TABLE 1.

Cell death pathways responsible for neuronal death in postmortem AD brains with evidence from various studies.

Post-mortem studies in AD brain
1. Apoptosis	DNA fragmentation and autophagic vacuoles in large number of neurons. Heightened apoptosis with AD. Higher TUNEL staining seen in neurons. Higher caspase 3 levels in neurons from entorhinal cortex, frontal cortex, and hippocampal area. Role of caspase 1, 6, 7, 8, 9 observed. Intracellular Aβ accumulation, p53-mediated transcriptional upregulation of BAX, reduction in bcl-2 and bcl-xl levels. Upregulation of Bad activity in frontal cortical and hippocampal tissue and Casp-3 in cortical neurons.	Smale et al., 1995 Troncoso et al., 1996; Selznick et al., 1999; Stadelmann et al., 1999; Su et al., 2001 Troncoso et al., 1996 Selznick et al., 1999; Stadelmann et al., 1999; Su et al., 2001 Rohn et al., 2001; Matsui et al., 2006; Albrecht et al., 2009; Burguillos et al., 2011 Kitamura et al., 1998 Zhang et al., 2021
2. Non-apoptosis	Cells with swollen morphology and DNA fragmentation imply non-apoptotic mechanism.	Lassmann et al., 1995; Lucassen et al., 1997
A. Autophagy	Accumulation of immature autophagic vacuoles in dystrophic neuritis. Autophagosomes with double membrane encapsulation around intracellular components. Coincidence of downregulated BECN1-PIK 3C3, ULK1/2-ATG13-FIP200, and NRBF2 with AD progression. Transcriptional upregulation of autophagy in entorhinal cortical region.	Nixon et al., 2005 Nixon, 2013 Lachance et al., 2019 Lipinski et al., 2010
B. Necroptosis	Necroptosis activation and its positive correlation with Braak staging; inverse correlation with cognitive scores and brain weight. Co-localization of granular, incipient pTau aggregates with increased chaperone immunoreactivity. Inverse correlation of granulovacuolar degeneration with neuronal density in CA1 region of hippocampus and frontal cortex layer III. Upregulation in MLKL or p-MLKL along with elevated TNF-α? signaling in AD. Link between TNF signaling with necroptosis activation and neuronal loss in CA1-2 hippocampal neurons.	Caccamo et al., 2017 Yamoah et al., 2020 Koper et al., 2020 Xu et al., 2021 Jayaraman et al., 2021
C. Pyroptosis	Enhanced expression of active caspase-1 expression in human MCI and AD brains.	Heneka et al., 2013
D. Parthanatos	Increased Parylation of nuclear proteins. Co-localization of PARP1/PAR with Aβ, Tau and microtubule-associated protein 2. CA1 region showed significant differences in nucleolar PARP-1 staining with Control > AD > MCI cases.	Love et al., 1999 Narne et al., 2017 Regier et al., 2019
E. mPTP	Elevation in CypD expression. Elevated CypD expression in mitochondria.	Du et al., 2008
F. Ferroptosis	Higher cortical iron content in MCI with plaque load, positive correlation of brain iron levels with AD progression and diminution in cognitive ability. Lipid peroxidation and depleted glutathione levels.	Hare et al., 2013; van Bergen et al., 2016; Ayton et al., 2017 Ansari and Scheff, 2010; Yoo et al., 2010; Chiang et al., 2017; Jenkins et al., 2020
Other human samples
Pyroptosis	Upregulated levels of mRNA for inflammasome components (NLRP1, NLRP3, PYCARD, caspase 1, 5 and 8) and downstream effectors (IL-1β, IL-18) in severe and mild AD cases. Increased mRNA and protein levels of caspase-1, NLRP3, GSDMD, and IL-1β in PBMCs of aMCI/AD patients, higher plasma and CSF IL-1β levels in aMCI and AD patients.	Saresella et al., 2016 Rui et al., 2021