Early‐onset Alzheimer's disease shows a distinct neuropsychological profile and more aggressive trajectories of cognitive decline than late‐onset

Abstract

Objectives: Early-and late-onset Alzheimer's disease (EOAD and LOAD) share the same neuropathological traits but show distinct cognitive features. We aimed to explore baseline and longitudinal outcomes of global and domainspecific cognitive function in a well characterized cohort of patients with a biomarker-based diagnosis. Methods: In this retrospective cohort study, 195 participants were included and classified according to their age, clinical status, and CSF AD biomarker profile: 89 EOAD, 37 LOAD, 46 young healthy controls (age ≤ 65 years), and 23 old healthy controls (>65 years). All subjects underwent clinical and neuropsychological assessment, neuroimaging, APOE genotyping and lumbar puncture. Results: We found distinct neuropsychological profiles between EOAD and LOAD at the time of diagnosis. Both groups showed similar performances on memory and language domains, but the EOAD patients displayed worsened deficits in visual perception, praxis, and executive tasks (p < 0.05). Longitudinally, cognitive decline in EOAD was more pronounced than LOAD in the global outcomes at the expense of these nonamnestic domains. We found that years of education significantly influenced the decline in most of the neuropsychological tests. Besides, the APOE e4 status showed a significant effect on the decline of memory-related tasks within the EOAD cohort (p < 0.05). Interpretation: Age of onset is a main factor shaping the cognitive trajectories in AD patients, with younger age driving to a steeper decline of the non-memory domains. Years of education are related to a transversal decline in all cognitive domains and APOE e4 status to a specific decline in memory performance in EOAD.

The influence of APOE status on cognitive decline

“…Our findings are comparable with those of early-onset AD. For example, individuals living with early-onset AD experience greater cognitive change compared to late-onset AD 26,27 . It is thought that these early changes result from genetic mutations in amyloid precursor protein (APP), Presenilin-1 (PSEN1), or Presenilin-2 (PSEN2) 28 .…”

Sex and APOE ε4 carrier effects on atrophy, amyloid PET, and tau PET burden in early‐onset Alzheimer's disease

“…The early‐onset AD (EOAD; onset < 65 years) variant is an atypical, insidious, and aggressive form of AD with an accelerated trajectory of cognitive decline and greater pathology burden compared to late‐onset AD (LOAD) 2–5 . EOAD manifests with more extensive neurodegeneration and tau burden in regions classically correlated with AD.…”

“…Chételat et al 11 . found EOnonAD populations to be a mix of limbic‐predominant pathologies that largely affect the medial temporal lobe, which makes the identification of succinct patterns of atrophy and tau PET deposition difficult 5 …”

“…11 Chételat et al 11 found EOnonAD populations to be a mix of limbic-predominant pathologies that largely affect the medial temporal lobe, which makes the identification of succinct patterns of atrophy and tau PET deposition difficult. 5 Among those diagnosed with AD, the prevalence of apolipoprotein E ε4 (APOE ε4) is upwards of 40%, compared to between 13% and 23% in non-AD individuals worldwide. 17 Compared to other isoforms, the APOE ε4 variant is associated with greater Aβ deposition in the brain.…”

Reduced Salivary Lactoferrin Levels in Early-Onset Alzheimer's Disease

“…AD is often separated according to age, whereby onset prior to age 65 years is considered to be early-onset AD (EOAD), while onset from an age of 65 years is termed late-onset AD (LOAD). Both AD forms follow a similar pathological and biochemical course, but show distinct cognitive features, and no correlation between the core biomarkers and age in AD patients [ 5 ]. It is known that age may influence salivary lactoferrin production.…”