Age is one of the highest risk factors for Alzheimer’s disease (AD) with approximately 5.5 million people age 65 and older living with AD in the U.S., a number estimated to grow to 13 million by 2050. AD is closely associated with decreased neuronal signaling and loss of synapses [and mitochondrial dysfunction]. The increasing number of individuals and rising healthcare costs associated with AD are further compounded by a growing population of younger Veterans, who have increased risk of AD and other forms of dementia. Although the accepted etiology of AD pathology is the buildup of toxic amyloid-b (Ab) plaques, interventional strategies intended to remove Ab plaques have demonstrated significant side effects resulting in failed clinical trials. Therefore, there is great demand for neuroprotective strategies to preserve [mitochondrial function], restore neuronal and cognitive function, independent of solely targeting Ab. [In the setting of AD, mitochondrial dysfunction significantly contributes to the neuropathology. Mitochondria dynamics (i.e., fusion and fission), which serve to maintain normal mitochondria structure and function during stress, are altered in AD. Therefore, targeting molecular complexes that transduce signaling from the plasma membrane to the mitochondria may afford neuroprotection and resilience within an otherwise neurotoxic environment.] One potential neuroprotective target is caveolin-1 (Cav-1), a membrane/lipid raft (MLR) and scaffolding protein. Pre- clinical and clinical evidence shows that Cav-1 and Cav-1 associated [synaptic] signaling complexes are decreased in degenerating neurons [during] AD, chronic traumatic encephalopathy (CTE), and amyotrophic lateral sclerosis (ALS). Recent work shows that Cav-1-mediated axodendritic growth is in part dependent upon Cav-1 phosphorylation at tyrosine 14 (Y14). [Preliminary data show that hippocampal Cav-1 is decreased in 6 month (m) old PSAPP mice, a time point at which these mice also exhibit impaired learning. Further evidence shows that hippocampal Cav-1 subcellular localization to mitochondria is significantly decreased in 12 m old PSAPP mice that exhibit severe memory deficits. Neuron-targeted Cav-1 re-expression using AAV-SynCav1 prevents hippocampal memory deficits and neurodegeneration in PSAPP] mice [through augmenting] synaptic strength and [resilience] to neurotoxic Aβ and astrogliosis. [Furthermore, SynCav1 delivery to PSAPP mice restores Cav-1 localization to mitochondria, mitigates mitochondria morphological damage, enhances mitochondria metabolism, and maintains mitochondria fission and fusion balance. A major limitation to our current findings is the use of a single AAV-SynCav1 dose (10 x 109 g.c./ul) in pre-symptomatic PSAPP mice (3 m) that produces Cav-1 protein expression considerably higher than wild type brains;; a dose that may lead to a ‘ceiling effect’ in terms of efficacy. Therefore, the objective ...