How beneficial is cholinesterase inhibition and for whom?

New evidence suggests that cholinesterase inhibition in prodromal Alzheimer’s disease (AD) reduces the annual rate of brain atrophy. It also indicates who to treat and at which stage of the disease, and why cholinergic neurons of the basal forebrain  are among the most vulnerable and earliest affected neurons. These issues were discussed at a well-attended symposium at AAT-ADPD. Cholinesterase inhibitors are cost-effective, but widely underused in the treatment of AD, said Ezio Giacobini, University of Geneva, Switzerland.

The cholinergic deficiency hypothesis for AD is based on the correlation between loss of cholinergic innervation in the cerebral cortex of patients and cognitive impairment.

Neurons with long axonal projections and many arbors exhibit selective neuronal vulnerability (SNV) to AD pathology, said Taylor Schmitz, Montreal Neurological Institute, Montreal, Canada. Full arborization of a human neuron can measure up to 100 meters in length, and Professor Schmitz postulated that reasons for SNV might include increased oxidative stress and accumulation of damaged proteins such as phosphorylated tau.

Are cholinergic neurons of the basal forebrain the first affected by AD pathology?

According to the SNV hypothesis, which is supported by recent work submitted for publication by Professor Schmitz colleagues, the cholinergic neurons of the basal forebrain with their extensive projections should be among the most vulnerable neurons and among the earliest affected in AD.

Use the right dose at the right stage of the disease

Cholinesterase inhibitors (ChEIs) increase acetylcholine levels and improve cholinergic transmission. They are beneficial for patients with mild to moderate, and severe AD, particularly in terms of improving attention and memory, said Professor Giacobini.

The symptomatic effect of ChEIs in AD is maximized by using the right dose at the right stage of the disease, he said, and they may provide benefits for patients with prodromal AD.

Fewer than 50% of AD patients are prescribed ChEIs despite their cost-effectiveness

Professor Giacobini highlighted that fewer than 50% of AD patients are prescribed ChEIs, and in the US, 82% of primary care physicians are ambivalent or negative about their use, despite their cost-effectiveness: each additional month of ChEI therapy lowers total all-cause care cost for patients with AD by 1%, for example by delaying nursing home placement, he said.

Initial nonresponders to ChEI show a lower rate of cognitive decline on therapy

Most clinical guidelines recommend discontinuing treatment with ChEIs in patients who do not show an initial response to therapy, but this advice is contradicted by the result of a recent study by Patrizia Mecocci, University of Perugia, Perugia, Italy and her colleagues. A “real life” retrospective longitudinal study of 628 elderly subjects treated with ChEIs over 3 years showed that compared with initial responders:

  • initial non-responders showed a lower rate of cognitive decline with a mean annual decline in the Mini-Mental State Examination (MMSE) of 1.0 point versus 1.6 points (p<0.0001)
  • old-old (≥76 years) non-responders had a significantly slower rate of cognitive (p<0.0001) and functional decline (p<0.0001)1

ChEIs may preserve brain morphology related to the cholinergic system

ChEIs may reduce the annual rate of brain atrophy in prodromal AD

Early and substantial denervation in the basal forebrain cholinergic system (BFCS) is seen in Alzheimer’s disease (AD), and BFCS may be considered a surrogate outcome in predementia AD clinical trials, said Enrica Cavedo from Sorbonne University, Paris, France.

Recent neuroimaging studies of the BFCS and broader brain areas suggest that use of ChEIs in the prodromal stage of AD reduces the annual rate of atrophy of the primary brain regions involved in AD progression, Dr Cavedo said. Use of ChEIs may therefore preserve brain morphology related to the cholinergic system, she added.


  1. Boccardi V et al. J Alzheimers Dis. 2017;56:239-248.