Allopregnanolone levels are reduced in temporal cortex in patients with Alzheimer's disease compared to cognitively intact control subjects

Abstract

The neurosteroid allopregnanolone has pronounced neuroprotective actions, increases myelination, and enhances neurogenesis. Evidence suggests that allopregnanolone dysregulation may play a role in the pathophysiology of Alzheimer's disease (AD) and other neurodegenerative disorders. Our prior data demonstrate that allopregnanolone is reduced in prefrontal cortex in male patients with AD compared to male cognitively intact control subjects, and inversely correlated with neuropathological disease stage (Braak and Braak). We therefore determined if allopregnanolone levels are also reduced in AD patients compared to control subjects in temporal cortex, utilizing a larger set of samples from both male and female patients. In addition, we investigated if neurosteroids are altered in subjects who are APOE4 allele carriers. Allopregnanolone, dehydroepiandrosterone (DHEA), and pregnenolone levels were determined in temporal cortex postmortem samples by gas chromatography/mass spectrometry, preceded by high performance liquid chromatography (40 subjects with AD/41 cognitively intact control subjects). Allopregnanolone levels are reduced in temporal cortex in patients with AD (median 2.68 ng/g, n=40) compared to control subjects (median 5.64 ng/g, n=41), Mann-Whitney p=0.0002, and inversely correlated with Braak and Braak neuropathological disease stage (Spearman r=-0.38, p=0.0004). DHEA and pregnenolone are increased in patients with AD compared to control subjects. Patients carrying an APOE4 allele demonstrate reduced allopregnanolone levels in temporal cortex (Mann-Whitney p=0.04). In summary, our findings indicate that neurosteroids are altered in temporal cortex in patients with AD and related to neuropathological disease stage. In addition, the APOE4 allele is associated with reduced allopregnanolone levels. Neurosteroids may be relevant to the neurobiology and therapeutics of AD.

Figure 1

Biosynthetic Pathways and Chemical Structures for Selected Neurosteroids.

Figure 2

Allopregnanolone levels in temporal cortex are significantly decreased in subjects with Alzheimer's disease (median 2.68 ng/g, n=40) compared to cognitively intact control subjects (median 5.64 ng/g, n=41), Mann-Whitney p=0.0002.

Figure 3

Allopregnanolone levels in temporal cortex are inversely correlated with neuropathological disease stage (Braak and Braak), Spearman r = −0.38, p=0.0004.

Figure 4

DHEA levels in temporal cortex are significantly increased in subjects with Alzheimer's disease (median 4.75 ng/g, n=40) compared to cognitively intact control subjects (median 2.23 ng/g, n=41), Mann-Whitney p=0.0185.

Figure 5

Pregnenolone levels in temporal cortex are significantly increased in subjects with Alzheimer's disease (median 22.24 ng/g) compared to cognitively intact control subjects (median 10.24 ng/g), Mann-Whitney p=0.022.

Figure 6

DHEA levels are positively correlated with neuropathological disease stage (Braak and Braak) in temporal cortex, Spearman r= 0.26, p=0.017.

Figure 7

Pregnenolone levels are positively correlated with neuropathological disease stage (Braak and Braak) in temporal cortex, Spearman r=0.24, p=0.032.

Figure 8

Allopregnanolone levels in temporal cortex are significantly decreased in subjects homozygous or heterozygous for the APOE4 allele (median 2.86 ng/g, n=36) compared to patients who are not APOE4 allele carriers (5.23 ng/g, n=44), p=0.04.