Subtypes of multiple-etiology dementias and the heterogeneous impact of APOE variants

Multiple-etiology dementias (MEDs) are frequently identified at autopsy but often missed in clinical diagnosis, limiting the efficiency of dementia research and treatment. This study aimed to characterize subtypes of MEDs, evaluate clinical underdiagnosis, and assess the heterogeneous impact of apolipoprotein E (APOE) variants on mortality across MED subtypes.

Data from the National Alzheimer's Coordinating Center (NACC) repository, which includes standardized clinical and autopsy assessments, were analyzed using competing risks survival models.

Pure Alzheimer's disease (AD) neuropathology was rare, whereas mixed neuropathologies were common and frequently misdiagnosed as AD alone. APOE ε4 decreased mortality risk in decedents without AD neuropathology and increased mortality in decedents with mixed AD neuropathology, but not in those with AD alone. APOE ε2 increased mortality in decedents having vascular neuropathology with cerebral amyloid angiopathy.

Heterogeneity in MEDs remains substantially underrecognized clinically. The effects of APOE variants vary by dementia subtype, emphasizing the need for refined diagnostic tools and personalized dementia treatment and care approaches.

Autopsy data revealed that pure Alzheimer's disease (AD) neuropathology is rare, whereas mixed pathologies are highly prevalent and frequently misdiagnosed as AD alone in clinical settings, underscoring the limitations of current diagnostic practices. Comprehensive neuropathological characterization of multiple-etiology dementia (MED) subtypes is crucial for uncovering the true complexity of dementia, which is often masked in clinical assessments. This approach enables a more accurate understanding of disease mechanisms and progression. We found that apolipoprotein E (APOE) ε4 was associated with increased mortality risk in AD with co-pathologies, but not in pure AD without other neuropathologies. Conversely, APOE ε4 was associated with decreased mortality risk in decedents who did not have AD neuropathology. APOE ε2 was protective in some AD-related subtypes but was associated with higher mortality risk in cerebral amyloid angiopathy with other vascular neuropathologies, highlighting the heterogeneous impact of genetic risk factors across subtypes. The differential effects of APOE variants across MED subtypes emphasize the need to evaluate biomarkers and risk factors within the context of underlying neuropathological profiles rather than broad clinical categories. These findings reinforce the need to develop and implement more refined, subtype-specific biomarkers and diagnostic protocols to enable precision prevention and personalized treatment strategies for the diverse forms of MED.