Amyloid-β (Aβ) is believed to directly affect memory and learning in Alzheimer’s disease (AD). It is widely suggested that there is a relationship between Aβ40 and Aβ42 levels and cognitive performance. In order to explore the validity of this relationship, we performed a meta-analysis of 40 peer-reviewed, published AD transgenic mouse studies that quantitatively measured Aβ levels in brain tissue after assessing cognitive performance. We examined the relationship between Aβ levels (Aβ40, Aβ42, or the ratio of Aβ42 to Aβ40) and cognitive function as measured by escape latency times in the Morris water maze or exploratory preference percentage in the novel object recognition test. Our systematic review examined five mouse models (Tg2576, APP, PS1, 3xTg, APP(OSK)-Tg), gender, and age. The overall result revealed no statistically significant correlation between quantified Aβ levels and experimental measures of cognitive function. However, enough of the trends were of the same sign to suggest that there probably is a very weak qualitative trend visible only across many orders of magnitude. In summary, the results of the systematic review revealed that mice bred to show elevated levels of Aβ do not perform significantly worse in cognitive tests than mice that do not have elevated Aβ levels. Our results suggest two lines of inquiry: 1) Aβ is a biochemical “side effect” of the AD pathology; or 2) learning and memory deficits in AD are tied to the presence of qualitatively “high” levels of Aβ but are not quantitatively sensitive to the levels themselves.

High-impact genetic variants associated with neurodevelopmental disorders provide biologically defined entry points for etiological discovery. The 3q29 deletion (3q29Del) is one such variant that confers a ~40-fold increased risk for schizophrenia, and a ~30-fold increased risk for autism. However, the specific neural mechanisms underlying this link remain largely unknown. Here, we report the first in vivo quantitative neuroimaging study in 3q29Del subjects (N = 24) and healthy controls (N = 1,608) using structural MRI. Given prior reports of posterior fossa abnormalities in 3q29Del, we focus our investigation on the cerebellum and its primary tissue-types. Additionally, we compare the prevalence of cystic/cyst-like malformations of the posterior fossa between 3q29Del subjects and controls, and examine the association between neuroanatomical findings and standardized behavioral measures to probe gene-brain-behavior relationships. 3q29Del subjects had smaller cerebellar cortex volumes than controls, both before and after correction for intracranial volume (ICV). 3q29Del subjects also had larger cerebellar white matter volumes than controls following ICV-correction. The 3q29Del group displayed an elevated rate of posterior fossa arachnoid cysts and mega cisterna magna findings independent of cerebellar volume. Sex played a moderating role in a subset of findings. Cerebellar white matter volume was positively associated with visual-motor integration skills and cognitive ability, while cystic/cyst-like malformations yielded no behavioral link. Abnormal development of posterior fossa structures may represent neuroimaging-based biomarkers in 3q29Del. Results reveal cerebellar associations with sensorimotor and cognitive deficits in 3q29Del and present a novel point of genetic convergence with cerebellar pathology reported in idiopathic forms of neurodevelopmental disease.