Association of Neurofibrillary Tangle Distribution With Age at Onset–Related Clinical Heterogeneity in Alzheimer Disease

Background and Objective Patients with earlier age at onset of sporadic Alzheimer disease (AD) are more likely than those with later onset to present with atypical clinical and cognitive features. We sought to determine whether this age-related clinical and cognitive heterogeneity is mediated by different topographic distributions of tau-aggregate neurofibrillary tangles (NFTs) or by variable amounts of concomitant non-AD neuropathology. Methods The relative distribution of NFT density in hippocampus and midfrontal neocortex was calculated, and α-synuclein, TAR DNA binding protein 43 (TDP-43), and microvascular copathologies were staged, in patients with severe AD and age at onset of 51–60 (n = 40), 61–70 (n = 41), and >70 (n = 40) years. Regression, mediation, and mixed effects models examined relationships of pathologic findings with clinical features and longitudinal cognitive decline. Results Patients with later age at onset of AD were less likely to present with nonmemory complaints (odds ratio [OR] 0.46 per decade, 95% confidence interval [CI] 0.22–0.88), psychiatric symptoms (β = −0.66, 95% CI −1.15 to −0.17), and functional impairment (β = −1.25, 95% CI −2.34 to −0.16). TDP-43 (OR 2.00, 95% CI 1.23–3.35) and microvascular copathology (OR 2.02, 95% CI 1.24–3.40) were more common in later onset AD, and α-synuclein copathology was not related to age at onset. NFT density in midfrontal cortex (β = −0.51, 95% CI −0.72 to −0.31) and midfrontal/hippocampal NFT ratio (β = −0.18, 95% CI −0.26 to −0.10) were lower in those with later age at onset. Executive function (β = 0.48, 95% CI 0.09–0.90) and visuospatial cognitive deficits (β = 0.97, 95% CI 0.46–1.46) were less impaired in patients with later age at onset. Mediation analyses showed that the effect of age at onset on severity of executive function deficits was mediated by midfrontal/hippocampal NFT ratio (β = 0.21, 95% CI 0.08–0.38) and not by concomitant non-AD pathologies. Midfrontal/hippocampal NFT ratio also mediated an association between earlier age at onset and faster decline on tests of global cognition, executive function, and visuospatial abilities. Discussion Worse executive dysfunction and faster cognitive decline in people with sporadic AD with earlier rather than later age at onset is mediated by greater relative midfrontal neocortical to hippocampal NFT burden and not by concomitant non-AD neuropathology.