In vivo detection of Alzheimer's and Lewy body disease concurrence: Clinical implications and future perspectives

Abstract

Introduction: The recent introduction of seed amplification assays (SAAs) detecting misfolded α-synuclein, a pathology-specific marker for Lewy body disease (LBD), has allowed the in vivo identification and phenotypic characterization of patients with co-occurring Alzheimer's disease (AD) and LBD since the early clinical or even preclinical stage.

Methods: We reviewed studies with an in vivo biomarker-based diagnosis of AD-LBD copathology.

Results: Studies in large cohorts of cognitively impaired individuals have shown that cerebrospinal fluid (CSF) biomarkers detect the coexistence of AD and LB pathology in approximately 20%-25% of them, independently of the primary clinical diagnosis. Compared to those with pure AD, AD-LBD patients showed worse global cognition, especially in attentive/executive and visuospatial functions, and worse motor functions. In cognitively unimpaired individuals, concurrent AD-LBD pathologies predicted longitudinal cognitive progression with faster worsening of global cognition, memory, and attentive/executive functions.

Discussion: Future research studies aiming for a better precision medicine approach should develop SAAs further to reach a quantitative evaluation or staging of each underlying pathology using a single biofluid sample.

Highlights: α-Synuclein seed amplification assays (SAAs) provide a specific marker for Lewy body disease (LBD). SAAs allow for the in vivo identification of co-occurring LBD in patients with Alzheimer's disease (AD). AD-LBD coexist in 20-25% of cognitively impaired elderly individuals, and ∼8% of those asymptomatic. Compared to pure AD, AD-LBD causes a faster worsening of cognitive functions. AD-LBD is associated with worse attentive/executive, memory, visuospatial and motor functions.

Keywords: Lewy body disease; RT‐QuIC; dementia; prions; real‐time quaking‐induced conversion; synuclein.

FIGURE 1

Schematic representation of LBD and AD copathology. (A) According to the McKeith/Braak staging, LB pathology initially involves the lower brainstem (left). Then, following an ascending course, it spreads to the limbic regions (middle) and eventually reaches the neocortices (right). As LBD progresses, the likelihood of coexisting AD pathology increases because of the older mean age and a likely synergistic effect between the two pathologies. (B) The amygdala‐predominant variant of LBD is almost invariably associated with AD pathology. Besides the amygdala, the area showing the greatest LB pathology load in this variant, LBs can sometimes be detected in the anterior cingulate gyrus, the entorhinal cortex and the upper brainstem (limited to the midbrain). Hemibrain sagittal sections (A, B‐left) and coronal sections at the level of the amygdala (B‐middle) and hippocampus (B‐right). AD , Alzheimer's disease; ADNC , AD neuropathologic change; LB , Lewy bodies; LBD , Lewy body disease; NFTs , neurofibrillary tangles. Figure created with BioRender.com.

FIGURE 2

Schematic representations of the α‐syn misfolding process and working principles of the α‐syn SAA. (A) The α‐syn monomer exists in two states: membrane‐bound (partially helical conformation) and in solution (unfolded); partially folded α‐syn states precede the formation of oligomers > protofibrils > fibrils with amyloidogenic properties. In the LBD, α‐syn fibril aggregates accumulate as cytoplasmic neuronal inclusions in cell bodies (Lewy bodies = i) and nerve terminals (Lewy neurites = ii). (B) In the SAA reaction, the tested biosample, in which misfolded α‐syn is detected, is loaded together with the reaction mixture, which includes a relatively large amount of recombinant α‐syn substrate and an amyloid‐sensitive dye, in a 96‐well plate (usually, each sample is loaded in multiple wells). Then, the plate is incubated at a given temperature, and the samples are subjected to intermittent rest/shaking cycles. During incubation, α‐syn seeds progressively elongate through recombinant substrate recruitment and conversion. The newly formed oligomers are partially fragmented by quaking, producing novel seeds, while in part, they continue to elongate to the status of protofibrils and, eventually, fibrils. By acquiring amyloid proprieties, the protofibrils/fibrils bind the amyloid‐sensitive dye (thioflavin T), which produces a fluorescent signal. The fluorescent signal intensity from each well is monitored through serial readings at fixed time intervals. In the reaction's readout, fluorescence intensity (y) is plotted as a function of time (x): if the curve crosses a defined threshold (dashed line), the well is deemed “positive”; if not, it is considered “negative.” α‐syn, α ‐synuclein; LBD, Lewy body disease; SAA, seed amplification assay. Figure created with BioRender.com.