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Alzheimer's disease — overview

TL;DR — Alzheimer's disease was redefined over the last decade from a clinical syndrome into a biological one: the 2018 NIA-AA research framework classified people by amyloid, tau and neurodegeneration biomarkers rather than symptoms, and the 2024 Alzheimer's Association revision carries that into diagnosis, defining AD as a process beginning with neuropathologic change while people are asymptomatic — a step the International Working Group explicitly declines to take (Jack 2018, PMID 29653606; Jack 2024, PMID 38934362; Dubois 2024, PMID 39483064). Burden grows largely through demography: 57.4 million people with dementia in 2019 rising to a projected 152.8 million by 2050 with age-standardised prevalence flat, and the largest increases in north Africa and the Middle East (367%) and eastern sub-Saharan Africa (357%) (GBD 2019 Dementia Forecasting Collaborators 2022, PMID 34998485). Anti-amyloid antibodies became the first treatments with positive phase 3 primary endpoints — lecanemab slowed 18-month CDR-SB decline by 0.45 points (95% CI 0.23–0.67) with ARIA-E in 12.6%; donanemab slowed 76-week iADRS decline by 3.25 points (1.88–4.62) in low/medium-tau participants with ARIA-E in 24.0% and three treatment-related deaths (van Dyck 2023, PMID 36449413; Sims 2023, PMID 37459141). Diagnosis is moving from CSF and PET to blood: plasma p-tau217 achieved pooled sensitivity 88.1% and specificity 88.7% against biological reference standards across 113 studies, and a mass-spectrometry-based score reached ~90% diagnostic accuracy in Swedish primary care against physicians' 61% (Therriault 2025, PMID 40818474; Palmqvist 2024, PMID 39068545). The field's unresolved core is whether a biologically defined disease that usually occurs alongside vascular and Lewy pathology — mixed pathology accounted for most community dementia at autopsy — can be treated as a single target (Schneider 2007, PMID 17568013; Boyle 2018, PMID 29244218).

What the condition is

Alzheimer's disease is defined pathologically by extracellular amyloid-β plaques and intracellular neurofibrillary tangles of hyperphosphorylated tau, and clinically — in the modal case — by an insidious amnestic syndrome progressing to global cognitive and functional loss. The two definitions no longer coincide. Under the 2024 criteria an abnormal Core 1 biomarker establishes the diagnosis regardless of symptoms; under the IWG position an amyloid-positive cognitively normal person is at risk for AD, not diseased (diagnostic criteria and the biological definition).

The quantitative case for each position is on that page. In brief: amyloid positivity reaches 44% (95% CI 37–51) in cognitively normal 90-year-olds, and 5-year progression to symptomatic disease is 11–20% with amyloid alone but 57% (45–71) when both amyloid and tau PET are positive (Jansen 2015, PMID 25988462; Vos 2013, PMID 24012374; Moscoso 2025, PMID 40522652).

The five things that structure the field

  1. Monogenic genetics places amyloid upstream; tau tracks clinical severity more closely. Every dominant early-onset mutation sits in the substrate or protease of the reaction that makes Aβ, and APP A673T, which cuts amyloidogenic peptide formation by ~40%, protects against AD (Selkoe 2016, PMID 27025652; Jonsson 2012, PMID 22801501). But cognitive severity correlates best with neocortical tangle burden, not plaque burden (Nelson 2012, PMID 22487856), and tau-PET topography predicts where atrophy will occur while amyloid-PET does not (La Joie 2020, PMID 31894103). See amyloid biology and tau biology and spread.
  2. Sporadic AD is a clearance disease. Metabolic labelling showed impaired Aβ40 and Aβ42 clearance with no average difference in production (Mawuenyega 2010, PMID 21148344) — which is why APOE, an Aβ-clearance and blood–brain-barrier gene, dominates the risk architecture (genetics).
  3. Mixed pathology is the norm. In 1,079 autopsies, 94% had at least one pathology and 78% had two or more; AD was present in 65% but alone in only 9%; more than 230 distinct pathology combinations were seen, and AD explained 22–100% of an individual's cognitive loss (Boyle 2018, PMID 29244218). See vascular and metabolic contributions, the shared border with vascular dementia.
  4. Immune pathways are genetically implicated, but their direction is not simply harmful. TREM2 R47H raises risk ~2.9-fold and GWAS keeps returning microglial and immune loci; yet higher baseline microglial-activation signal predicted slower decline while a rising signal predicted faster decline (Jonsson 2013, PMID 23150908; Hamelin 2018, PMID 29608645). The first TREM2-agonist phase 2 (AL002, INVOKE-2) engaged target without slowing CDR-SB and produced ARIA-like MRI (Mummery 2026, PMID 41787076). See neuroinflammation and glia.
  5. Effect sizes are small and contested. The two successful antibodies produced group-mean differences below published minimal clinically important differences for the same instruments (Muir 2024, PMID 38561021), and the FDA, EMA and NICE reached three different conclusions on the same trials (guidelines).

Burden in one table

Measure Estimate Year Source
People living with dementia 57.4 million (95% UI 50.4–65.1) 2019 PMID 34998485
Projected 152.8 million (130.8–175.9) 2050 PMID 34998485
Change in age-standardised prevalence +0.1% (−7.5 to 10.8) 2019→2050 PMID 34998485
US dementia prevalence, adults 65+ 10% (95% CI 9–11); MCI 22% (20–24) 2016 Manly 2022, PMID 36279130
US lifetime risk from age 55 42% (95% CI 41–43) — Fang 2025, PMID 39806070
Global societal cost US$1,313.4 billion, 50% informal care 2019 Wimo 2023, PMID 36617519
Mean survival from AD diagnosis 5.8 years (SD 2.0) — Liang 2021, PMID 36097997

Full detail, including the incidence declines in Western cohorts (13% per decade) and the Japanese exception, is on epidemiology and burden.

What can be done, and how well it works

Intervention Best effect estimate Page
Lecanemab CDR-SB difference −0.45 (95% CI −0.67 to −0.23) at 18 months; ARIA-E 12.6% anti-amyloid immunotherapy
Donanemab iADRS difference 3.25 (1.88–4.62) at 76 weeks, low/medium tau; ARIA-E 24.0% anti-amyloid immunotherapy
Cholinesterase inhibitors −2.7 ADAS-Cog points (95% CI −3.0 to −2.3) over 6–12 months symptomatic and supportive therapy
Memantine, moderate-severe AD 3.11 SIB points (2.42–3.92); no benefit in mild AD symptomatic and supportive therapy
Cognitive stimulation Cognition SMD 0.40 (0.25–0.55); communication SMD 0.53 (0.36–0.70) symptomatic and supportive therapy
Brexpiprazole for agitation CMAI difference −5.32 (−8.77 to −1.87), Cohen d 0.35 neuropsychiatric symptoms
Person-centred care with antipsychotic review QoL +2.54 (0.81–4.28) with a cost saving neuropsychiatric symptoms
Multidomain prevention (FINGER) 0.022 z-points/year (0.002–0.042) risk reduction and prevention
Intensive blood-pressure lowering MCI HR 0.81 (0.69–0.95); probable dementia HR 0.83 (0.67–1.04) risk reduction and prevention
Herpes zoster vaccination (natural experiment) 3.5 percentage-point absolute reduction over 7 years (0.6–7.1) risk reduction and prevention

Nothing on this list is curative, and every disease-modifying entry carries a monitoring burden and an ARIA risk that scales with APOE ε4 dose and disease stage (red flags and safety concerns).

Map of this condition

Definition and presentation - Diagnostic criteria and the biological definition — NIA-AA 1984→2024, IWG counter-position, disclosure consequences. - Clinical presentation and staging — the continuum, atypical variants, staging instruments, rates of decline. - Epidemiology and burden — incidence, prevalence, forecasts, disparities, cost.

Mechanism - Genetics — APOE, autosomal dominant disease, Down syndrome, GWAS, testing ethics. - Amyloid biology — APP processing, clearance failure, the cascade hypothesis and the case against it. - Tau biology and spread — Braak staging, tau-PET subtypes, propagation, tau therapeutics. - Neuroinflammation and glia — microglial states, TREM2, astrocytes, the direction-of-effect problem. - Vascular and metabolic contributions — mixed pathology, CAA, BBB failure, metabolic risk. Shared border with vascular dementia.

Measurement - Fluid biomarkers — CSF and plasma assays, p-tau217, thresholds, confounders. - Imaging and neuropathology — amyloid and tau PET, Centiloids, MRI, the ABC autopsy score.

Treatment - Anti-amyloid immunotherapy — the trials, ARIA, eligibility, cost. - Symptomatic and supportive therapy — cholinesterase inhibitors, memantine, non-drug therapy, deprescribing. - Neuropsychiatric symptoms — agitation, psychosis, depression, apathy, sleep; antipsychotic mortality. - Risk reduction and prevention — PAFs versus trials.

Systems and people - Care, caregiving and health systems — cost structure, caregiver health, care models, capacity. - Guidelines — criteria, appropriate use, regulators and where they disagree. - Clinical trials landscape — the 2025 pipeline and the graveyard. - Red flags and safety concerns — ARIA, iatrogenic harm, mimics, suicide risk, driving. - Patient experience and advocacy — diagnosis experience, stigma, organisations.

Research frontier - OPEN-QUESTIONS.md — tiered questions and cross-domain junctions.

What a wider evidence base changes

Several apparently simple propositions split when tested against topic-specific evidence. “Amyloid excess” means increased relative Aβ42 production in presenilin-mutation carriers but impaired clearance in sporadic disease (Potter 2013, PMID 23761040; Mawuenyega 2010, PMID 21148344). “A blood p-tau test” spans assay AUCs from 0.642 to 0.947 for the same outcome in one head-to-head comparison — mass-spectrometry p-tau217 at the top, several p-tau181 and p-tau231 immunoassays at the bottom — so analyte name alone is not a performance specification (Janelidze 2023, PMID 36087307). “Lifestyle intervention” covers a 296-person active-control exercise trial with no intensity difference and a 51-person bundled programme with several positive 20-week endpoints, neither of which establishes prevention of dementia (Baker 2025, PMID 40271888; Ornish 2024, PMID 38849944).

The same discipline applies to care. Centralised collaborative care reduced caregiver depression by 1.14 points (95% CI 0.13–2.15), burden by 1.90 (0.08–3.89) and emergency-department visits by 0.14 (0.01–0.29), but those effects do not imply that every navigation programme works (Possin 2019, PMID 31566651). Conversely, a biomarker or scan changing management in 59.0% of patients does not establish improved health outcomes (Windon 2025, PMID 40728069). The useful unit of evidence is the intervention, population, comparator and endpoint—not the field’s preferred noun.

Where this knowledge base thinks the field is stuck

  1. A definition whose prognosis depends on biomarker stage. Amyloid positivity alone predicts substantially lower five-year progression than combined amyloid and tau positivity; whether the lower short-horizon risk warrants a disease label is the unresolved AA–IWG dispute (diagnostic criteria).
  2. A treatment whose benefit is real and sub-threshold. Every party to the meaningfulness debate is arguing from the same numbers (anti-amyloid immunotherapy).
  3. A target that is one of several in most patients. Single-target therapy in a population with 230 pathology combinations is a structural mismatch, not a trial-design problem (vascular and metabolic contributions).
  4. Diagnostics that have outpaced delivery. A blood test that beats specialists exists; the diagnosis delay is still 31–44 months and differs by ethnicity (fluid biomarkers; care, caregiving and health systems).
  5. A prevention agenda supported by association and not by trials. Weighted PAF of 32.0% for seven factors, against no multidomain trial that has reduced dementia incidence (risk reduction and prevention).

Open questions

The full tiered agenda is in OPEN-QUESTIONS.md. The three that organise the rest:

  • Is amyloid removal beneficial because of the amyloid, or because of a downstream effect on tau that could be targeted more directly (Nelson 2012, PMID 22487856; Selkoe 2016, PMID 27025652)?
  • Can a single-pathology treatment produce meaningful benefit in a population whose remaining pathology is unmeasured in life (Boyle 2018, PMID 29244218)?
  • What is the lifetime, competing-risk-adjusted probability that a biomarker-positive asymptomatic person develops dementia — the number that would settle the definitional dispute (Vos 2013, PMID 24012374; Moscoso 2025, PMID 40522652)?

Every page in this condition is listed in the map above. The companion condition is vascular dementia; the reciprocal overlap page, mixed-pathology-and-alzheimer-overlap.md, is on that condition's canonical page list but has not yet been written. Cerebrovascular material is curated under stroke.

References

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  2. Jack CR, et al. Revised criteria for diagnosis and staging of Alzheimer's disease: Alzheimer's Association Workgroup. Alzheimers Dement. 2024;20:5143-5169. PMID 38934362.
  3. Dubois B, et al. Alzheimer disease as a clinical-biological construct — an International Working Group recommendation. JAMA Neurol. 2024;81:1304-1311. PMID 39483064.
  4. GBD 2019 Dementia Forecasting Collaborators. Estimation of the global prevalence of dementia in 2019 and forecasted prevalence in 2050. Lancet Public Health. 2022;7:e105-e125. PMID 34998485.
  5. van Dyck CH, et al. Lecanemab in early Alzheimer's disease. N Engl J Med. 2023;388:9-21. PMID 36449413.
  6. Sims JR, et al. Donanemab in early symptomatic Alzheimer disease: the TRAILBLAZER-ALZ 2 randomized clinical trial. JAMA. 2023;330:512-527. PMID 37459141.
  7. Therriault J, et al. Blood phosphorylated tau for the diagnosis of Alzheimer's disease: a systematic review and meta-analysis. Lancet Neurol. 2025;24:740-752. PMID 40818474.
  8. Palmqvist S, et al. Blood biomarkers to detect Alzheimer disease in primary care and secondary care. JAMA. 2024;332:1245-1257. PMID 39068545.
  9. Schneider JA, et al. Mixed brain pathologies account for most dementia cases in community-dwelling older persons. Neurology. 2007;69:2197-204. PMID 17568013.
  10. Boyle PA, et al. Person-specific contribution of neuropathologies to cognitive loss in old age. Ann Neurol. 2018;83:74-83. PMID 29244218.
  11. Jansen WJ, et al. Prevalence of cerebral amyloid pathology in persons without dementia: a meta-analysis. JAMA. 2015;313:1924-38. PMID 25988462.
  12. Vos SJ, et al. Preclinical Alzheimer's disease and its outcome: a longitudinal cohort study. Lancet Neurol. 2013;12:957-65. PMID 24012374.
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  14. Selkoe DJ, et al. The amyloid hypothesis of Alzheimer's disease at 25 years. EMBO Mol Med. 2016;8:595-608. PMID 27025652.
  15. Jonsson T, et al. A mutation in APP protects against Alzheimer's disease and age-related cognitive decline. Nature. 2012;488:96-9. PMID 22801501.
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  17. La Joie R, et al. Prospective longitudinal atrophy in Alzheimer's disease correlates with the intensity and topography of baseline tau-PET. Sci Transl Med. 2020;12. PMID 31894103.
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  20. Hamelin L, et al. Distinct dynamic profiles of microglial activation are associated with progression of Alzheimer's disease. Brain. 2018;141:1855-1870. PMID 29608645.
  21. Muir RT, et al. Minimal clinically important difference in Alzheimer's disease: rapid review. Alzheimers Dement. 2024;20:3352-3363. PMID 38561021.
  22. Manly JJ, et al. Estimating the prevalence of dementia and mild cognitive impairment in the US. JAMA Neurol. 2022;79:1242-1249. PMID 36279130.
  23. Fang M, et al. Lifetime risk and projected burden of dementia. Nat Med. 2025;31:772-776. PMID 39806070.
  24. Wimo A, et al. The worldwide costs of dementia in 2019. Alzheimers Dement. 2023;19:2865-2873. PMID 36617519.
  25. Liang CS, et al. Mortality rates in Alzheimer's disease and non-Alzheimer's dementias: a systematic review and meta-analysis. Lancet Healthy Longev. 2021;2:e479-e488. PMID 36097997.
  26. Mummery CJ, et al. The TREM2 agonistic antibody AL002 in early Alzheimer's disease: a phase 2 randomized trial. Nat Med. 2026;32:1708-1716. PMID 41787076.
  27. Potter R, et al. Increased in vivo amyloid-β42 production, exchange, and loss in presenilin mutation carriers. Sci Transl Med. 2013;5:189ra77. PMID 23761040.
  28. Janelidze S, et al. Head-to-head comparison of 10 plasma phospho-tau assays in prodromal Alzheimer's disease. Brain. 2023;146:1592-1601. PMID 36087307.
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  30. Ornish D, et al. Effects of intensive lifestyle changes on the progression of mild cognitive impairment or early dementia due to Alzheimer's disease. Alzheimers Res Ther. 2024;16:122. PMID 38849944.
  31. Possin KL, et al. Effect of collaborative dementia care via telephone and internet on quality of life, caregiver well-being, and health care use. JAMA Intern Med. 2019;179:1658-1667. PMID 31566651.
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