Memory Resilience in Alzheimer Disease With Primary Progressive Aphasia

Neurology. 2021 Feb 9;96(6):e916-e925. doi: 10.1212/WNL.0000000000011397. Epub 2021 Jan 13.


Objective: To determine whether memory is preserved longitudinally in primary progressive aphasia (PPA) associated with Alzheimer disease (AD) and to identify potential factors that maintain memory despite underlying neurofibrillary degeneration of mediotemporal memory areas.

Methods: Longitudinal memory assessment was done in 17 patients with PPA with autopsy or biomarker evidence of AD (PPA-AD) and 14 patients with amnestic dementia of the Alzheimer type with AD at autopsy (DAT-AD).

Results: In PPA-AD, episodic memory, tested with nonverbal items, was preserved at the initial testing and showed no decline at retesting 2.35 ± 0.78 years later, at which time symptoms had been present for 6.26 ± 2.21 years. In contrast, language functions declined significantly during the same period. In DAT-AD, both verbal memory and language declined with equal severity. Although imaging showed asymmetric left-sided mediotemporal atrophy in PPA-AD, autopsy revealed bilateral hippocampo-entorhinal neurofibrillary degeneration at Braak stages V and VI. Compared to DAT-AD, however, the PPA-AD group had lower incidence of APOE ε4 and of mediotemporal TAR DNA-binding protein 43 (TDP-43) pathology.

Conclusions: Memory preservation in PPA is not just an incidental finding at onset but a core feature that persists for years despite the hippocampo-entorhinal AD neuropathology that is as severe as that of DAT-AD. Asymmetry of mediotemporal atrophy and a lesser impact of APOE ε4 and of TDP-43 on the integrity of memory circuitry may constitute some of the factors underlying this resilience. Our results also suggest that current controversies on memory in PPA-AD reflect inconsistencies in the diagnosis of logopenic PPA, the clinical variant most frequently associated with AD.

Clinicaltrialsgov identifier: NCT00537004 and NCT03371706.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aged
  • Alzheimer Disease* / pathology
  • Alzheimer Disease* / physiopathology
  • Amnesia* / pathology
  • Amnesia* / physiopathology
  • Aphasia, Primary Progressive* / pathology
  • Aphasia, Primary Progressive* / physiopathology
  • Apolipoprotein E4 / genetics
  • Atrophy
  • Autopsy
  • DNA-Binding Proteins / metabolism
  • Disease Progression
  • Entorhinal Cortex / pathology*
  • Female
  • Hippocampus / pathology*
  • Humans
  • Longitudinal Studies
  • Male
  • Memory, Episodic
  • Middle Aged
  • Neurofibrillary Tangles / pathology
  • Severity of Illness Index


  • Apolipoprotein E4
  • DNA-Binding Proteins
  • TARDBP protein, human

Associated data