Alzheimer's disease (AD) is characterized by severe cognitive impairment and memory loss. AD is classified both into the "protein conformational" and the "endoplasmic reticulum-mitochondria stress" disorders. AD is a very complex, multifactorial disease of heterogeneous genetic and environmental background. The amyloid hypothesis of AD cannot fully explain the various clinical forms of the disease. Protein folding and misfolding in the endoplasmic reticulum (ER), and accumulation of several misfolded proteins (β-amyloid, Tau, alpha-synuclein, etc.) in ER and mitochondria (MT) may play a key role in the development of AD. Functional degradation of the synapse and the synapse holding neurites represents the first step in the pathogenesis of neurodegeneration. MT and ER are tightly coupled both physically and functionally with a special lipid raft called mitochondria-associated ER-membrane (MAM). MAM is crucial for Ca2+ signalling and metabolic regulation of the cell. In turn, the impairment of ER-MT interplay is a common mechanism of different neurodegenerative diseases. In this review, we discuss recent findings focusing on the protein conformational and metabolic dysfunction, and the role of MAM and ER-MT crosstalk in neurodegeneration.