Alzheimer’s Disease Therapeutics: Alternatives to Amyloid 2021

Identifying secreted mediators driving the cognitive benefits of exercise holds great promise for the treatment of cognitive decline in aging or Alzheimer’s disease (AD). Here, we show that irisin, the cleaved and circulating form of the exercise-induced membrane protein FNDC5, is sufficient to confer the exercise benefits on cognitive function. Genetic deletion of FNDC5/irisin (global F5KO mice) impairs cognitive function in exercise, aging, and AD. Diminished pattern separation in F5KOs can be rescued by delivering irisin directly into the dentate gyrus, suggesting that irisin is the active moiety. In F5KO mice, adult-born neurons in the dentate gyrus are morphologically, transcriptionally, and functionally abnormal. Importantly, elevation of circulating irisin levels by peripheral delivery of irisin via adeno-associated viral overexpression in the liver, results in enrichment of central irisin and is sufficient to improve both the cognitive deficit and neuropathology in AD mouse models. Irisin is a crucial regulator of cognitive benefits of exercise and potential therapeutic for treating cognitive disorders including AD.

Aging drives cellular and cognitive impairments in the adult brain. It is imperative to gain mechanistic insight into what drives aging phenotypes in the brain in order to maintain, and even restore, functional integrity in the elderly. We, and others, have shown that systemic manipulations - such as heterochronic parabiosis (in which a young and old circulatory system are joined) and young blood plasma administration - can reverse age-related impairments in regenerative and synaptic processes, as well as rescue cognitive faculties in the aged brain. More recently, my lab demonstrated that administration of exercise-induced blood factors can likewise partially reverse age-related loss of plasticity in the aged brain. As a consequence, we can now consider reactivating latent plasticity dormant in the aged brain as a means to rejuvenate regenerative, synaptic and cognitive functions late in life. The goal of my research program is to elucidate cellular and molecular mechanisms that can be targeted to halt the aging process or promote rejuvenation in the old brain. Understanding how to reverse aging in the brain could enable us to sidestep the effects of aging that promote vulnerability to neurodegenerative diseases, including Alzheimer’s disease, providing a unique therapeutic approach.

Female-specific reproductive history events have been implicated in Alzheimer’s disease (AD) risk. We examined associations between indicators of estrogen exposure from women’s reproductive history and brain MRI biomarkers of AD in midlife. A total of 128 cognitively normal women and men ages 40-65 years were evaluated, with reproductive history data, neuropsychological testing, and volumetric MRI scans. Exposure variables included menopause status, age at menarche, age at menopause, reproductive span, hysterectomy status, number of children and pregnancies, use of menopause hormonal therapy (HT) and hormonal contraceptives (HC). We used multiple regressions to examine associations between exposures, voxel-wise gray matter volume (GMV), memory and global cognition scores, adjusting for demographics and midlife health indicators. We found that all menopausal groups exhibited lower GMV in AD-vulnerable regions as compared to men, with peri-menopausal and post-menopausal groups also exhibiting lower GMV in temporal cortex as compared to the pre-menopausal group. Reproductive span, number of children and pregnancies, use of HT and HC were positively associated with GMV in temporal cortex, frontal cortex, and precuneus, independent of age, APOE-4 status, and midlife health indicators. Our findings demonstrate reproductive history events signaling more estrogen exposure were associated with larger GMV in midlife women.

Sensory-evoked 40Hz gamma oscillation diminishes Alzheimer’s disease pathology, neurodegeneration, and brain atrophy, synaptic and learning dysfunctions in transgenic mice carrying AD-related human pathological genes (Adaikkan & Tsai, 2020). These results initiated the development and validation of non-invasive, gamma sensory stimulation as a potential therapeutic for AD treatment. Participants on AD spectrum were randomized to receive daily, one-hour, EEG-calibrated, audio-visual stimulation, or sham stimulation in a 6-month clinical trial (NCT03556280) using Cognito Therapeutics medical device. Long-term sensory stimulation was found to be both safe and well tolerated. Over the 6-month period, changes in ADCS-ADL scores were significantly better in the treatment group (n=33) compared to sham group (n=20), indicating a 78% slowing in functional decline (P<0.0003). The treatment group also demonstrated a statistically significant 83% (p<0.013) reduction in cognitive decline, shown by changes in MMSE scores.  MRI analysis revealed that whole brain volume loss in the treatment group had a significant, 72% reduction in brain atrophy (p<0.01) compared to sham group.  Reduced lateral ventricle enlargement and diminished loss in cortical thickness in the occipital cortex have been also observed. Via multiple downstream mechanisms, sensory-evoked gamma oscillation leads to maintained cognitive and functional abilities and reduced brain atrophy in AD patients.

There are many challenges faced by clinical trials in Alzheimer's disease (AD) and AD-related dementias (ADRD), hindering progress to better treatments and preventions. The parallel-group randomized controlled trial is a gold-standard for regulatory approval of new medicines in later stage development, and while still the overwhelming design used in early phase trials, it is inefficient and poorly informative. For AD/ADRDs in particular, this design requires very large sample sizes and broad outcome measures to accommodate the marked heterogeneity of symptoms, progression rates, co-morbidities, concomitant medications, risk factors, mixed pathologies and multiple pathophysiological drivers in older adults. Enabled by advances in digital health technologies and blood-based biomarkers, we consider novel "single case experimental design" (SCED) approaches as an alternative for early phase development. Individuals serve as their own controls in relatively short-term trials with frequently repeated biomarker and clinical outcome measures during placebo lead-in and active treatment periods. SCED trials can be personalized with biomarker profiles guiding assignment of treatment and outcomes can be selected to maximize sensitivity for hypothesized responses. Analyses of outcomes' values and variability repeated over time can determine differences or trends in biomarkers of target and disease engagement as well as clinical symptomatology under baseline and experimental conditions. Such trials may be especially efficient early phase screening tools to either quickly fail or advance a medicine into subsequent developmental trials.