Biological subtypes of Alzheimer disease: A systematic review and meta-analysis

Abstract

Objective: 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.

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

Results: 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.

Conclusion: We identified 2 core dimensions of heterogeneity: typicality and severity. We propose that these 2 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, 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.

Figure 1. Study selection flowchart

A total of 64 records were considered as candidates for the meta-analysis. Of those, 40 records were excluded because of the reasons listed in data available from dryad table e-5, doi.org.10.5061/dryad.h70rxwdf3, and the remaining 24 studies were included in the meta-analysis. FDG = fluorodeoxyglucose; HC = healthy control; MCI = mild cognitive impairment; SCD = subjective cognitive decline.

Figure 2. Frequency of the AD subtypes

The frequency of the subtype partially depends on the number of subtypes included in each study. The figure shows frequency estimates for all the studies pooled together (A, n = 22); studies including 3 subtypes (generally typical, limbic-predominant, and hippocampal-sparing AD) (B, n = 11); and studies including 4 subtypes (C, n = 10). Other factors that may influence these estimates are the modality of the data subtyping is performed on such as postmortem vs MRI data, as well as the subtyping method. The seminal subtyping algorithm is used in all the postmortem studies and in 1 MRI study, and frequency values relate to the 25th and 75th percentiles applied on the hippocampus-to-cortex NFT/atrophy ratio (D, n = 15). Studies not using this algorithm use a variety of subtyping methods and include mostly MRI studies, except for a tau-PET study and a postmortem study, both excluded from this subanalysis) (E, n = 8). AD = Alzheimer disease; NFT = neurofibrillary tangle.

Figure 3. Framework for future studies on AD subtypes

The figure represents 2 dimensions: typicality and severity. We propose that the combination of risk factors, protective factors, and diverse brain pathologies will determine individuals' location along the typicality and severity dimensions, giving 4 distinct subtypes: typical AD, limbic-predominant AD, hippocampal-sparing AD, and minimal atrophy AD. The blue and red ellipsoids on the brain representations show the regions defining these 4 subtypes according to previous studies.^, The figure also lists the risk factors, protective factors, and brain pathologies. In orange, the risk factors, including age, sex, and APOE. In blue, the protective factors, including cognitive reserve and related concepts such as brain resilience and brain resistance. In red, brain pathologies including AD pathologies and concomitant non-AD pathologies. AD pathologies can be organized using the A/T/N classification scheme. In this meta-analyses, characterization of A/T/N categories across subtypes was performed through CSF biomarkers (table 2): an amyloid biomarker should be positive in our model and its load is similar across subtypes, the reason why amyloid is not depicted in the figure; tau-related pathology was assessed with CSF phosphorylated tau (p-tau), and neurodegeneration was assessed with CSF total tau (t-tau). Concomitant non-AD pathologies include cerebrovascular disease (forms of small vessel disease such as cerebral amyloid angiopathy and hypertensive arteriopathy) and other pathologies such as Lewy body pathology, hippocampal sclerosis, and TDP-43. All these factors increase heterogeneity within AD and lead to subtypes according to the spread and location of pathology (neuropathologically and neuroimaging-defined subtypes) often aligning with clinically defined subtypes according to the age at onset and the cognitive presentation (in green in the figure). AD = Alzheimer disease.