Atrophy subtypes in prodromal Alzheimer’s disease are associated with cognitive decline

Abstract

Alzheimer’s disease is a heterogeneous disorder. Understanding the biological basis for this heterogeneity is key for developing personalized medicine. We identified atrophy subtypes in Alzheimer’s disease dementia and tested whether these subtypes are already present in prodromal Alzheimer’s disease and could explain interindividual differences in cognitive decline. First we retrospectively identified atrophy subtypes from structural MRI with a data-driven cluster analysis in three datasets of patients with Alzheimer’s disease dementia: discovery data (dataset 1: n = 299, age = 67 ± 8, 50% female), and two independent external validation datasets (dataset 2: n = 181, age = 66 ± 7, 52% female; dataset 3: n = 227, age = 74 ± 8, 44% female). Subtypes were compared on clinical, cognitive and biological characteristics. Next, we classified prodromal Alzheimer’s disease participants (n = 603, age = 72 ± 8, 43% female) according to the best matching subtype to their atrophy pattern, and we tested whether subtypes showed cognitive decline in specific domains. In all Alzheimer’s disease dementia datasets we consistently identified four atrophy subtypes: (i) medial-temporal predominant atrophy with worst memory and language function, older age, lowest CSF tau levels and highest amount of vascular lesions; (ii) parieto-occipital atrophy with poor executive/attention and visuospatial functioning and high CSF tau; (iii) mild atrophy with best cognitive performance, young age, but highest CSF tau levels; and (iv) diffuse cortical atrophy with intermediate clinical, cognitive and biological features. Prodromal Alzheimer’s disease participants classified into one of these subtypes showed similar subtype characteristics at baseline as Alzheimer’s disease dementia subtypes. Compared across subtypes in prodromal Alzheimer’s disease, the medial-temporal subtype showed fastest decline in memory and language over time; the parieto-occipital subtype declined fastest on executive/attention domain; the diffuse subtype in visuospatial functioning; and the mild subtype showed intermediate decline in all domains. Robust atrophy subtypes exist in Alzheimer’s disease with distinct clinical and biological disease expression. Here we observe that these subtypes can already be detected in prodromal Alzheimer’s disease, and that these may inform on expected trajectories of cognitive decline.

Data-driven FDG-PET subtypes of Alzheimer’s disease-related neurodegeneration

“…Indeed, the hypometabolic pattern of the "limbic-predominant" subtype identi ed in the present study shows a striking resemblance with a recently described FDG-PET pattern of pathologically con rmed patients with AD dementia with comorbid TDP-43 pathology and hippocampal sclerosis (42). Other studies suggested that the medial-temporal subtype could be additionally affected by small vessel disease (4,43), which would coincide with the numerically highest WMH volume in the "limbic-predominant" subtype in our study. However, this difference did not reach statistical signi cance in our analysis.…”

“…The "typical" subtype included the largest portion of AD dementia cases and was characterized by a typical posterior temporo-parietal pattern of hypometabolism that is commonly linked to AD (13,36). The "limbicpredominant" subtype had most pronounced hypometabolism in the hippocampus and related medial temporal structures which showed similarities to the MRI-de ned medial temporal-predominant atrophy subtypes (4,30,37,38). However, the "limbic-predominant" subtype in the current study also showed hypometabolism in more widespread limbic areas and the frontal lobe.…”

“…Interestingly, these atrophy subtypes could already be detected in patients with prodromal AD (i.e. amyloid-beta [Aβ] positive patients with mild cognitive impairment [MCI]), who showed similar biomarker characteristics as the subtypes identi ed in patients with AD dementia and were associated with differential clinical trajectories (4,5).…”

Evolution of brain atrophy subtypes during aging predicts long-term cognitive decline and future Alzheimer's clinical syndrome

“…Previous works studying the differential hippocampal-to-cortical distribution of neurofibrillary tangles or the hippocampal-to-cortical volume ratio in patients with Alzheimer's disease or Alzheimer's clinical syndrome concluded that a hippocampal sparing disease process was linked to poorer cognitive and functional prognoses, especially if cortical atrophy predominate in parietal lobes (Na et al, 2016;Risacher et al, 2017;Ten Kate et al, 2018). Indeed, "hippocampal sparing" damage define atypical variants of Alzheimer's disease, known to have faster evolutions due to impairment in executive functions, language or visuospatial abilities, which strongly impact autonomy (Scheltens et al, 2016).…”

Distinct tau PET patterns in atrophy‐defined subtypes of Alzheimer's disease

“…Various structural neuroimaging approaches have been used to identify subtypes of Alzheimer's disease (AD) based on patterns of regional atrophy . These studies identified reproducible AD subtypes, namely “limbic‐predominant”, “hippocampal‐sparing”, “typical” (i.e., a combination of limbic‐predominant and hippocampal‐sparing) AD, and, to a lesser extent, “mild atrophy” AD .…”