A Unified Hypothesis of Early- and Late-Onset Alzheimer's Disease Pathogenesis

Abstract

Early-onset familial Alzheimer's disease (EOFAD) and late-onset sporadic AD (LOSAD) both follow a similar pathological and biochemical course that includes: neuron and synapse loss and dysfunction, microvascular damage, microgliosis, extracellular amyloid-β deposition, tau phosphorylation, formation of intracellular neurofibrillary tangles, endoreduplication and related cell cycle events in affected brain regions. Any mechanistic explanation of AD must accommodate these biochemical and neuropathological features for both forms of the disease. In this insight paper we provide a unifying hypothesis for EOFAD and LOSAD that proposes that the aberrant re-entry of terminally differentiated, post-mitotic neurons into the cell division cycle is a common pathway that explains both early and late-onset forms of AD. Cell cycle abnormalities appear very early in the disease process, prior to the appearance of plaques and tangles, and explain the biochemical (e.g. tau phosphorylation), neuropathological (e.g. neuron hypertrophy; polypoidy) and cognitive changes observed in EOFAD and LOSAD. Genetic mutations in AβPP, PSEN1, and PSEN2 that alter amyloid-β precursor protein and Notch processing drive reactivation of the cell cycle in EOFAD, while age-related reproductive endocrine dyscrasia that upregulates mitogenic TNF signaling and AβPP processing toward the amyloidogenic pathway drives reactivation of the cell cycle in LOSAD. In essence, AβPP and presenilin mutations initiate early, what endocrine dyscrasia initiates later: aberrant cell cycle re-entry of post-mitotic neurons leading to neurodegeneration and cognitive decline in AD. Inhibition of cell cycle re-entry in post-mitotic neurons may be a useful therapeutic strategy to prevent, slow or halt disease progression.

Keywords: Alzheimer’s disease; amyloid-β protein precursor; cell cycle re-entry; endocrine dyscrasia; hypothalamic-pituitarygonadal axis; luteinizing hormone; menopause; neuron presenilin; tau.

Figure 1

Endocrine dyscrasia and AD-related genetic mutations intersect at the cell cycle to drive neurodegeneration and cognitive decline in AD. Model of aberrant cell cycle reentry initiated by 1) aging-related endocrine dyscrasia leading to LOSAD and 2) genetic mutations in APP, PS1, and PS2 leading to EOFAD. Endocrine dyscrasia and genetic mutations of APP, PS1, and PS2 alter TNF and AβPP metabolism to reactivate the cell cycle in a post-mitotic, terminally differentiated neuron. This abortive cell cycle reentry drives neuron hypertrophy, autophagy, synapse and neuron loss, neuron dysfunction, amyloid deposition, neurofibrillary tangle formation, and ultimately cell death.