Objective: We conducted a systematic review and meta-analysis on subtype studies of Alzheimer’s disease (AD) based on postmortem and neuroimaging data, with the ultimate goal of advancing our understanding of mechanisms driving heterogeneity in AD.

Methods: EMBASE, PubMed and Web of Science databases were consulted until July 2019.

Results: Neuropathology and neuroimaging studies have consistently identified three 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 e4 genotype, and CSF biomarker levels.

Conclusion: We identified two core dimensions of heterogeneity: “typicality” and “severity”. We propose that these two dimensions determine individuals’ 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, results interpretation, and understanding mechanisms in future subtype studies. Unraveling the heterogeneity within AD is critical for implementing precision medicine approaches and for ultimately developing successful disease-modifying drugs for AD.