Memory loss

Linda A Hershey MD PhD (Dr. Hershey of the University of Oklahoma Health Sciences Center received research grants from Forum.)
Ferenc Deak MD PhD (Dr. Deak of the University of Oklahoma Health Sciences Center has no relevant financial relationships to disclose.)
Calin I Prodan MD (Dr. Prodan of the University of Oklahoma Health Sciences Center has no relevant financial relationships to disclose.)
Martin R Farlow MD, editor. (Dr. Farlow of Indiana University received research grant support from Accera, Biogen, Eisai,  Eli Lilly, Genentech, Roche, Lundbeck, Chase Pharmaceuticals and Boehringer Ingelheim; honorariums from Eisai, Forest Laboratories, Pfizer, Eli Lilly and Company and Novartis for speaking engagements; and fees from Accera,  Alltech, Avanir,   Biogen, Eisai Med Res, Inc., Eli Lilly and Company, FORUM Pharmaceuticals, Genentech, Inc., Grifols, Helicon, INC Research, Lundbeck, Medavante, Medivation, Merck,  Neurotrope Biosciences, Novartis, Pfizer, Prana, QR Pharm., Riovant Sciences Inc., Roche, Sanofi-Aventis, Schering-Plough, Toyama Pharm and UCB Pharma for consultancy. His spouse was employed by Eli Lilly.)
Originally released November 24, 1997; last updated June 8, 2016; expires June 8, 2019

This article includes discussion of memory loss, amnesia, amnestic disorder, cognitive impairment, dementia, anterograde amnesia, retrograde amnesia, short-term memory loss, mild cognitive impairment, chronic traumatic encephalopathy, Alzheimer disease, Wernicke-Korsakoff syndrome, vascular dementia, dementia with Lewy bodies, and subjective cognitive impairment. The foregoing terms may include synonyms, similar disorders, variations in usage, and abbreviations.


In this article, the authors provide an overview of memory loss and its most common presentations in the clinical setting (mild cognitive impairment, Alzheimer disease, vascular dementia, dementia with Lewy bodies, Wernicke-Korsakoff syndrome, and chronic traumatic encephalopathy). Risk factors for mild cognitive impairment are reviewed, along with lifestyle changes that have been suggested to slow progression from mild cognitive impairment to dementia.

Key points


• Early-onset Alzheimer disease patients are more likely to have atrophy in both parietal lobes, rather than in medial temporal lobes, as is commonly seen in late-onset Alzheimer disease. They also have more problems with language, attention, visuospatial function, and executive tasks, compared to their late-onset peers.


• Chronic traumatic encephalopathy causes early memory loss in boxers, football players, and war veterans. The neurofibrillary tangles and extracellular plaques in the brains of these patients at autopsy are similar to those seen in the brains of Alzheimer disease patients. Significantly more changes in subcortical white matter are seen in cognitively impaired retired football players compared to age-matched controls.


• Longitudinal studies in older adults have demonstrated that a higher level of total daily physical activity is associated with reduced risk of Alzheimer disease. Experiments in animal models of Alzheimer disease have shown that physical activity improves spatial learning and reduces brain levels of markers of oxidative stress.


• The rate of hippocampal atrophy in Alzheimer disease patients has been shown to be influenced by several factors, including age of disease onset, APOE-4 genotype, and use of donepezil therapy. Memory decline and hippocampal atrophy both begin in normal middle-aged and older individuals before changes are seen on amyloid PET imaging, suggesting that cognitive changes in these subjects may be associated with the aging process and not with amyloid deposits in the brain.

Historical note and terminology

Wernicke-Korsakoff syndrome. In 1881, Carl Wernicke described 2 male alcoholics and 1 female with persistent vomiting who presented with acute confusion and ataxia (all 3 died by the end of 2 weeks). In 1887, Sergei Korsakoff reported 20 patients with either alcoholism or vomiting who developed chronic memory loss and polyneuropathy. We now use the term “Wernicke-Korsakoff syndrome” to describe this biphasic illness, where the acute phase is called Wernicke encephalopathy, and the chronic disorder is known as Korsakoff syndrome (Sechi and Serra 2007). MRI signs of Wernicke-Korsakoff syndrome include the chronic signs of shrunken mammillary bodies and acute signs of hyperintense T2 signal in thalami and periaqueductal grey (Sullivan and Pfefferbaum 2009).

Vascular dementia. In 1894, Otto Binswanger wrote about 8 patients who were middle-aged when they developed acute confusion, then chronic memory loss, focal neurologic signs, gait disorder, and functional impairment. Their memory disorder fluctuated over time, but at autopsy all of them showed evidence of diffuse subcortical demyelination with sparing of cortical neurons. Hypertension and diabetes are the most important risk factors for vascular dementia, especially the subtype known as Binswanger disease (Hershey 2008; Moorhouse and Rockwood 2008).

Alzheimer disease. In 1906, Alois Alzheimer described 2 women who experienced the insidious onset of memory problems in their 50s. Their memory disorders steadily progressed, and when they died several years later, Dr. Alzheimer found microscopic changes (tangles and plaques) in and around cortical neurons. Genetic analysis from 1 of these first patients identified a point mutation in the presenilin 1 gene, leading to a Phe176Leu amino acid substitution (Muller et al 2013). This could explain the early memory loss in this first case.

In the 1950s, we learned the pivotal importance of the hippocampus to memory function (Williams and Pennybacker 1954; Scoville and Milner 1957). More recently, transient hippocampal hypoperfusion was shown to be the cause of transient global amnesia (Tanabe et al 1991), and hippocampal atrophy was recognized as the first MRI sign of Alzheimer disease (Jack et al 1992).

Dementia with Lewy bodies. Lennox and others described diffuse Lewy body disease as being different from Alzheimer disease in that it has a more fluctuating clinical course, extrapyramidal signs, well-formed visual hallucinations, and increased sensitivity to neuroleptic drugs (Lennox et al 1989). McKeith and others have updated the clinical criteria for dementia with Lewy bodies to include repeated falls, syncope, and depression (McKeith et al 2005).

Mild cognitive impairment. In 1999, Petersen and others described mild cognitive impairment as being a transitional state between normal aging and dementia (Petersen et al 1999). A large epidemiologic study in 2002 showed that cognitive impairment without dementia affected approximately 5 million elderly people in the United States, more people than are affected by Alzheimer disease (Plassman et al 2008). Symptoms of mild cognitive impairment can vary depending on whether they are preclinical manifestations of Alzheimer disease (memory complaints), vascular dementia (executive dysfunction), dementia with Lewy bodies (fluctuations in cognition), or other dementias (Ingles et al 2007; Molano et al 2010). Duff and others showed that nearly 40% of those genetically at risk for Huntington disease meet criteria for mild cognitive impairment (Duff et al 2010), just as about 40% of Parkinson patients have mild cognitive impairment (Kim et al 2009).

Chronic traumatic encephalopathy. In 2009, McKee and others described a condition in football players and war veterans that is now known as chronic traumatic encephalopathy (McKee et al 2009). In these brains, there are deposits of neurofibrillary tangles of tau protein and extracellular amyloid plaques that are similar to those seen in Alzheimer disease. These brains also look similar to those of boxers (dementia pugilistica). Jordon and others earlier showed that the risk of dementia was higher in victims of sports injuries if they had 1 or 2 of the apolipoprotein E epsilon 4 alleles (Jordan et al 1997).

Subjective cognitive impairment. In 2012, Scheef and others performed PET scans on patients in their 60s who complained of memory impairment, but did not have objective evidence of impairment on examination (Scheef et al 2012). PET scans on these patients showed reduced metabolism in the right precuneus, as well as hypermetabolism in the right hippocampus. On longitudinal testing, they showed decline on memory tests, but not on tests of executive function.

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