Alzheimer disease (AD) was first described in 1906 by German psychiatrist and neuroanatomist Dr. Alois Alzheimer [1]. In that landmark paper, Dr. Alzheimer presents evidence of distinctive plaques and neurofibrillary tangles (NFTs) in the brain histology of a 50 year old woman who exhibited paranoia, progressive sleep and memory disturbances, aggression, and confusion until her death. Today, we know AD as the most common form of dementia, accounting for 60–70 % of all cases [2]. Dementia, which entails brain disturbances that give rise to impaired function, is a general term for the inability to remember, think, or make decisions related to the execution of everyday tasks, likely stemming from the extensive neuronal dysfunction, neuronal cell loss, nervous system circuitry deterioration, and associated brain atrophy seen in patients [3]. Fatality of AD-affected individuals usually results from general inanition, malnutrition or pneumonia [4], [5]. Based on current rates of development, aging, and diagnosis, AD is predicted to affect more than 150 million people worldwide by the year 2050 [6], emphasizing the importance of understanding the underlying disease mechanisms.

AD is a multifactorial and complex neurodegenerative disease characterized by hallmark pathological changes, most notably extracellular plaques composed of amyloid beta (Aβ) peptides and NFTs comprised of aggregated, hyperphosphorylated Tau protein (p-Tau) within neurons [7], [8]. These pathological hallmarks are generally associated with loss of neurons and neuronal network functions in brain regions involved in memory, such as the entorhinal cortex and hippocampus. Later on, atrophy occurs in the cerebral cortex, before widespread brain damage is observed [7], [8]. At present, AD diagnosis is conducted by cognitive tests; fluorodeoxyglucose or amyloid/Tau positron emission tomography (PET) scans, of which the former identifies changes in glucose metabolism and the latter Aβ/Tau accumulation; and detection of proteins in the cerebrospinal fluid (CSF). The currently validated CSF biomarkers include a low Aβ42 peptide concentration, low Aβ42/Aβ40 ratio, high total Tau protein, and high phosphorylated Tau Thr181 (p-Tau181). Recent developments in the field of biofluid biomarkers may extend or complement these tests by measuring these and other markers (i.e., Aβ42/Aβ40 ratio, Tau/p-Tau ratio, glial fibrillary acid protein, among others) in plasma and/or serum for diagnostic purposes, facilitating improved testing [9], [10], [11].

Neurodegenerative diseases, such as AD, are driven by a collection of interrelated hallmarks [12]. While the involvement of several of these hallmarks, particularly pathological protein aggregation, is well established in AD, the mechanisms that lead specifically to neuronal cell loss remain more elusive. In this review, we discuss the evidence that supports the hypothesis that abnormal processing and aggregation of Aβ and Tau leads to excessive genomic stress and altered genome maintenance mechanisms that can result in neuronal cell death.