Modifiable Risk Factors for Alzheimer Disease and Related Dementias Among Adults Aged ≥45 Years - United States, 2019.

Alzheimer disease,* the most common cause of dementia, affects an estimated 6.5 million persons aged ≥65 years in the United States (1). A growing body of evidence has identified potential modifiable risk factors for Alzheimer disease and related dementias (ADRD) (1-3). In 2021, the National Plan to Address Alzheimer's Disease (National Plan) introduced a new goal to "accelerate action to promote healthy aging and reduce risk factors for Alzheimer's disease and related dementias" to help delay onset or slow the progression of ADRD (3). To assess the status of eight potential modifiable risk factors (i.e., high blood pressure, not meeting the aerobic physical activity guideline, obesity, diabetes, depression, current cigarette smoking, hearing loss, and binge drinking), investigators analyzed data from the cognitive decline module that was administered to adults aged ≥45 years in 31 states and the District of Columbia (DC)† in the 2019 Behavioral Risk Factor Surveillance System (BRFSS) survey. Among the risk factors, prevalence was highest for high blood pressure (49.9%) and lowest for binge drinking (10.3%) and varied by selected demographic characteristics. Adults with subjective cognitive decline (SCD),§ an early indicator of possible future ADRD (4), were more likely to report four or more risk factors than were those without SCD (34.3% versus 13.1%). Prevalence of SCD was 11.3% overall and increased from 3.9% among adults with no risk factors to 25.0% among those with four or more risk factors. Implementing evidence-based strategies to address modifiable risk factors can help achieve the National Plan's new goal to reduce risk for ADRD while promoting health aging.¶,*.

Lack of BACE1 S-palmitoylation reduces amyloid burden and mitigates memory deficits in transgenic mouse models of Alzheimer's disease.

Alzheimer's disease (AD) is a devastating neurodegenerative disorder characterized by pathological brain lesions and a decline in cognitive function. ß-Amyloid peptides (Aß), derived from proteolytic processing of amyloid precursor protein (APP), play a central role in AD pathogenesis. ß-Site APP cleaving enzyme 1 (BACE1), the transmembrane aspartyl protease which initiates Aß production, is axonally transported in neurons and accumulates in dystrophic neurites near cerebral amyloid deposits in AD. BACE1 is modified by S-palmitoylation at four juxtamembrane cysteine residues. S-palmitoylation is a dynamic posttranslational modification that is important for trafficking and function of several synaptic proteins. Here, we investigated the in vivo significance of BACE1 S-palmitoylation through the analysis of knock-in mice with cysteine-to-alanine substitution at the palmitoylated residues (4CA mice). BACE1 expression, as well as processing of APP and other neuronal substrates, was unaltered in 4CA mice despite the lack of BACE1 S-palmitoylation and reduced lipid raft association. Whereas steady-state Aß levels were similar, synaptic activity-induced endogenous Aß production was not observed in 4CA mice. Furthermore, we report a significant reduction of cerebral amyloid burden and BACE1 accumulation in dystrophic neurites in the absence of BACE1 S-palmitoylation in mouse models of AD amyloidosis. Studies in cultured neurons suggest that S-palmitoylation is required for dendritic spine localization and axonal targeting of BACE1. Finally, the lack of BACE1 S-palmitoylation mitigates cognitive deficits in 5XFAD mice. Using transgenic mouse models, these results demonstrate that intrinsic posttranslational S-palmitoylation of BACE1 has a significant impact on amyloid pathogenesis and the consequent cognitive decline.

Loss of interleukin receptor-associated kinase 4 signaling suppresses amyloid pathology and alters microglial phenotype in a mouse model of Alzheimer's disease.

Alzheimer's disease (AD) is typified by the deposition of amyloid in the brain, which elicits a robust microglial-mediated inflammatory response that is associated with disease exacerbation and accelerated progression. Microglia are the principal immune effector cells in the brain and interact with fibrillar forms of Aß (fAß) through a receptor complex that includes Toll-like receptors (TLR) 2/4/6 and their coreceptors. Interleukin receptor-associated kinases (IRAKs) are essential intracellular signaling molecules for transduction of TLR signals. Studies of mouse models of AD in which the individual TLRs are knocked out have produced conflicting results on roles of TLR signaling in amyloid homeostasis. Therefore, we disrupted a common downstream TLR signaling element, IRAK4. We report that microglial IRAK4 is necessary in vitro for fAß to activate the canonical pro-inflammatory signaling pathways leading to activation of p38, JNK, and ERK MAP kinases and to generate reactive oxygen species. In vivo the loss of IRAK4 function results in decreased Aß levels in a murine model of AD. This was associated with diminished microgliosis and astrogliosis in aged mice. Analysis of microglia isolated from the adult mouse brain revealed an altered pattern of gene expression associated with changes in microglial phenotype that were associated with expression of IRF transcription factors that govern microglial phenotype. Further, loss of IRAK4 function also promoted amyloid clearance mechanisms, including elevated expression of insulin-degrading enzyme. Finally, blocking IRAK function restored olfactory behavior. These data demonstrate that IRAK4 activation acts normally to regulate microglial activation status and influence amyloid homeostasis in the brain.