Sleep, Aging and Risk for Alzheimer's Disease

Sleep disordered breathing (SDB) is a common disorder with an estimated prevalence in the
elderly ranging from 30-80%. The relevance of this high frequency in late life is emerging,
as recent evidence suggests that SDB may be associated with the development of mild cognitive
impairment and dementia. Alzheimer's disease (AD) is the most common form of dementia and
affects nearly 45% of the population older than 85. Hippocampal atrophy and glucose
hypometabolism, as well as changes in cerebrospinal fluid (CSF) levels of amyloid beta-42
(Aβ42), phosphorylated-tau (P-Tau) and total-tau (T-Tau), have been shown to be useful in
predicting future decline in cognitively normal older adults, which suggests that AD
pathology is detectable prior to cognitive impairment in at-risk subjects. This
"presymptomatic phase", in which tissue damage is minimal and whose detection precedes
clinical symptoms, is an ideal stage for risk factor analysis and intervention trials. Our
preliminary data show, for the first time in cognitively-normal elderly, that the severity of
SDB (as measured by respiratory events with 4% desaturation, Apnea Hypopnea Index 4% [AHI4%])
is associated with the increase of CSF P-Tau and T-Tau, a decrease in glucose uptake
(measured by FDG-PET) in the medial temporal lobe, reduced hippocampal volume, and
longitudinal memory decline. These findings raise the question as to whether AD tissue damage
causes SDB in the elderly, or alternatively, if SDB acts as a risk factor for
neurodegeneration. The proposed parent grant for this project conducted at the NYU Center for
Brain Health (CBH), is a 5-year NIH-funded longitudinal study of 180 normal elderly (50-95
years), who will undergo complete baseline and 24 month follow-up evaluations. The exams
include MR imaging: both structural and cerebral blood flow (CBF) using a novel NYU arterial
spin labeling (ASL) protocol and regional brain vasoreactivity estimates after CO2 breathing
(VR-CO2); as well as both plasma and CSF biomarkers. The present ancillary proposal,
performed in collaboration with NYU's Sleep Disorders Center, will investigate: 1) SDB as a
longitudinal predictor of changes in memory, levels of P-tau and T-Tau, hippocampal atrophy,
and the blunted VR-CO2 response (all these effects of SDB were observed in cross-section in
our pilot work); and 2) if these SDB related phenomena in normal elderly are susceptible to
intervention with nasal continuous positive airway pressure (CPAP) in moderate-to-severe SDB
subjects. This study has the potential to identify: 1) a highly prevalent AD-related
mechanism by which SDB contributes to cognitive decline; 2) the alternative hypothesis, the
presence of biomarker features of AD as risks factors for SDB; and 3) that the treatment of
SDB with CPAP improves cognition through an AD-related pathway in the elderly.

Inclusion Criteria:

- Male and female subjects with normal cognition and >50 years of age will be enrolled.
Younger subjects are not included as the risk for cognitive impairment is too low.
Moreover, by selecting this age-range we minimize the possibility of including
early-onset genetic forms of neurodegenerative diseases such as Alzheimer's disease
and Frontotemporal Dementia.

- Normal subjects will be within normal limits on neurological and psychiatric
examinations. All subjects enrolled will have both a Clinical Dementia Rating = 0 and
Global Deterioration Scale < 3.

- All subjects will have had a minimum of 12 years education.The education restriction
reduces performance variance on cognitive test measures and improves the sensitivity
for detecting pathology and disease progression using the robust norms available at
NYU School of Medicine.

- All subjects will have an informed family member or life partner interviewed to
confirm the reliability of the subject interview. All subjects will agree to the MRI
imaging, the lumbar puncture, apolipoprotein E (ApoE) genotyping and DNA banking

Exclusion Criteria:

- Diagnosis of any brain disease or MRI evidence of brain damage including significant
trauma, hydrocephalus, seizures, mental retardation or other serious neurological
disorder (e.g. Parkinson's disease or other movement disorders). Persons with silent
cortical infarcts are excluded. Subcortical infarcts and white matter lesions are not
exclusions.

- History of brain tumor.

- Any radiation or chemotherapy anywhere in the body in the past 3-years.

- Significant history of alcoholism or drug abuse.

- History of psychiatric illness (e.g., schizophrenia, mania, PTSD, or life long history
of major depression).

- Hamilton Depression Scale >16 only with history of life long depressive episodes.
Otherwise not excluded.

- Evidence of clinically relevant and uncontrolled cardiac, pulmonary, or hypothyroid or
hematological conditions. Insulin dependent diabetes and/or history or treated
hypertension are not an exclusion. Normal subjects with current levels of HbA1c >5.9%
or diabetics >7.0% (American Diabetes Association, 2010) and/or current blood pressure
levels >140/90 mm Hg (JNC on Prevention, Detection, Evaluation and Treatment of High
Blood Pressure, 2003) will be advised to seek referral.

- Physical impairment of such severity as to adversely affect the validity of
psychological testing.

- Hostility or refusal to cooperate.

- Any prosthetic devices (e.g., pacemaker or surgical clips) that constitutes a hazard
for MRI imaging.

- History of a first-degree family member with early onset (before age 65) dementia.

- Medications adversely affecting cognition will result in exclusion. The excluded
medications include:

- Antidepressants with anti-cholinergic properties.

- Regular use of narcotic analgesics (>2 doses per week).

- Use of neuroleptics with anti-cholinergic properties.

- Other medications with central nervous system anticholinergic activity.

- Use of Anti-Parkinsonian medications.

- At the baseline individuals taking physician ordered or off-label memory or other
cognitive enhancing medications (e.g. cholinesterase inhibitors or memantine) are
excluded. At the follow-up these medications are allowed. Also excluded at baseline
are individuals taking physician ordered, but off-label memory enhancements.
Individuals taking over the counter memory enhancing or protecting medications (e.g.
ginkgo biloba, vitamins) are not excluded.

- Patients with significant physical changes (e.g. amputations or loss of sensory input)
as these may affect the MRI blood flow measures.