African American Alzheimer's Progression Markers - CSF and Neuro-Imaging

African Americans represent about 10% of the population in the US, but are under-represented
in biomarker-related aging studies such as the Alzheimer's Disease Neuro-imaging Initiative
(ADNI) and World Wide ADNI. Epidemiologic studies show that, compared to non-Hispanic white
(NHW) Americans, African Americans (AA) are more likely to develop mild cognitive impairment
(MCI) and Alzheimer's disease (AD), have different genetic risks of developing AD, and
experience different rates of cognitive decline after cognitive symptoms develop. All these
point to the existence of an MCI/AD endophenotype for AA, although few of these
epidemiological studies involve modern chemical or imaging biomarkers associated with AD
pathology and progression. Preliminary studies using AA subjects who have undergone CSF
analysis (n=36) show that AA MCI subjects are more likely to have normal CSF AD biomarkers
than NHW MCI subjects, yet at the same time greater hippocampal atrophy on MRI. The
investigators hypothesize that endothelial dysfunction is an alternate mechanism which
independently contributes to cognitive impairment in AA subjects with sub-threshold AD
pathology in a race-independent fashion, and endothelia dysfunction further enhances the
neurotoxicity of AD-associated brain changes in a race-dependent fashion. The investigators
propose to build on their success in recruiting AA volunteers into memory and aging studies
at the Emory's Registry for Remembrance to recruit a cross-sectional cohort of 75 AA
subjects along with 75 NHW subjects with normal cognition, MCI, or mild AD. They will test
this hypothesis through two aims. In Aim 1, they will determine whether endothelial
dysfunctions independently contribute to cognitive decline in AA and NHW subjects by
measuring cerebrospinal fluid (CSF) levels of AD, endothelial, and inflammatory markers.
Each subject will also undergo MRI analysis for total area of white matter hyperintensities
as an imaging marker of endothelial dysfunction. Based on the hypothesis, they predict that
AA MCI/AD subjects are more likely than NHW MCI subjects to have normal CSF AD biomarkers,
abnormal CSF endothelial markers, and greater number and area of white matter
hyperintensities on MRI. In Aim 2, the investigators will determine if an endothelial marker
- intercellular adhesion molecule 1 or ICAM-1 - gene variant unique to AA enhances AD
neurotoxicity to explain the greater hippocampal atrophy among AA MCI subjects. The Lys56Met
ICAM1 gene variant associated with low ICAM-1 levels is uniquely found in 16-20% of AA, and
these subjects may have impaired downstream activation of neprilysin, an Abeta-degrading
enzyme. If the hypothesis is true, AA subjects with the Lys56Met gene variant will be more
likely to have hippocampal atrophy, temporal-parietal cerebral hypoperfusion, and cerebral
amyloid deposition than AA subjects and NHW subjects without the gene variant. This may
occur in the setting of CSF Abeta2 pseudo-normalization if low neprilysin levels lead to
increased Abeta42 levels. Successful completion of the current proposal will confirm the
preliminary finding of a unique AA endophenotype within the broader AD-spectrum disorders,
directly examine whether endothelial dysfunctions additively and synergistically lead to
cognitive decline in AD among AA in a cross-sectional cohort, and help power and design a
future a multi-center, multi-racial longitudinal biomarker study to validate these
cross-sectional findings.

Inclusion Criteria:

- Ages 60-85.

- Has normal cognition, a diagnosis of mild cognitive impairment, or a diagnosis of
Alzheimer's disease or mild cognitive impairment.

- Self-reported race of African American or non-Hispanic white.

- Able to undergo neuropsychological testing, lumbar puncture, and MRI.

- English speaking.

Exclusion Criteria:

- History of stroke.

- Diagnosis of Parkinson's disease, amyotrophic lateral sclerosis, or another
progressive neurological disorder which may spare cognition.

- MMSE < 17