We provide the first evidence of structural and functional impairment of the NBM, a key cholinergic forebrain hub, linked to anticholinergic prescription in the ADNI3 cohort highlighting a possible mechanism of the reported elevated risk of dementia linked to AC medication. Importantly, the detrimental central cholinergic effects were demonstrated in both cognitive healthy and mild cognitively impaired participants with a prescription history of at least one year of drugs with mainly mild anticholinergic burden. AC medication strata were matched for APOE Ɛ4 carrier or amyloid status and did not differ in established MRI AD markers arguing against bias effect from preclinical AD and for a specific central cholinergic effect.
We found NBM-GM density loss associated with use of the mild-moderate AC medication that was carefully matched on demographics, ApoE and amyloid markers. This is the first NBM morphometric study on AC medication effects, but findings are generally in line with two previous MRI studies in CN on anticholinergic medication that reported increased brain atrophy and temporal cortical thinning 33, 34. It has been suggested that global brain atrophy in AC medication may indirectly arise from affected central cholinergic pathways that may render the brain more vulnerable to stress-related neurotoxicity. In our study, there was only a trend reduction of hippocampal GM volume, but no change was seen in precuneus GM volume, which would favour an increased cholinergic rather than general brain vulnerability. Selective vulnerability of the basal forebrain cholinergic neurons, and in particular those in Ch4 (NBM), to oxidative stress is well established 35. Beyond oxidative stress, basal forebrain cholinergic neurons are also strongly dependent on target-derived nerve growth factor for preservation of cholinergic phenotype which led to the notion of retrograde NBM atrophy in AD 36, but links between NGF and long-term anticholinergic medication remain to be investigated.
We report reduced NBM-GM density in MCI compared to CN which is well in line with early cholinergic failure in MCI and previous studies demonstrating NBM atrophy 37. Importantly, we observed NBM-GM density loss in MCI with AC medication use compared to those without, providing the first evidence of accelerated NBM neuronal tissue injury associated with anticholinergic medication despite the absence of differences in the severity of cognitive impairment. These findings are further in support of a putative neurotrophic role of cholinergic tone orchestrated through the emerging understanding of modulated gene expression, translation and cellular signalling cascades 38.
We demonstrate the detrimental effects of AC medication use on the NBM cholinergic network in keeping with the hypothesised central hypocholinergic state. The NBM-FC map was generated in an independent subsample of older participants using a Ch4/NBM template seed to increase anatomical specificity over expert manual seeds 27 which allowed robust reconstruction of the medial and lateral cholinergic pathways 39 similar as previously reported in a younger sample 32. NBM-FC was significantly reduced in CN and MCI AC+ compared to AC−. In parallel, we confirm previous reports that AC medication use is associated with impaired global cognitive performance in CN 12, 24, 34, but surprisingly not in MCI. We further showed that cholinergic network functional integrity partially mediated the association between AC medication use and global cognitive performance. These findings provide a potential biological basis for the impaired cognition associated with AC medication use through the functional changes of the cholinergic network.
The effect size of AC medication on NBM imaging metrics was large in MCI and small-medium in CN suggesting a preferential vulnerability to AC in the at-risk population. This interpretation is further supported by the observed significant anticorrelation between NBM-FC and ACB burden in MCIAC+ with only a trend association between NBM-FC and ACB burden in CNAC+. Also, cognition was weakly correlated with NBM-FC only in the MCI cohort. It is conceivable that MCI status and AC medication have superadditive effects on NBM impairment. In keeping with previous studies, we show significant cognitive cohort effects on the NBM imaging metrics with GM loss in MCI vs CN 40 and NBM-FC reduction in MCI vs CN 20, and additionally report that the effect sizes of MCI status for both metrics were small in AC−, but large in AC+. Taken together this suggests a more complex multifactorial interplay which could lead to increased vulnerability of the central cholinergic pathways to AC medication in MCI with some pre-existing NBM disruption.
Several limitations were noted in this study. First, according to the ADNI3 protocol, medication use was based on self-report which may lead to underreporting of AC medication use. There is also no accurate information of the duration of AC medication available in the ADNI3 study. Future studies using medical/prescription records would be needed to further characterise the specific medication effects. Second, we excluded participants using ChEI so cannot comment on the degree to which AC related NBM effects may be reversible. Third, while the groups were well matched for demographics, AD risk and showed no differences in AD general MRI markers due to the cross-sectional nature we cannot exclude biases from comorbidities and as expected by indications for commonly prescribed AC medication, we found a higher vascular risk factor score in CNAC+ vs CNAC− and in general somewhat higher frequencies of cardiovascular, neurological, respiratory and gastrointestinal comorbidities in AC+ subgroups.