Chronic Excitatory Insufficiency

The hypothesis, argued by Moosmann & Sohre (Chronic excitatory insufficiency as proximate cause of Alzheimer's disease, OFP 2020 #145; experimental companion bioRxiv 418566, 2018; see Bernd Moosmann, Excitatory Neurotransmission), that the disparate established AD risk factors — APOE4, PSEN1, estrogen loss, neurotrauma, Trisomy 21 — share one proximate consequence: inhibition of glutamatergic, NMDA-type excitatory neurotransmission. In this reading, amyloid-β and phospho-tau are not primary toxins but compensatory glutamatergic sensitizers — the brain's decades-long, for-long-successful, finally-lost attempt to restore excitatory tone.

This node is a cross-link and a graded verdict: it records where CEI meshes with the corpus, where it forks from it, and fixes the sign the corpus rendered backwards. A five-cluster primary-literature fact-check (2026-07-23; see CORRECTIONS C-016) found CEI citation-honest at the level of individual findings but built on directional cherry-picking, with a legitimate physiological core and load-bearing inversions that are contradicted by intervention data. The underlying preprint was never peer-reviewed and is essentially uncited — CEI is a dormant minority provocation, not a live rival to reconcile as a peer.

Where CEI meshes with the corpus

1. Through ApoER2 — CEI's genetic arm is the reelin axis. (Strongest leg; fact-check ✔ validated.) Moosmann's APOE4 mechanism is ApoE4 sequestering surface NMDA receptors by intracellular trapping of ApoER2, and suppressing reelin-evoked Ca²⁺ influx, LTP and CREB — because reelin and ApoE compete at ApoER2 (Chen 2010, PMID 20547867). This is a real, reproducible Herz-lab mechanism, and it is the exact receptor the corpus's reelin series is built on: Reelin-ApoE receptor axis disruption, Matrix Sulfation Node. (The "3–5× NMDA-R depletion" figure the corpus previously attached to Chen 2010 is not in that paper and has been removed.)
2. Through development — a shared idea, not an endorsed claim. For the Aβ-dosage factors (APP duplication, Trisomy 21), CEI proposes a prenatal origin — "glutamatergic hypogenesis" (Moosmann's own coinage, no independent literature) — the same whole-chromosome, time-compressed logic as the Down-syndrome thesis The Compressed Architecture (research/down-syndrome/). But the strong form ("elevated Aβ causes AD only via prenatal/perinatal exposure") is refuted by inducible adult-onset APP models (Jankowsky 2005, PMID 16279840) and by adult anti-amyloid benefit. The decisive counterexample is partial-trisomy-21: DS phenotype but only two copies of APP → reaches the 70s without dementia or amyloid (Doran 2017, PMID 27983553) — AD-in-DS is APP/amyloid-driven, the side the Compressed Architecture already takes.

Where CEI forks from the corpus — the valence of Aβ and tau

CEI holds that Aβ (at physiological, picomolar concentrations) and phospho-tau are purposeful enhancers of excitatory transmission. The corpus treats them as pathogenic drivers. This is a straight inversion of causality — and the fact-check found the inversion asymmetrically supported:

• The physiological core is real. Picomolar Aβ enhances LTP/memory (Puzzo 2008; even conceded by Mucke & Selkoe), and phospho-tau is not uniformly toxic (site-specific adaptive phosphorylation, Ittner 2016 T205, PMID 27856911; reversible non-fibrillar torpor tau, Arendt 2003). The corpus should concede these.
• The inversion itself is contradicted where it is testable. (i) Moosmann's "µM-toxicity is an artifact" is refuted by human-brain-derived Aβ dimers that impair LTP at low-nanomolar (Shankar 2008; Walsh 2002). (ii) His "loss of excitation induces Aβ" runs against the replicated "activity drives Aβ" (Cirrito 2005; Bero 2011). (iii) Decisively, removing amyloid slows decline (lecanemab, PMID 36449413; donanemab, PMID 37459141) — if Aβ were protective, removal should accelerate it.

Held as an open but asymmetric fork: a defensible provocation, an indefensible mechanism as stated. Its mirror inside the corpus is the deliberate amyloid steelman (research/amyloid-steelman/).

The sign — do not flip it

CEI's E/I imbalance runs toward inhibition — "excitatory insufficiency (meaning too much inhibition)." Its seizures are compensatory over-amplification of sparse excitatory signals in an over-inhibited background (silent/absence-seizure model). This is the opposite topology from the corpus's terminal disinhibition model — PV⁺ net digestion → loss of inhibition → excitotoxicity (Perineuronal Nets; Terminal Collapse, Phase 6). Crucially, the corpus's disinhibition model is the consensus-aligned one (Palop & Mucke 2016; Verret 2012, PMID 22541439 — restoring inhibition rescues), whereas Moosmann's over-amplification account is the minority reading of AD seizures. So where the corpus rendered CEI as disinhibition, the error is one of attribution/fidelity (it misstates Moosmann's sign), not of picking the wrong mechanism — see CORRECTIONS C-016.

Honest reconciliation (two axes, not one). "Insufficient meaningful excitation" (throughput) is not the same variable as "hyperexcitability / excitotoxicity" (pathological over-firing). The late AD brain is globally hypometabolic and locally excitotoxic / seizing at once — low signal, high noise. CEI and the terminus's disinhibition model are rivals on the cause of Aβ/tau, but their late-stage electrophysiology coexists.

Convergence Nodes

• APOE4 Hub — the shared ApoE / lipoprotein-receptor hub where CEI's genetic arm and the reelin axis meet
• Matrix Sulfation Node — the sulfated ApoER2 surface that stages reelin, the co-receptor CEI's ApoE4 mechanism disrupts

See Also

• Reelin-ApoE receptor axis disruption · Excitatory Neurotransmission · Perineuronal Nets
• Primary source: Moosmann & Sohre, OFP 2020 submission #145 (Bernd Moosmann)
• Fact-check basis and the seizure-sign fix: CORRECTIONS C-016
• Corpus fork: The Case for the Cascade (research/amyloid-steelman/)
• Developmental mesh (and its limit): The Compressed Architecture (research/down-syndrome/)