Psychology

Apolipoprotein E

Alzheimer's disease

Biochemistry

Atrophy

Neuroscience

Disease

Biology

Meta-analysis

Alzheimer's Disease Neuroimaging Initiative

Neuropathology

Neuropsychology

Hippocampal formation

Cognition

Pathology

Dementia

Oncology

Biomarker

Neuroimaging

Medicine

Neurology

<h3>Objective</h3> To test the hypothesis that distinct subtypes of Alzheimer disease (AD) exist and underlie the heterogeneity within AD, we conducted a systematic review and meta-analysis on AD subtype studies based on postmortem and neuroimaging data. <h3>Methods</h3> EMBASE, PubMed, and Web of Science databases were consulted until July 2019. <h3>Results</h3> Neuropathology and neuroimaging studies have consistently identified 3 subtypes of AD based on the distribution of tau-related pathology and regional brain atrophy: typical, limbic-predominant, and hippocampal-sparing AD. A fourth subtype, minimal atrophy AD, has been identified in several neuroimaging studies. Typical AD displays tau-related pathology and atrophy both in hippocampus and association cortex and has a pooled frequency of 55%. Limbic-predominant, hippocampal-sparing, and minimal atrophy AD had a pooled frequency of 21%, 17%, and 15%, respectively. Between-subtype differences were found in age at onset, age at assessment, sex distribution, years of education, global cognitive status, disease duration, APOE ε4 genotype, and CSF biomarker levels. <h3>Conclusion</h3> We identified 2 core dimensions of heterogeneity: typicality and severity. We propose that these 2 dimensions determine individuals9 belonging to one of the AD subtypes based on the combination of protective factors, risk factors, and concomitant non-AD brain pathologies. This model is envisioned to aid with framing hypotheses, study design, interpretation of results, and understanding mechanisms in future subtype studies. Our model can be used along the A/T/N classification scheme for AD biomarkers. Unraveling the heterogeneity within AD is critical for implementing precision medicine approaches and for ultimately developing successful disease-modifying drugs for AD.

Biological subtypes of Alzheimer disease