Newly learned items form long-term memory in severe Alzheimer’s disease despite hippocampal atrophy

Abstract

Alzheimer’s disease is a neurodegenerative disorder marked by a progressive decline in episodic memory and impaired encoding of new information. While hippocampal atrophy is a hallmark of the disease, several observations suggest that some mechanisms may remain preserved, including familiarity-based recognition. Artistic items, such as music and paintings, are particularly suitable to elicit these spared processes, as they engage reward, emotional and implicit learning networks that remain intact in this condition. However, the extent to which patients with moderate to severe Alzheimer’s disease can learn new information in these domains remains unclear.

Thirty-three patients with Alzheimer’s disease (79.30 ± 5.82 years; mean Mini-Mental State Examination (MMSE) score = 14.76 ± 5.42) and twenty-four healthy control participants (77.17 ± 4.62 years; mean MMSE score = 28.83 ± 0.92) were included in the protocol. A data-driven stratification based on neuropsychological scores identified two subgroups of patients, classified as moderate and severe cognitive impairments. Participants first completed repeated exposure sessions to unknown musical and pictorial items until they reported a sense of familiarity, assessed by a six-point scale designed for this population. One to two days later, a recognition session during which target items and distractor items were presented was conducted; participants’ performance was also evaluated using the familiarity scale. Structural MRI was acquired to quantify hippocampal atrophy and examine the relationship between grey matter volume and recognition performance.

Despite significantly different learning rates across clinical groups (cumulative link mixed model, all pairwise comparisons P < 0.001), 31 patients out of 33 reached the learning criterion for at least one of the two artistic materials. In the recognition session, pairwise comparisons confirmed that all clinical groups significantly discriminated target from distractor items (cumulative link mixed model, all pairwise comparisons P < 0.001), with a gradient of discrimination consistent with disease severity, indicating preserved but modulated familiarity-based recognition. Structural imaging confirmed substantial hippocampal atrophy in both patient subgroups relative to healthy controls (P < 0.001). Multiple regression revealed that higher familiarity scores in recognition session were associated with greater grey matter volume in the right caudate nucleus (cluster-level, PFWE < 0.05).

These findings demonstrate that patients with moderate to severe Alzheimer’s disease retain the ability to encode new musical and pictorial information despite pronounced hippocampal atrophy. Familiarity-based mechanisms, supported by subcortical regions, appear to underpin this preserved learning and may offer promising perspectives for care in patients with Alzheimer’s disease.