Biological subtypes of Alzheimer’s disease: a systematic review and meta-analysis

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.