The higher incidence rate of Alzheimer's disease (AD) in elderly women indicates that gender plays a role in AD pathogenesis. Evidence from clinical and pharmacologic studies, neuropathological examinations, and models of hormone replacement therapy suggest that cholinergic basal forebrain (CBF) cortical projection neurons within the nucleus basalis (NB), which mediate memory and attention and degenerate in AD, may be preferentially vulnerable in elderly women compared to men. CBF neurons depend on nerve growth factor (NGF) and their cognate receptors (trkA and p75(NTR)) for their survival and maintenance. We recently demonstrated a shift in the balance of NGF and its receptors toward cell death mechanisms during the progression of AD. To address whether gender affects NGF signaling system expression within the CBF, we used single cell RNA amplification and custom microarray technologies to compare gene expression profiles of single cholinergic NB neurons in tissue specimens from male and female members of the Religious Orders Study who died with a clinical diagnosis of no cognitive impairment (NCI), mild cognitive impairment (MCI), or mild/moderate AD. p75(NTR) expression within male cholinergic NB neurons was unchanged across clinical diagnosis, whereas p75(NTR) mRNA levels in female NB neurons exhibited a ∼40% reduction in AD compared to NCI. Male AD subjects displayed a ∼45% reduction in trkA mRNA levels within NB neurons compared to NCI and MCI. In contrast, NB neuronal trkA expression in females was reduced ∼50% in both MCI and AD compared to NCI. Reduced trkA mRNA levels were associated with poorer global cognitive performance and higher Braak scores in the female subjects. In addition, we found a female-selective reduction in GluR2 AMPA glutamate receptor subunit expression in NB neurons in AD. These data suggest that cholinergic NB neurons in females may be at greater risk for degeneration during the progression of AD and support the concept of gender-specific therapeutic interventions during the preclinical stages of the disease.
Pubmed ID: 21397006 RIS Download
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THIS RESOURCE IS NO LONGER IN SERVICE. Documented on January 4, 2023.Consortium that developed brief, standardized and reliable procedures for the evaluation and diagnosis of patients with Alzheimer's disease (AD) and other dementias of the elderly. These procedures included data forms, flipbooks, guidebooks, brochures, instruction manuals and demonstration tapes, which are now available for purchase. The CERAD assessment material can be used for research purposes as well as for patient care. CERAD has developed several basic standardized instruments, each consisting of brief forms designed to gather data on normal persons as well as on cognitively impaired or behaviorally disturbed individuals. Such data permit the identification of dementia based on clinical, neuropsychological, behavioral or neuropathological criteria. Staff at participating CERAD sites were trained and certified to administer the assessment instruments and to evaluate the subjects enrolled in the study. Cases and controls were evaluated at entry and annually thereafter including (when possible) autopsy examination of the brain to track the natural progression of AD and to obtain neuropathological confirmation of the clinical diagnosis. The CERAD database has become a major resource for research in Alzheimer's disease. It contains longitudinal data for periods as long as seven years on the natural progression of the disorder as well as information on clinical and neuropsychological changes and neuropathological manifestations.
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