Comorbid neuropathological diagnoses in early vs late-onset Alzheimer’s disease

Copathologies play an important role in the expression of the AD clinical phenotype and may influence treatment efficacy. Early-onset AD (EOAD), defined as manifesting before age 65, has been viewed as a relatively pure form of AD with a more homogenous neuropathological substrate. We sought to compare the frequency of common neuropathological diagnoses in a consecutive autopsy series of 96 patients with EOAD (median age of onset = 55 years, 44 females) and 48 with late-onset AD (LOAD) (median age of onset = 73 years, 14 females). The UCSF Neurodegenerative Disease Brain Bank database was reviewed to identify patients with a primary pathological diagnosis of AD. Prevalence and stage of Lewy body disease (LBD), limbic age-related TDP-43 encephalopathy (LATE), argyrophilic grain disease (AGD), hippocampal sclerosis (HS), cerebral amyloid angiopathy (CAA), vascular brain injury (VBI) and aging-related tau astrogliopathy (ARTAG) were compared between the two cohorts. We found at least one non-AD pathological diagnosis in 98% of patients with EOAD (versus 100% of LOAD), and the number of comorbid diagnoses per patient was lower in EOAD than in LOAD (median=2 versus 3, Mann-Whitney Z=3.00, p=0.002). LBD and CAA were common in both EOAD and LOAD (CAA: 86% versus 79%, Fisher exact p=0.33; LBD: 49% versus 42%, p=0.48, respectively), although amygdala-predominant LBD was more commonly found in EOAD than LOAD (22% versus 6%, p=0.02). In contrast, LATE (35% versus 8%, p<0.001), HS (15% versus 3%, p=0.02), AGD (58% versus 41%, p=0.052), and VBI (65% versus 39%, p=0.004) were more common in LOAD than EOAD, respectively. The number of copathologies predicted worse cognitive performance at the time of death on MMSE (1.4 points/pathology (95%CI [−2.5, −0.2]) and Clinical Dementia Rating – Sum of Boxes (1.15 point/pathology, 95%CI [0.45, 1.84]), across the EOAD and the LOAD cohorts. Prevalence of at least one ApoE e4 allele was similar across the two cohorts (52%) and was associated with a greater number of copathologies (+0.42, 95%CI [0.01, 0.82], p=0.04), independent of age of symptom onset. Our findings suggest that non-AD pathological diagnoses play an important role in the clinical phenotype of EOAD with potentially significant implications for clinical practice and clinical trials design.