Central role of brain regulatory T cells in the inflammatory cascade in Alzheimer’s disease

Alzheimer’s disease (AD) is a chronic, progressive, and irreversible neurodegenerative disease comprising around 80% of all dementia cases and is recognized as the sixth leading cause of death in the United States of America. Remarkably, the precise etiology of AD has not been elucidated, although aging, genetics, environment, and lifestyle factors are part of the risk profile (1, 2). The majority of AD presentations are sporadic and late-onset (90 to 95%) (i.e., after 65 y of age), whereas less than 5% are early-onset, a subset of which are familial autosomal dominant. Onset as early as the fourth decade of life may occur, particularly in patients with a PSEN1 mutation (3). The amyloid cascade hypothesis, now over 30 y old, posits amyloid β (Aβ) as the driver of disease and the cause of dementia in AD (4), while roles for immune cells are usually conceptualized as secondary, or part of a host response. Besides resident glial cells (including oligodendrocytes, astrocytes, microglia, and ependymal cells), peripheral immune regulatory T cells are recently recognized as part of the systemic immunological network of the brain (5). In PNAS, Panwar et al. describe a specific CD8 T cell population as an abnormal immune factor that modulates AD-like neurodegeneration, including Aβ/tau deposition, altered transcriptomic signatures, and other upstream molecular responses that resemble sporadic AD neuropathological features (6).

AD is associated with two histopathological hallmarks: Senile plaques and neurofibrillary tangles (NFT) (7), which have been known to co-occur since their description by Alzheimer in 1906. Genetic mutations and polymorphisms identified many decades later (e.g., APP, PSEN1, PSEN2, APOE) provided the foundation for the view that Aβ was causal or “rate-limiting”, such that Aβ emerged as the favored target for potential disease-modifying therapy (8). Subsequent, extensive efforts have since demonstrated target engagement particularly with anti-Aβ antibody therapeutics, although cognitive benefit has been modest at best even in carefully selected subjects, and toxicity of target engagement has been substantial, with cerebral edema and hemorrhage in a significant number of subjects (9, 10), and some deaths. A dispassionate view of the evidence base to date indicates that disease etiology is left unaddressed with anti-Aβ therapy. Furthermore, animal models of AD where Aβ is overproduced by employing mutant forms of genes APP and PSEN1/PSEN2 do show deposition of senile plaques but do not demonstrate other critical neuropathological features, such as the extensive neuronal loss or neurobehavioral traits analogous to AD. Overall, these studies indicate a critical role for Aβ but do not fully demonstrate that it is the primary initiator and certainly are not consistent with the amyloid cascade narrative, opening the idea for other critical or overlooked contributors for the development of AD and related dementia. Considering that AD is a complex disease with well-documented pleiotropic changes in the brain, including high oxidative stress, mitochondrial dysfunction, autophagy, cytoskeleton alterations, neuroinflammation, and more, each being proposed as critical features, more research is needed.