problems that may affect function 2

Step 8: Synthesize Diagnostic Formulation

Integrate all information to determine: (1) whether cognitive-behavioral syndrome is present, (2) the severity level, and (3) the most likely etiology. 1, 3

• Dementia is diagnosed when cognitive or behavioral symptoms interfere with ability to function at work or usual activities, represent a decline from previous functioning, and are not explained by delirium or major psychiatric disorder 2
• Key cognitive domains to assess include memory, executive function, visuospatial abilities, language functions, and personality/behavior changes 2

Step 9: Consider Advanced Testing in Specific Scenarios

Reserve biomarker testing for diagnostic uncertainty, early-onset presentations (<65 years), atypical features, or rapidly progressive dementia. 2, 3

When to Consider CSF or Amyloid PET:

• Early age-of-onset (<65 years) 4, 2
• Atypical presentations (prominent apraxia, language problems, or executive dysfunction rather than memory loss) 5
• Rapidly progressive course 3
• Diagnostic uncertainty after completing Tier 1 evaluation 2, 3
• When high diagnostic confidence is required for therapeutic decisions 2

Biomarker Options:

• CSF analysis for reduced Aβ1-42 and elevated total tau and phosphorylated tau 2, 3
• Amyloid PET imaging 4, 3
• Plasma biomarkers (especially phosphorylated tau 217) are emerging as accurate alternatives 4, 6

Critical caveat: Do NOT order routine biomarker testing in cognitively normal individuals with subjective cognitive decline alone, as this cannot reliably predict short- or medium-term decline and may cause psychological harm. 2

Step 10: Establish Follow-Up and Monitoring Plan

Schedule follow-up visits every 6-12 months with serial cognitive assessments to document progression. 1, 2

• Use the MMSE as the primary tool for tracking cognitive changes over time 2
• Employ a multi-dimensional approach assessing cognition, functional autonomy, behavioral symptoms, and caregiver burden 1, 2
• Patients with prominent behavioral symptoms require more frequent reassessment (every 3-6 months) 2
• Serial assessments help distinguish static conditions from progressive neurodegenerative disease 2

Special Considerations for Subjective Cognitive Decline (SCD)

If cognitive testing is normal but the patient reports persistent concerns, complete the standard workup to identify reversible causes, but recognize that most people with SCD will not develop dementia. 2

• When the informant reports no observable changes, provide reassurance and arrange follow-up only if deterioration occurs 2
• If the informant confirms changes despite normal testing, schedule annual follow-ups and consider referral for detailed neuropsychological testing 2
• Anxiety and depression are the most frequent reversible causes of SCD 2
• Do not order amyloid PET or CSF biomarkers routinely in cognitively normal individuals with SCD, as biomarker positivity without clinical symptoms cannot reliably predict progression and may cause catastrophic psychological reactions 2

Common Pitfalls to Avoid

• Never rely solely on patient self-report without informant corroboration—lack of insight leads to missed diagnoses 2
• Do not use a single cognitive test or clinical domain for diagnosis—combining cognitive tests with functional screens and informant reports significantly improves diagnostic accuracy 2
• Do not overlook delirium—this acute disorder of cognition and attention represents a medical emergency and, when superimposed on dementia, accelerates decline and increases mortality 4
• Do not dismiss sensory deficits—hearing loss and vision loss are potentially reversible dementia risk factors that can be treated or mitigated 4, 1