The cholinergic system and treatment response in subtypes of Alzheimer’s disease

Abstract

BACKGROUND: The heterogeneity within Alzheimer's disease (AD) seriously challenges the development of disease modifying treatments. We investigated volume of the basal forebrain, hippocampus, and precuneus in atrophy subtypes of AD, and explored the relevance of subtype stratification in a clinical trial on encapsulated cell biodelivery (ECB) of nerve growth factor (NGF) to the basal forebrain. METHODS: Structural MRI data was collected for 90 amyloid-positive patients and 69 amyloid-negative healthy controls at baseline, 6-, 12-, and 24-month follow-up. The effect of the NGF treatment was investigated in 10 biopsy verified AD patients with structural MRI data at baseline and at 6- or 12-months follow-up. Patients were classified as typical, limbic-predominant, hippocampal-sparing, or minimal atrophy AD, using a validated visual assessment method. Volumetric analyses were performed using a region-of-interest approach. RESULTS: All AD subtypes showed reduced basal forebrain volume as compared with controls. Limbic-predominant subtype showed fastest basal forebrain atrophy rate, whereas minimal atrophy subtype did not show significant volume decline over time. Atrophy rates of hippocampus and precuneus also differed across subtypes. The NGF treatment seemed to slow the rate of atrophy in precuneus and hippocampus, particularly in the hippocampal-sparing AD subtype. CONCLUSIONS: The cholinergic system is differentially affected in distinct atrophy subtypes of AD, possibly contributing to their differential response to cholinergic treatment. Our findings suggest that future clinical trials should target specific subtypes of AD, or at least report treatment effects stratifying by subtype.

Biological subtypes of Alzheimer disease

“…22,23 MRI studies have also consistently identified a fourth subtype displaying minimal brain atrophy. [16][17][18][19][20][21][23][24][25][26] In contrast, data-driven methods do not depend on a priori selection of brain regions but investigate interindividual variation in measures of volume or cortical thickness. Several algorithms have been used.…”

“…12 Hence, neurodegeneration measures are another plausible vein to defining biological subtypes. Several hypothesis-driven MRI studies have reported data on these subtypes by using visual rating scales of brain atrophy [16][17][18][19][20][21] or automated methods for estimating regional brain volume. 22,23 MRI studies have also consistently identified a fourth subtype displaying minimal brain atrophy.…”

“…Several hypothesis-driven MRI studies have reported data on these subtypes by using visual rating scales of brain atrophy [16][17][18][19][20][21] or automated methods for estimating regional brain volume. 22,23 MRI studies have also consistently identified a fourth subtype displaying minimal brain atrophy. [16][17][18][19][20][21][23][24][25][26] In contrast, data-driven methods do not depend on a priori selection of brain regions but investigate interindividual variation in measures of volume or cortical thickness.…”

Comparison of subtyping methods for neuroimaging studies in Alzheimer’s disease: a call for harmonization

“… Risacher et al (2017) also corrected for age, sex and ICV, but they based this correction on a reference group of amyloid-beta negative (Aβ−) healthy controls and used a different correction method additionally including the MRI field strength. Ferreira et al and follow-up studies from our lab used visual rating scales of brain atrophy in medial temporal, frontal and posterior cortices ( Ferreira et al , 2017 , 2018 , 2019 ; Persson et al , 2017 ; Ekman et al , 2018 ; Oppedal et al , 2019 ; Machado et al , 2020 ) and determined clinical cut points for abnormality ( Ferreira et al , 2015 ). We also used unsupervised clustering in another cross-sectional study by Poulakis et al (2018) , which was recently extended for subtyping on longitudinal data ( Poulakis et al , 2020 ).…”

Towards harmonizing subtyping methods for neuroimaging studies in Alzheimer’s disease

“…Risacher et al (6) also corrected for age, sex, and ICV, but they based this correction on the amyloid-beta negative (Aβ-) healthy controls as the reference group, and used a different correction method that also included the MRI field strength. Studies from our lab used visual rating scales of brain atrophy in medial temporal, frontal, and posterior cortices (7)(8)(9)(10)(11)(12)(13), and determined abnormality based on clinical cut points (14). We also used an unsupervised clustering method in another cross-sectional study (15), which has recently been extended for subtyping on longitudinal data (16).…”