How do I differentiate Alzheimer’s disease (AD) from Lewy‑body dementia (LBD) in an older adult patient?

Differentiating Alzheimer's Disease from Lewy Body Dementia

The clinical phenotype trumps biomarkers: actively screen for the distinctive triad of fluctuating cognition, recurrent visual hallucinations, and parkinsonism—if any of these "red flags" are present, diagnose Lewy body dementia (LBD) as the primary diagnosis, even if amyloid biomarkers are positive. 1, 2

Core Clinical Features That Distinguish LBD from AD

Temporal Pattern and Cognitive Profile

• LBD presents with fluctuating cognition showing pronounced variations in attention and alertness, assessed using the Mayo Fluctuations Scale or Clinician Assessment of Fluctuation—this is a core distinguishing feature absent in typical AD 1, 3
• AD characteristically presents with prominent memory loss as the earliest and most severe symptom, with relatively preserved attention early in the disease course 2
• Visuospatial/constructional impairment is present in 74% of early LBD cases at first presentation, making it the most sensitive clinical marker, whereas this appears later in AD 4
• The MMSE orientation subscore can help: if the orientation score × 3 ≥ the total MMSE score, this suggests LBD over AD with 100% sensitivity in patients with MMSE 21-27 5

Hallmark Neuropsychiatric Features

• Recurrent, well-formed, detailed visual hallucinations are characteristic of LBD and represent the most specific positive predictor (99% specificity, 83% positive predictive value) when present at initial evaluation 1, 4
• Visual hallucinations occur in only 22% of early LBD cases, so their absence does not exclude the diagnosis 4
• Hallucinations, apathy, dysphoria, anxiety, and aberrant motor behavior are the most discriminating neuropsychiatric symptoms between LBD and AD 6

Motor Symptoms

• Parkinsonism (bradykinesia, rigidity, tremor, postural instability) is a core feature of LBD but is less prominent than in Parkinson's disease 1
• Spontaneous extrapyramidal signs at presentation are present in only 26% of early LBD cases, making them less useful for early differentiation 4
• REM sleep behavior disorder is a supportive feature for LBD 3

Imaging Biomarkers for Differentiation

Structural Imaging (First-Line)

• MRI head without contrast is the optimal initial imaging modality to exclude other causes and assess structural patterns 1, 3
• LBD shows relative preservation of medial temporal lobe structures and hippocampi compared to the marked atrophy characteristic of AD 7, 3, 8
• Loss of the swallow tail sign on susceptibility-weighted imaging (SWI) has been demonstrated in LBD patients, similar to Parkinson's disease 7
• Medial temporal atrophy is present in 82% of AD cases but absent in 67% of LBD cases; when present in LBD, it indicates concurrent AD pathology 8

Functional Imaging (Second-Line)

• FDG-PET/CT demonstrates occipital lobe hypometabolism in LBD, which is the distinguishing feature from AD 7, 3
• The "cingulate island sign" (preservation of FDG metabolism in the posterior cingulate gyrus) is a biomarker for LBD and helps distinguish it from AD, where posterior cingulate hypometabolism is characteristic 7
• DaTscan (I-123 Ioflupane SPECT) shows decreased dopamine transporter uptake in LBD with loss of the normal comma shape in the putamina, achieving 78% sensitivity and 90% specificity for differentiating LBD from AD 7, 3

Amyloid Imaging (Limited Utility)

• Do not rely on amyloid PET/CT alone for differentiation, as LBD frequently has coexistent AD pathology (up to 63% in patients >80 years) 7, 3
• The Society of Nuclear Medicine states that brain amyloid PET/CT is rarely appropriate in patients with suspected LBD 7

Practical Diagnostic Algorithm

1. Establish dementia diagnosis: Confirm cognitive or behavioral symptoms interfering with daily function that represent a decline from previous levels 7

2. Screen for LBD "red flags" before defaulting to AD diagnosis 2:

   • Fluctuating cognition with variations in attention/alertness
   • Recurrent visual hallucinations (well-formed, detailed)
   • Parkinsonism or REM sleep behavior disorder

3. Assess cognitive profile 4, 5:

   • Calculate MMSE orientation subscore × 3 vs. total MMSE score
   • Test visuospatial function with clock drawing and cube copying
   • If orientation score × 3 ≥ total MMSE score AND impaired clock drawing: 93% sensitivity, 70% specificity for LBD

4. Obtain MRI head without contrast to assess medial temporal lobe preservation (LBD) vs. atrophy (AD) 7, 3

5. Consider functional imaging if diagnosis remains uncertain 7:

   • FDG-PET/CT for occipital hypometabolism and cingulate island sign
   • DaTscan for dopamine transporter uptake assessment

Critical Clinical Pitfalls

Medication Safety

• Traditional antipsychotics are absolutely contraindicated in suspected LBD due to severe neuroleptic sensitivity that can precipitate life-threatening reactions and may double or triple mortality rates 1, 2, 3
• This neuroleptic sensitivity is a distinguishing feature that does not occur in AD 9

Overlapping Pathology

• Recognize that 50-60% of clinically diagnosed AD cases have contributing copathologies, including LBD 2
• When LBD core features are present alongside positive amyloid biomarkers, the clinical phenotype determines the primary diagnosis and treatment approach 1, 2
• Brainstem-predominant Lewy body disease with cognitive impairment should prompt consideration of other contributing diseases 7, 3

Treatment Implications

• For LBD, cholinesterase inhibitors are first-line treatment for both cognitive symptoms and visual hallucinations, with greater response expected than in AD due to more severe cholinergic dysfunction 2, 9
• For AD, cholinesterase inhibitors and memantine are standard, with antipsychotics used cautiously if needed for behavioral symptoms 2