Based on Polsinelli, A. J., & Apostolova, L. G. (2022). Continuum, 28(3), 676-701

Introduction

Alzheimer's disease (AD) is most commonly associated with progressive memory loss in elderly individuals. However, a growing body of evidence underscores the clinical diversity of AD, particularly in younger individuals and in non-amnestic syndromic presentations. These atypical forms of AD, though less recognized, account for a significant proportion of early-onset cases and often manifest as language disorders, visuospatial impairments, or changes in executive and behavioral functions. Because of their resemblance to other neurodegenerative and psychiatric conditions, these variants are frequently misdiagnosed, resulting in treatment delays and increased caregiver burden. This study guide explores the main subtypes, diagnostic strategies, and management approaches relevant to atypical AD.

Key Concepts

1. What Are Atypical AD Variants?

Atypical Alzheimer's disease variants refer to clinical presentations of AD in which memory loss is not the initial or most prominent symptom. These syndromes typically involve early degeneration of non-medial temporal lobe brain regions and are more common in individuals under the age of 65, known as early-onset AD (EOAD). Unlike typical AD, which is dominated by amnestic symptoms, these atypical presentations affect regions such as the parietal, occipital, frontal, and left temporoparietal cortices.

2. Importance of Accurate Diagnosis

Due to their non-amnestic and younger-onset presentation, atypical AD variants are often mistaken for psychiatric conditions, primary progressive aphasias, frontotemporal dementia (FTD), or even functional neurological disorders. This misdiagnosis can delay access to appropriate pharmacologic therapies, specialized care services, genetic counseling, and essential family planning. Additionally, misclassification of the disease can cause confusion and psychological distress for both patients and caregivers.

3. The Role of Biomarkers

Recent advances in AD diagnostics rely on in vivo biomarkers to confirm underlying pathology. These include:

• Amyloid PET Imaging: Detects beta-amyloid plaques.
• Tau PET Imaging: Identifies tau neurofibrillary tangle distribution.
• Cerebrospinal Fluid (CSF) Analysis: Measures levels of Aβ42 (reduced in AD), total tau, and phosphorylated tau (both elevated in AD).
• Emerging Plasma Biomarkers: Blood-based tests measuring Aβ42/40 ratio and phosphorylated tau (e.g., p-tau181, p-tau217) are being validated for broader clinical use.

These tools are especially critical in early or atypical presentations, where clinical assessment alone is insufficient.

Clinical Syndromes and Their Features

Neuropsychological Profiles

Each atypical variant exhibits a distinct cognitive signature:

• PCA: Profound visuospatial deficits (e.g., simultaneous agnosia, constructional apraxia); poor Rey-Osterrieth Complex Figure recall.
• lvPPA: Word-finding difficulties, impaired sentence repetition, spared single-word comprehension and grammar.
• Dysexecutive AD: Marked deficits in set shifting, inhibition, abstraction, and planning; preserved memory in early stages.
• bvAD: Personality changes with executive dysfunction; poor impulse control, altered empathy, and inappropriate behaviors.
• CBS-AD: Asymmetric motor signs with ideomotor apraxia, agraphesthesia, and visuospatial neglect; constructional difficulty with preserved recognition.

Diagnostic Challenges

Because symptoms of these syndromes overlap with non-AD neurodegenerative diseases and psychiatric disorders, misdiagnosis is common:

• PCA vs. CBS: Both feature visuospatial dysfunction and limb apraxia.
• Dysexecutive AD vs. lvPPA: Working memory deficits appear in both; timing and domain prominence help differentiate.
• bvAD vs. bvFTD: Both involve personality changes, but bvAD more commonly includes early memory impairment, hallucinations, and amyloid positivity.

Strategies for differentiation include:

• Utilizing amyloid and tau PET scans or CSF studies
• Documenting initial symptom domains and progression patterns
• Considering patient age, speed of progression, and neuropsych testing results

Treatment Overview

Pharmacologic Management

• Cholinesterase Inhibitors: Donepezil, rivastigmine, galantamine - standard of care for symptomatic relief.
• Memantine: NMDA receptor antagonist used in moderate to severe stages.
• Aducanumab: FDA-approved anti-amyloid therapy with limited clinical use due to risk of ARIA and access restrictions.

Nonpharmacologic Interventions

• Behavioral Interventions: Redirection strategies, behavioral therapy for apathy or disinhibition.
• Environmental Modification: Visual cues, home safety evaluations, use of color contrast in PCA.
• Caregiver Education: Planning for financial management, driving safety, durable power of attorney.
• Multidisciplinary Support: Occupational therapy, speech-language pathology, and social work involvement.

Glossary Essentials

• Balint Syndrome: Visual attention disorder (simultanagnosia, optic ataxia, oculomotor apraxia); seen in PCA.
• Logopenic PPA: AD-related primary progressive aphasia with word retrieval difficulty and sentence repetition impairment.
• Amyloid/Tau PET: PET scans visualizing hallmark AD pathologies.
• Corticobasal Syndrome: Motor-predominant disorder with asymmetric rigidity, apraxia, and alien limb phenomena-can be caused by AD or CBD.
• Frontal Release Signs: Primitive reflexes (grasp, snout, palmomental) indicating frontal lobe dysfunction; may be seen in frontal variants of AD.

Conclusion

Atypical Alzheimer's disease variants expand the clinical spectrum of AD beyond amnesia. Recognition of these syndromes is critical to providing accurate diagnosis, appropriate treatment, and holistic support. Behavioral neurologists, neuropsychologists, and general neurologists must develop fluency in recognizing the variant-specific clinical signatures and interpreting relevant biomarker data. As research progresses, particularly through initiatives like the LEADS study, our understanding of these variants will sharpen, enabling earlier detection and more personalized care for this underserved subset of patients.